Immuno-Oncology: An Evolving Approach to Cancer Care
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Immuno-Oncology: An Evolving Approach to Cancer Care

Review a downloadable slide deck by Thomas F. Gajewski, MD, PhD, covering the most clinically relevant new data reported from Immuno-Oncology: An Evolving Approach to Cancer Care.


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This activity is designed to meet the educational needs of oncologists and other healthcare professionals involved in cancer care.

Format: Microsoft PowerPoint (.ppt) | File size: 26.2 MB | Date posted: 6/20/2012


Slide Deck Disclaimer

This slide deck in its original and unaltered format is for educational purposes and is current as of June 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CE 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.

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  • Figure 2. T cell and dendritic cell interaction in draining lymph nodes.
  • Figure 2. T cell and dendritic cell interaction in draining lymph nodes.
  • Phase I trial of ipilimumab (IPI) alone and in combination with radiotherapy (XRT) in patients with metastatic castration resistant prostate cancer (mCRPC). Beer TM, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2008;26(15S): Abstract 5004.
  • 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.
  • 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.
  • 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
  • Haraoka et al, British Journal Cancer 2006: 94:275-80 (Japan) Kaplan – Meier analysis of overall survival according to the simultaneous presence of high levels of infiltrating CD8þ T cells and CD4þ T cells in cancer stroma in patients with NSCLC.
  • 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).
  • Kawai et al, Cancer 2008; 113:1387-95 (Japan) Kaplan-Meier analysis of overall survival is shown according to distribution in 4 groups of macrophages and CD81 T cells. Patients whose tumors contained macrophages in the nest and more CD81 T cells in the nest had significantly better survival (macrophages, nest > stroma; CD81 T cells, nest > stroma) than patients with macrophages nest > stroma and CD81 T cells nest < stroma (P 5 .0070), patients with macrophages nest < stroma and CD81 T cells nest > stroma (P 5 .0010), and patients with macrophages nest < stroma and CD81 T cells: nest < stroma (P < .0001).
  • Dieu-Nosjean et al, JCO 2008, 26: 4410-17 (France) Evaluation of DC-Lamp as a marker of tumor-induced bronchus- associated lymphoid tissue (Ti-BALT) and its prognostic value. Kaplan-Meier curves of disease-free survival for 74 patients with non–small-cell lung cancer depending on the density of tumor-infiltrating DC-Lamp+ mature DC.
  • Al-Shibli et al, Histopathology 2009, 55: 301-12 (Norway)Disease-specific survival curves for stromal CD56+ cells in NSCLC.
  • Immunologic synapse. Target recognition by T cells is two-step process. Specific interaction of T-cell receptor (TCR) with major histocompatibility complex (MHC) –peptide complexes displayed by tumor cells or antigen-presenting cells (APCs; eg, dendritic cells) provides first signal for T-cell recognition. Second event is coregulatory signal that determines whether T cell will become activated or anergic (nonreactive). T-cell coreceptors transmitting stimulatory (+) or inhibitory (-) signals on engagement of specific ligands expressed by tumor cells or APCs are depicted. Molecules in B7-CD28 and tumor necrosis factor receptor (TNFR) families are now being targeted for cancer immunotherapy.
  • 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.
  • Two cohorts: NSCLung and Small Cell ED Lynch et al, WCLC 2011, ESMO 2010, Reck et al WCLC 2011
  • Lynch et al, WCLC 2011, ESMO 2010, Reck et al WCLC 2011
  • Lynch et al, WCLC 2011, ESMO 2010, Reck et al WCLC 2011 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 Kaplan-Meier Plots for progression-free survival per modified WHO criteria (mWHO-PFS). Per modified WHO criteria (mWHO), a reduction in index lesions by ≥ 25% or any new lesions (measurable or not) or a progression of nonindex lesions were considered an mWHO progression. mWHO-PFS was defined as the time from random assignment to mWHO progression (as determined by an independent radiologic review committee) or death. As indicated by symbols, patients who neither progressed nor died were censored on the date of last tumor assessment. P values were based on an unstratified log-rank test with a one-sided a of 0.1. HR, hazard ratio; Ipi, ipilimumab. (A) Control v phased Ipi.
  • Lynch et al, WCLC 2011, ESMO 2010, Reck et al WCLC 2011
  • Lynch et al, WCLC 2011, ESMO 2010, Reck et al WCLC 2011 Phased ipilimumab + chemotherapy appeared to show improved efficacy in first-line ED-SCLC vs. chemotherapy alone Improvement in irPFS Numerically higher irBORR Trend for improved OS Concurrent-ipilimumab regimen showed no such activity Safety profile in this trial generally consistent with previous ipilimumab studies Ipilimumab did not appear to exacerbate toxicities observed with chemotherapy alone Adverse events were generally manageable using protocol-defined treatment guidelines Results of this study support further investigation of the phased-ipilimumab regimen in previously untreated ED-SCLC
  • Konishi et al, Clinical Cancer Research 2004; 10:5094-100 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 um.
  • Brahmer, Drake, Powderly, Topalian et al, JCO 2010 28:3167
  • Brahmer, Drake, Powderly, Topalian et al, JCO 2010 28:3167
  • ASCO 2012, Brahmer J, et al Chart subscripts: a= Response evaluable patients. B = CR or PR = OR C= unconfirmed PR D= Response rate (OR +uPR) / n
  • This patient is still in a durable partial remission at 3 years later
  • 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.
  • 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).
  • R. Ramlau et al, Journal of Thoracic Oncology, 2008;3: 735-44 A multicenter, randomized phase II study has explored two schedules of the combination of TG4010 with first line chemotherapy in patients with stage IIIB/IV non-small cell lung cancer. In Arm 1, TG4010 was combined upfront with cisplatin (100 mg/m2 day 1) and vinorelbine (25 mg/m2 day 1 and day 8). In Arm 2, patients were treated with TG4010 monotherapy until disease progression, followed by TG4010 plus the same chemotherapy as in Arm1. Response rate was evaluated according to RECIST. Median time to progression and median overall survival were calculated according to the Kaplan–Meier method. Results: Sixty-five patients were enrolled, 44 in Arm 1 and 21 in Arm 2, in accordance with the two stage Simon design of the statistical plan. In Arm 1, partial response was observed in 13 patients out of 37 evaluable patients (29.5% of the intent to treat population, 35.1% of the evaluable patients). In Arm 2, two patients experienced stable disease for more than 6 months with TG4010 alone (up to 211 days), in the subsequent combination with chemotherapy, one complete and one partial response were observed out of 14 evaluable patients. Arm 2 did not meet the criteria for moving forward to second stage. The median time to progression was 4.8 months for Arm 1. The median overall survival was 12.7 months for Arm 1 and 14.9 for Arm 2. One year survival rate was 53% for Arm 1 and 60% for Arm 2. TG4010 was well tolerated, mild to moderate injection site reactions, flu-like symptoms, and fatigue being the most frequent adverse reactions. A MUC1-specific cellular immune response was observed in lymphocyte samples from all responding patients evaluable for immunology. Conclusions: The combination of TG4010 with standard chemotherapy in advanced non-small cell lung cancer is feasible and shows encouraging results. A randomized study evaluating the addition of TG4010 to first line chemotherapy in this population is in progress OS according to cellular immune response against MUC1 for the whole study population. Patients with (-------) or without (——) MUC1-specific ELISpot at any timepoint. O = complete data, + = censored. Differences between the 2 populations are statistically significant with p = 0.001.
  • E Vinageras, et al, JCO 2008; 26: 1452-58 (Cuba) Survival functions for patients younger than 60 years (vaccinated, n = 22; controls, n = 28; log-rank P = .0124).
  • 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.
  • Left image: Right image: Immunohistochemical stains of renal cancer tissue using the MN-75 anti-CAIX antibody representative of high CAIX staining. Table: The proposed new model for combining pathology predictive group with CAIX staining. Three pathologic risk groups previously reported by Upton et al. can theoretically be collapsed into two groups having distinct response rates to IL-2 therapy and survivals.
  • Hodi et al, DFHCC Melanoma Phase I, ASCO 2011 #8511
  • As per previous slide, but with MDSC this time
  • Figlin et al, 2012 – ASCO. Presented at the Genitourinary Cancers Symposium.
  • Figlin et al, 2012 – ASCO. Presented at the Genitourinary Cancers Symposium.
  • IMA091 is a vaccine comprised of multiple RCC tumor-associated peptides
  • Slide 22
  • Synthroid = levothyroxine sodium tablets, USP
  • 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?

Immuno-Oncology: An Evolving Approach to Cancer Care Immuno-Oncology: An Evolving Approach to Cancer Care Presentation Transcript

  • DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is current as of June 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.
  • 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.
  • Disclosure of Conflicts of InterestThomas F. Gajewski, MD, PhD, reported a financial interest/relationship or affiliationin the form of: Consultant, Amgen, Bristol-Myers Squibb Company, GlaxoSmithKlineplc, Merck & Co., Inc., Roche Pharmaceuticals, Inc.; Contracted Research, Bristol-Myers Squibb Company, CureTech Ltd., GlaxoSmithKline plc, Morphotek, Inc.,Roche-Genentech.Charles G. Drake, MD, PhD, reported a financial interest/relationship or affiliation inthe form of: Royalty, Amplimmune, Inc., Bristol-Myers Squibb Company; Receipt ofIntellectual Property Rights/Patent Holder, Amplimmune, Inc., Bristol-Myers SquibbCompany; Consultant, Amplimmune, Inc., Bristol-Myers Squibb Company, DendreonCorporation, ImmuneXcite, 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, Inc.;Consulting Fees, Amplimmune, Inc., Bristol-Myers Squibb Company, GenentechBioOncology; Speakers Bureau, Bristol-Myers Squibb Company; ContractedResearch, Amplimmune, Inc., Bristol-Myers Squibb Company, GenentechBioOncology; Company Ownership Interest, BioCytics, Inc.Michael B. Atkins, MD, reported a financial interest/relationship or affiliation in theform of: Consultant, AstraZeneca Pharmaceuticals LP, AVEO Pharmaceuticals, Inc.,Bristol-Myers Squibb Company, Genentech BioOncology, Prometheus.
  • Welcome and Activity Overview Thomas F. Gajewski, MD, PhDThe University of Chicago Medicine
  • Learning Objectives L Upon completion of this activity, participants should be better able to: Enhance knowledge on the biological foundations of immuno- oncology approaches to the treatment of cancer Describe the roles, targets, and mechanisms of action of novel and emerging immuno-oncologic agents Evaluate new safety and efficacy data on recently approved and emerging immuno-oncologic agents across tumor types Identify unique patterns of clinical response in patients treated with immuno-oncologic agents Monitor and manage immune-related adverse effects associated with immuno-oncologic agents Describe how new immuno-oncologic agents are being integrated into existing treatment evidence-based guidelines
  • Activity Agenda7:30 – 7:35 pm Welcome and Activity Overview7:35 – 7:50 pm Immuno-Oncology: Understanding the Biological Foundations of the Immune System in Cancer7:50 – 8:10 pm Melanoma: A Classic Tumor Model for Immunotherapy8:10 – 8:25 pm The Evolving Role of Immunotherapy for Prostate Cancer8:25 – 8:40 pm The Emerging Role of Immunotherapy for Lung Cancer8:40 – 8:55 pm Emerging Immunotherapies for Renal Cell Carcinoma8:55 – 9:15 pm Interactive Case Studies: Applying Current Immunotherapies Into Practice9:15 – 9:25 pm Expert Panel Perspectives: Placing Current and Emerging Immunotherapies in Clinical Context9:25 – 9:30 pm Questions & Answers and Activity Conclusion
  • Immuno-Oncology: Understanding BiologicalFoundations of the Immune System in Cancer Thomas F. Gajewski, MD, PhDThe University of Chicago Medicine
  • The Genetic Instability of Cancer Cells Creates Antigens That Can Be Recognized by the Immune System Normal cell presents self peptides bound to MHC molecules New peptides created by mutation or increased expression Normal cell A point mutation in a self protein allows A point mutation in a self peptide creates binding of a new peptide to MHC molecules a new epitope for recognition by T cells Tumor cell Tumor cellMHC = major histocompatibility complex.www.immunoweb.com/tu10.htm
  • Generation of Tumor Antigens Point mutations in normal genes Overexpressed normal genes Molecular mishaps (reverse strand, intron sequences, alternative splicing) Embryonic genes Tissue-restricted differentiation antigens Translocation fusion proteins Viral genes Alternative glycosylation
  • Two Principal Means to Promote Immune-Mediated Tumor Destruction: Cytolytic T Lymphocytes and AntibodiesNK = natural killer.
  • CD8+ Cytotoxic T Lymphocyte Killing an Antigen-Expressing Tumor Cell How Do These CD8+ T Cells Initially Become Activated to Fight Tumors?TCR = T-cell receptor.Boissonnas et al, 2007.
  • T Cells Traffic Between the Tissues, Lymphatics, and the Blood in Two Major Differentiation States Lymphocytes and Naïve lymphocytes lymph return to blood enter lymph nodes via thoracic duct from blood heart Lymph node Antigens from sites of Infected infection reach lymph Tumor peripheral nodes via lymphatics tissueJaneway et al, 2001.
  • Dendritic Cells (DCs) Pick Up Antigens From Infected Tissues and Migrate to Lymph Nodes Antigen uptake by Langerhans’ cells leave the skin Langerhans’ cells in the skin and enter the lymphatic system Langerhans’ cells enter the B7-positive dendritic cells lymph node to become dendritic stimulate naïve T cells cells expressing B7 Discovery of dendritic cells by Ralph Steinman earned Nobel Prize in 2011Banchereau et al, 1998.
  • The Main Costimulatory Receptor on T Cells is CD28, Which Binds to B7-1/B7-2 on Activated Dendritic Cells T cell TCR/CD3 CD28 complex CD4 B7.1 or B7.2 APC MHC class IIAPC = antigen presenting cell.Janeway et al, 1996; Topalian et al, 2011.
  • Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo MHC I MHC II Immature DC Migration From Tumor Tumor granzymes TCR eCD8 B7 APC Mature DC Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  • Theoretical Reasons for Failure of Immune System to Prevent Cancer Outgrowth  Failure to activate specific T cells – Inadequate antigen processing/presentation – Insufficient T-cell repertoire – Available T cells below activation threshold setpoint  Ineffective T-cell differentiation into effector cells  Inadequate expansion of T cells to needed frequency  Lack of homing of primed T cells to tumor sites  Immunosuppression in tumor microenvironment – CTLA-4 on T cells (inhibitory receptor) – PD-1 on T cells (binds PD-L1 on tumor cells) – T-cell anergy (deficient B7 costimulation) – CD4+CD25+FoxP3+ Tregs (extrinsic suppression) – Indoleamine-2,3-dioxygenase (IDO tryptophan catabolism)Gajewski et al, 2007; Zou, 2005.
  • Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo: Interventions TLR ligands Blockade of suppression MHC I MHC II Immature DC Migration From Tumor Vaccines Tumor granzymes TCR eCD8 B7 Costimulation APC Mature DC Cytokines Chemokines Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  • Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo: Interventions (cont.) TLR ligands Blockade of suppression MHC I MHC II Immature DC Migration From Tumor Vaccines Tumor granzymes TCR eCD8 B7 Costimulation APC Mature DC Cytokines Chemokines Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  • Toll-Like Receptors (TLRs) First identified in Drosophila as receptor recognizing pathogens for innate immunity At least 11 mammalian homologues identified Expressed on DCs and other APCs Mediate activation and maturation of APCs to render them optimal for T-cell activation Ligands should be excellent vaccine adjuvants Discovery of Innate Immune Sensing Systems by Bruce Beutler and Jules Hoffmann Earned Nobel Prize in 2011Takeda et al, 2004.
  • TLR Pathway Plants Drosophila Mammals PAM P Protease PAM Spätzle P IL-1 Toll TLR4 IL-1R Extracellular Pathogen Cytoplasm or PAMP MyD88 TIRAP MyD88 MyD88 RPP5, N, L6 Immune response Immune response Immune response Triggers activation of dendritic cells and other APCsMedzhitov et al, 2001.
  • Imiquimod for Basal Cell Carcinoma (BCC) Imiquimod is a TLR7 agonist that activates DCs Randomized clinical trial done in patients with BCC 100% RR with BID dosing compared to 19% with vehicle alone! Also active on warts and cutaneous metastases of melanoma Other TLR ligands are in clinical trials, including CpG 7909 (TLR9 agonist) TLR agonists being combined with tumor antigens in cancer vaccines (eg, GSK-Bio MAGE3 vaccine)RR = response rate.Sapijaszko, 2005; Goldman et al, 2009.
  • Key Takeaways  CD8+ T cells can recognize neoantigens expressed by tumor cells  In order for antigen-specific T cells to become activated to differentiate into cytolytic effector cells, they need to be stimulated by activated DCs in lymph nodes  DCs must be activated via innate immune sensing pathways (TLRs)  Activated CTL recirculate and traffic tumor tumors where they have a chance to destroy cancer cells  In cancer, failure can occur at various stages of this process, which generates multiple opportunities for therapeutic interventionCTL = cytotoxic T lymphocyte.
  • Melanoma: A Classic Tumor Model for Immunotherapy Thomas F. Gajewski, MD, PhD The University of Chicago Medicine
  • Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo: Interventions (cont.) Blockade of suppression MHC I MHC II Immature DC Migration From Tumor Vaccines Tumor granzymes TCR eCD8 B7 Costimulation APC Mature DC Cytokines Chemokines Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  • Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo: Interventions (cont.) Blockade of suppression MHC I MHC II Immature DC Migration From Tumor Vaccines Tumor granzymes TCR eCD8 B7 Costimulation APC Mature DC Cytokines Chemokines Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  • Immunization Modalities Antigen delivery strategy – Targeting endogenous APCs • Synthetic peptides or protein in adjuvant • Recombinant viruses, bacteria • Irradiated tumor transfectants • Antigen/antibody complexes • Antigen/TLR ligand fusions • Plasmids (CpG oligonucleotides) – Ex vivo loaded APCs • Peptide, protein, tumor lysates, etc. Additional modulators – Cytokines, adjuvants, modulatory antibodies
  • Induction of Specific CTL Responses in Mice Using Tumor Antigen Peptide-Loaded PBMC + IL-12 PBMC-P1A PBMC-P1A + IL-12 PBMC + IL-12 PBS Percent Specific Lysis E:T RatioPBMC = peripheral blood mononuclear cells; IL-12 = interleukin-12.Fallarino et al, 1999.
  • Resolution of Subcutaneous Metastases Following Immunization With MelanA Peptide-Pulsed PBMC + rhIL-12 After 3 Vaccines After 9 Vaccines ORR ~ 10%, With Another 20% SDrhIL-12 = recombinant human IL-12; ORR = overall response rate; SD = stable disease.Peterson et al, 2003.
  • Vaccination of Patients With Multiple Melanoma Antigen Peptides + IL-12 Can Induce High Levels of Functional Specific T Cells in the Blood However, only a minority of patients (10%) have clinical responses. (Why? – We will return to this question later [predictive biomarkers])Peterson et al, 2003.
  • Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo: Interventions (cont.) Blockade of suppression MHC I MHC II Immature DC Migration From Tumor Vaccines Tumor granzymes TCR eCD8 B7 Costimulation APC Mature DC Cytokines Chemokines Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  • CTLA-4 Blockade for Immunopotentiation CTLA-4 is receptor induced on activated T cells Ligation inhibits T cell activation CTLA-4 deficient mice develop autoimmunity  dominant role is negative Two defined ligands expressed largely on APC populations: B7-1 and B7-2 Neutralizing mAbs against CTLA-4 augment T-cell activation and promote tumor rejection in several mouse models Two anti-CTLA-4 mAbs explored in clinical trials Ipilimumab approved by FDA in 2011CTLA-4 = cytotoxic T lymphocyte antigen-4; mAbs = monoclonal antibodies.Pardoll, 2012; YervoyTM prescribing information, 2012.
  • CTLA-4 Is a Negative Regulator of T-Cell Activation Resting T Cell Activated T Cell B7 B7 CD28 CD28 T Cell TCR APC T Cell TCR APC CTLA4 B7Pardoll, 2012; Korman et al, 2006.
  • Randomized Study of Vaccine Vs. Ipilimumab Vs. Combination in Advanced MelanomaIpi = ipilimumab.Hodi et al, 2010.
  • Clinical Response in Melanoma With Single Agent Anti-CTLA-4 mAb Screening Week 12: Progression Week 20: Regression Week 36: Still RegressingWolchok et al, 2008.
  • T-Cell Infiltration in Skin and Gut Following Anti-CTLA-4 mAb TreatmentSarnaik et al, 2009.
  • Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo: Interventions (cont.) Blockade of suppression MHC I MHC II Immature DC Migration From Tumor Vaccines Tumor granzymes TCR eCD8 B7 Costimulation APC Mature DC Cytokines Chemokines Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  • IL-2 in Melanoma: RR 16%Atkins et al, 1999.
  • Modified gp100 Peptide in Montanide +/- Exogenous IL-2 Additional 19 patients treated with high-dose IL-2 after gp100 209M vaccination In this study, 8 patients (42%) showed objective tumor regression Suggests IL-2 may help expand relevant T cells or support their trafficking Caveat: Effect of IL-2 alone?Rosenberg et al, 1998.
  • High-Dose IL-2 ± Peptide Vaccine Phase IIISchwartzentruber et al, 2011.
  • Model for CD8+ T-Cell Mediated Anti- Tumor Immune Response In Vivo (cont.) MHC I MHC II Immature DC Migration From Tumor Tumor granzymes TCR eCD8 B7 APC Mature DC Adoptive T-cell therapy eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  • Adoptive T-Cell Therapy T cells are isolated, from tumor site or generated in vitro Adoptive transfer Ex vivo enrichment and into expansion of antigen-specific patient In vitro effector T cells expansion and activation T cells are reintroduced back to the patient T cells Usually the patient is isolated “conditioned” first with lympho from depleting chemotherapy or patient other agentsYee, 2009.
  • TIL Therapy for Melanoma: Rosenberg Approach  Tumor harvested, TILs collected and expanded for infusion  In interim, patients receive lymphoablative chemotherapy to “make space”  T cells are transferred and patients are given IL-2  Results: 6 of 13 patients respondedTILs = tumor-infiltrating lymphocytes.Dudley et al, 2003.
  • Phase II Trial: Adoptive-Cell Therapy • Stage IV melanoma (N = 35) • Received autologous, tumor- reactive, expanded tumor- infiltrating lymphocytes + IL-2 after lymphodepleting conditioning with cyclophosphamide and fludarabine • Results – 3 CR; 15 PR (RR: 51%; DOR: 11.5 mos) – Adoptively transferred CTLs persisted in several patients > 1 year • > 50% RR has held up with further studiesCR = complete response; PR = partial response; RR = response rate; DOR = duration of response.Dudley et al, 2005.
  • Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo: Interventions (cont.) Blockade of suppression MHC I MHC II Immature DC Migration From Tumor Vaccines Tumor granzymes TCR eCD8 B7 Costimulation APC Mature DC Cytokines Chemokines Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  • Hypothesis  Clinical benefit when it does occur with potent cancer vaccines (and other immunotherapies) has generally not correlated with T cell responses as measured in the blood  Features of the tumor microenvironment could dominate at the effector phase of the anti-tumor T-cell response – T-cell trafficking into tumor – Immune suppressive mechanisms at tumor site – Tumor cell biology and susceptibility to immune-mediated killing – Complexities of the tumor stroma (vasculature, fibrosis)  Reasoned these features could be interrogated through pre- treatment gene expression profiling of tumor site in each individual patient  Such an analysis could identify a predictive biomarker profile associated with clinical response, and also highlight new biologic barriers that need to be overcome to optimize therapeutic efficacy of vaccinesGajewski et al, 2009.
  • Expression of a Subset of Chemokine Genes Is Associated With Presence of CD8 Transcripts CD8b CCL2 CCL4 CCL5 CXCL9 CXCL10 CCL19 CCL21Harlin et al, 2009.
  • Gene Expression Pattern of Tumor Microenvironment Identified That Is Associated With Favorable Clinical Outcome Survival Based on Survival Groups Clinical Response Short Long G G G G G G G G G G G G G G G G 3 2 1 5 4 9 8 1 0 0 6 4 6 7 4 6 5 0 6 3 0 5 5 7 6 5 3 1 0 0 8 3 2 5 9 2 7 8 8 8 7 8 7 7 6 7 8 6 8 6 6 6 7 8 C O L 1 1 A 1 : c o l l a g e n , t y p . . . F L T 1 : F m s - r e l a t e d t y r o s . . . C O L 1 1 A 1 : c o l l a g e n , t y p . . . C O L 1 1 A 1 : c o l l a g e n , t y p . . . S T C 1 : s t a n n i o c a l c i n 1 D S G 2 : d e s m o g l e i n 2 D S G 2 : D e s m o g l e i n 2 P E G 1 0 : p a t e r n a l l y e x p r e . . . 100 S T C 1 : S t a n n i o c a l c i n 1 L D L R : l o w d e n s i t y l i p o p r . . . F L T 1 : F m s - r e l a t e d t y r o s . . . S E R P I N H 1 : s e r p i n p e p t i . . . M A L A T 1 : m e t a s t a s i s a s . . . P T P 4 A 1 : p r o t e i n t y r o s i n . . . S N T B 1 : s y n t r o p h i n , b e t a . . . D H C R 2 4 : 2 4 - d e h y d r o c h . . . S Q L E : s q u a l e n e e p o x i d . . . S E R P I N E 1 : s e r p i n p e p t i . . . I G F 2 B P 3 : i n s u l i n - l i k e g r . . . E E D : e m b r y o n i c e c t o d e r . . . P D K 1 : p y r u v a t e d e h y d r o . . . R A P G E F 6 : R a p g u a n i n e . . . R N F 4 3 : R i n g f i n g e r p r o t . . . S L C 1 6 A 1 : s o l u t e c a r r i e r . . . S T C 1 : s t a n n i o c a l c i n 1 F u l l l e n g t h i n s e r t c D N A c . . . I L 1 R 1 : i n t e r l e u k i n 1 r e c e . . . A K R 1 C 1 : a l d o - k e t o r e d u . . . U C P 2 : u n c o u p l i n g p r o t e i . . . F L J 2 2 0 2 8 : h y p o t h e t i c a l . . . S T A U 2 : S t a u f e n , R N A b i . . . R P S 1 1 : R i b o s o m a l p r o t e . . . U S P 4 0 : u b i q u i t i n s p e c i f i c . . . M R N A ; c D N A D K F Z p 5 8 . . . F u l l l e n g t h i n s e r t c D N A c . . . K B T B D 1 1 : k e l c h r e p e a t . . . F M O 2 : f l a v i n c o n t a i n i n g . . . M S R B 2 : m e t h i o n i n e s u l f . . . H C S T : h e m a t o p o i e t i c c e . . . H o m o s a p i e n s , c l o n e I M . . . F A M 1 0 7 B : f a m i l y w i t h s e . . . P L A C 9 : p l a c e n t a - s p e c i f i . . . M R N A ; c D N A D K F Z p 4 3 . . . M P S T : m e r c a p t o p y r u v a t . . . C 1 8 o r f 4 5 : c h r o m o s o m e . . . 80 P D E 3 B : P h o s p h o d i e s t e r . . . R A S E F : R A S a n d E F - h a . . . K L F 1 2 : K r u p p e l - l i k e f a c t . . . T r a n s c r i b e d l o c u s Prolonged SD Survival probability (%) H O X C 1 0 : h o m e o b o x C 1 0 T S P A N 3 3 : t e t r a s p a n i n 3 3 H O X C 4 : h o m e o b o x C 4 T S T : t h i o s u l f a t e s u l f u r t r a . . . W F D C 9 : W A P f o u r - d i s u l f . . . C 1 8 o r f 3 7 : c h r o m o s o m e . . . C D 2 8 : C D 2 8 m o l e c u l e R A S E F : R A S a n d E F - h a . . . I Q C E : I Q m o t i f c o n t a i n i n . . . T R I M 4 : t r i p a r t i t e m o t i f - c . . . T H Y 1 : T h y - 1 c e l l s u r f a c . . . L O C 3 9 2 6 1 7 / / / L O C 6 4 1 . . . g b : N M _ 0 1 6 9 4 7 . 1 / D B _ X . . . S N O R D 5 0 A / / / S N H G 5 / / . . . C D N A c l o n e I M A G E : 4 8 2 . . . C D N A c l o n e I M A G E : 5 2 6 . . . K I A A 0 9 4 7 : K I A A 0 9 4 7 p r . . . C Y P 1 B 1 : c y t o c h r o m e P 4 . . . C T S G : c a t h e p s i n G R E C K : r e v e r s i o n - i n d u c i n . . . C D N A c l o n e I M A G E : 5 2 6 . . . A K R 1 C 2 : a l d o - k e t o r e d u . . . L O C 2 8 4 7 0 1 / / / F L J 1 4 1 8 . . . P R R 1 4 : p r o l i n e r i c h 1 4 M A D 1 L 1 : M A D 1 m i t o t i c . . . C D R 2 : C e r e b e l l a r d e g e n . . . G A T A 3 : G A T A b i n d i n g p . . . G I M A P 7 : G T P a s e , I M A P . . . g b : B C 0 4 3 6 0 1 . 1 / D B _ X R . . . g b : A I 7 6 1 5 7 3 / D B _ X R E F . . . C 8 o r f 1 3 : C h r o m o s o m e . . . OS < 24 months C D 3 3 L 3 : C D 3 3 m o l e c u l . . . Z N F 6 7 7 : Z i n c f i n g e r p r o t . . . M S X 1 : m s h h o m e o b o x h . . . 60 E T V 5 : E t s v a r i a n t g e n e . . . Thy1 T H Y 1 : T h y - 1 c e l l s u r f a c . . . M T A C 2 D 1 : m e m b r a n e t . . . I L 2 7 R A : i n t e r l e u k i n 2 7 r . . . P T E R : p h o s p h o t r i e s t e r a . . . E M C N : e n d o m u c i n B T G 1 : B - c e l l t r a n s l o c a t i . . . A P L P 2 : A m y l o i d b e t a ( A . . . E M L 1 : e c h i n o d e r m m i c r . . . R A M P 3 : r e c e p t o r ( c a l c i t . . . OS > 24 months E M L 1 : e c h i n o d e r m m i c r . . . g b : N M _ 0 1 8 0 4 1 . 1 / D B _ X . . . F u l l l e n g t h i n s e r t c D N A . . . F B L N 1 : f i b u l i n 1 L O C 6 4 3 7 4 9 : H y p o t h e t i c . . . T r a n s c r i b e d l o c u s L P L : l i p o p r o t e i n l i p a s e CD28 C C D C 6 9 : c o i l e d - c o i l d o . . . D N A H 3 : D y n e i n , a x o n e . . . C D N A : F L J 2 3 5 6 6 f i s , c l o . . . P O L D I P 3 : P o l y m e r a s e ( . . . M R G P R F : M A S - r e l a t e d . . . L R R C 1 5 : l e u c i n e r i c h r e . . . H o m o s a p i e n s , c l o n e I M . . . D C N : d e c o r i n F K S G 4 9 : F K S G 4 9 C D N A F L J 3 6 5 8 2 f i s , c l o . . . L H P P : p h o s p h o l y s i n e p h . . . L O C 6 4 4 4 5 0 : H y p o t h e t i c . . . A K R 1 C 3 : a l d o - k e t o r e d u . . . M R N A , c l o n e I C R F p 5 0 7 . . . C D N A F L J 3 0 6 3 8 f i s , c l o . . . R U N X 3 : r u n t - r e l a t e d t r a . . . T I M M 8 A : t r a n s l o c a s e o f . . . CCL19 C D N A F L J 1 2 9 3 2 f i s , c l o . . . I G F 1 : i n s u l i n - l i k e g r o w t h . . . P C N X : p e c a n e x h o m o l o . . . 40 S E P T 1 : s e p t i n 1 C P A 3 : c a r b o x y p e p t i d a s e . . . P R K C B 1 : P r o t e i n k i n a s e . . . g b : B F 4 3 3 2 1 9 / D B _ X R E . . . T-Cell Markers Z F H X 1 B : Z i n c f i n g e r h o . . . C X C L 1 2 : c h e m o k i n e ( C - . . . H o m o s a p i e n s , S i m i l a r t . . . g b : N M _ 0 1 4 1 3 6 . 1 / D B _ X . . . I S L R : i m m u n o g l o b u l i n s . . . C D N A c l o n e I M A G E : 5 2 6 . . . A R P C 5 : A c t i n r e l a t e d p r . . . H O X A 7 : h o m e o b o x A 7 L O C 2 3 1 1 7 : K I A A 0 2 2 0 - l i . . . LTbeta g b : B F 5 1 0 5 0 6 / D B _ X R E . . . F u l l l e n g t h i n s e r t c D N A . . . L R P 1 1 : L o w d e n s i t y l i p o . . . T R 2 I T 1 : T h i o r e d o x i n r e d . . . F u l l l e n g t h i n s e r t c D N A c . . . g b : A I 6 8 4 8 3 1 / D B _ X R E F . . . C L U : c l u s t e r i n and Chemokines M Y O 1 D : M y o s i n I D T T L L 5 : t u b u l i n t y r o s i n e l i . . . F L J 2 0 5 8 1 : h y p o t h e t i c a l . . . A K R 1 C 2 : a l d o - k e t o r e d u . . . C D N A : F L J 2 3 5 7 2 f i s , c l o . . . O I P 5 : O p a i n t e r a c t i n g p r . . . A G T R L 1 : a n g i o t e n s i n I I . . . R B P 7 : r e t i n o l b i n d i n g p r . . . R U N X 1 : R u n t - r e l a t e d t r a . . . IL-27Ralpha O G N : o s t e o g l y c i n ( o s t e o . . . H T R A 3 : H t r A s e r i n e p e p . . . P R K C B 1 : P r o t e i n k i n a s e . . . F O X O 1 A : F o r k h e a d b o x . . . W B S C R 1 9 : W i l l i a m s B e u . . . B C L 1 1 B : B - c e l l C L L / l y m . . . L O C 3 8 9 6 3 4 : H y p o t h e t i c . . . C L U : c l u s t e r i n I K Z F 1 : I K A R O S f a m i l y z i . . . 20 C L U : c l u s t e r i n C X C L 1 4 : c h e m o k i n e ( C - . . . T P S T 1 : T y r o s y l p r o t e i n s . . . A P C : a d e n o m a t o s i s p o l y . . . W T A P / / / L O C 6 5 3 1 5 0 : . . . R A R R E S 2 : r e t i n o i c a c i d . . . N A R G 2 : N M D A r e c e p t o r . . . IL-1R M G C 7 2 1 0 4 : S i m i l a r t o F . . . B C L 1 1 B : B - c e l l C L L / l y m . . . C D N A c l o n e I M A G E : 5 2 6 . . . C C D C 3 : c o i l e d - c o i l d o m . . . g b : B G 3 8 9 7 8 9 / D B _ X R E . . . K I A A 0 2 5 1 : K I A A 0 2 5 1 p r . . . C C L 1 9 : c h e m o k i n e ( C - C . . . R A R A : r e t i n o i c a c i d r e c e . . . L F N G : l u n a t i c f r i n g e h o . . . F N D C 1 : f i b r o n e c t i n t y p e . . . Progressive Dz M G S S C g T N C P C b r D X O R F a O : N A N A I N 6 X n R 9 N : P M s 7 2 : c n A A 5 1 _ D C r u : : 5 1 0 i b : c D m s : : 1 e g p l e S c 6 4 i c d l u o y o c 9 1 r n a r t o o t a 1 l o m e d v c f i b 4 c m d i n e o h . 1 u o n a r l e r s x 1 o i l l a g t c e / D , i n m e u e r r r B e l e e x r a _ c t r e c s X e c . . . . . . . . . . . . . . . . . . g b : A K 0 2 2 3 4 3 . 1 / D B _ X R . . . L O C 2 8 3 0 2 7 : h y p o t h e t i c . . . M R N A ; c D N A D K F Z p 5 6 . . . D A R C : D u f f y b l o o d g r o u . . . A T A D 1 : A T P a s e f a m i l y , . . . C l o n e 2 4 9 0 0 m R N A s e q . . . F C R L 1 : F c r e c e p t o r - l i k e 1 g b : N M _ 0 1 5 8 7 0 . 1 / D B _ X . . . U n k n o w n m R N A s e q u e n . . . R H O H : R a s h o m o l o g g e . . . L T B : l y m p h o t o x i n b e t a ( . . . 0 g b : N M _ 0 1 8 5 7 5 . 1 / D B _ X . . . A D R A 2 A : a d r e n e r g i c , a l . . . D P T : d e r m a t o p o n t i n S C D 5 : s t e a r o y l - C o A d e s . . . M F A P 5 : m i c r o f i b r i l l a r a s . . . C D N A c l o n e I M A G E : 5 2 7 . . . S P O N 1 : s p o n d i n 1 , e x t r . . . S L F N 5 : s c h l a f e n f a m i l y . . . F A B P 4 : f a t t y a c i d b i n d i n . . . I G F 2 / / / I N S - I G F 2 : i n s u l i . . . C D N A c l o n e I M A G E : 5 2 8 . . . F C R L 2 : F c r e c e p t o r - l i k e 2 O G N : o s t e o g l y c i n ( o s t e o . . . P R K D 2 : p r o t e i n k i n a s e D 2 C O M P : c a r t i l a g e o l i g o m . . . C D N A c l o n e I M A G E : 4 8 2 . . . 0 10 20 30 40 50 60 70 80 C A S C 4 : C a n c e r s u s c e p t i . . . N A R S 2 : A s p a r a g i n y l - t R . . . A B C A 8 : A T P - b i n d i n g c a . . . D P T : d e r m a t o p o n t i n g b : B C 0 3 8 6 7 2 . 1 / D B _ X R . . . S P I N L W 1 : s e r i n e p e p t i d . . . O M D : o s t e o m o d u l i n g b : A K 0 9 4 9 7 4 . 1 / D B _ X R . . . S F R P 4 : s e c r e t e d f r i z z l e . . . C D N A F L J 1 2 2 0 4 f i s , c l o . . . g b : A W 1 1 7 1 8 1 / D B _ X R E . . . T r a n s c r i b e d l o c u s S F R P 4 : s e c r e t e d f r i z z l e . . . L O C 4 4 1 2 0 4 : h y p o t h e t i c . . . M F A P 5 : m i c r o f i b r i l l a r a s . . . A D I P O Q : a d i p o n e c t i n , C . . . C D C 2 7 : C e l l d i v i s i o n c y c . . . Months R A B G A P 1 : R A B G T P a s . . . P L A 2 G 2 A : p h o s p h o l i p a s . . . S S X 3 : s y n o v i a l s a r c o m a . . . S Q S T M 1 : S e q u e s t o s o m . . . L O C 6 4 3 6 7 5 : H y p o t h e t i c . . . - 3 . 0 - 2 . 6 - 2 . 1 - 1 . 7 - 1 . 3 - 0 . 9 - 0 . 4 0 0 . 4 0 . 9 1 . 3 1 . 7 2 . 1 2 . 6 3 . 0 Number at risk No Correlation With Immune Group: 1 9 Response in Blood0 8 2 0 0 0 0 0 Group: 2 22 22 22 21 20 10 6 4 1Gajewski et al, 2011.
  • ‘‘Inflamed’’ Gene Expression Signature Is Associated With Survival Following GSK MAGE3 Protein Vaccine 100 90 80 70 AS15 GS+ % Patients AS02B GS+ 60 50 40 30 20 AS15 GS- 10 AS15: HR (GS+ vs. GS-) = 0.268 (95%CI [0.08;0.90]) AS02B GS- AS02B: HR (GS+ vs. GS-) = 0.433 (95%CI [0.17;1.14]) Time (mos)HR = hazard ratio; CI = confidence interval.Louahed et al, 2009.
  • Ipilimumab (anti-CTLA4 mAb) Clinical Responders Also Appear to Show an “Inflamed” Tumor Gene Expression Profile  CXCL9, 10, 11  CCL4, CCL5  Granzyme B  Perforin  CD8a No Benefit BenefitJi et al, 2011.
  • Two Broad Categories of Melanoma Metastases Defined by Gene Expression Profiling and Confirmatory Assays CD8 IHC  T cell “poor” – Lack chemokines for A recruitment 2/3 – Low indicators of inflammation  T cell “rich” – Chemokines for T-cell recruitment B – CD8+ T cells in tumor 1/3 microenvironment – Broad inflammatory signature – Apparently predictive of clinical benefit to vaccines and other immunoRxGajewski et al, 2010.
  • Candidate Strategies to Promote Effector T-Cell Migration Into Tumor Sites  Introduce chemokines directly – CXCR3-binding chemokines (CXCL9, CXCL10) – Others (CCL2, CCL3, CCL4, CCL5)  Induce chemokine production from stromal cells – LIGHT, lymphotoxin: Bind LTβR  Elicit appropriate local inflammation that includes chemokine production – Type I IFNs – TLR agonists – Radiation?  Alter signaling pathways in melanoma cells themselves to facilitate local inflammation and promote traffickingINF = interferon; LIGHT = name derived from homologous to lymphotoxins.Gajewski et al, 2010.
  • Intratumoral LIGHT Adenovirus in B16 Melanoma  It promotes chemokine production, CD8+ T-cell recruitment, primary tumor control, and rejection of non-injected distant metastases CD8+ T-Cell Infiltrate Tumor Rejection 1st Tumor 2nd Tumor 4000 Tumor Volume (mm3) Ad-LIGHT 3000 17.2% 14.9% 2000 Ad- Ad- Control LIGHT 1000 Ad-Control 4.56% 3.52% 0 0 10 20 30 10 20 30 CD8 Days After Tumor ChallengeYu et al, 2007.
  • Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo: Interventions (cont.) Blockade of suppression MHC I MHC II Immature DC Migration From Tumor Vaccines Tumor granzymes TCR eCD8 B7 Costimulation APC Mature DC Cytokines Chemokines Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  • Why Are Melanomas That Attract CD8+ T Cells Not Rejected Spontaneously? Presence of Inhibitory Pathways  IDO (indoleamine-2,3- dioxygenase: metabolizes tryptophan)  PD-L1 (engages PD-1: inhibitor receptor)  CD4+CD25+FoxP3+Tregs (extrinsic suppression)  T-cell anergy (B7-poor: T cell-intrinsic desensitization)FoxP3 = forkhead box P3; PD-1 = Programmed death-1; PD-L1 = PD ligand 1.Gajewski et al, 2006; Gajewski, 2007.
  • IHC for IDO, FoxP3, and PD-L1 Shows Expression in Distinct Cell Subsets in Melanoma Metastases A: IDO B: FoxP3 C: PD-L1Munn et al, 2007; Blank et al, 2004; Quaglino et al, 2011.
  • Correlated Expression of IDO, FoxP3, and PD-L1 Transcripts in Individual TumorsGajewski et al, 2006; Gajewski, 2007.
  • Interfering With PD-L1/PD-1 Interactions Leads to Tumor Rejection In Vivo Days Post Tumor InjectionBlank et al, 2004.
  • Anti-PD-1 mAb Phase I (MDX-1106; BMS 936558): Tumor Response 60.00 Melanoma 40.00 20.00 0.00 -20.0 -40.0 -60.0 -80.0 -100 Patients Responses Also Seen in NSCLC and RCCNSCLC = non-small cell lung cancer; RCC = renal cell carcinoma.Sznol et al, 2010.
  • Clinical Trials Ongoing to Block Negative Regulatory Pathways Acting in the Tumor Microenvironment  Depletion of Tregs – Denileukin diftitox (DT; IL-2: DT fusion protein) – Anti-CD25 mAbs (Basilixumab)  Blockade of PD-1/PD-L1 interactions – Anti-PD-1 mAb – Anti-PD-L1 mAb  Inhibition of IDO – 1-methyltryptophan – Incyte compound INCB24360  Reversal of anergy – Adoptive transfer into lymphopenic host – Exogenous IL-7, IL-15  Soon: Combinations to block two pathways synergisticallyclinicaltrials.gov, 2012.
  • Key Takeaways New strategies for the immunotherapy of melanoma are emerging through a careful dissection of the mechanisms of anti-tumor immune responses New approaches include more potent vaccines, agents to block immune inhibitory pathways like CTLA-4, and adoptive T-cell therapy The next wave of new agents are targeting immune suppressive mechanisms within the tumor microenvironment Predictive biomarkers are being evaluated to better select patients with tumors amenable to the benefit of immunotherapies (HER2 expression and trastuzumab)
  • Translational Research Is Like Scuba DivingHawaii, 2011.
  • The Evolving Role of Immunotherapy for Prostate Cancer Charles G. Drake, MD, PhDThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Outline Prostate Cancer Vaccines – Sipuleucel-T – ProstVac VF Immune Checkpoint Blockade in Prostate Cancer – Anti-CTLA-4, Ipilimumab – Anti-PD-1, BMS-936558 Combining Immunotherapy With Conventional Therapy – Radiation Therapy – Androgen-Ablation The Evolving Landscape of Prostate Cancer Treatments
  • Active Cellular Immunotherapy Sipuleucel-T Patient WBC harvested Short-term culture with protein “cassette” GM-CSF 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. q2wks x 3
  • Cancer Vaccines: Immunological MOA CD4 T Cell Activated TCR Dendritic Cell Class II MHC Cytokines = HELP TCR Tumor Antigen Class I MHC CD8 T Cell Activated CD8 T Cells Traffic to Tumor and Lysis CellsMOA = mechanism of action.Burch et al, 2000; Small et al 2000; Fong et al, 1997.
  • IMPACT OS: Primary End Point ITT Population 100 p = 0.032 (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 66OS = overall survival; ITT = intent-to-treat. Survival (Months)Kantoff et al, 2010a.
  • A Viral Vaccine Approach: ProstVac VF Co-Stimulatory Molecules PSA LFA-3 ICAM-1 B7-1 Target Antigen Vaccinia Virus Fowlpox Virus Plasmid DNA Packaging Cell Line rV-PSA-TRICOM rF-PSA-TRICOM VaccineDNA = deoxyribonucleic acid; PSA= prostate-specific antigen.Madan et al, 2009; Sonpavde et al, 2011; Drake, 2010.
  • 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 CD8 T Cell Cell Death: NecrosisMadan et al, 2009; Sonpavde et al, 2011.
  • TBC-PRO-002 Survival Data Time (mos) Design: Nearly identical to IMPACT but NO crossover Patients: Metastatic CRPC with either no or minimal symptoms Primary end point: TTPCRPC = castration-resistant prostate cancer; TTP = time to progression.Kantoff et al, 2010b.
  • Prospect Trial: Design (SPA) Phase III Global (US-CAN-AUS/WE/EE/Latin America) PROSTVAC-(V)(F) TRICOM + low dose S adjuvant GM-CSF U Non/Minimally R Symptomatic PROSTVAC-(V)(F) Standard V TRICOM of Care Adjuvant placebo I Metastatic CRPC No Crossover V A Vector Placebo Adjuvant placebo L Primary end point: OSStudy is currently recruiting.SPA = special protocol assessment.US NIH, 2012a.
  • CTLA-4 Blockade in Prostate Cancer T Cell CTLA-4 TCR CD28 Signal 1 Signal 2 Antigen HLA B7.1/2 CTLA-4 Antigen Presenting CellKirkwood et al, 2008; Ribas et al, 2005; Attia et al, 2005.
  • CTLA-4 Blockade in Prostate Cancer Anecdotal Response: Subject 3020, 10 mg/kg MonotherapyuCR = unconfirmed complete response; TFTs = thyroid function tests; irAEs = immune-related adverse events.Beer et al, 2008.
  • Ipilimumab: Pre-Chemotherapy Phase III TrialScreening Induction MaintenanceDay -28 to Rand Randomization – Wk 24 Wk 24 – 48+ Tox & PD Survival Ipilimumab Ipilimumab ObservationRandomization 10 mg/kg 10 mg/kg F/U q12wks2:1 F/U q12wks for toxicity for survival Placebo Observation Placebo and/or PD N = 600 Dosing Dosing OS: Primary Wk 1, 4, 7, 10 q12wks End Point After treatment is discontinued subjects enter F/U phasePD = progressive disease.US NIH, 2012b.
  • CTLA-4 and an Immune-Mediated Abscopal Effect  33-yr-old with metastatic melanoma – Enrolled on ipilimumab trial – SD x 1 yr – Enlarging paraspinal mass, new splenic lesions  RX 2850 cGy to mass (3 fxn, 7 days)  1-month post RT – No response primary site – Responding lesions in spleen  Immunological correlates – 30x increase in anti-NY-ESO-1 titer – Increase in NY-ESO-1 reactive T cellsRT = radiotherapy.Postow et al, 2012.
  • Ipilimumab: Post-Chemotherapy Phase III Trial SCREENING INDUCTION MAINTENANCE Ipilimumab 10 mg/kg Ipilimumab 10 mg/kg CRPC Wks 1, 4, 7, 10 q12wks RT (8 gy) to Prior 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 Day -2 Day -2 to Wk 24 Wk 24 to Wk 48+Completed Accrual 1/2012.TA = tumor assessment; OA = outcome assessment; ICF = informed consent form; IVRS = interactive voice response system.US NIH, 2012c.
  • Effect of Androgen-Ablation on T-Cell ResponseDrake et al, 2005.
  • A Randomized, Open-Label, Phase II Trial Examining the Sequencing of Sipuleucel-T and Androgen Deprivation Therapy Study Participation Concludes Treatment Arm 1 RESPONSE 27 Sipuleucel-T ADT Immune, PSA mos Eligibility • Post primary RX (RP or XRT or RP + XRT) N = 30 SAFETY visit • PSADT ≤ 12 mos • Non-metastatic (bone and CT scan) Stratification • PSADT ≤ 3 mos or > 3 mos and ≤ 12 mos Treatment Arm 2 RESPONSE 24 • RP or XRT or RP + XRT ADT Sipuleucel-T Immune, PSA mos N = 30 SAFETY visit Primary Objective: To determine Primary End Point: Exploratory end whether ADT started before or Immune response, which point: PSA after sipuleucel-T leads to will be evaluated with an Progression post RX superior augmentation of immune INF-γ ELISPOT specific response for PA2024ADT = androgen deprivation therapy; RP = radical prostatectomy; XRT = radiation therapy; CT = computed tomography.Antonarakis et al, 2011; US NIH, 2012d.
  • Sequencing Therapy in Prostate Cancer: 2012 Androgen Docetaxel Sipuleucel-T* Chemotherapy* Cabazitaxel* Ablation Abiraterone** Abiraterone* Ipilimumab*** Alpharadin** ProstVac VF*** MDV3100** Ipilimumab**** FDA approved.** Announced positive.*** In progress.
  • Key Takeaways Prostate Cancer Is Immunologically Responsive – Sipuleucel-T FDA Approved – ProstVac VF in Phase III Immune Checkpoint Blockade in Prostate Cancer – Objective Response(s) With CTLA-4 Blockade – Phase III Trials in Progress – Good Evidence for PD-1 Expression on TIL Combining Immunotherapy With Conventional Therapy – Radiation Therapy + CTLA-4 Blockade – Androgen-Ablation + Sipuleucel-T
  • The Emerging Role ofImmunotherapy for Lung Cancer John Powderly II, MD, CPI Carolina BioOncology Institute, PLLC Cancer Therapy & Research Center
  • Background NSCLC remains the leading cause of cancer-related mortality worldwide Increased tumor-infiltrating lymphocytes in lung cancer are prognostic for improved survival Any tumor may be antigenic (induce immune recognition) – Rarely, tumors are immunogenic (induce immune destruction) Lung cancers are highly mutated, therefore express large repertoire of “neoantigens” as targets of immune recognition – Lung cancers are tolerogenic (induce immune tolerance)
  • Concurrent Infiltration by CD8+ and CD4+ T Cells Is a Favorable Prognostic Factor in NSCLC 109 Patients Stage I–IIIa Surgically Resected Survival Period (mos)High-CD8+/high-CD4+ group (n = 26) vs. others (n = 83).Hiraoka et al, 2006.
  • 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.
  • Predominant Infiltration of Macrophages and CD8+ T Cells in Cancer Nests Is a Significant Predictor of Survival in Stage IV NSCLC The Kaplan-Meier of Curves of Four Groups Survival (days)Kawai et al, 2008.
  • Long-Term Survival for Patients With NSCLC With Intratumoral Lymphoid Structures 74 patients resected NSCLC tertiary lymphoid structures “tumor-induced bronchus-associated lymphoid tissue” Ti-BALT follicle density of mature DCs correlated with survival Better predictor than all other clinical-pathologic parameters Time (mos)DFS = disease-free survival; Ti-BALT = tumor-induced bronchus-associated lymphoid tissue.Dieu-Nosjean et al, 2008.
  • Prognostic Value of Stromal Innate Immune Cells in NSCLC  335 patients resected stage I–IIIa NSCLC  Stromal CD56+ NK cells were independent prognostic factor for disease-specific survival Time (mos)Al-Shibli et al, 2009.
  • Cancer Self-Tolerance Blockade  Human cancers harbor genetic alterations, generating neo-antigens  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, PD-1L) abort immune responses – Co-opted by tumors to evade immune destruction – “Tumor adaptive immune resistance” • Immune checkpoint inhibitors can block self-tolerance of cancer, and enable anti-tumor immune destructionPD-1 = programmed cell death protein-1.Topalian et al, 2011.
  • Immunological Synapse4-1BBL = 4-1BB ligand; BTLA = B- and T-lymphocyte attenuator; ICOS = inducible T-cell costimulator.Topalian et al, 2011.
  • Targeting the PD-1/B7-H1 (PD-1L) Pathway to Anti-Tumor Activate Immunity B7.1/2 CD28 DC CTLA-4 to DC Signal 1 cell surface Signal 1 Naïve/resting T cell CTLA-4 Costim. lignad Costim. receptor Antigen experienced T cell Tissue Traffic DC to periphery Signal 1 Signal 1 B7-H1 T cell priming Infla mma PD-1 t ionDC = dendritic cell.Topalian et al, 2012.
  • 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 (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-1L – MDX-1105 (fully human IgG4, Medarex/BMS) – MPDL3280A (Genentech/Roche)Pierard et al, 2012; Brahmer et al, 2010; Topalian et al, 2012; Paradoll et al, 2012.
  • Ipilimumab With Paclitaxel/Carboplatin as First-LineTreatment in Lung Cancer: Phase II Trial CA184-041P = placebo; C = chemotherapy (Pac/Carbo); Pac = paclitaxel; Carbo = carboplatin; Ipi = ipilimumab (10 mg IV).Lynch et al, 2011.
  • CA184-041: Stage IIIB/IV NSCLC Cohort OSLynch et al, 2011.
  • CA184-041: Stage IIIB/IV NSCLC Cohort mWHO PFSPFS = progression-free survival.Lynch et al, 2011.
  • CA184-041: Stage IIIB/IV NSCLC Cohort OS Squamous SubsetLynch et al, 2011.
  • CA184-041: Extensive Stage Small Cell Lung Cohort OS Phased or Concurrent Vs. ControlLynch et al, 2011.
  • Ongoing Lung Cancer Ipilimumab Trials  NSCLC – CA184-104: Randomized, Multicenter, 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 Ipilumumab 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  Small Cell Lung Cancer (SCLC) – CA184-156: Trial in 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.
  • 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.
  • MDX-1106 001: Phase I Study of Single-Agent Anti–PD-1 (MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, Pharmacodynamics, and Immunologic Correlates  39 patients – Dose escalation 6 patient cohorts (0.3, 1, 3, 10 mg/kg) – 1 CR (colon cancer), 2 PR (melanoma, renal), 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 steroids) – Among 9 patients examined, tumor expression of B7-H1 (PD-1L) showed correlation with likelihood of responseMTD = maximum-tolerated dose; DLT = dose-limiting toxicity.Brahmer et al, 2010.
  • MDX-1106 001: Phase I Study of Single-Agent Anti–PD-1 (MDX-1106) in Refractory Solid Tumors (cont.)  61-yr-old BF Stage IV May 2007 July 2007 NSCLC (squamous) bilateral lung metastasis, bone mets. Prior treatment carboplatin/vinorelbine/beva cizumab.  May 2007, RX single dose of MDX-1106, anti-PD-1 mAb (1 mg/kg IV)  8-wk 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.
  • Clinical Activity and Safety of Anti-PD-1 (BMS-936558, MDX-1106) in Patients With Advanced NSCLC  Phase Ib, 240 patients solid tumors stage IV – 75 NSCLC, failed prior chemo (60% > 3 regimens) – RX monotherapy mAb up to 12 cycles (4 doses/cycle) until PD or CR (RECIST criteria) – Grade 3/4 toxicity 8%, including 1 death from pulmonary toxicitya Response evaluable patientsb CR or PRc Unconfirmed PRd RR [(OR + uPR) ÷ n]Brahmer et al, 2012.
  • Anti-PD-1 mAb Lung Cancer Response  60-yr-old male patient – 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.
  • Anti-PD-1 mAb Responder  69-yr-old white male recurrent stage IV NSCLC, progressed after carboplatin/paclitaxel/bevacizumab. Started on MDX-1106. February 2009 September 2009Courtesy of John Powderly II, MD, CPI.
  • B7-H1 (PD-1L) Profiling of Circulating Tumor CellsCarolina BioOncology Institute and BioCytics, Inc.
  • 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  PCD4989g: Study of the Safety and Pharmacokinetics of MPDL3280A (anti-PD-1 mAb) Administered Intravenously As a Single Agent to Patients With Locally Advanced or Metastatic Solid Tumors (NCT01375842) US 88 Patientsclinicaltrials.gov, 2012.
  • Vaccines in NSCLC: Rational, Combination Strategies, and Update on Clinical Trials  Stage IIIB/IV Setting – L-BLP25 (Liposomal MUC1 core peptide, 25 AA, Oncothyreon/Merck) • Phase III 1,300 patients stage IIIB START trial, Global • Phase III 420 patients stage IIIB INSPIRE trial, Asia – TG4010 (Modified vaccinia virus Ankara expressing MUC, IL-2, Transgene/Novartis) • Phase IIB/III – EGF (conjugated to an immunoadjuvant, “Cuban Vaccine”) • Phase III – GVAX (Autologous NSCLC cells, Adenoviral Vector modified GM-CSF) Cell Genesys-BioSante Pharma • Phase II broncho-alveolar – Belagenpumatucel-1 (4 allogeneic NSCLung lines transfected TGF-B2 antisense, irradiated) NovaRX • Phase III 700 patients, Stage IIIA, B, IV, STOP trial, maintenance therapy after chemo  Adjuvant Stage I–IIIA Setting – GSK1572932A MAGE-A3 liposomal AS15 adjuvant system GSK • Phase III, 2,270 patients, MAGRIT trial, stage IB–IIIAMAGE-A3 = melanoma-associated antigen-A3; AA = amino acid; START = Stimulating Targeted Antigenic Responses To NSCLC;INSPIRE = Stimuvax trial In Asian NSCLC Patients: Stimulating Immune Response; MAGRIT = MAGE-A3 as Adjuvant NSCLCImmunotherapy.DePas et al, 2012.
  • 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.
  • Phase II Study of Tg4010 (Mva-Muc1-IL2) in Association With Chemotherapy in Patients With Stage III/IV NSCLC  65 patients, multicenter randomized phase II cisplatin/vinorelbine + vaccine vrs vaccine alone until progression, followed by chemo  1-yr survival 53% vs. 60% not statistically significant, but trend favored vaccine  Subgroups analysis, showed patients with MUC1 cellular Time (mos) ---- = patients with MUC1-specific ELISpot at any timepoint immune response had statistically __ = patients without MUC1-specific ELISpot at any timepoint better OS, p = .001 o = complete data; + = censored; p = .001Ramlau et al, 2008.
  • Phase II Randomized Trial of EGF Vaccine in Advanced NSCLC  80 patients stage IIIB/IV completed first-line chemo randomized vaccine vs. BSC  Survival trend favors vaccination vs. BSC  Subgroup analysis age < 60, vaccine survived longer (n = 50, p = .012)  Good antibody response survived significantly more compared to poor antibody response (.0002) SurvivalEGF = epidermal growth factor.Vinageras et al, 2008.
  • Ongoing Adjuvant MAGRIT Study  GSK1572932A (MAGE-A3) vaccine • Liposomal AS15 adjuvant, synthetic CpG motifs, purified monophosphoral lipid from salmonella, tree saponin  2,270 Resected Stage IB–IIIA NSCLC – 4 cycles platinum-based chemotherapy • Cohort without chemo due to low stage or contra-indications – Randomized 2:1 vaccine or placebo – 11,000 patients screened, 10,000 tumors tested, 3,235 tested + MAGE A3, just completed accrual May 2012 (largest lung cancer trial ever)clinicaltrials.gov; NCT00480025.
  • Emerging Immunotherapies for Renal Cell Carcinoma Michael B. Atkins, MDGeorgetown Lombardi Comprehensive Cancer Center
  • Six Years of Impressive Progress Setting Phase III Alternative Sunitinib Good or Pazopanib High-Dose First-Line Intermediate Risk* IL-2 Therapy Bevacizumab + IFNα Poor Risk* Temsirolimus Sunitinib Sunitinib or Prior Cytokine Sorafenib Bevacizumab Second- Everolimus Prior VEGFR Line Clinical Trials Inhibitor Axitinib Therapy Prior mTOR Clinical Trials Inhibitor Does Immunotherapy Have Any Role?*MSKCC risk status.VEGFR = vascular endothelial growth factor; mTOR = mammalian target of rapamycin; MSKCC = Memorial Sloan-Kettering Cancer Center.Atkins, 2006; Figlin, 2007; Escudier, 2007; Cho et al, 2007; Atkins et al, 2005.
  • Immunotherapy for RCC  High-dose IL-2 – Contemporary clinical experience – Patient selection opportunities  Checkpoint inhibitors – Anti-CTLA4 – PD-1 pathway blockade  Vaccine approachesRosenblatt et al, 2011.
  • Activity of IL-2 Is > 20 Years Ago Response* % Historical Rate 14 IL-2 Select Trial (all patients n = 120)* 25 p = .0014 95% CI = 17.5%–33.7% Likely explanations for improved RR include: 3) Improved screening • Smaller non-clear cell population 2) Fewer patients treated with original tumor in place 3) Impact of new therapies on IL-2 referral patterns*Using WHO Criteria.McDermott et al, 2010.
  • Overall Survival Estimates
  • IL-2 Select RCC Survival CurveMcDermott et al, 2010.
  • Combined UCLA/DFHCC Model + CA-9 Staining Pathology Risk Group Low High Good Intermed Good PoorCA = carbonic anhydrase. PoorAtkins et al, 2005.
  • Response by Tumor Features Tumor risk group RR (95% CI) p Value* Good (n = 11) 27% (6%–61%) .89 Intermediate (n = 83) 24% (15%–35%) 28% (12%–49%) Poor (n = 25) CA-9 Score High (> 85% n = 77) 22% (13%–33%) .19 Low (≤ 85% n = 39) 33% (19%–50%) Combined Score Good (n = 74) 23% (14%–34%) .39 Poor (n = 42) 30% (17%–46%)CA-9 = cancer antigen-9; RR = relative risk.McDermott et al, 2010.
  • IL-2 Select Trial: Commentary  Potential explanations for this result: – Tumor factors are important but markers other than CA-9 will be more predictive – Samples analyzed are not “representative” given the lack of standards for tumor processing at community centersMcDermott et al, 2010.
  • Gerlinger et al, 2012.
  • IL-2 Select Trial: Commentary  Potential explanations for this result: – Tumor factors are important but markers other than CA-9 will be more predictive – Samples analyzed are not “representative” given the lack of standards for tumor processing at community centers – Host factors (eg, patient immune response, tumor microenvironment) may play are larger role in determining responseMcDermott et al, 2010.
  • Non-Inflamed Phenotype Endothelial Cells Arginase/ iNOS Poor Migration Arginine eCD8 Chemokines Tumor Fibroblasts High expression of vascular markers, macrophages, fibroblasts + Low inflammation and chemokines, few lymphocytes = Poor effector cell traffickingGajewski et al, 2011.
  • Inflamed Phenotype Tryptophan B7-1/B7-2 IDO Migration eCD8 Tumor PD-L1 Granules Chemokines Cytokines eCD8 Anergy Treg High levels of innate immune signals, chemokines for T-cell recruitment but negative immune regulators dominateGajewski et al, 2011.
  • Response to IL-2 May Be Associated With Tumor Expression of PD-L1/L3 RR (%) p Value* PD-L1 Tumor Negative (n = 95) 19 .012 Positive (n = 18) 50 PD-L3 Tumor Negative (n = 28) 10.7 .075 Positive (n = 85) 29.4IHC performed at Mayo Clinic by Kwon, Leibovich, et al.
  • Status of the Immunotherapy Selection Project In this trial, analysis of tumor based predictive markers through central pathology review and staining for CA-9 was unable to improve the selection criteria for high-dose IL-2 Expression of B7-H1 and H3 by IHC associated with response to IL-2, requires confirmation in an independent dataset Efforts to confirm other proposed biomarkers are ongoing to understand tumor and host factors that predict IL-2 response – eg, KIR ligand mismatch, HLA-DQα expression, etc. Lessons from this work may guide the development of “targeted immunotherapies” (eg, CTLA-4, PD-1 antibodies) in mRCC
  • CTLA-4 Blockade in mRCC  Ipilimumab phase II trial – Single institution (NCI)  Major RR = 9%  Max dose tested 3 mg/kg (dose response in melanoma)  Survival effect in melanoma despite low response rate  Additional studies warranted – CTLA-4 blockade + bevacizumabYang et al, 2007; Hodi et al, 2011.
  • PD-1/PD-L1 Pathway: The Basics  Several tumor types, including RCC, have been shown to express PD-L1  Over expression of PD-L1 by RCC tumors has been shown to be associated with adverse clinical/pathologic features, including the following: – More aggressive disease – Shorter survival – Also reported to impair antitumor immunity  Can PD-1 pathway blockade lead to clinical benefit?Thompson et al, 2004. 127
  • Clinical Activity and Safety of Anti-PD1 (BMS-936558, MDX-1106) in Patients with Previously Treated Metastatic Renal-Cell CarcinomaD.F. McDermott,1 C.G. Drake,2 M. Sznol,3 T.K. Choueiri,4 J.D. Powderly,5 D.C. Smith,6 J.M. Wigginton,7 D. McDonald,7 G. Kollia,7 A. Gupta,7 M.B. Atkins11 Beth Israel Deaconess Medical Center, Boston, MA; 2Sidney Kimmel CancerCenter at Johns Hopkins University, Baltimore, MD; 3Yale Cancer Center, New Haven, CT; 4Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston, MA; 5Carolina BioOncology Institute, Huntersville, NC; 6University of Michigan, Ann Arbor, MI; 7Bristol-Myers Squibb, Princeton, NJ
  • MethodswPD = worsening progressive disease.McDermott et al, 2011. 129
  • Safety Results: All Patients  For the entire study group, MTD was not reached at Doses 1, 3, and 10 mg/kg  There was no apparent relationship between drug dose and AE frequency  Total with an SAE = 11%SAE = serious adverse event.McDermott et al, 2011. 130
  • Baseline Characteristics Baseline Characteristic n=34 Median age, years (range) 58 (35-74) Male, no. (%) 26 (76) ECOG PS, no. (%) 0 13 (38) 1 21 (62) 2 0 Number of prior therapies, no. (%) 1-2 19 (56) ≥3 15 (44) Nature of prior therapy, no. (%) Immunotherapy 20 (59) Anti-angiogenic therapy 25 (74) Lesions at baseline, no. (%) Bone 10 (29) Liver 9 (26) Lung 30 (88) Lymph node 28 (82) Other 20 (59)
  • Clinical Activity of BMS-936558 in mRCC Patients, Efficacy Population ORR Duration of SD ≥24 wk PFSR at 24 wks Dose PatientsPopulation n (%) response n (%) n (%) (mg/kg) (n) [95% CI] (months)** [95% CI] [95% CI] 9 (27) 9 (27) 56All RCC 1, 10 33 As Below [13-46] [13-46] [39-73] 4 (24) 17.5+, 9.2+, 4 (24) 47 1 17 [7-50] 9.2, 5.6+ [7-50] [23-71] RCC 22.3+, 5 (31)* 5 (31) 67 10 16 21.7+, 12.9, [11-59] [11-59] [43-91] 12.0, 8.4*One CR**Time from first response to time of documented progression, death, or for censored data (denoted by “+”), time to last tumor assessment.
  • Changes in Tumor Burden Over Time for mRCC Patients Treated with 1 mg/kg BMS-936558
  • Changes in Tumor Burden Over Time forRCC Patients Treated with 10 mg/kg BMS-936558 Of 8 patients with OR who were treated ≥1 year, 5 had a response of ≥1 year
  • Response to PD1 Ab in Young Woman With Sarcomatoid RCC With Progression After Sunitinib10/2/09 12/9/09 5/24/10
  • Correlation of PD-L1 Expression in Pretreatment Tumor Biopsies with Clinical OutcomesPD-L1 expression by IHC in 61 pretreatment tumorbiopsies across tumor types from 42 pts *2 patients still under evaluation Patient samples: 18 MEL, 10 NSCLC, 7 CRC, 5 RCC, 2 CRPC
  • PD-1 Antibody Summary At this early point, BMS 936558 has displayed manageable side effects at all dose levels tested Anti-tumor activity observed in a small number of patients with RCC – Potential for selection Subsequent trials launched in RCC: – Dose finding phase II study in patients with prior therapy – Biomarker trial – Combination Rx + VEGF TKI (phase I)
  • PD-1/PD-L1 Pathway Agents in Development
  • Future PD-1/PD-L1 Ab Development in RCC Trials worth considering – First-Line – Adjuvant – Combinations • PD-1 or PD-L1 Ab + bevacizumab or VEGFR TKI • PD-1 Ab + T-cell agonist – IL-2, IL-21, CD-137 Ab • PD-1 Ab + vaccine
  • Myeloid Derived Suppressor Cells in RCC Patients on Sunitinib a p = < .05 (compared to normal) b b p = < .001 (compared to normal) b c p = < .05 (compared to pre-treatment) d p = < .001 (compared to pre-treatment) c c d d d a N = 10 N = 34 N = 30 N = 23 N = 20Ko et al, 2009.
  • Phase II Trial of AGS-003 + Sunitinib OS Results: 21 Patients  Estimated median OS = 29.3 mos per Kaplan Meier method  Encouraging OS compared to expected sunitinib OS in similar risk mRCC subjectsFiglin et al, ASCO GU 2012.
  • Phase 3 ADAPT Survival Trial Initiate 2Q’12 • Study PIs: Robert Figlin, MD (Cedars- Sinai); Christopher G. Wood, MD (MD Anderson Cancer Center) • In collaboration with the SUO-CTCFiglin et al, ASCO GU 2012.
  • IMA901 RCC Phase III Trial: Study Design N = 330 Primary End Point: OS – First-line metastatic and/or locally Secondary End Points advanced RCC – OS in biomarker-defined subgroup – HLA-A*02-positive – Documented tumor lesions – PFS – Favorable or intermediate risk – Safety and tolerability – Cellular immunomonitoringIMA091 is a vaccine comprised of multiple RCC tumor-associated peptides.US NIH, 2012e.
  • Is There a Role for Immunotherapy for mRCC? There has been progress in the field of immunology in the last 30 yrs Immunotherapy can be “targeted” Opportunities exist for selection (PD-L1 expression/ Inflamed phenotype) Opportunities for exciting combinations exist Immunotherapy is worth preserving
  • Immunotherapy Can Achieve the Patients Goal Treatment stops Median – 23.3 months Probability (%) Benefit continues Durable Responders = 15 (13%) DOR (mos)McDermott et al, 2010 Targets trial.
  • Interactive Case Studies:Applying Current Immunotherapies Into Practice Thomas F. Gajewski, MD, PhD Charles G. Drake, MD, PhD
  • Melanoma Case StudyThomas F. Gajewski, MD, PhD
  • Melanoma Case Study Introduction  57-yr-old male with metastatic melanoma, prior metastectomy of liver lesion, presented with single major lung metastasis. Asymptomatic, PS = 0, no autoimmunity. Normal LDH.  Biopsy confirmed melanoma. As part of a clinical trial had gene expression profiling: High expression of chemokines and inflamed signature present. HLA-A2+.PS = performance status; LDH = lactate dehydrogenase; HLA = human leukocyte antigen.
  • Melanoma Case Study (cont.)  Enrolled on multipeptide vaccine trial with IL-12  Completed 12 mos of immunization  PR; lesion became PET-  3 yrs later recurred with pelvic mass—not resectable  Treated with dacarbazine  PR  Enrolled on new vaccine trial combined with reagent for Treg depletion  PR after 12 mos, now PET-IL-12 = Interleukin-12; PET = positron emission tomography; Treg = regulatory T cells.
  • Question 1 Did well for 2 yrs, when he recurred with a large pelvic mass and several additional sites of metastasis. Does have clinical symptoms now. Now in the contemporary era, mutation testing revealed B-Raf V600E. Which treatment option would you consider first? 1) Vemurafenib 2) Ipilimumab 3) Carboplatin/paclitaxel 4) Clinical trial of new anti-angiogenic agentNCCN, 2012.
  • Melanoma Case Study (cont.)  Given his clinical symptoms and exposure to prior immunotherapies, he was treated with vemurafenib  major PR  Complicated by multiple new SCCs of skin, resected by dermatology  Also significant sun sensitivity and sunburns, found to be better prevented by UVA+UVB sunscreen of SPF50SCCs = squamous cell carcinoma; UVA = ultraviolet A; UVB = ultraviolet B; SPF = sun protection factor.
  • Question 2 Had disease control for 7 mos when he experienced regrowth of same metastatic sites. Started to become symptomatic again. Which treatment option would you consider next? 1) Ipilimumab 2) Clinical trial of a MEK inhibitor combined with vemurafenib 3) Carboplatin/paclitaxel 4) Clinical trial of a new antiangiogenic agentMEK = MAPK/ERK kinase.NCCN, 2012.
  • Melanoma Case Study (cont.)  Because of recent evidence that secondary resistance to B-Raf inhibitors frequently involves re-activation of the Ras/MAPK pathway, enrollment on a clinical trial combining a MEK inhibitor with vemurafenib was pursued  Experienced minor response that remained stable for 4 mos, then began to progress again  LDH now ~ 300MAPK = mitogen-activated protein kinase; MEK = MAPK/ERK kinase; LDH = lactate dehydrogenase.
  • Question 3 Which therapy would you consider next? 1) Ipilimumab 2) Carboplatin/paclitaxel 3) Surgical resection of the largest metastasis 4) Clinical trial of a new melanoma vaccineNCCN, 2012.
  • Melanoma Case Study (cont.) Conclusion  Patient was treated with commercial ipilimumab at 3 mg/kg q3wks x 4 doses  Complicated by mild pruritic rash—treated with antihistamines only. Also fatigue—found to have elevated TSH, treated with levothyroxine with symptomatic improvement.  CT scan done at 12 wks  major PR. Now asymptomatic. Being followed clinically with history, physical, labs, and periodic CT scanning. In durable PR for 6 mos currently.TSH = thyroid-stimulating hormone; CT = computed tomography.YervoyTM prescribing information, 2012.
  • Prostate Cancer Case Study Charles G. Drake, MD, PhD
  • Clinical States Model Sipuleucel-T Metastatic Disease Cabazitaxel (De novo) Metastatic Metastatic Metastatic Castrate Castrate Castrate Primary Rising PSA Resistant Resistant Resistant Hormone Asymptomatic Symptomatic Post Docetaxel Disease Naive Non-Metastatic Castrate Resistant Abiraterone ADT Docetaxel MDV3100PSA = prostate-specific antigen; ADT = androgen deprivation therapy.Modified from Scher et al, 2008.
  • Prostate Cancer Case Study Introduction  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: InsignficantPSA = prostate-specific antigen; DRE = digital rectal exam; Bx = biopsy; CT = computed tomography; PMH = past medical history;PSH = past surgical history.
  • 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) CryotherapyNCCN, 2012.
  • Prostate Cancer Case Study (cont.)  Patient undergoes radical retropubic prostatectomy – Gleason 7 (3 + 4) – Organ confined – Negative margins – 5/5 LNs negativeLNs = lymph nodes.
  • Question 2 Which subsequent therapy would you choose? 1) Observation 2) Adjuvant RT 3) Adjuvant ADT 4) Clinical trialNCCN, 2012.
  • Prostate Cancer 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 (at 6-mos intervals)  Referred to radiation oncology  Salvage RT (66 Gy over 8 wks) – Well toleratedNCCN, 2012.
  • Prostate Cancer 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 PD – Bone scan = negative for evidence of metastasesNCCN, 2012.
  • Question 3 What would you recommend at this time? 1) Continued observation 2) Intermittent androgen ablation 3) Continuous androgen ablation 4) Refer for Sipuleucel-T 5) Refer for clinical trialNCCN, 2012.
  • Prostate Cancer 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, 2012.
  • Question 4 Current recommendation? (asymptomatic, metastatic CRPC) 1) Switch bicaluatmide to nilutamide 2) DC bicalutamide (anti-androgen withdrawal) 3) Ketoconazole + hydrocortisone 4) Abiraterone Acetate 5) Sipuleucel-T 6) Docetaxel chemotherapyNCCN, 2012.
  • Case Study (cont.) Course of Treatment  Patient choses RX with Sipuleucel-T  PSA continues to rise  What is next treatment modality? 1) Abiraterone acetate + prednisone 2) MDV3100 3) Docetaxel + prednisone 4) CabazitaxelNCCN, 2012.
  • Clinical States Model (cont.) Sipuleucel-T Metastatic Disease Cabazitaxel (De novo) Metastatic Metastatic Metastatic Castrate Castrate Castrate Primary Rising PSA Resistant Resistant Resistant Hormone Asymptomatic Symptomatic Post Docetaxel Disease Naive Non-Metastatic Castrate Resistant Abiraterone ADT Docetaxel MDV3100Modified from Scher et al, 2008.