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Immuno-Oncology: A Colloquium on the State of the Science for Oncology Clinicians
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Immuno-Oncology: A Colloquium on the State of the Science for Oncology Clinicians

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More information about this activity can be found here: http://bit.ly/ST0uRp

Chairperson
Jedd D. Wolchok, MD, PhD
Memorial Sloan-Kettering Cancer Center

Faculty
Antoni Ribas, MD, PhD
University of California, Los Angeles

Mary L. Disis, MD
University of Washington School of Medicine

Charles G. Drake, MD, PhD
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

John Powderly II, MD, CPI
Carolina BioOncology Institute, PLLC
Cancer Therapy & Research Center

Activity Overview

Advances in basic immunology have led to an improved understanding of the interactions between the immune system and tumors, generating renewed interest in novel immunologic approaches to the treatment of cancer. Indeed, there have been multiple FDA approvals of immunologic agents in recent years and there are many ongoing trials of novel immunotherapies in lung cancer, colorectal cancer, and other tumor types.

In this series of half-day conferences, leading oncologists will provide an overview of immune system–cancer interactions, the safety and efficacy of recently approved immunologic agents for the treatment of melanoma and prostate cancer, the latest data from ongoing trials in non-small cell lung cancer, colorectal cancer, and others, and the management of immune-related adverse events (IRAEs). These sessions will include case studies to stimulate interactive discussion of real-world treatment scenarios.

Learning Objectives
Upon completion of this activity, participants should be better able to:

• Describe the biological foundations of immunotherapy approaches to the
treatment of cancer
• Identify the mechanisms of action of immuno-oncologic agents such as
vaccines and immune system-modulating antibodies
• Evaluate new safety and efficacy data on recently approved and emerging
immunotherapies across tumor types
• Describe how new immunotherapies are integrated into existing treatment
evidence-based guidelines
• Identify ongoing research efforts in immuno-oncology including how to
appropriately select patients who would be candidates for clinical trials

More information about this activity can be found here: http://bit.ly/ST0uRp

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  • Outline: 1) Brief history of immunotherapy, which is really a history of single agent immunotherapy. 2) A. Introduce immunological checkpoints and checkpoint blockade describing interesting data on the potential for single agent efficacy 3) New data showing how conventional therapy, especially radiotherapy can have immunological effects 4) Show some data on combination immunotherapy which is the future
  • Figure 2. T cell and dendritic cell interaction in draining lymph nodes.
  • Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med . 2004;351:1502-1512.
  • Figure 2. T cell and dendritic cell interaction in draining lymph nodes.
  • Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med . 2004;351:1502-1512.
  • From Jedd ’s article: A male patient aged 52 years from study 2 had resection of an isolated retroperitoneal metastasis in 2004 and then developed recurrent disease in visceral lymph nodes and soft tissue in 2006. He was treated with high-dose IL-2, but unfortunately, after 2 cycles of therapy, a computed tomography (CT) scan performed in July revealed progression of disease. Ipilimumab was started in November 2006, at which time he had soft tissue disease of the chest wall and pelvis, retroperitoneal metastasis, and iliac nodal disease. The patient exhibited PD on clinical exam through week 10 of ipilimumab administration with discomfort due to enlargement of an axillary mass. Radiographic analysis at week 12 in fact revealed enlargement of multiple subcutaneous masses. However, when the patient was examined a few days later at his week 12 visit, he reported shrinkage of his palpable tumors in the axilla and abdominal wall and this was confirmed on physical exam. These radiographic and clinical findings are consistent with an initial increase in tumor size through week 10 followed by a decrease in size. The initial tumor enlargement was suspected to be caused by inflammation. The only toxicity he experienced was a mild erythematous rash and discomfort at the site of the axillary mass, perhaps related to inflammation. The patient received 4 doses of induction on study 2, but was then taken off study at week 12 for progression of disease. He was then enrolled on study 3, where he has exhibited slow regression of palpable lesions through 4 additional doses of ipilimumab given as re-induction therapy, reached a partial response (PR) at week 31 and his PR is ongoing now at week 48 after initial ipilimumab therapy. He continues to receive maintenance dosing q12wk.
  • Two general mechanisms of expression of immune-checkpoint ligands on tumour cells. The examples in this figure use the programmed cell death protein 1 (PD1) ligand, PDL1 (also known as B7-H1), for illustrative purposes, although the concept probably applies to multiple immune-checkpoint ligands, including PDL2 (also known as B7-DC). Innate immune resistance: In some tumours, constitutive oncogenic signalling can upregulate PDL1 expression on all tumour cells, independently of inflammatory signals in the tumour microenvironment. Activation of the AKT and signal transducer and activator of transcription 3 (STAT3) pathways has been reported to drive PDL1 expression. Adaptive immune resistance: In some tumours, PDL1 is not constitutively expressed, but rather it is induced in response to inflammatory signals that are produced by an active antitumour immune response. The non-uniform expression of PDL1, which is commonly restricted to regions of the tumour that have tumour-infiltrating lymphocytes, suggests that PDL1 is adaptively induced as a consequence of immune responses within the tumour microenvironment. Adaptive induction may be a common mechanism for the expression of multiple immune-checkpoint molecules in tumours.
  • Was not correlated with any one dose or tumor type
  • Point out not sure whether the PD-1 / B7-H1 was: Causing the T cells in there to die, so this is just survival Stopping T cells from coming in Stopping the few cells there from proliferating, so this is a increased proliferation in situ
  • Melanoma, Kidney Cancer, Colon Cancer, Lung Cancer
  • Melanoma and RCC
  • Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med . 2004;351:1502-1512.
  • Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med . 2004;351:1502-1512.
  • Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med . 2004;351:1502-1512.
  • Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med . 2004;351:1502-1512.
  • While 1, 2 and 4 are wrong the rest or not either wrong or right. Ask panel which they favor also ask if they use nomograms to assess risk.
  • Again no “right answer” 5 will be wrong. To some extent 3 and 4 will be wrong. Ask panel which they favor – extent of postive margin, number of LN
  • Again no “right answer”
  • Point is that patient now has CRPC. Is definition the same everywhere?
  • Again no right answer in my mind – with the clear issue that nothing is approved in this space. Thoughts?
  • Point is that patient now has CRPC. Is definition the same everywhere?
  • N=73 Patients 74 patients are available at the immune-monitoring facility 1 was removed because of leukemia Without stratification, 38.9% of these patients have clinical benefit at week 24 Not all patients had ALC available for all time-points
  • Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer This phase 1 study assessed the safety, anti- tumor activity, and pharmacokinetics of BMS- 936558, a fully human IgG4-blocking monoclonal antibody directed against PD-1, in patients with selected advanced solid tumors. Activity of Anti–Programmed Death 1 (PD-1) Antibody in Patients with Treatment- Refractory Melanoma, Non–Small-Cell Lung Cancer, or Renal-Cell Cancer.In Panel A, a representative plot shows changes from baseline in the tumor burden, measured as the sum of the longest diameters of target lesions, in 27 patients with melanoma who received anti–PD-1 antibody ata dose of 1.0 mg per kilogram of body weight every 2 weeks. In the majority of patients who had an objec- tive response, responses were durable and evident by the end of cycle 2 (16 weeks) of treatment. The vertical dashed line marks the 24-week time point at which the progression-free survival rate was calculated, and the horizontal dashed line marks the threshold for objective response (partial tumor regression) according to modi- fied Response Evaluation Criteria in Solid Tumors. Tumor regression followed conventional as well as immune- related patterns of response, such as prolonged reduc- tion in tumor burden in the presence of new lesions
  • Fig. 1. Survival of mice challenged with 5 × 104 B16-BL6 cells and vaccinated on days 3, 6, and 9 with 1 × 106 Gvax (A) or Fvax (B) intradermally and the indicated antibody or combination i.p.. Lack of survival was defined as death or tumor size >1,000 mm3. Each curve represents three to four independent experiments of 5–15 mice per group.
  • Sumimoto et al (2006). The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med, June 26; 203 (7): 1651-1656. Boni et al (2010). Selective BRAF V600E Inhibition Enhances T-Cell Recognition of Melanoma Without Affecting Lymphocyte Function . Cancer Res, Jul 1; 70 (1): 5213-5219. Comin-Anduix et al (2010). The Oncogenic BRAF Kinase Inhibitor PLX4032/G7204 Dose Not Affect the Viability or Function of Human Lymphocytes across a Wide Range of Concentrations. Clin Cancer Res, Dec 15; 16 (24): 6040-6048.
  • Koya et al (2012). BRAF Inhibitor Vemurafenib Improves the Antitumor Activity of Adoptive Cell Immunotherapy. Cancer Res, Aug 15;72(16):3928-3937.
  • Hooijkaas et al, (2012). Selective BRAF Inhibition Decreases Tumor-Resident Lymphocyte Frequencies in a Mouse Model of Human Melanoma. OncoImmunology, 1 (6): 1-9.
  • Wilmott et al, (2012). Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanomaClin Cancer Res 2012 March 1; 18 (5): 1386-1394. Hong et al, (2012). BRAF(V600) Inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency. Clin Cancer Res 2012 April 15; 18 (8): 2326-35.
  • 7 studies showed TIL correlated with lung cancer survival (slides in syllabus)
  • Ruffini et al, Annals Thorcic Surgery 2009; 87:365-72 (Italy) Survival according to the presence or absence of tumor-infiltrating lymphocytes (TIL) in total population of patients with lung neoplasms who underwent resection (p = 0.20).
  • PD-1 and CTLA-4 play distinct roles in regulating T cell immunity. CTLA-4 modulates the early phases of activation of naı¨ve or memory T cells in response to TCR stimulation by MHC-peptide complexes displayed by antigen presenting cells ( ‘signal 1’). In contrast, PD-1 is expressed on antigenexperienced T cells in the periphery, and serves to limit the activity of T cells at the time of an inflammatory response, thereby protecting normal tissues from collateral destruction. DC, dendritic cell.
  • PD-1 and CTLA-4 play distinct roles in regulating T cell immunity. CTLA-4 modulates the early phases of activation of naı¨ve or memory T cells in response to TCR stimulation by MHC-peptide complexes displayed by antigen presenting cells ( ‘signal 1’). In contrast, PD-1 is expressed on antigenexperienced T cells in the periphery, and serves to limit the activity of T cells at the time of an inflammatory response, thereby protecting normal tissues from collateral destruction. DC, dendritic cell.
  • 14th World Conference on Lung Cancer. July 3 – 7, 2011. Amsterdam Rai, Netherlands
  • Phased schedule significantly improved mWHOPFS • No significant improvement for concurrent schedule The study met its primary endpoint of significantly improved irPFS in NSCLC for the Phased-ipilimumab regimen Significant improvement in mWHO-PFS and a trend for improved OS Subset analysis appeared to show greater efficacy in squamous than non-squamous patients with Phased-ipilimumab Small sample size warrants caution in interpretation Safety profile in this trial generally consistent with previous ipilimumab studies Safety profiles for squamous and non-squamous appeared similar No apparent exacerbation of toxicities seen with chemotherapy alone Adverse events generally manageable using protocol-defined treatment guidelines
  • In the Phased-Ipilimumab arm, improvements in irPFS, mWHO-PFS and OS vs. Control appeared greater for squamous histology than for non-squamous Small sample size warrants caution in interpretation
  • Highlighted in green are AEs typically associated with ipilimumab; *As reported by investigators (standardized MedDRA query term †Calculated na - 0%; ALT 17 scope); from laboratory values; na, not applicable; , ALT, alanine aminotransferase; AST, aspartate aminotransferase 􀁺 Majority of grade 3/4 events were grade 3 1 death in the control arm due to treatment-related neutropenic sepsis 1 grade 3 hypophysitis, 1 grade 3 hypopituitarism, and 1 death due to treatment-related toxic epidermal necrolysis in the Concurrent arm
  • Two general mechanisms of expression of immune-checkpoint ligands on tumour cells. The examples in this figure use the programmed cell death protein 1 (PD1) ligand, PDL1 (also known as B7-H1), for illustrative purposes, although the concept probably applies to multiple immune-checkpoint ligands, including PDL2 (also known as B7-DC). Innate immune resistance: In some tumours, constitutive oncogenic signalling can upregulate PDL1 expression on all tumour cells, independently of inflammatory signals in the tumour microenvironment. Activation of the AKT and signal transducer and activator of transcription 3 (STAT3) pathways has been reported to drive PDL1 expression. Adaptive immune resistance: In some tumours, PDL1 is not constitutively expressed, but rather it is induced in response to inflammatory signals that are produced by an active antitumour immune response. The non-uniform expression of PDL1, which is commonly restricted to regions of the tumour that have tumour-infiltrating lymphocytes, suggests that PDL1 is adaptively induced as a consequence of immune responses within the tumour microenvironment. Adaptive induction may be a common mechanism for the expression of multiple immune-checkpoint molecules in tumours.
  • Fig. 4 Representative immunohistochemical staining in B7-H1-posi tive tumor regions (A) and B7-H1-negative tumor regions (B) on the same non-small cell lung cancer sections. On consecutive tumor sections, TILs were identified by CD45 staining (C and D), and PD-1 expression was identified immunohistochemically (E and F). A low proportion of TILs in B7-H1-positive tumor regions is shown in C. A high proportion of TILs in B7-H1-negative tumor regions is shown in D. Expression of PD-1 is lower on TILs in B7-H1-positive tumor regions (E) compared with that on TILs in B7-H1-negative tumor regions (F). Scale bar, 100 􏰅m.
  • Published CT scan from NEJM
  • Courtesy of Dr. Gettinger
  • Activity of Anti–PD-L1 Antibody in Patients with Advanced Melanoma and Non–Small-Cell Lung Cancer. Shown is the tumor burden (assessed as the longest linear dimension) over time in patients with non–small-cell lung cancer who received 10 mg of anti–PD-L1 antibody per kilogram of body weight. In most patients who had an objective response, responses were durable and were evident by the end of cycle 2 (12 weeks) of treatment, regardless of the drug dose or tumor type. The vertical dashed line marks the 24-week time point at which the rate of progression-free survival was calculated. Tumor regression followed both conven- tional and immune-related patterns of response, such as a prolonged reduction in the tumor burden in the pres- ence of new lesions.
  • Computed Tomography after Receipt of Anti–PD-L1 Antibody. a partial response at 15 months in the liver (arrows) and right lung pleura (arrowheads) in a patient with non–small- cell lung cancer (nonsquamous subtype) who received 10 mg of anti–PD- L1 antibody per kilogram.
  • MAGE-A3 (melanoma associated antigen A3) expressed in placenta and testes, not in normal cells, but + in 35-48%% of NSCLC ’s AS15 Adjuvant = A vaccine adjuvant containing CpG 7909, monophosphoryl lipid, and QS-21 with potential antineoplastic and immunostimulatory activities. CpG 7909 is a synthetic 24-mer oligonucleotide containing 3 CpG motifs that selectively targets Toll-like receptor 9 (TLR9), thereby activating dendritic and B cells and stimulating cytotoxic T cell and antibody responses against tumor cells bearing tumor antigens. Monophosphoryl lipid is a detoxified derivative of lipid A, a component of Salmonella minnesota lipopolysaccharide (LPS); this agent may enhance humoral and cellular responses to various antigens. QS-21 is a purified, naturally occurring saponin derived from the South American tree Quillaja saponaria Molina and exhibits various immunostimulatory activities. Combinations of monophosphoryl lipid and QS-21 may be synergistic in inducing humoral and cellular immune responses. Check for active clinical trials or closed clinical trials using this agent. ( NCI Thesaurus) About half of all NSCLC patients whose tumours have been completely removed by surgery have a recurrence within two years. A phase II trial of the MAGE-A3 ASCI in these patients with completely resected NSCLC expressing MAGE-A3 showed 25% fewer recurrences among patients at the final analysis, and the difference between the two arms has held now for almost six years (but the disease free interval and DFS were not statistically significant). The phase III trial, which aims to enrol around 2300 NSCLC patients positive for the MAGE-A3 antigen – “the largest lung cancer trial ever conducted in the adjuvant setting” – is being carried out using a ‘new and improved’ immunological adjuvant, which GSK hopes will give even better results.
  • R. Sangha, C. Butts, Clinical Cancer Research 2007; 13:4652-54 an open-label randomized phase II trial was undertaken (21). Patients with stable disease or responding stage IIIB or IV NSCLC after any first-line chemotherapy were randomly assigned to either L-BLP25 plus best supportive care or best supportive care alone. Patients in the L-BLP25 arm received a single i.v. dose of cyclophosphamide (300 mg/m2)followed by eight weekly s.c. immunizations of L-BLP25 (1,000 A g). Subsequent immunizations were administered at 6-week intervals. Updated survival analysis, with median follow-up of 53 mo, for stage IIIB locoregional patients.Median survival 30.6mo (mo) for L-BLP25^ treated patients, and 13.3 mo for best supportive care (BSC).
  • Sponsor Nova Rx
  • T. De Pas, et al , Critical Reviews in Oncology/Hematology, 2012 (Italy) L-BLP25 = Stimuvax; EGF = CIMAvax; belagenpumatucel-1 = Lucanix survival; tumor-free, overall, pro-gression free (STOP) trial in NSCLC. Here the vaccine is made up of four NSCLC cell lines that are engineered to express an anti-sense to TGF- 2 that decreases the expres- sion of this immunosuppressive cytokine [49]. The results of the phase II trial were encouraging demonstrating safety of the patients and some clinical response. The results of the phase III trial are expected in October 2011[50]. MAGE-A3 (melanoma associated antigen A3) expressed in 35-48%% of NSCLC ’s AS15 Adjuvant = A vaccine adjuvant containing CpG 7909, monophosphoryl lipid, and QS-21 with potential antineoplastic and immunostimulatory activities. CpG 7909 is a synthetic 24-mer oligonucleotide containing 3 CpG motifs that selectively targets Toll-like receptor 9 (TLR9), thereby activating dendritic and B cells and stimulating cytotoxic T cell and antibody responses against tumor cells bearing tumor antigens. Monophosphoryl lipid is a detoxified derivative of lipid A, a component of Salmonella minnesota lipopolysaccharide (LPS); this agent may enhance humoral and cellular responses to various antigens. QS-21 is a purified, naturally occurring saponin derived from the South American tree Quillaja saponaria Molina and exhibits various immunostimulatory activities. Combinations of monophosphoryl lipid and QS-21 may be synergistic in inducing humoral and cellular immune responses. Check for active clinical trials or closed clinical trials using this agent. ( NCI Thesaurus) About half of all NSCLC patients whose tumours have been completely removed by surgery have a recurrence within two years. A phase II trial of the MAGE-A3 ASCI in these patients with completely resected NSCLC expressing MAGE-A3 showed 25% fewer recurrences among patients at the final analysis, and the difference between the two arms has held now for almost six years. The phase III trial, which aims to enrol around 2300 NSCLC patients positive for the MAGE-A3 antigen – “the largest lung cancer trial ever conducted in the adjuvant setting” – is being carried out using a ‘new and improved’ immunological adjuvant, which GSK hopes will give even better results.
  • Thought precarinal LN may have been inflammatory;
  • Dafni U, Pectasides D, Tsoutsos D, et al (2008). Prognostic significance of autoimmunity during adjuvant treatment of melanoma with interferon: Updated follow-up. ASCO Annual Meeting. J Clin Oncol 26: 2008 (May 20 suppl; abstr 9024).
  • Evolution of partial response to complete response [21]. Prior treatment included surgery, interferon-α, GM-CSF, bacille Calmette-Guerin, interleukin-2, and an unspecified biologic. Immune-related adverse effects included grade 1 diarrhea and grade 1 rash.
  • Transcript

    • 1. DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is current as of September 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice,diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity. Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
    • 2. DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline forpatient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. DISCLOSURE OF UNLABELED USE This activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. PIM and IMER do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of PIM and IMER. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
    • 3. Disclosure of Conflicts of InterestJedd D. Wolchok, MD, PhD, reported a financial interest/relationship or affiliationin the form of: Consultant, Bristol-Myers Squibb Company.Mary (Nora) L. Disis, MD, reported a financial interest/relationship or affiliation inthe form of: Consultant, Bristol-Myers Squibb Company, EMD Serono, Inc.,Immunovaccine, Inc., Hoffmann-La Roche, Inc., VentiRX Pharmaceuticals;Contracted Research, GlaxoSmithKline plc.; Ownership Interest, Epigenomics AG.Charles G. Drake, MD, PhD, reported a financial interest/relationship or affiliationin the form of: Royalty, Amplimmune, Inc., Bristol-Myers Squibb Company; Receiptof Intellectual Property Rights/Patent Holder, Amplimmune, Inc., Bristol-MyersSquibb Company; Consultant, Bristol-Myers Squibb Company, DendreonCorporation, Pfizer, Inc.; Ownership Interest, Amplimmune, Inc.John Powderly II, MD, CPI, reported a financial interest/relationship or affiliation inthe form of: Receipt of Intellectual Property Rights/Patent Holder, BioCytics®;Consultant, Amplimmune, Inc., Bristol-Myers Squibb Company; Speakers Bureau,Bristol-Myers Squibb Company; Contracted Research, Amplimmune, Inc., Bristol-Myers Squibb Company, Genentech, Inc.; Ownership Interest, BioCytics®.
    • 4. 5 Disclosure of Conflicts of InterestAntoni Ribas, MD, PhD, reported a financial interest/relationship or affiliation in theform of: Consultant, Amgen, Inc., Celgene Corporation, Genentech- A member ofthe Roche Group, GlaxoSmithKline plc., Millennium Pharmaceuticals, Inc.,Prometheus.Scott N. Gettinger, MD, has no real or apparent conflicts of interest to report.Mario Sznol, MD, reported a financial interest/relationship or affiliation in the formof: Consultant, Anacor Pharmaceuticals, Inc., BeiGene LTD, Bristol-Myers SquibbCompany, Genesis Biopharma, Necktar Pharmaceuticals Inc., Prometheus;Ownership Interest, Genesis Biopharma.
    • 5. Welcome and Introduction Jedd D. Wolchok, MD, PhDMemorial Sloan-Kettering Cancer Center
    • 6. Immuno-Oncology: The Biological Foundations Mary L. Disis, MDUniversity of Washington School of Medicine
    • 7. Immuno-Oncology: The Biological Foundations The immune system Cancer and the immune system The basics of immune therapy
    • 8. The Immune System T cell (orange) killing a cancer cell (magenta) CHARACTERISTICS INNATE ADAPTIVE Specificity Non-Specific Specific Antigens Not Needed Required Memory None Generated Time Course Immediate Slowly Developing Duration Transient Lifelong Cell Types MØ, DC, NK, T Cells, B Cells Neutrophil First Line of Defense Effectors Immune SensorsMØ = macrophages; DC = dendritic cell; NK = natural killer cell.Alberts et al, 2002; Murphy et al, 2008.
    • 9. Cells of the Innate Immune System Neutrophil Phagocytosis and debris clean up Secrete chemokines that call in other innate immune cells Dendritic Cell Potent antigen presenting cells (APC) Uptake and process antigen Both “class I” and “class II” pathways Will stimulate both CTL and T helper (Th) cells Macrophage Phagocytosis and cleaning up debris, secrete cytokines Type 1 can turn on adaptive immunity Type 2 will limit adaptive immunity Natural Killer Cell Can directly kill tumor without docking to MHC Secrete high levels of IFN-gamma (critical cytokine) Antibodies can activate them via FC receptor (ADCC)ADCC = antibody-dependent cell-mediated cytotoxicity; MHC = major histocompatibility center; IFN = interferon; CTL = cytotoxic T lymphocytes.Alberts et al, 2002; Murphy et al, 2008.
    • 10. Cells of the Adaptive Immune System Humoral Immunity Cellular Immunity Extracellular microbes (e.g., bacteria) Intracellular microbes (e.g., viruses) B lymphocytes Processed and B Antigen-presenting B presented antigen cell Helper Secreted T-cell antibody T T-cell receptor Cytokines Cytokine Proliferation and receptor Neutralization activation of effector cells Lysis (complement) (cytotoxic T-cells, Phagocytosis natural killer cells, (PMN, macrophage) macrophages) Lysis of infected cellPMN = polymorphonuclear leukocyt.Kumar, et al 2007.
    • 11. Critical Link Between Innate and Adaptive Immunity MHC II TCR CD4 CD4+ Activation T-cell Apoptotic cell CD40L CD40 Immature MHC I dendritic cell Necrotic cell • Activation TLR • Proliferation • CTL generation Activation Mature CD8 dendritic cell Immature CD8+ dendritic cell Pathogen T-cellTCR = T cell receptor; TLR = Toll-like receptors.Bevan, 2004.
    • 12. The Immune System Is All About “Checks and Balances” Tumor Regression Regulatory loops Tumor Progression NK/NKT T H1 TH17 TH17 B cell T H2 TREG DC1 N1 N2 DC2 M1 M2 Myeloid Phenotype Angiostatic Pro- angiogenic Direct Tissue cytotoxicity remodeling Immune Immune surveillance suppression IL-12, IL-2, IFN-g, TNF-a IL-4, IL-5, IL-10, TGF-bIL = Interleukin; TNF = tumor necrosis factor; TGF = transforming growth factor.DeNardo et al, 2010.
    • 13. Immuno-Oncology: The Biological Foundations The immune system Cancer and the immune system The basics of immune therapy
    • 14. Steps in Stimulating Cancer Specific Immunity Melanoma “Danger” e.g. HSP IFN-α CD28 MAGE I B7 CD8 MARTI CTL Help (TAAs) APC e.g. CD40 CD40 IL-2 CD4 Immature DC CD40L TH Activated mature DC Lymph node B7 CD40L CD40 CD8 CD28 CD40 CD4 TCR Migration from TCR lymph node MHC I MHC II DC Migration to lymph node
    • 15. Epitope Spreading Is the Endpoint of an Effective Immune Response in CancerMIP-1α= macrophage inflammatory protein 1α.Vanderlught et al, 2002.
    • 16. What Is Needed for Clinical Effective Antitumor Immunity? High Density of T Cells Modulation of Type I Inflammation Penetrating Tumor Self-Regulation 0 .1 6 10 105 Murine TNBC 4 10 < F IT C - A > : F O X P 3 3 10 2 10 Murine TNBC 0 43 46 FOXP3 2 3 4 5 0 10 10 10 10 < P e rC P -C y 5 -5 -A > : C D 4 0 .8 8 1 .1 105 4 10 < F IT C -A > : F O X P 3 Murine ER+BC 3 10 2 10 Murine breast tumor Murine ER+ BC 0 after activating the 46 52 2 3 4 5 Immune system 0 10 10 1 0 10 < P e rC P -C y 5 -5 -A > : C D 4  75 colorectal cancers  7 gene classifier  186 advanced ovarian cancers CD4  Inverse correlation of gene  MVA: Intratumoral T cells  237 breast cancers expression and relapse independent predictor survival  MVA: Density of Treg+ in ER+ tumors predictor of survivalMVA = multivariate regression analysis; ER+ = estrogen receptor positive; Treg = regulatory T cells.Galon et al, 2006; Zhang et al, 2003; Bates et al, 2006.
    • 17. Optimal Immune Reaction Many cancer patients have demonstrated an “optimal immune reaction”VEGF = vascular endothelial growth factor; CT = center; IM = invasive margin.Bindea et al, 2010.
    • 18. What Does the Immune System See in Cancer? Cell and Cell and Tumor Cell and Self Virus Antigen Protein Only Antigens Associated With Clinical Response Foreign Self Antigens Antigens LMP2 HER2 GD2 HPV WT1 CEA HepB MUC1 MART-1 Dangerous Weak Tolerizing • Cell damage • None of MAGE A2 gp100 • No danger (uric acid) signals these NY-ESO-1 PR1 • Innate • No CD40 signals immunity signals PSMA Tyrosinase activated • Pro- • TLRs PSA PAP inflammatory triggered cytokines PSCA NA17 • Inflammation • Cytokines • CD40 signals • OthersLake et al, 2005; Cheever et al, 2009.
    • 19. Why Do Most Tumors Evade Immune Recognition?Murphy et al, 2008.
    • 20. Multiple Factors Impact the Tumor Immune Microenvironment Pro-Tumorigenic Anticancer Inflamation Immunosurveillance Cell Types M2 macrophages Dendritic cells Myeloid-derived suppressor M1 macrophages cells cytotoxic CD8+ T cells with a Neutrophils memory effector phenotype Foxp3+ T reg. Th17 cells Cytokine Th2, Th17 Th1 Profiles CX3CL1 CXCL9, CXCL10 Distribution Peritumoral Intratumoral, close to cancer cells, as well as in the invasive front Associated Stat3 phosphorylation High endothelial venules Features Functional Negative prognostic impact Positive prognostic and Impact predictive impactFoxp3 = forkhead box P3.Fridman et al, 2011; Disis, 2010a.
    • 21. Immuno-Oncology: The Biological Foundations The immune system Cancer and the immune system The basics of immune therapy
    • 22. Types of Immune Therapy PASSIVE ACTIVE Transferred Generated Ready Made Must Be Developed Immediate Protection Takes Time No Memory Long Lived Immune System May Requires Functional Immune Function Poorly System Ig Infusions, Some MoAB Vaccines, Anti-CTLA-4 Therapy, T-Cell TransferIg = immunoglobulins; MoAB = monoclonal antibody; CTLA-4 = cytotoxic T-lymphocyte antigen-4.Murphy et al, 2008.
    • 23. Monoclonal Antibody Therapy: TrastuzumabHER-2/neu = human epidermal growth factor receptor 2. Time (Weeks)Ferris et al, 2010; Taylor et al, 2007; Ladoire et al, 2011.
    • 24. Adoptive T Cell Therapy Factors Associated With Clinical Response Diversity Objective Response  Unfractionated TIL 34%-50% polyclonal  Selected tumor- reactive TIL 49%-72% TCR gene transfer (MART-1/Melan-A, 13%-30% gp100,NY-ESO-1) 50% response rate 20/93 complete responders monoclonal  Individual T cell clones (MART-1/Melan-A, 0%-11% gp100,NY-ESO-1) SpecificityTIL = tumor-infiltrating lymphocytes; CR = complete response; PR = partial response; NR = no response; MART-1/ Melan-A = melanomaantigen recognized by T-cells, gp100 = glycoprotein 100; NY-ESO-1 = immunogenic peptide derived from the cancer-testis antigen.Topalian et al, 2011; Rosenberg et al, 2011.
    • 25. Immuno-Oncology: The Biological Foundations T1 T2Tx = treatment.Disis, 2010b.
    • 26. Key Takeaways Innate immunity, our first responders that don’t require antigen recognition, can support and enhance the efficacy of adaptive immunity cells that are specific to an invader Therapeutic immunity can be either passive (supplying an antibody response) or active (vaccinating to create your won antibody response) which requires your immune system to do the work There is strong evidence that most cancers stimulate the immune system Efficacy of cancer-induced immunity is limited by both factors secreted by the tumor and stroma, but also normal defense mechanisms activated to prevent autoimmunity Our improved understanding of tumor-immune system interactions has led to design of therapeutic approaches that both stimulate immunity and address mechanisms of immune escape There are now several promising immunologic agents that have demonstrated significant antitumor efficacy in advanced stage clinical trials or have been approved for standard of care use
    • 27. Audience Q&A: The Biological Foundations of Immunotherapy Mary L. Disis, MDUniversity of Washington School of Medicine
    • 28. Immuno-Oncology: Genitourinary Cancers Charles G. Drake, MD, PhDThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    • 29. Outline  Cancer “Vaccines”  Combination – Sipuleucel-T Immunotherapy – ProstVac VF – With androgen-ablation – Argos AGS-003 – With TKIs  Immune Checkpoint  Integrating immunotherapy Blockade into the current (and future) prostate cancer – Anti-CTLA-4, ipilimumab treatment paradigm – Anti-PD-1, BMS-936558 (MDX-1106) – Phase III trial designPD-1 = programmed cell death protein-1; TKIs = tyrosine kinase inhibitors.
    • 30. Cancer Vaccines: An Immunological MOA CD4 T Cell Activated TCR Dendritic Cell Class II MHC TCR Cytokines = HELP Tumor Antigen Class I MHC CD8 T Cell Activated CD8 T Cells Traffic to Tumor and Lyse Tumor CellsMOA = mechanism of action.Burch et al, 2000; Small et al 2000; Fong et al, 1997.
    • 31. Active Cellular Immunotherapy Sipuleucel-T Patient WBC Harvested GM-CSF Short-Term Culture With Protein “Cassette” PAP Shipping Cells Infused BACK Into Patient (IV)WBC = white blood count; GM-CSF = granulocyte-macrophage colony stimulating factor;PAP = prostatic acid phosphatase; IV = intravenous.Burch et al, 2000; Small et al, 2000.
    • 32. D9902B – IMPACT Immunotherapy Prostate Adenocarcinoma Treatment P R R A Placebo q2wks Eligible for x3 O Sipuleucel-Ta N  mCRPC G D  No Visceral R O Mets E  N = 512 M S I Sipuleucel-T Physician’s S Z q2wks x 3 Discretion I E O N  Patients: Asymptomatic or minimally symptomatic mCRPC  Primary end point: OS  Secondary end point: TTPa Prepared from cryo-preserved lymphocytes.mCRPC = metastatic castration-resistant prostate cancer; OS = overall survival; TTP = time to progression.Kantoff et al, 2010a.
    • 33. IMPACT OS: Primary End Point ITT Population 100 p = .032 (Cox model) HR = 0.775 [95% CI 0.614, 0.979] 75 Percent Survival Median Survival Benefit = 4.1 mos 50 Sipuleucel-T (n = 341) Median Survival = 25.8 mos Placebo (n = 171) 25 Median Survival = 21.7 mos 0 0 6 12 18 24 30 36 42 48 54 60 66ITT = intent-to-treat; HR = hazard ratio; CI = confidence interval.Kantoff et al, 2010a.
    • 34. Madan et al, 2009; Sonpavde et al, 2011. DNA = deoxyribonucleic acid; PSA = prostate-specific antigen. Co-Stimulatory Molecules PSA B7-1 ICAM-1 LFA-3 Target Antigen Vaccinia Virus Fowlpox Virus Plasmid DNA Packaging Cell Line rV-PSA- TRICOM rF-PSA- TRICOM VaccineA Viral Vaccine Approach: ProstVac VF
    • 35. Viral Vaccines – Same Idea: But Starting At A Different Step ProstVac VF CD4 T Cell TCR Class II MHC TCR Class I MHCEpithelial Cells CD8 T Cell ACTIVATED Cell Death - Necrosis CD8 T CellMadan et al, 2009; Sonpavde et al, 2011.
    • 36. TBC-PRO-002 Survival Data Time (mos) Design: Nearly identical to IMPACT but NO crossover Patients: mCRPC with either no or minimal symptoms Primary end point: TTPCRPC = castration-resistant prostate cancer; TTP = time to progression.Kantoff et al, 2010b.
    • 37. Prospect Trial: Design (SPA) Phase III Global (US-CAN-AUS/WE/EE/Latin America) PROSTVAC-(V)(F) TRICOM + Low-Dose S Adjuvant GM-CSF Non/Minimally U Symptomatic R mCRPC PROSTVAC-(V)(F) V TRICOM Standard Adjuvant Placebo of Care I No Crossover V Vector Placebo A Adjuvant Placebo L Primary End Point: OSSPA = special protocol assessment.US NIH, NCT01322490.
    • 38. Using RNA to Load Dendritic Cells Argos AGS-003 Kidney Cancer Sample Tumor Load DC With RNA RNA Isolation And Activate (AGS-003) Cryopreserve Leukapheresis DC Product Manufacture Intranodal InjectionRNA = ribonucleic acid.Figlin et al, 2012.
    • 39. ADAPT: Autologous Dendritic Cell Immunotherapy With AGS-003 Plus Sunitinib for the Treatment of Advanced RCC R AGS-003 A 1 Cycle Sunitinib AGS-003 5 doses q3mos  Metastatic, N (6 wks) q3wks Unfavorable D Risk Clear O Cell RCC M  N = 450 I 1 Cycle Sunitinib Placebo Z (6 wks) q3mos E Ongoing Sunitinib (4 wks on, 2 wks off)  Primary end point: OS  Secondary end point: PFS (30% increase), ORR, safety  FDA approved the SPA for the phase III clinical study of AGS-003 for the treatment of metastatic RCC  Study has initiated and is expected to begin dosing patients in the second half of 2012RCC = renal cell carcinoma; ORR = overall response rate; PFS = progression-free survival.US NIH, NCT01582672.
    • 40. Normal T-Cell Activation T Cell TCR CD28 Signal 1 Signal 2 antigen HLA B7.1/2 Antigen Presenting CellHLA = human leukocyte antigen.Kirkwood et al, 2008; Ribas et al, 2005; Attia et al, 2005.
    • 41. Immune Checkpoints (CTLA-4) Prevent Normal T-Cell Activation T Cell CTLA-4 TCR CD28 Signal 1 Signal 2 antigen HLA B7.1/2 Antigen Presenting CellKirkwood et al, 2008; Ribas et al, 2005; Attia et al, 2005.
    • 42. Ipilimumab (Anti-CTLA-4) Blocks the CTLA-4 Checkpoint, Restoring T-Cell Activation Antigen Presenting Cell HLA B7.1/2 CTLA-4 antigen Signal 1 Signal 1 Signal 2 Signal 2 TCR CD28 CTLA-4 T CellKirkwood et al, 2008; Ribas et al, 2005; Attia et al, 2005.
    • 43. CTLA-4 Blockade: (Ipilimumab, Tremelimumab)  Single-agent activity – RR = 15%–20%  Regressions = durable  Regressions = delayed  Grade III/IV SAE = 10%–15% – Colitis – Hypophysitis  PSA Responses in PC (N = 200) – 20%RR = response rate; SAE = serious adverse event; PSA = prostate-specific antigen; PC = prostate cancer.Saenger et al, 2008; courtesy of Jedd D. Wolchok, MD, PhD.
    • 44. Ipilimumab in Melanoma: The First “Drug” Ever to Show a Survival Benefit in a Randomized Clinical Trial Comparison HR P-value Arm A vs C 0.68 0.0004 Arm B vs C 0.66 0.0026 Arm A vs B 1.04 0.7575 Ipilimumab + gp100 (A) Ipilimumab alone (B) gp100 alone (C) 1 2 3 4 Years Survival Rate Ipilimumab + gp100 Ipilimumab alone gp100 alone 1-yr 44% 46% 25% 2-yr 22% 24% 14%Hodi et al, 2010.
    • 45. Randomized, Double-Blind, Phase III Trial Comparing Ipilimumab Vs. Placebo Following Radiotherapy in Subjects With CRPC That Have Received Prior Treatment With Docetaxel (CA184-043) SCREENING INDUCTION MAINTENANCE Ipilimumab 10 mg/kg Ipilimumab 10 mg/kg CRPC Wks 1, 4, 7, 10 q12wks Radiotherapy (8 gy) Prior to bone metastases Docetaxel IVRS Day -2 or -1 Placebo Placebo N = 800 Wks 1, 4, 7, 10 q12wks ICF, Baseline TA: Wks 12, 24 TA: q12wks PSA: Wks 7, 12, 18, 24 PSA: q6wks Assessments OA: Wks 7, 10, 12, 18, 24 OA: q12wks Day -28 to -2 Day -2 to Wk 24 Wk 24 to 48+Completed Accrual 1/2012TA = tumor assessment; OA = outcome assessment; ICF = informed consent form; IVRS = interactive voice response system.US NIH, NCT00861614.
    • 46. Immune Checkpoint Blockade 2: PD-1 Tumor Cell or Antigen Presenting Cell T Cell Signal 2 B7.1/2 CD28 Signal 1 CTLA- 4 HLA antigen TCR Class II LAG-3 MHC B7-H1 PD-1 (PD-L1) Others: ICOS, GITR, Tim-3Weber, 2010; Pardoll, 2012a.
    • 47. Immune Resistance: PD-1 Innate Immune Resistance MHC + Peptide TCR Tumor T Cell Oncogene-Driven PD-L1 Expression Oncogenic Pathway PD-1 PD-L1 Adaptive Immune Resistance Tumor T Cell Tumor T Cell PD-L1 Adaptive Up-Regulation Interferon g Of PD-L1 Turns T Cell OFFPardoll, 2012a.
    • 48. First BMS-936558 (MDX-1106) Phase I Trial Follow Up or Additional 1st Treatment Cycle Treatment Cycle(s) Day 1 Day 29 Day 57 Day 85 2 years 60 minute IV Optional tumor bx Or until PD Scans infusion 10mg/kg Optional tumor bx 2 doses 4 wks apart, follow SD or mixed response 12 more weeks, can repeat Follow up every month x 2 PR or CR then every 2 months, Re-treat on progressionSD = stable disease; MR = mixed response; PD = progression disease.Brahmer et al, 2010.
    • 49. BMS-936558 (MDX-1106) Phase I: Summary Toxicities (39 patients)  Grade 1: Pruritis, rash, fatigue  Grade 2: – Polyarticular arthropathy, 2 patients (3 mg/kg and 10 mg/kg), treated with oral steroids – TSH elevation, 4 patients (1 patient requiring levothyroxine)  Grade 3: Colitis, 1 patient after multiple doses at 1 mg/kg Response – MR (2), PR (2), CR (1)Brahmer et al, 2010.
    • 50. PD-1 Blockade: Results in Increased CD8 T Cells in Tumors Pre-Rx c m 12-wk Post Dose 1cm 8-wk Post Dose 3 cm 3.9 2.6 2.4 Anti-CD8 Anti-CD8 Anti-CD8 Pre-Rx 4-wk Post Dose 1 4-wk Post Dose 3Rx = treatment.Brahmer et al, 2010.
    • 51. Durable Responses to Anti-PD-1 OFF THERAPY Pt 2- 2013 CR Stop Rx Latest Evaluation: CR 0 1 yr 2 yr 3 yr 4 yr ? new brain met on MRI Pt 1- Stop Best resected: - no viable tumor 4033 Rx resp.(PR) Latest Evaluation: CR Sustained PR 0 1 yr 2 yr 3 yr 4 yr Pt 1- Stop Best New LN mets Restart a PD-1 3019 Rx resp.(PR) Sustained PR 0 1 yr 2 yr 3 yr 4 yrMRI = magnetic resonance imaging; LN = lymph node.Brahmer et al, 2010.
    • 52. Multidose Phase Ib Trial of Anti-PD-1 (BMS-936558/MDX 1106)cCR = confirmed complete response; uCR = unconfirmed complete response; uPD = unconfirmed progressive disease;wPD = worsening progressive disease.McDermott et al, 2011.
    • 53. Efficacy Results: RCC Patients Changes in Target Lesions Over Time in RCC PatientsMcDermott et al, 2012.
    • 54. Anti-PD-1 (BMS-936558) Dose Finding Study CA209010 Arm 1 n = 50 Prior Anti- BMS-936558 (0.3 mg/kg) IV q3wks Angiogenic Tx Arm 2 n = 50 (1:1:1 Randomization) BMS-936558 (2 mg/kg) IV q3wks N = 150 Arm 3 n = 50 BMS-936558 (10 mg/kg) IV q3wks 1° end point: PFS as measured by TA 2° end points: PFS, ORR, OS Completed Accrual 12/2011US NIH, NCT01354431.
    • 55. Anti-PD-1 (BMS-936558) Biomarker Study CA209009 Arm 1 n = 20 Prior Anti- BMS-936558 (0.3 mg/kg) IV q3wks Angiogenic Tx (1:1:1 Arm 2 n = 20 Randomization) BMS-936558 (2 mg/kg) IV q3wks N = 80 Arm 3 n = 20 BMS-936558 (10 mg/kg) IV q3wks Treatment Arm 4 n = 20 (treatment naïve arm) Naïve BMS-936558 (10 mg/kg) IV q3wks 1° end point: Measurement of immunomodulatory activity 2° end points: PFS, ORR, safety, and tolerability Treatment Naïve Cohort Closed 2/2012 Other Cohorts OpenUS NIH, NCT01358721.
    • 56. Why Has Immunotherapy Been Successful in Prostate Cancer?  Better “Vaccines” ? – Sipuleucel-T = Ex-Vivo Culture – ProstVac = Heterologous Prime Boost (+ costimulation)  Better Antigens? – PAP (no tolerance in animals) – PSA (role in tumor progression)  Prostate Cancer = Better Target? – Slow Growing – Patient Selection (asymptomatic or minimally symptomatic) – Patients = CastrateCha et al, 2011; Makarov et al, 2009.
    • 57. Effect of Androgen-Ablation on T-Cell ResponseDrake et al, 2005.
    • 58. Testing the Optimal Sequencing of Androgen-Ablation and “Vaccination” P10-2 Study Participation Concludes Eligibility Treatment Arm 1 • Post Primary Rx (RP or XRT or RP + XRT) • PSADT ≤ 12 mos Sipuleucel-T ADT • Non-Metastatic (bone and CT scan) N = 30 Stratification Immune 18-mos • PSADT ≤ 3 mos or > 3 mos and ≤ 12 mos Response, visit • RP or XRT or RP + XRT Treatment Arm 2 Safety ADT  Sipuleucel-T N = 30 Primary Objective: To determine whether ADT started before or after sipuleucel-T Primary End Point: Immune response, leads to superior augmentation of immune which will be evaluated with an INF-γ response ELISPOT specific for PA2024ADT = androgen deprivation therapy; RP = radical prostatectomy; XRT = radiation therapy; CT = computed tomography;PSADT = prostate-specific antigen double time; ELISPOT= enzyme-linked immunospot; INF= interferon.Antonarakis et al, 2011.
    • 59. Combining PD-1 Blockade With TKIs in RCC Orthotopic RENCA Model  Hypoxia Anti-PD-1  High VEGF Levels 10 mg/kg  Growth Inhibition With Sunitinib Days -8 -3 0 3 6 9 Day 12 RENCA Treatment Ends Orthotopic (0.5M Cells) Sunitinib 40 mg/kg dailyCourtesy of Hans Hammers, MD, PhD.
    • 60. Tumor ResponseCourtesy of Hans Hammers, MD, PhD.
    • 61. Antibody Response 14x 49xCourtesy of Hans Hammers, MD, PhD.
    • 62. Phase I Study Combining Anti-PD-1 With Sunitinib or Pazopanib in Patients With Metastatic RCC Metastatic RCC Arm S Escalation Arm S Expansion MTD (Prior Pazopanib) Sunitinib + BMS-936558 Sunitinib + BMS-936558 Metastatic RCC Arm P Escalation Arm P Expansion MTD (Prior Sunitinib) Pazopanib + BMS-936558 Pazopanib + BMS-936558 Primary End Points: Safety, Tolerability, MTDMTD = maximum tolerated dose.US NIH, NCT01472081.
    • 63. Integrating Immunotherapy Into theProstate Cancer Treatment Paradigm 2004 Androgen Docetaxel Ablation Chemotherapy 2010Androgen Docetaxel Ablation Sipuleucel-T Chemotherapy Sipuleucel-T
    • 64. 2012Androgen Sipuleucel-T Docetaxel Ablation Chemotherapy Sipuleucel-T Abiraterone Cabazitaxel Abiraterone and beyond… Enzalutamide (MDV3100) Iplimumab?
    • 65. Key Takeaways Sipuleucel-T  In development for kidney – FDA approved in US for cancer CRPC – AGS-003 – Precise MOA under • Randomized phase III investigation ongoing – T cell and antibody data – Anti-PD-1 (BMS-936558) consistent with an adaptive • Phase II dose finding immune response completed In development for prostate • Biomarker study ongoing cancer • TKI combination trial ongoing – ProstVac VF • Phase III ongoing – Anti-CTLA-4 (ipilimumab) • Post-Tax phase III trials ongoing
    • 66. Case Study: Prostate Cancer Charles G. Drake, MD, PhDThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    • 67. Clinical States Model Sipuleucel-T Metastatic Disease Cabazitaxel (de novo) Metastatic Metastatic Metastatic Castrate Primary Rising PSA Resistant Castrate Castrate Resistant Resistant Hormone Asymptomatic Disease Symptomatic Post Docetaxel Naive Non-Metastatic Castrate Resistant Docetaxel Abiraterone ADT Enzalutamide (MDV3100)Modified from Scher et al, 2008.
    • 68. Case Study  64-yr-old man presented with an elevated PSA of 4.5 ng/mL  Negative DRE  Prostate Bx: Gleason 7 (3+4)  4/12 cores positive, all on right  10%–50% of each core involved  Bone scan and CT negative  PMH/PSH: NoneDRE = digital rectal exam; PNBx = prostate needle biopsy; PMH = past medical history; PSH = past surgical history.
    • 69. Question 1 What would you suggest as primary therapy? 1. RT alone 2. Brachytherapy in combination with RT 3. RT with ADT 4. Primary ADT 5. Radical prostatectomy 6. CryotherapyRT = radiation therapy; ADT = androgen deprivation therapy.NCCN, 2012a.
    • 70. Case Study (cont.) Patient undergoes radical retropubic prostatectomy – Gleason 7 (3+4) – Organ Confined – Negative Margins – 5/5 LN negative
    • 71. Question 2 Which subsequent therapy would you choose? 1. Observation 2. Adjuvant RT 3. Adjuvant ADT 4. Clinical TrialNCCN, 2012a.
    • 72. Case Study (cont.) Course of Treatment  Observed 3 yrs later presents with rising PSA – Post-surgery nadir = 0.1 – 0.2, 0.2, 0.5  Referred to radiation oncology  Salvage RT (66 Gy over 8 wks) – Well toleratedNCCN, 2012a.
    • 73. Case Study (cont.) Course of Treatment  Post RT PSA continues to rise 3 mos post RT = 2.3 6 mos = 7.0 9 mos = 16.5  Asymptomatic – CT scan = negative for recurrent or progressive disease – Bone scan = negative for evidence of metastasesNCCN, 2012a.
    • 74. Question 3 What would you recommend at this time? 1. Continued observation 2. Initiate intermittent androgen ablation 3. Initiate continuous androgen ablation 4. Refer for Sipuleucel-T 5. Refer for clinical trialNCCN, 2012a.
    • 75. Case Study (cont.) Course of Treatment  Based on rapidly rising PSA (doubling time < 12 mos), patient starts continuous androgen-ablation  3 mos later PSA nadirs at 0.4 – Stable x 2 yrs – 2 yrs 3 mos 1.2 – 2 yrs 6 mos 3.5 – 2 yrs 9 mos 11.2  Bone scan + (3 small rib lesions, R femur)NCCN, 2012a.
    • 76. Question 4 Current recommendation? Asymptomatic, mCRPC 1. Switch bicalutamide to nilutamide 2. DC bicalutamide (antiandrogen withdrawal) 3. Ketoconazole + hydrocortisone 4. Abiraterone acetate 5. Sipuleucel-T 6. Docetaxel chemotherapyNCCN, 2012a.
    • 77. Case Study (cont.) Course of Treatment  Patient choses Rx with Sipuleucel-T  PSA continues to rise  What is next treatment modality? – Abiraterone acetate + prednisone – Enzalutamide (MDV3100) – Docetaxel + prednisone – CabazitaxelNCCN, 2012a.
    • 78. Clinical States Model Sipuleucel-T Metastatic Disease Cabazitaxel (de novo) Metastatic Metastatic Metastatic Rising PSA Castrate Castrate Castrate Primary Resistant Resistant Resistant Hormone Asymptomatic Symptomatic Post Docetaxel Disease Naive Non-Metastatic Castrate Resistant Docetaxel Abiraterone ADT Enzalutamide (MDV3100)Modified from Scher et al, 2008.
    • 79. Immuno-Oncology: Melanoma Jedd D. Wolchok, MD, PhDMemorial Sloan-Kettering Cancer Center
    • 80. Agents Used for Cancer Immunotherapy  Immune modulators  Vaccines – BCG (bladder cancer) – Hepatitis vaccine – Alpha interferon (melanoma, – HPV vaccine kidney, leukemia) – BCG? – IL-2 (melanoma, kidney  Adoptive cellular therapy cancer) – Allogeneic bone marrow – CTLA-4 blockade transplant  Monoclonal antibodies – Anti-CD20, CD19 (lymphoma) – Anti-HER2 (breast cancer) – Anti-EGF receptor (colorectal cancer)BCG = Bacillus Calmette-Guerin; HPV = human papillomavirus.
    • 81. High-Dose IL-2 Therapy  RR: 16% (43/270) Probability of Continuing Response (%) 1.0  Durable responses CR (n = 17) PR (n = 26) – Median 8.9 mos 0.8 CR + PR (n = 43) – CR: not reached 0.6 0.4 0.2 0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 Duration of Response (mos)Atkins et al, 1999.
    • 82. Ipilimumab, A CTLA-4 Blocking MoAB, Augments T-Cell Activation T-Cell Remains Active T-Cell Activation T-Cell Inactivation CTLA-4 T Cell Resting T Cell T Cell TCR CD28 CTLA-4 CTLA-4 HLA B7 Ipilimumab APC APC APCKorman et al, 2006.
    • 83. Anti-CTLA-4 and GM-CSF Tumor Cell Vaccine Synergize to Eradicate Established B16 Melanomavan Elsas et al, 1999.
    • 84. Clinical Response in Melanoma: NCI  Experienced complete resolution of 2 subcutaneous nodules, 31 lung metastases and 0.5 cm brain metastasisPhan et al, 2003.
    • 85. Immune-Related Adverse Events  Rash (20%)  Colitis/Enteritis (15%)  Elevated AST/ALT (10%)  Thyroiditis (3%–5%)  Adrenal Insufficiency (< 1%)  Hypophysitis (3%–5%) Severity is inversely related to vigilance of surveillance. If detected early, most are easily treated and reversible.Wolchok, 2010.
    • 86. MDX010-20 Study Schema ≥ 1 Re-Induction Screening Induction (eligible patients) 3:1:1 R A Ipilimumab + gp100 PD Ipilimumab + gp100 Previously N (n = 403) treated, HLA-A2*0201+ D Follow-Up patients with Ipilimumab alone PD Ipilimumab alone O advanced (n = 137) melanoma M (N = 676) I gp100 alone gp100 alone PD Z (n = 136) E Induction: Ipilimumab at 3 mg/kg, with or without gp100, q3wks for 4 treatments Reinduction: Patients with SD for 3 mos’ duration from Wk 12, or a confirmed CR or PR, could receive additional therapy with their assigned treatment regimen upon PDHodi et al, 2010.
    • 87. Kaplan-Meier Analysis of Survival Comparison HR P-value Arm A vs C 0.68 0.0004 Arm B vs C 0.66 0.0026 Arm A vs B 1.04 0.7575 Ipilimumab + gp100 (A) Ipilimumab alone (B) gp100 alone (C) 1 2 Years 3 4 Survival Rate Ipilimumab + gp100 Ipilimumab alone gp100 alone 1-yr 44% 46% 25% 2-yr 22% 24% 14%Hodi et al, 2010.
    • 88. Study 024: Overall Survival Estimated Survival 1 Yr 2 Yr 3 Yr* Rate Ipilimumab + DTIC 47.3 28.5 20.8 N = 250 Placebo + DTIC 36.3 17.9 12.2 N = 252*3-yr survival was a post-hoc analysis.Wolchok et al, 2011.
    • 89. 11/28/06 1/9/07Wolchok , 2010.
    • 90. Ipilimumab Pattern of Response: Responses After the Appearance and Subsequent Disappearance of New Lesions Pre-Treatment Wk 12: Progression July 2006 3 mg/kg Ipilimumab q3wks X 4 New lesions Wk 20: Regression Wk 36: Still RegressingWolchok et al, 2008a.
    • 91. Four Patterns of Response to Ipilimumab Therapy Were Observed  2 conventional – Response in baseline lesions – SD with slow, steady decline in total tumor volume  2 novel – Response after initial increase in total tumor volume – Response in index plus new lesions at or after the appearance of new lesionsWolchok et al, 2009.
    • 92. irRC Identifies Survivors in Patients With Progressive Disease by mWHO Pooled data from phase II studies CA184-008 and CA184-022: Ipilimumab monotherapy 10 mg/kg (N = 227)mWHO = modified World Health Oncology criteria.Wolchok et al, 2009.
    • 93. CTLA-4 Blockade: A Case Study for Immunotherapy in Need of Biomarkers Knowns Unknowns  Clinical benefit for a  Biomarkers for response subset of patients with  Biomarkers for toxicities refractory melanoma  Effect on effector vs  Reversible mechanism- regulatory T cells in based side effects humans  Tumor responses tend to  Antigens recognized after be durable infusion  Kinetics of response  Importance of vaccination unlike cytotoxics before treatment  Relevance of PBMC vs.PBMC = peripheral blood mononuclear cell. tumor site findingsWolchok, 2010.
    • 94. ALC Correlates With Clinical Benefit Mean longterm ALC 4 clinical benefit 3 ALC [K/mcl] no clinical benefit 2 1 -4 months -3 months -2 months -1 month week 10 week 12 week 24 week 36 week 1 week 4 week 7  This patient population comprises all patients (N = 73) available at the Immune Monitoring Facility of Memorial Sloan-Kettering Cancer Center, New YorkALC = absolute lymphocyte count.Ku et al, 2010.
    • 95. NY-ESO-1 Antibody and CD4 TCR Were Detected After Full-Length NY-ESO-1 Protein Vaccination % IFNg+ CD4 T Cells Reciprocal Titer NY-ESO-1 recombinant protein NY-ESO-1 peptide poolModified from Adams et al, 2008.
    • 96. NY-ESO-1 CD4 and CD8 T-Cell Specific Response After CTLA-4 Blockade (Patient IMF-11) Percent of IFN-g+MIP-1b+ or IFN- g+TNF-a+ T CellsReciprocal Titer IMF-11 Experiencing CR CD8 T Cells CD4 T CellsYuan et al, 2011a.
    • 97. Grand Serology in CTLA-4 Treated Patients (peak response): Correlation With Clinical Benefit NY-ESO-1 LAGE-1 MAGE-1 MAGE-3 MAGE-4 MAGE-10 Melan-A CT7 CT10 CT45 CT46 CT47 SSX1 SSX2 SSX4 PLAC1 SOX2 p53 XAGE-1 NY-ESO-1 LAGE-1 MAGE-1 MAGE-3 ZH1347 MAGE-4 MAGE-10 Melan-A ZH_P24 CT7 CT10 CT45 DHFR CT46 CT47 SSX1 GAGE7 SSX2 SSX4 CXorf48 PLAC1 SOX2 p53 PASD1 XAGE-1 ZH1347 ZH_P24 CXorf61 DHFR GAGE7 CSAG2 CXorf48 PASD1 ERG CXorf61 CSAG2 NXF2 11 1 3 5 5 7 2 6 8 2 3 1 2 3 4 62 8 1 1 2 2 ERG 8 3 7 3 2 3 4 4 52 5 6 NXF2 3 6 4 8 9 3 1 8 5 0 22 26 3 0 31 3 5 36 3 44 4 49 5 5 4 6 7 9 10 15 SAGE1 SAGE1 8 6 3 9 19 20 27 39 40 42 45 50 51 54 57 63 64 65 67 70 71 72 ACTL8 CR 75 61 47 66 68 73 74 76 ACTL8 PR 78 79 80 SD POD DOD Awaiting Clinical Benefit No Clinical BenefitYuan et al, 2011b; Gnjatic et al, 2008.
    • 98. Correlation of NY-ESO-1 Antibody With Clinical Course Following Anti-CTLA-4 Treatment* Patients With NY-ESO-1 Antibodies At Any Time Point During study # Patients # NY-ESO-1 # NY-ESO-1 Response Status at SERONEGATIVE SEROPOSITIVE Wk 24 (%) Status Wk 24 (%) Status Wk 24 (%) CR 4 (2.8%) 2 2 PR 15 (10.4%) 9 6 SD 32 (22.2%) 23 9 Clinical Benefit 51 (35.4%) 34 (30.1%) 17 (54.8%) No Clinical Benefit 93 (64.6%) 79 (69.9%) 14 (45.2%) Total 144 (100%) 113 31 According to Immune-related response criteria: Fishers exact test Clinical Benefit No Clinical Benefit (two-tailed): CR: Complete Response POD: Progression of Disease (includes MR) p Value .0186 PR: Partial Response DOD: Dead of Disease RR = 1.8 (1.2–2.8) SD: Stable Disease*In collaboration with Jedd Wolchok, MSKCC/Ludwig Center, Ruth Halaban and Mario Sznol, Yale University.Yuan et al, 2011b, Gnjatic et al, 2008.
    • 99. Positive and Negative Signals Regulate T-Cell Activation Ipilimumab, Tremelimumab BMS-663513 PF-05082566 Anti-OX40 AMP-224, CT-011, MDX-1106, MK- 3475Wolchok et al, 2008b, 2010.
    • 100. PD-1: Role in T-Cell Activation Dendritic Cell, T Cell Parenchymal Cell, Tumor Cell  Member of CD28 family involved in T-cell regulation What is PD-1?  Expressed by activated T cells, memory T cells, and regulatory T cells  Down regulates T-cell activity upon binding to PD-L1/L2  Tumor PD-L1 expression may correlate with negative prognosis  potential mechanism of tumor self defenseSznol et al, 2010.
    • 101. MDX-1106 (BMS-936558/ONO-4538) Human Anti-PD-1 Antibody  IgG4 (S228P) – no ADCC/CDCC activity  High affinity binding to human and cynomolgus PD- 1  Blocks binding of PD-1 to PD-L1 and PD-L2  In vitro, BMS-936558 – Promotes cytokine production/proliferation • Human allogeneic MLR • Antigen reactive T cells in response to CMV or tumor antigen – Reverses T reg-mediated suppression of allogeneic MLRCDCC = complement-dependent cellular cytotoxicity; MLR = mixed lymphocyte reaction; CMV = cytomegalovirus.Sznol et al, 2010.
    • 102. Change in Tumor Burden  296 patients with advanced solid tumors, including 104 melanoma patients – 26 objective responses observed at doses ranging from 0.1–10.0 mg/kg – 3.0 mg per kilogram: Objective responses noted in 41% – SD lasting 24 wks or more was observed in 6 patients (6%)Topalian et al, 2012.
    • 103. Preclinical Data PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors Time (days)Curran et al, 2010.
    • 104. 09-155 – Study Design Dosing/Evaluation Schedule Induction Maintenance Ipilimumab MDX-1106 Dose Escalation Imaging Studies Cohort MDX-1106 Ipilimumab 1 0.3 mg/kg 3 mg/kg 2 1 mg/kg 3 mg/kg 3 3 mg/kg 3 mg/kg 4 3 mg/kg 10 mg/kg 5 10 mg/kg 10 mg/kgUS NIH, NCT01024231.
    • 105. PET Scans at Baseline and Day 15 After PLX4032 #63 MSKCC #69 MDA #56 Vanderbilt #59 Peter MacCallumPET = positron emission tomography; MDA = The University of Texas M. D. Anderson Cancer Center;MSKCC = Memorial Sloan-Kettering Cancer Center.Chapman, 2009.
    • 106. How Can BRAF Targeted Therapy Increase the Activity of Tumor Immunotherapy? Increased antigen Cross-presentation DC Increased direct antigen presentation BRAF BRAFi Activation of T cells and Decreased immune increased homing suppressive factor releaseDC = dendritic cell
    • 107. Pre-clinical Evidence Supporting the Feasibility of Combinations of BRAFi + Immunotherapy Oncogenic BRAF-induced production of immune suppressive factors (IL-6, IL-10, VEGF) is inhibited with a MEK inhibitor (Sumimoto et al, 2006) Vemurafenib increases melanosomal antigen expression and T cell recognition (Boni et al, 2010) Human T cells exposed to vemurafenib are fully functional (Comin-Anduix et al, 2010)
    • 108. Pre-clinical Evidence Supporting the Feasibility of Combinations of BRAFi + Immunotherapy (cont.) Goel, Haluska et al. Oncogene. 2009 100 80 % Tumor-Free Animals pmel-1 ACT+PLX4032 (n = 19) PLX4032 60 40 pmel-1 ACT (n = 19) BRAF CRAF 20 PLX4032 (n = 14) 0 Vehicle Control (n = 14) 0 5 10 15 20 25 MEK1/2 Days P 3 replicated experiments, p < 0.0001 by log rank test PLX4032 (µM) ERK VC 1 5 15 BRAFV600E mutation P pERK ERK MAPK signaling TubulinKoya et al, 2012.
    • 109. Pre-clinical Evidence Against the Feasibility of Combinations of BRAFi + Immunotherapy PLX4720 treatment leads to a decreased frequency of immune cells in BRAFV600E/PTEN-/- melanomas and this cannot be restored by CTLA-4 blockade Addition of anti-CTLA-4 mAb treatment to PLX4720 treatment does not further improve tumor growth controlHooijkaas et al, 2012.
    • 110. Clinical Evidence Supporting the Feasibility of Combinations of BRAFi + Immunotherapy  CD8+ T cell infiltration in regressing melanoma lesions after BRAFi therapy T cells from patients treated with dabrafenib are fully functionalWilmott et al, 2012; Hong et al, 2012.
    • 111. Results of Diagnostic and Radiotherapy Simulation Imaging Throughout the Disease CoursePostow et al, 2012.
    • 112. NY-ESO-1 Expression and Antibody Response to Ipilimumab and RadiotherapyPostow et al, 2012.
    • 113. Seromics Analysis (Sacha Gnjatic, LICR-NY Branch)  Tested serum against > 9,000 human antigens  10 antigenic targets had increased (> 5x) antibody responses (2 with decreased)  Interesting targets include – Focal adhesion kinase 1 – NY-REN-28 (described in patients with RCC)NY-REN-28 = mediator complex subunit 6 (MED6).Postow et al, 2012.
    • 114. Results of Flow Cytometry of Peripheral Blood Mononuclear CellsPostow et al, 2012.
    • 115. Key Takeaways Checkpoint blockade is an effective treatment with durable responses New and promising immune modulators are in clinical development Combination therapy will be necessary for immunotherapy to achieve full potential (other immune modulators, vaccines, radiation, chemotherapy, targeted therapy, antiangiogenic therapy)
    • 116. Case Study: Melanoma Antoni Ribas, MD, PhD University of California, Los Angeles
    • 117. Case Study 1 A 55-yr-old man is diagnosed with melanoma, and further examination reveals metastatic disease Discussion – What factors should be considered when selecting frontline therapy for this patient? – What indications would lead to your recommendation of a specific treatment? – Under what circumstances might you suggest this patient participate in a clinical trial?
    • 118. Case Study 1: Follow-Up  The patient is treated with ipilimumab; after 12 wks of therapy, he has not responded and new hepatic lesions are observed – How might this patient’s progression affect your recommended treatment strategy? – At what point might you consider alternative therapeutic approaches? – What factors might affect your treatment decisions?NCCN, 2013.
    • 119. Case Study 1: Follow-Up (cont.)  The patient has remained on ipilimumab and has begun to suffer from a grade 2 rash and diarrhea – What concomitant medications can be used to reduce the severity of this AE? – Can dose reductions/omissions be used for these AEs? – How might this affect your recommended treatment strategy?NCCN, 2013.
    • 120. Case Study 2  A 61-yr-old woman is diagnosed with metastatic melanoma and receives alkylating agents as frontline therapy. After 20 wks, there has been no measurable response. Testing of the tumor tissue reveals a V600E mutation. The patient wishes to discuss treatment options for refractory disease, including the possibility of clinical trial enrollment. – What factors might help to determine an alternative treatment strategy? – Which late-stage trials might be most promising for patients with this mutation? – What other molecular approaches might help to direct potential therapies?NCCN, 2013.
    • 121. Immuno-Oncology:Non-Small Cell Lung Cancer John Powderly II, MD, CPI Carolina BioOncology Institute, PLLC Cancer Therapy & Research Center
    • 122. Background  NSCLC remains the leading cause of cancer-related mortality in the US and worldwide  NSCLC long considered non-immunogenic, that is, unable to induce immune destruction  However, there is evidence to suggest that the immune system can recognize NSCLC: – Tumor-infiltrating lymphocytes have been identified in NSCLC patients, and correlates with survival – T cells reactive to tumor associated antigens can be found in patients with NSCLCNSCLC = non-small cell lung cancer.
    • 123. Background (cont.) Why have prior attempts to modulate the immune system in NSCLC patients failed to show consistent benefit? – Not the right immunotherapy – Need for combination therapy to fully enable immune attack- e.g. immunotherapy with other immunotherapy, chemotherapy and/or radiation Problem of immune tolerance- lack of immune attack despite recognition (e.g. immune checkpoints) Newer therapies, including immune checkpoint inhibitors and novel vaccines are beginning to show promise in NSCLC
    • 124. Clinical Significance of Tumor-Infiltrating Lymphocytes in Lung Neoplasms Resected Squamous Cell Lung Cancer, Stage I–IIIa p = .03 Time (yrs)Ruffini et al, 2009.
    • 125. Cancer Self-Tolerance Blockade  Endogenous immune response to cancer is observed in patients, however it is ineffective – Tolerance: Cancer is viewed as self – Tumors exploit mechanisms to suppress the host immune response • Immune checkpoints (CTLA-4, PD-1) abort immune responses – Co-opted by tumors to evade immune destruction – “Tumor adaptive immune resistance” • Immune checkpoint inhibitors may block self-tolerance of cancer, and enable antitumor immune destructionTopalian et al, 2011.
    • 126. Normal T Cell Activation and Attack Priming phase Effector phase Lymph Peripheral node tissueDendritic Cancercell Cell T cell T cell MHC TCR MHC TCR B7 CD28 Release of : - Perforin/ granzyme - CytokinesRibas, 2012.
    • 127. Immune Checkpoints – CTLA4 & PD1 Priming phase Effector phase ll Lymph Peripheral ce node tissue TDendritic Cancercell Cell T cell MHC TCR R TC Negative regulation -1 PD C B7 CD28 MH PD-L1 Inhibitory signals B7 CTLA4 Antibody Antibody AntibodyRibas, 2012.
    • 128. Self-Tolerance Blockade Drugs in Development  Anti-CTLA-4 – Ipilimumab (fully human IgG1, Medarex/BMS) – Tremelimumab (fully human IgG2, Pfizer/Medimmune)  Anti-PD-1 – MDX-1106/BMS-936558 (fully human IgG4, Medarex/BMS) – CT-011 (humanized IgG1, Curetech/Teva) – MK-3475 (humanized IgG4, Merck) – AMP-224 (B7-DC/IgG1fusion protein, Amplimmune/GSK)  Anti-PD-L1 – MDX-1105/BMS-936559 (fully human IgG4, Medarex/BMS) – MPDL3280A (Genentech/Roche)Pierard et al, 2012; Brahmer et al, 2010; Topalian et al, 2012; Paradoll et al, 2012b.
    • 129. Ipilimumab in Combination With Paclitaxel and Carboplatin as First-Line Treatment in Lung Cancer: Phase II Trial CA184-041  Ipilimumab 10 mg/kg, Paclitaxel 175 mg/m2, Carboplatin AUC = 6 – Randomized 3 Arms 1:1:1 • Concurrent Ipilimumab + Paclitaxel/Carboplatin • Phased Ipilimumab + Paclitaxel/Carboplatin • Placebo Control + Paclitaxel/Carboplatin  Stratified by 2 Cohorts – Stage IIIB/IV NSCLC, n = 203 – Extensive Disease SCLC (ED-SCLC), n = 128  Eligibility: ECOG 0–1; ECOG 0–2; at least 1 measurable lesion, no prior lung cancer therapy, no prior auto-immune disease, no active brain metsECOG = European Cooperative Oncology Group.Lynch et al, 2011; Reck et al, 2011.
    • 130. CA184-041: Study Schema Stage IIIB/IV NSCLC Cohortp = placebo; c = chemotherapy (Pac/Carbo) Ipi (10 mg IV).Lynch et al, 2011.
    • 131. CA184-041: Stage IIIB/IV NSCLung irPFS Time (mos)Lynch et al, 2012.
    • 132. CA184-041: Stage IIIB/IV NSCLung Overall Survival Time (mos)Lynch et al, 2012.
    • 133. CA184-041: Stage IIIB/IV NSCLung Summary Conclusions Phased Concurrent Control Median irPFS 5.7 mos 5.5 mos 4.6 mos Median PFS 5.1 mos 4.1 mos 4.2 mos irBORR 32% 21% 18% BORR 32% 21% 14% Median OS 12.2 mos 9.7 mos 8.3 mos Grade 3/4 irAEs 15% 20% 6% Any Grade 4 AEs 12% 27% 11% Treatment-Related Deaths 0 1 patient 1 patientLynch et al, 2012.
    • 134. CA184-041: Stage IIIB/IV NSCLC Cohort Activity of Phased-IPI by Baseline HistologyLynch et al, 2011.
    • 135. CA184-041: Stage IIIB/IV NSCLC Cohort Overall Survival Squamous SubsetLynch et al, 2011.
    • 136. CA184-041: Stage IIIB/IV NSCLC Cohort Most Common (> 15% Any Arm) Adverse EventsLynch et al, 2011.
    • 137. Ongoing Lung Cancer Ipilimumab Trials  NSCLC – CA184-104: Randomized, Multi-Center, Double-Blind, Phase III Trial Comparing Efficacy of Ipilimumab in Addition to Paclitaxel and Carboplatin in Subjects With Stage IV/Recurrent NSCLC (NCT01285609) Global 920 Patients – CA184-124: Randomized, Open-Label, Phase II Safety and Efficacy Trial of Ipilimumab Vs. Pemetrexed in Subjects With Recurrent/Stage IV Non-Squamous, NSCLC Who Have Not Progressed After Four Cycles of Platinum-Based First-Line Chemotherapy (NCT01471197) Global 200 Patients  SCLC – CA184-156: Extensive-Disease SCLC Subjects Comparing Ipilimumab Plus Etoposide and Platinum Therapy to Etoposide and Platinum Therapy Alone (NCT01450761) Global 912 Patients – The Addition of Ipilimumab to Carboplatin and Etoposide Chemotherapy for Extensive Stage SCLC (NCT01331525) EuropeClinicaltrials.gov, 2012.
    • 138. Immune Resistance: PD-1 Innate Immune Resistance MHC + Peptide TCR Tumor T Cell Oncogene-Driven PD-L1 Expression Oncogenic Pathway PD-1 PD-L1 Adaptive Immune Resistance Tumor T Cell Tumor T Cell PD-L1 Adaptive Up-Regulation Interferon g Of PD-L1 Turns T Cell OFFPardoll, 2012a; Slide from Immuno-Oncology GU presentation by Charles Drake.
    • 139. B7-H1 (PD-1L) on Cancer Cells In Vitro Is Inducible by Gamma InterferonHaile et al, 2011.
    • 140. B7-H1 (PD-1L) Expression on NSCLC and Relationship With TIL PD-1 Expression 52 resected lung cancers Fewer TIL in B7-H1+ regions p = .01 Fewer PD-1+ TIL in B7-H1 regions p = .02 Concluded: Expression of B7-H1 on tumor cells in local areas reciprocally correlated With # TIL, and may contribute to negative regulation in antitumor immune responseKonishi et al, 2004.
    • 141. Phase Ia Study of Single-Agent Anti-PD-1 (MDX-1106/BMS-936558/ONO-4538) in Refractory Solid Tumors – Fully human IgG4 anti-human PD-1 blocking Ab - No ADCC/CD – High affinity for PD-1 (KD ~ 3 nM) – Blocks binding of both PD-L1 (B7-H1) and PD-L2 (B7-DC) – Among 39 Patients: • 1 CR (CRC), 2 PRs (Melanoma, RCC), 12 SD > 3 mos, including 2 significant mixed responses (NSCLC, Melanoma) • CR and PR were ongoing 3–21+ mos – Toxicities: No DLT; MTD not reached • Grade 3 colitis (1 melanoma patient, after 5 doses) • Grade 2 hypothyroidism (1 patient) • Grade 2 polyarticular arthropathies (2 patients, required oral steriods) – Among 9 patients examined, tumor expression of B7-H1 (PD-1L) showed correlation with likelihood of responseDLT = dose-limiting toxicity.Brahmer J, et al. J Clin Oncol 2010;28:3167-75
    • 142. MDX-1106 001: Phase I Study of Single-Agent Anti-PD-1 (MDX-1106) in Refractory Solid Tumors (cont.) May 2007 July 2007 61-yr-old BF stage IV NSCLC (squamous) bilateral lung metastasis, bone mets. Prior treatment carboplatin/vinorelbine/bevacizumab. May 2007, Rx single dose of MDX- 1106, anti-PD-1 mAb (1 mg/kg IV) 8 wks 41% RECIST PR, but 12-wk scans showed new spine mets (mixed response) Rechallenged MDX-1106, progressedRECIST = Response Evaluation Criteria in Solid Tumors.Brahmer et al, 2010.
    • 143. BMS-936558 (Anti-PD1) Study Design: Phase Ib Multi-dose RegimenTopalian et al, NEJM, 2012.
    • 144. BMS-936558 (Anti-PD-1):Expansion Cohorts for NSCLC
    • 145. Baseline Characteristics
    • 146. Summary of Key Safety Results MTD was not identified at doses up to 10 mg/kg There was no apparent relationship between drug dose and AE frequency in all treated patients or NSCLC patients In the total patient population across all tumor types:  Grade 3-4 drug-related AEs occurred in 14% of patients  Grade 1-2 pneumonitis was noted in 6 (2%) patients  Three drug-related deaths occurred in patients with pneumonitis (2 with NSCLC and 1 with CRC) In NSCLC patients:  Grade 3-4 drug-related AEs occurred in 8% of patients  Grade 1-2 pneumonitis was noted in 4 (3%) patients  The most common grade 3-4 AEs were fatigue, pneumonitis, and elevated AST (2 pts each)
    • 147. Clinical Activity of BMS-936558 in NSCLC Patients
    • 148. Clinical Activity by Histology, Efficacy Population
    • 149. Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody (BMS-936558, MDX-1106) in Cancer (cont.) NSCLC Patient With Immune-Related Pattern of Delayed Response Baseline 2 Mos 4 MosTopalian et al, 2012.
    • 150. Pre/ Post BMS 936558 (Jun / Oct ’11)- 58 y/o ex smoker with squam NSCLC- 4 prior tx for Stage IV disease- Left flank pain resolved within 2 mos
    • 151. Anti-PD-1 mAb Lung Cancer Response  60-yr-old man – Diagnosed in 2002  Intermittent responses but eventual progression on multiple prior combination chemotherapies and RT  RX MDX-1106 10 mg/kg  A: Baseline  B: Cycle 2 assessmentCourtesy of Dr. Brahmer and Dr. Topalian, John Hopkins.
    • 152. Correlation of PD-L1 Expression in Pretreatment Tumor Biopsies with Clinical Outcomes
    • 153. Ongoing PD-1 Blockade Trials That Include Lung Cancer  CA209-012: Multi-Arm Study of BMS-936558 (MDX- 1106, anti-PD-1 mAb) in Combination With 3 Platinum-Based Doublet Chemotherapy Regimens in Subjects With Treatment-Naive Stage IIIB/IV NSCLC (NCT01454102) North America, 60 Patients  Phase I Study of Single Agent MK-3475 in Patients With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung Carcinoma (NCT01295827)Clinicaltrials.gov, 2012.
    • 154. Pending PD-1 Blockade Registration NSCLC Trials An Open-Label Randomized Phase III Trial of BMS- 936558 Versus Docetaxel in Previously Treated Advanced or Metastatic Squamous Cell Non-small Cell Lung Cancer (NCT01642004) An Open-Label Randomized Phase III Trial of BMS- 936558 Versus Docetaxel in Previously Treated Advanced or Metastatic Non-squamous Cell Non-small Cell Lung Cancer (NCT016738677)
    • 155. Safety and Activity of Anti-PD-L1 Antibody in Patients With Advanced Cancer  Phase Ia, 207 patients solid tumors stage IV – Rx monotherapy anti-PD-L1 antibody q2wks (3 doses over 6-wk cycles) up to 16 cycles until PD or CR – Cumulative objective response • Melanoma 17% • RCC 12% • NSCLC 10% (75 patients with NSCLC) – 50% of responders durable > 1 yr – Immune-related events 39% (rash, hypothryoidism, hepatitis, myasthenia gravis) – Drug related grade 3–4 AEs 9% – NSCLC 12% SD; Clinical benefit (CR + PR + SD) = 22%Brahmer et al, 2012.
    • 156. Safety and Activity of Anti-PD-L1 Antibody in Patients With Advanced CancerBrahmer et al, 2012.
    • 157. Safety and Activity of Anti-PD-L1 Antibody in Patients With Advanced CancerBrahmer et al, 2012.
    • 158. Lung Cancer Vaccines
    • 159. GSK1572932A (MAGE-A3) Vaccine  MAGE-A3 (melanoma associated antigen A3) genes constitute a family of ‘cancer-germline’ or ‘cancer testis’ genes (testes, placenta, cancers)  30-50% of NSCLCs express MAGE-A3 on their surface (higher expression in squamous cell NSCLC)  GSK1572932A (MAGE-A3) vaccine • Recombinant protein vaccine combined with immunological adjuvant ASO2BUS NIH, NCT00480025
    • 160. MAGRIT MAGE-A3 as Adjuvant Non- Small Cell LunG CanceR ImmunoTherapy Primary endpt: DFS overall and DFS in a gene signature positive population 11,000 patients screened, 10,000 tumors tested, 3,235 tested + MAGE A3, 2270 randomized (Largest lung cancer trial ever)
    • 161. L-BLP (Stimuvax) MUC-1 is a cell surface mucinous glycoprotein overexpressed or aberrantly glycosylated in a number of epithelial malignancies Aberrant glycosylation appears to expose the core peptide of MUC-1 to immune effector cells L-BLP-25: MUC-1 vaccine consisting of the BLP 25 peptide, monophosphoryl lipid A adjuvant and liposomal cholesterol, dimyristoyl phosphatidylglycerol (DMPG) and dipalmitoyl phosphatidylcholine (DPPC) to facilitate immune recognition RPhII of Stimuvax in advanced NSCLC- Subgroup analysis suggested benefit in Stg IIIB (but not SS)
    • 162. L-BLP25: A Peptide Vaccine Strategy in NSCLC  Randomized Phase IIB 171 Patients Stage IIIB–IV Canada & UK  Post hoc subgroup Analysis IIIB (65 patients)  p Value non- significant But trend favorable. Led to phase III trial with stage III patients Survival Time (mos) ongoing.BSC = best supportive care.Sangha et al, 2007.
    • 163. START Phase III Trial: L-BLP-25 in Un-resectable, Stage III NSCLC •Eligibility Criteria III Unresectable, stage R Maintenance until A progression NSCLC N L-BLP-25 930 μg L-BLP-25 930 μg •Stable or responding D q7d x 8 cycles q6w disease after chemoradio- O therapy M Placebo Placebo •PS 0-1 I q7d x 8 cycles q6w Z (Adjusted N=1476) E • Primary endpoint: survival • Secondary endpoints: TTP; TTSP; 1-, 2-, and 3-year survival; and safety TTSP=time to symptom progression.US NIH, NCT01015443
    • 164. Belagenpumatucel-L (Lucanix) One mechanism used by tumors to escape immune surveillance is secretion of transforming growth factor beta (TGF-β) which: – Inhibits T and B cell activation – Inhibits dendritic cell maturation and antigen presentation – Inhibits NK and lymphokine activated (LAK) cells – Induces immunosuppressive FoxP3 Treg cells Lucanix- allogeneic whole tumor vaccine consisting of four irradiated NSCLC tumor cell lines modified to block TGF- β2 secretion PhII (primarily IIIb/IV), n=75, 3 doses  tolerated well with encouraging survival
    • 165. Lucanix Phase III NSCLC trial Lucanix Stage III-IV NSCLC 18 monthly inj  without POD after 2 quarterly inj 1-6 cycles of 1st line Randomization + BSC Survival platinum based chemo Placebo (n=1322) + BSC • Primary endpoint: • Secondary endpoints: – Overall survival – Safety – PFS* 420/ 506 accrued as of 2-09-2012US NIH, NCT00676507 – OR
    • 166. Talactoferrin Alfa (TLF)  Recombinant human lactoferrin with immunomodulatory properties  After ingestion, TLF acts of GI epithelium to release chemokines which recruit immature dendritic cells to gut- associated lymphoid tissue where they undergo maturation/ activation – Initiate both active immunity (via NK cells) and adaptive immunity by antigen presentation to CD8+ T cells that seek out tumor  Encouraging survival data in RPhII trials as monotherapy and with chemotherapyParikh et al, 2011; Digumarti, 2011
    • 167. FORTIS-M (LF-0207) R TLF 1.5 g BID 742 patients A 12 wks on, 2 wks off enrolled N up to 5 cycles Stage IIIB/IV D + BSC NSCLC who have O 2:1 Placebo BID failed two or more M 12 wks on, 2 wks off prior regimens I up to 5 cycles ECOG PS 0-2 Z + BSC E Primary Endpoint: Overall Survival Secondary Endpoints: 6-month & 1-year survival rate, PFS, ORR, Disease Stabilization Rate (PR+CR+SD), TLF safety and tolerabilityUS NIH, NCT00707304
    • 168. FORTIS-C (LF-0208) R TLF 1.5g BID TLF until disease A + Carboplatin (AUC 6) progression + Paclitaxel (200mg/m2) 1,100 patients N q3 weeks for 6 cycles (up to 18 months) previously D untreated Stage IIIB/IV O 1:1 NSCLC M ECOG PS 0-1 I Placebo BID Placebo until disease + Carboplatin (AUC 6) Z progression (up to 18 + Paclitaxel (200mg/m2) E months) q3 weeks for 6 cycles Co-Primary Endpoints: PFS & OS Secondary Endpoints: Objective Response Rate, Duration of Response, Safety Stratifications: gender; disease stage; geographical regionUS NIH, NCT00706862
    • 169. Additional Immunotherapies Being Evaluated in NSCLC & SCLC NSCLC – TG4010 (modified vaccine virus Ankara expressing MUC, IL-2, Transgene/Novartis) • Phase IIB/III (NCT01383148) – EGF (conjugated to an immunoadjuvant, “Cuban Vaccine”) • Phase III (NCT01444118) – Reolysin (naturally occurring unmodified oncolytic virus) • Phase I/II (NCT00861627; NCT00998192) SCLC – -SVV1 (Seneca Valley Virus; replication competent picovirus with selective tropism for tumors with neuroendocrine features) • Phase II (NCT01017601) – Autologous dendritic cell-adenovirus p53 vaccine +/- tretinoin • Phase II (NCT00618891)
    • 170. Key Takeaways Tumor infiltrating lymphocytes in lung cancer predict improved survival Lung cancer can be immunogenic, with self-tolerance blockade drugs – Anti-CTLA4 (randomized phase II durable responses) – Anti-PD1/PDL1 (early phase IB durable responses) – Phase III trials launched Phase III Vaccine trials close to completing accrual
    • 171. Case Study:Non-Small Cell Lung Cancer John Powderly II, MD, CPI Carolina BioOncology Institute, PLLC Cancer Therapy & Research Center
    • 172. Case Study: Diagnostic Work-Up  69-yr-old Caucasian man, prior smoker, presenting with cough and night sweats – 1/06 CT Chest: RUL necrotic mass 5.7 x 5.9 cm (? abscess vs. cancer) – 1/06 Bronchoscopy RUL lung biopsy (Bx): Poorly differentiated adenocarcinoma with extensive tumor necrosis – PET: RUL mass SUV 14.7; precarinal LN SUV 4.0 – CT brain: NegRUL = right upper lobe; LN = lymph node; SUV = standardized uptake value.
    • 173. Initial Treatment  1/06 bronchoscopy, R thoracotomy, RUL lobectomy, mediastinal lymphadenectomy  Path: – 5 cm SCC, high grade, 0 of 18 LNs • Incidental lymphoid follicular hyperplasia in level 10 LNs – pT3pN0, initial stage IIB – Patient declined chemotherapyICU = intensive care unit.NCCN, 2012b.
    • 174. Surveillance and Relapse  Surveillance q6mos CT scan • 9/07 CT scan: New R adrenal nodule 2.4 cm • 1/08 PET/CT scan: R adrenal mass larger 5.4 x 3.8 cm, SUV 10  1/08 Bx R adrenal mass: Poorly differentiated, non-small cell, mixed adenocarcinomatous with squamoid features  Stage IV with solitary R adrenal mass (oligometastatic)NCCN, 2012b.
    • 175. Stage IV Metastectomy  4/08 R adrenalectomy, Path: 4.5 cm lung carcinoma poorly differentiated (EGFR PCR wild-type) – Rendered surgical no evidence of disease  8/08 Started chemotherapy. Carboplatin/Paclitaxel/Bevacizumab x 4 cycles, with maintenance bevacizumab until progression.PCR = polymerase chain reaction.NCCN, 2012b.
    • 176. Second Recurrance  2/09 CT scan: Enlarging contralateral L adrenal mass 5.5 cm  2/09 Brain MRI: Negative  3/09 Informed consent for phase I clinical trial with MDX- 1106 (anti-PD-1 mAb)  3/09 First dose MDX-1106 (3 mg/kg) IV q2wks  Baseline ANA 1:40, + Rheumatoid Factor = 19, CRP = 23CTC = circulating tumor cell; CRP = C-reactive protein.NCCN, 2012b.
    • 177. Immunotherapy Response  5/09 CT scan: Decreased L adrenal mass 3.0 x 2.8 cm (PR)  5/09 Hospitalization COPD exacerbation, Rx azithromycin, methylprednisolone, then prednisone taper (MDX-1106 delayed until 2 wks after last dose of prednisone)  6/09 Resumed MDX-1106  7/09 CT scan: Further decrease L adrenal mass 2.7 x 2.9 cmNCCN, 2011.
    • 178. Durable Partial Response (cont.) February 2009 September 2009
    • 179. Durable Partial Response 2/11 Completed 2 yrs of bi-wkly MDX-1106 8/12 Remains with durable PR, with only measurable disease at L adrenal nodule 2.0 cm
    • 180. Circulating Tumor Cell Count Correlated With Tumor Response L adrenal metastasis R adrenal metastectomy Pre-Immunotherapy baseline ANA 1:40, CRP 23, RF 19 MDX-1106 Anti-PD-1 mAb durable response Carbo/Paclitaxel/Bevacizumab ANA 1:40 CRP 8.7 RF 19RF = rheumatoid factor.
    • 181. Evaluation and Prognostic Significance of CTCs in Patients With NSCLC CTC / 7.5 mL N (%) Median OS in 101 100 at Baseline Mo. (95% CI) patients < 5 CTC 92 (91%) 8.1 (7.8 to 8.4) Stage ≥ 5 CTC 9 (9%) 4.3 (2.8 to 5.8) 80 Overall Survival (%) III–IV 60 40 20 p < .001 0 2 4 6 8 10 12 14 16 18 20 Time From Baseline Blood Draw (months)Krebs et al, 2011.
    • 182. B7-H1 (PDL1) Profiling of Circulating Tumor CellsCarolina BioOncology Institute and BioCytics Inc.
    • 183. Immuno-Oncology: Other Tumor Types Mary L. Disis, MDUniversity of Washington School of Medicine
    • 184. What Defines an Immunogenic Tumor? Immune response detected? Antigens identified? Immunity associated with prognosis? Spontaneous tumor regression? TIL that can kill tumor? There Is Evidence of Immunogenicity in Nearly Every Tumor Type
    • 185. Why Has it Been So Difficult to Develop Immune-Based Therapies That Work? Therapeutic Adjuvant  Successes with: – Combination therapy – Targeted populations – Low burden diseaseFinn, 2003
    • 186. Anti-GD2 Antibody With GM-CSF, IL-2, and Isotretinoin for Neuroblastoma, Phase III  Monoclonal antibody targeting a tumor-associated ganglioside-GD2 with enhanced activity when administered with IL-2 (increases T cells) and GM-CSF (increases innate immune cells)  226 high risk neuroblastoma patients post induction and transplant, randomized 1:1, standard therapy (isoretinoin) or anti-GD2, IL-2, GM-CSF + isoretinoin  Immunotherapy superior for EFS: 67% vs. 46% at 2 yrs, p = .01  Immunotherapy superior for OS: 86% vs. 76% at 2 yrs, p = .02  52% with grade 3–5 toxicity about 25% with capillary leak syndromeEFS = event-free survival.Yu et al, 2010.
    • 187. In Situ TLR-9 With Radiotherapy in Low Grade B Cell Lymphoma, Phase II Treg inducers Treg noninducers Patient 14 Patient 13 Patient 9 Patient 3 Patient 15 Patient 11 Radiation PF-3512676 Time of Best Response (weeks) CD25 5.5x 4.5x 5.0x 0.9x 1.5x 1.3x Treg Fold Induction Patient No. Clinical response assessment Log (PFS or censored Time (weeks) follow-up [weeks])TLR-9 = toll-like receptor 9; PFS = progression-free survival, FOXP3 = forkhead box protein P3; T-reg = regulatory T cells.Brody et al, 2010.
    • 188. EGFRvIII Vaccination in Glioblastoma p=0.041 EGFRvIII Immunohistochemistry Before and After Vaccination Before Vaccination At Recurrence Positive Negative Positive Negative Positive Negative Positive Positive (< 1%) p=0.001 Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Positive Positive Negative Percent negative after vaccine is 82% (95% CI, 48%–97%) p=0.03 or nine of 11; binomial test p < .001EGFRvIII = epidermal growth factor receptor variant III.Sampson et al, 2010; Camp et al, 2005.
    • 189. Randomized Phase III Trial Recruiting Inclusion Criteria • ≥ 18 yrs old • Newly diagnosed glioblastoma • Attempted surgical resection followed by conventional chemoradiation • Documented EGFRvIII positive tumor • No evidence of progressive disease from the post-operative period to the post-chemoradiation period • Candidate for, and agrees to receive, adjuvant (maintenance) temozolomide therapy ESTIMATED ENROLLMENT: 440KLH = keyhole limpet hemocyanin.US NIH, NCT01480479.
    • 190. HER2 Vaccination in Early Stage Breast Cancer (node +) All Patients Time (mos)HER2 LowExpressing Time (mos)LE = low expressor; OE = overexpressor; DTH = delayed-type hypersensitivity; HER2 = human epidermal growth factor receptor 2.Mittendorf et al, 2011; Benavides et al, 2009.
    • 191. Randomized Phase III Trial Recruiting Inclusion Criteria: • ≥ 18 yrs old • Pathological diagnosis of invasive adenocarcinoma of the breast • Breast cancer completely excised • Node + disease • Primary tumor stage T1–3 • HER2- (HER2 1+ by IHC or HER2 2+ by IHC/FISH) • HLA-A2 or HLA-A3 haplotype • Completed NCCN approved neo- adjuvant/adjuvant chemotherapy or both • Completed radiation therapy • No evidence of disease ESTIMATED ENROLLMENT: 700WFI = water for injection; NCCN = National Comprehensive Cancer Network; IHC = immunohistochemistry;FISH = fluorescence in-situ hybridization; HLA = human leukocyte antigen.US NIH, NCT01479244.
    • 192. Autologous Tumor Cell Vaccine With GM-CSF and bi-shRNA Downregulation TGF-Beta (FANG) FANG mean TGFβ1 - ELISA (n = 42)Paired t-test Days Days Since Procurement*< .05, **< .01, ***≤ .001 FANG mean TGFβ2 - ELISA (n = 42)  Could generate vaccine in 91%  Common solid metastatic tumors  Majority vaccinated achieved SD  Survival significantly associated with number of vaccinesPaired t-test Days*< .05, **< .01, ***≤ .001bi-shRNA = bifunctional short hairpin ribonucleic acid; TGF = transforming growth factor.Senzer et al, 2012.
    • 193. Randomized Phase II Trial Recruiting Inclusion Criteria: • ≥ 18 yrs old • Histologically confirmed colorectal carcinoma with synchronous or metachronous liver metastases +/- pulmonary metastases • Maximum total number of metastatic lesions ≤ 6 • Candidate for surgical excision +/= ablation with curative intent • Planned resected viable tumor in sufficient quantity ("golf ball size" estimated weight ~ 30 grams) for vaccine processing • ECOG performance status (PS) 0–2 • Estimated > 4-mos survival probability ESTIMATED ENROLLMENT: 60US NIH, NCT01505166.
    • 194. Clinical Trials  Approximately 2,380 open cancer immune therapy trials  1,444 open phase II and III trials 355 Open Cancer Vaccine Trials 180 Open Phase II and III Trials ….and multiple myeloma, renal, brainClinicaltrials.gov, 2012.
    • 195. Key Takeaways Immunotherapy clinical trials integrate treatment into current standard of care regimens – Recent studies suggest some of the most common chemotherapeutic agents we use have profound immunologic effects There are immunotherapy approaches being studied in almost every common cancer, both hematopoietic and solid tumors Both adults and children with cancer have shown benefit with immune- based therapies in published clinical trials Most immune therapies are associated with tolerable toxicities (or even rare toxicity in the case of cancer vaccines) There are numerous immune-based clinical trials, at all stages, open for enrollment in the US
    • 196. Management of Immunotherapy- Related Adverse Events Mary L. Disis, MD University of Washington School of Medicine
    • 197. Successful Anti-Cancer Immunity Is AutoimmunityDisis, 2010a.
    • 198. Autoimmunity Associated With Clinical Response to Immune Therapy  Prospective observational study of 3,000 patients evaluated clinical factors associated with favorable outcome − Vitiligo predictive in multivariate analysis (p = .006 for OS)  Study evaluating the laboratory and clinical characteristics of 374 patients treated with IL-2 to determine biomarkers of response (NCI) − Thyroid dysfunction (p = .01) and vitiligo (p < .01) were predictors of increased survival  Trial of 198 MM or RCC patients treated with ipilimumab suggested a higher response rate in patients who developed enterocolitis compared to those that did not (p = .0065) (NCI)  Evaluation of 200 stage II/III melanoma patients treated with interferon; development of autoimmunity correlated with longer relapse-free survival (p < .001) as well as OS (p < .001) − Some immunity was sub-clinical (serologic only) and still demonstrated effectDisis, 2011.
    • 199. Autoimmunity Associated With Improved Prognosis After IFN Therapy in Melanoma Patients with autoimmunity Patients with autoimmunity Patients without autoimmunity Patients without autoimmunity 0.0 25.0 50.0 75.0 100.0 125.0 0.0 20.0 40.0 60.0 80.0 100.0 120.0 Months from start of treatment Months from start of treatment • 26% incidence • Clinical and serologicGogas et al, 2006; Dafni et al, 2008.
    • 200. Autoimmunity Associated With Clinical Response After Ipilimumab Response rate to ipilimumab Attia Beck Maker Study Study Study 2005 2006 2005Mellman et al, 2011; Weber, 2008b.
    • 201. irAE Associated With Ipilimumab: Covers All Bases IRAEs From lpilimumab in Phase II and III Trials Patient number Phase III Phase-III Phase-II (n=) Ipi and DTIC Ipi monotherapy Ipi monotherapy (Ipi at 10 mg/kg) (3 mg/kg) different doses 217 (71 each 250 131 at 3 mg/kg and 10 mg/kg) All grade irAE % 77.7 61.1 65 at 3 mg/kg [7] [Grade 3, 4%] [31.6, 10.1] [12.2, 2.3] 70 at 10 mg/kg [25] MORE COMMON Dermatologic % 43.5 45 at 3 mg/kg [1.5] [Grade 3, 4%] [1.5, 0] 46 at 10 mg/kg [4.2] Pruritus% 26.7 [2.0, 0] 24.4 [0, 0] 21.3 at 3 mg/kg[1.4] 32.4 at 10 mg/kg [2.8] Rash 22.3 [1.2, 0] 19.1 [0.8, 0] 23.9 at 3 mg/kg [1.4] 22.5 at 10 mg/kg [0] Vitiligo 2.3 [0, 0] Gastrointestinal % 29 32 at 3 mg/kg [2.8] [Grade 3, 4%] [7.6, 0] 39.4 at 10 mg/kg [15.5] Diarrhoea % 32.8 [4.0, 0] 27.5 [4.6, 0] 25.3 at 3 mg/kg [1.4] 39.4 at 10 mg/kg [14.0] Colitis 4.5 [1.6, 0.4] 7.6 [5.3, 0] 5.6 at 3 mg/kg [1.4] 5.6 at 10 mg/kg [2.8] Endocrine % 7.6 5.6 at 3 mg/kg [2.8] LESS COMMON [Grade 3, 4%] [2.3, 1.5] 4.2 at 10 mg/kg [1.5] Hypothyroid % 1.5 [0, 0] Hypopituitarism 2.3 [0.8, 0.8] Hypophysitis 1.5 [1.5, 0] Adrenal insufficiency 1.5 [0, 0] Increase thyrotropin 0.8 [0, 0] Decrease corticotrophin 1.5 [0, 0.8] Hepatic % 3.8 0 at 3 mg/kg [Grade 3, 4%] [0, 0] 2.8 at 10 mg/kg [2.8] Increase ALT % 29.1 [15.0, 5.7] 1.5 [0, 0] Increase AST 26.7 [13.8, 3.6] 0.8 [0, 0] Hepatitis 1.6 [1.2, 0] 0.8 [0, 0]DTIC = dacarbazine; Ipi = ipilimumab; ALT = alanine aminotransferase; AST = aspartate aminotransferase.Lemech et al, 2012.
    • 202. irAE Management: Reticular Erythematous Rash Rash ~ 40% Grade 3–4 ~ 2% Grade 1, 2: • Topical steroids or topical creams (urea based) • May require anti-pruritic management (diphenhydramine) • Avoid direct contact with sunlight, sunscreen (prophylactic) Grade Persistent Grade 2 or Grade 3: • Withhold dose • Treat with 4-wk tapering oral steroid (1 mg/kg/day) Grade 4: • Discontinue drug permanently • Consider IV steroids Perivascular CD8Hodi et al, 2008; Lemech et al, 2012.
    • 203. irAE Management: GI Effects Diarrhea ~ 40% Colitis ~ 5% Grade 1, 2: Loperamide and close follow-up Small frequent meals Bland diet No lactose containing products Electrolyte replacement (oral) Grade Persistent Grade 2: Treat with slow tapering oral steroid (1 mg/kg/day) Oral budesonide (9 mg daily) x8 wks (last 2 taper) Consider endoscopy (R/O colitis), rapid progression can occur Grade 3, 4: Endoscopy HD IV steroids, slow taper No response to steroids: infliximab (5 mg/kg IV) Rare case of perforation (1%) Discontinue drug permanentlyHD = high dose; R/O = rule out; GI = gastrointestinal.Lemech et al, 2012; Weber, 2007.
    • 204. Determine baseline LFTs, Lemech et al, 2012; Weber, 2007. T Bili at screening T Bili = total bilirubin. ANA = antinuclear antibody; creat = creatinine; LFTs = liver function tests; SMA = smooth muscle antibody; Baseline LFTs. Baseline LFTs. s T Bili = T Bili= grade 1 or 2 NORMAL Ye Routine Routine monitoring of No No monitoring of LFTs and T Bili Discontinue drug permanently LFTs and T Bili LFTs and/or LFTs and/or consider mycophenolate mofetil T Bili grade ≥2x T Bili grade baseline ≥2? values ? s No response to steroids at 48 hrs: Ye Daily LFTs Trigger point #1 No No intensified monitoring Workup for autoimmunity: HD IV steroids, slow taper (over 1 mos) 1. Clinical signs 2. Labs: ANA, SMA, LFTs., T Bili, creat, other Grade 3, 4: 3. Check LFTs, T Bili q 3 days Workup to do non-IRAE causes: improvement 48–72 hrs 1. Imaging to do mets 2. Consider liver biopsy if suggestion of Initiate oral steroids if no autoimmune etiology Monitor course: Monitor course: Check labs q 3 LFTs >8x ULN? Check labs q 3 LFTs daily x3 sdays until stable or days until stable or s And/or T Bili >5x decreasing, then ULN? decreasing, then Ye Ye once per week once per week causes Monitor course: 1. Hold further Ipilimumab Withhold drug, w/u non-immune 2. Repeat LFTs within 24 hrs No No Grade 2: LFTs still rising over 24-48 hrs? Monitor closely and/or suspect IRAE Therapeutic intervention Grade 1: (recommended sequence): 1. Admit to hospital Trigger point #2 2. Check labs daily Therapeutic 3. Steroids (IV) Hepatic ~ 5% intervention 4. Mycophenolate mofetil 5. Tacrolimus 6. Infliximab irAE Management: Hepatic Effects
    • 205. irAE Management: Endocrinopathies Endocrine ~ 7% Grade 3–4 < 2% Symptoms: Headache, visual field changes, nausea, vomiting, hypotension, electrolyte abnormalities Work-Up: TSH, free T4/T3, ADH, serum cortisol, LH, FSH, prolactin, MRI of the head Treatment: • Hold drug • Stress does IV steroids • Gonadal and thyroid replacement, may need permanently • Ongoing monitoring • May consider restarting ipilimumab is grade 1–2 after symptoms resolvedADH = adrenocorticotropic hormone; LH = luteinizing hormone; FSH = follicle stimulating hormone; TSH=thyroid-stimulating hormone;T4= thyroxine; T3= triiodothyronine ;MRI = magnetic resonance imaging.Lemech et al, 2012.
    • 206. T Cells Continue to Evolve Even After Drug Is Cleared Evolving Immune Response Treatment SD = First efficacy assessment • When toxicities occur is variable • Early and late PR Ongoing 57 + wk no new • Prolonged treatment lesions • May need to treat again CR Post-Treatment Initiation (wks) Responses as late as 106 wksWeber, 2008b.
    • 207. Key Takeaways The development of autoimmune phenomenon may be an expected toxicity associated with some immune-based therapies Autoimmunity may demonstrate immune activation and has been associated with improved outcome in studies of some immune- based treatments Autoimmunity induced by current immune-based therapies is self- limited once the treatment has been discontinued • If toxicity not life-threatening, consideration may be given to reinstituting therapy once symptoms have resolved If the autoimmune toxicities are mild, symptoms can be managed medically while the patients remain on treatment Autoimmune adverse events may occur at anytime in the course of treatment