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

    1. 1. 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.
    2. 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. 3. 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.
    4. 4. Welcome and Activity Overview Thomas F. Gajewski, MD, PhDThe University of Chicago Medicine
    5. 5. 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
    6. 6. 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
    7. 7. Immuno-Oncology: Understanding BiologicalFoundations of the Immune System in Cancer Thomas F. Gajewski, MD, PhDThe University of Chicago Medicine
    8. 8. 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
    9. 9. 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
    10. 10. Two Principal Means to Promote Immune-Mediated Tumor Destruction: Cytolytic T Lymphocytes and AntibodiesNK = natural killer.
    11. 11. 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.
    12. 12. 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.
    13. 13. 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.
    14. 14. 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.
    15. 15. 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.
    16. 16. 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.
    17. 17. 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.
    18. 18. 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.
    19. 19. 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.
    20. 20. 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.
    21. 21. 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.
    22. 22. 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.
    23. 23. Melanoma: A Classic Tumor Model for Immunotherapy Thomas F. Gajewski, MD, PhD The University of Chicago Medicine
    24. 24. 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.
    25. 25. 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.
    26. 26. 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
    27. 27. 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.
    28. 28. 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.
    29. 29. 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.
    30. 30. 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.
    31. 31. 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.
    32. 32. 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.
    33. 33. Randomized Study of Vaccine Vs. Ipilimumab Vs. Combination in Advanced MelanomaIpi = ipilimumab.Hodi et al, 2010.
    34. 34. 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.
    35. 35. T-Cell Infiltration in Skin and Gut Following Anti-CTLA-4 mAb TreatmentSarnaik et al, 2009.
    36. 36. 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.
    37. 37. IL-2 in Melanoma: RR 16%Atkins et al, 1999.
    38. 38. 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.
    39. 39. High-Dose IL-2 ± Peptide Vaccine Phase IIISchwartzentruber et al, 2011.
    40. 40. 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.
    41. 41. 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.
    42. 42. 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.
    43. 43. 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.
    44. 44. 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.
    45. 45. 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.
    46. 46. 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.

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