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Guillermo Lerzo Especialista en Oncología

INTRODUCCIÓN A LA INMUNOTERAPIA. Guillermo Lerzo Especialista en Oncología. Tumor Immunology: Overview. perforin granzyme. cytokines. Resting T cell. Activated T cell. TUMOR. LYMPH NODE. T cell clonal expansion. Tumor antigen. CD28. TCR. MHC. B7. Dendritic cell.

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Guillermo Lerzo Especialista en Oncología

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  1. INTRODUCCIÓN A LA INMUNOTERAPIA Guillermo Lerzo Especialista en Oncología

  2. Tumor Immunology: Overview perforingranzyme cytokines Resting T cell Activated T cell TUMOR LYMPH NODE T cell clonal expansion Tumor antigen CD28 TCR MHC B7 Dendritic cell

  3. Tumor-Derived Immune Suppression • Tumors go to great lengths to evade the immune response. • Systematic studies have identified multiple mechanisms cancers employ to defeat the immune response: • Immunosuppressive cytokines: TGF-β, IL-4, -6, -10. • Immunosuppressive immune cells: T-regs, macrophage. • Disruption of immune activation signaling: loss of MHC receptor, IDO production. • Goal: therapy strategies that “liberate” underlying anticancer immune responses. Weiner LM. N Engl J Med. 2008;358:2664-2665.

  4. Immunotherapeutic approaches to breast cancer Mary L. (Nora) Disis University of Washington Fred Hutchinson Cancer Research Center Seattle, WA ndisis@uw.edu

  5. Major categories of the immune system Non-specific No antigens No memory Immediate Transient Specific Antigens Memory Slowly developing Lifelong drrajivdesaimd.com

  6. Clinically effective anti-tumor immunity Fridman et al, Nat Rev Ca, 2012 Bindea et al, Curr Opin Immunol, 2010 High magnitude Type I CD4 (Tbet+), CD8 (GZB+) Memory Low levels of regulatory cells

  7. Approaches to optimizing a therapeutic immune response Butt et al Oncogene, 2013 Enhance existing immunity Increase effector T-cells Modulate the tumor microenvironment Trastuzumab Vaccines Adoptive T-cell Therapy Checkpoint inhibitors Cytokine Therapy (IL-15, IL-7) Depletion Tregs, MDSC MoAB (X-IL-10, TGFb)

  8. What is the optimal receptor-ligand interaction to target? Activate Stimulatory signals Suppress Inhibitory signals **** Topalian et al, JCO, Use early in treatment course in a subset of breast cancer: mutation status, high levels of TIL?

  9. Approaches to optimizing a therapeutic immune response Butt et al Oncogene, 2013 Enhance existing immunity Increase effector T-cells Modulate the tumor microenvironment Trastuzumab Vaccines Adoptive T-cell Therapy Checkpoint inhibitors Cytokine Therapy (IL-15, IL-7) Depletion Tregs, MDSC MoAB (X-IL-10, TGFb)

  10. Trastuzumab induced Type I immunity IFN-g secretion Ferris et al, JCO, 2010 n=97, Stage III/IV HER2+ Stanton et al, 2014

  11. Immunotherapeutic approaches to breast cancer • Tumor immune environment • Level of TIL • Phenotype of TIL • (Type I, II and regulatory) Provide Type I immunity Elicit Type I immunity Release Type I immunity Disis et al, CCR Focus, 2013 Propagate immune response

  12. San Antonio Breast Cancer Symposium, December 9-13, 2014 Tumor Infiltrating Lymphocytes (TILs) in Breast Cancer Associate Professor Sherene Loi, MD, PhD Consultant Medical Oncologist Head, Translational Breast Cancer Genomics and Therapeutics lab Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia This presentation is the intellectual property of the author/presenter.  Contact sherene.loi@petermac.org for permission to reprint and/or distribute.

  13. San Antonio Breast Cancer Symposium, December 9-13, 2014 What is the evidence that immunity is important in breast cancer? • Breast cancer incidence increases in age • Breast cancer in young women is more aggressive • Immunosuppressed patients have worse outcomes from breast cancer • TILs and immune-related gene signatures have been shown to have associations with prognosis in some breast cancer subtypes • Objective responses to T cell checkpoint inhibitors have observed in breast cancer (data this meeting) This presentation is the intellectual property of the author/presenter.  Contact sherene.loi@petermac.org for permission to reprint and/or distribute.

  14. Tumor infiltrating lymphocytes (TILs)- why evaluate TILs? • First publication in EJC in 1992 Aaltomaa et al 1992 • Immune gene signatures are associated with prognosis in ER-negative breast cancer Desmedt et al, 2008; Teschendorff et al 2007; Alexe et al,2007; Rody et al 2009 • TILs represented a feasible way of evaluating the prognostic and predictive role of immunity in large cohorts of well annotated breast cancer samples (ultimate marker will depend on clinical utility) This presentation is the intellectual property of the author/presenter.  Contact sherene.loi@petermac.org for permission to reprint and/or distribute.

  15. Predefined parameters for TILs evaluation intratumoral TILs = direct contact to tumor cells stromal TILs = between the tumor cells LPBC = Lymphocyte-predominant breast cancer „more lymphocytes than tumor cells“ (≥60% TILs /≥50% TILs ) TLS (tertiary lymphoid structures)= follicular aggregates outside of the tumor Salgado, Denkert et al, Guidelines for TILs Evaluation in Breast Cancer- Annals of Oncology 2014 This presentation is the intellectual property of the author/presenter.  Contact sherene.loi@petermac.org for permission to reprint and/or distribute. Courtesy C Denkert

  16. Predefined parameters for TILs evaluation intratumoral TILs = direct contact to tumor cells stromal TILs = between the tumor cells LPBC = Lymphocyte-predominant breast cancer „more lymphocytes than tumor cells“ Salgado, Denkert et al, Guidelines for TILs Evaluation in Breast Cancer- Annals of Oncology 2014 This presentation is the intellectual property of the author/presenter.  Contact sherene.loi@petermac.org for permission to reprint and/or distribute. Courtesy C Denkert

  17. Higher levels in HER2+ and TNBC This presentation is the intellectual property of the author/presenter.  Contact sherene.loi@petermac.org for permission to reprint and/or distribute. Loi et al, JCO 2013; Ann Oncol 2014

  18. Higher TILs=better survival in primary TNBC Primary TNBC, prior to Chemo P=0.01 MFS OS Post-neoadjuvant setting in TNBC Dieci et al, AoO 2014; Loi et al, JCO 2013; AoO 2014

  19. TILs prognostic in HER2+ treated with anti-HER2 agents and CT For every 1% increase in TILs, 3% decrease in risk of an event, independent of treatment arm (trastuzmab, lapatinib and combination). Unpublished data- NeoALTTO study This presentation is the intellectual property of the author/presenter.  Contact sherene.loi@petermac.org for permission to reprint and/or distribute.

  20. Clinical implication of TILs • Pre-existing host anti-tumor immune responses • The more you have, the better outcome from • Primary HER2+ breast cancer treated with anti-HER2 agents and chemo • Primary TNBC treated with adjuvant anthracycline-based chemo • Probably also in metastatic disease • Role in clinical decision making? • Role in predicting response to T cell checkpoint inhibitors and other immunotherapies This presentation is the intellectual property of the author/presenter.  Contact sherene.loi@petermac.org for permission to reprint and/or distribute.

  21. Converting tumors from low TILs into high TILs • Immunogenic chemotherapy- anthracyclines, metronomic chemo, gemcitabine • Radiotherapy can drive a T cell response. • Dose and schedule could be critical • Combinations with immunotherapies could be beneficial BOSTON-II study- NCT02303366 Verbrugge et al 2012; Dewan et al, 2009; Klug et al, 2013

  22. Conclusions • TILs represent functional pre-existing Th1 immunity • Why some breast cancers do and do not have varying levels of TILs remains to be elucidated • Role of TILs in clinical decision making • Analytical validity of TILs biomarker ongoing • Clinical utility of TILs remains to be determined • However prognostic associations of TILs supports the concept that immune approaches may improve outcome in HER2+ BC and TNBC • TNBC- combination therapy This presentation is the intellectual property of the author/presenter.  Contact sherene.loi@petermac.org for permission to reprint and/or distribute.

  23. Abstract S1-06: Edith A. Perez et al. • Stromal tumor-infiltrating lymphocytes (Str-TILs): In the Alliance N9831 trial Str-TILs are associated with chemothetapy benefit but not associated with trastuzumab benefit.

  24. N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy. • 945 patientswith HER2 positive breastcancer. • 3 Arms: A. AC – T B. AC – T – H C. AC – T + H • Str-TILsdefined as % tumor stromalthatcontainslymphocyticinfiltrate (LI). • Str-TILsmeasurements: > 60% classified as “lymphocytepredominantbreastcancer (LPBC).

  25. Univariable Str-TILs Results (1) • TumorswithhighStr-TILswere more likely to be hormone receptronegative (p< 0.0001) • In Arm A (chemotherapy): - LPBC patients: 10ys RFS = 90.9%. - non-LPBC patients: 10ys RFS = 64.3%. - HR = 0.22; 95% CI 0.07 to 0.68, p=0.009 . In Arm C (chemptherapy + trastuzumab): - LPBC patients: 10ys RFS = 80.0% - non-LPBC patients: 10ys RFS = 79.6%. - HR = 1.13;95% CI 0.45 to 2.84, p=0.79.

  26. Univariable Str-TILs Results (2) • In LPBC patientsgroup (Str-TILs > 60%): - Arm A: 10ys RFS = 90.9%. - Arm C: 10ys FRS = 80.0%. - HR = 2.43%; 95% CI 0.58 to 10.22, p = 0.22. . In non-LPBC patientsgroup (Str-TILs < 60%): - Arm A: 10ys RFS = 64.3%. - Arm C: 10ys RFS = 79.6%. - HR = 0.49; 95% CI 0.35 to 0.60, p<0.0001.

  27. Str-TILs: Multivariable Results. • Variables: nodal status, HR status, tumor size, tumor grade, age. . Dichotomouscutoff of Str-TILs: LPBC status - associatedwith RFS in Arm A HR= 0.19;95% CI 0.66 to 0.61, p=0.005 - notassociatedwith RFS in Arm C HR= 1.01; 0.95% CI 0.39 to 2.6, p=0.98 . IncreasingStr-TILsdeciles - associatedwith RFS in Arm A (p<0.0001) - notassociatedwith RFS in Arm C (p=0.13)

  28. CONCLUSIONS • Provocativeresults: - increasing % Str-TILscorrelateswithbenefit of chemotherapy in earlystage HER2+ BC. - impact of addingadjuvanttrastuzumabnot as clear in patientswith LPBC. . Plans: corroborate in a separatecohort. . Identifysubtypes of Str-TILs. . CorrelateStr-TILswith inmune gene profiles. . Determine whetherchangingtheamount and type of Str-TILswillimprovepatientsoutcome.

  29. Str-TILs in Early Stage HER2+ BC:Conclusions. • IncreasingStr-TILsassociatedwithincreased RFS in ptstreatedwithchemotherapy. - notfoun to be associatedwithincreased RFS in ptstreatedwithchemotherapy plus trastuzumab. . Patientswith non-LPBC hadbetter RFS whentreatedwithchemotherapy + trastuzumabcompared to chemotherapyalone. - butptswith LPBC didnothavebetter RFS whentreatedwithchemotherapy + trastuzumabthanchemotherapyalone.

  30. Checkpoint Protein Inhibition2014 San Antonio Breast Cancer Symposium San Antonio, TXDecember 9th, 2014Jeffrey Weber M.D. Ph.D.Moffitt Cancer Center

  31. Immune Checkpoint Pathways CTLA-4 = cytotoxic T-lymphocyte-associated antigen 4 ; MHC = major histocompatibility complex; PD-1 = programmed death-1;PD-L1 = programmed death ligand 1; TCR = T-cell receptor.

  32. Immunotherapy for breast cancer: Myth or Fact? • Tumor infiltrating lymphocytes (TIL) in primary triple negative breast cancer after neo-adjuvant chemotherapy are associated with better RFS, DMFS, OS1 • TIL in stroma and tumor tissue are associated with RFS and OS after adjuvant chemotherapy2 • PD-L1 expression and TIL in primary breast cancer are associated with a better outcome3 • Myeloid derived suppressor cells are associated with high likelihood of nodal metastases in breast cancer4 1: Adams, S et al JCO 2014 2: Loi, Y et al JCO 2013 3: Schalper, K et al CCR 2014 4: Yu, J et al J Immunol 20132

  33. PD-1/PD-L1 blocking agents in development • Pembrolizumab - humanized IgG4 anti PD-1 antibody, approved for second line therapy of melanoma • Nivolumab, human IgG4 anti PD-1 antibody, approval for melanoma pending • MPDL-3280A, humanized PD-L1 antibody • MEDI 4736, human IgG1 PD-L1 antibody • AMP 224, fusion of Fc and anti-PD-L1

  34. Immunotherapy for breast cancer: Myth or Fact? • Tumor infiltrating lymphocytes (TIL) in primary triple negative breast cancer after neo-adjuvant chemotherapy are associated with better RFS, DMFS, OS1 • TIL in stroma and tumor tissue are associated with RFS and OS after adjuvant chemotherapy2 • PD-L1 expression and TIL in primary breast cancer are associated with a better outcome3 • Myeloid derived suppressor cells are associated with high likelihood of nodal metastases in breast cancer4 1: Adams, S et al JCO 2014 2: Loi, Y et al JCO 2013 3: Schalper, K et al CCR 2014 4: Yu, J et al J Immunol 20132

  35. PD-1 blockade: Myth or Fact? • PD-L1 staining is a predictive marker useful for choosing melanoma patients for PD-1/PD-L1 blockade • There appears to be an association between ORR and tumor PD-L1 positivity by IHC in most trials • Patients may still respond even if tumor PD-L1 staining is negative • Equivocal data on association of PD-L1 staining with overall survival.

  36. PD-L1 expression and response rate Urba, W ASCO 2014

  37. Efficacy Based on Tumor PD-L1 Expression (Central Review, RECIST v1.1) 100 100 80 80 P = 0.0007a PD-L1+ 60 60 P = 0.0051 OS, % PD-L1– 40 PFS, % 40 20 20 PD-L1+ 0 PD-L1– 0 0 20 40 60 80 0 20 40 60 80 P = 0.3165 Time, weeks Time, weeks a1-sided P values calculated by logistic regression, adjusting for dose/schedule. PD-L1 positivity defined as staining in ≥1% of tumor cells. Analysis cut-off date: 18 October 2013. Daud A et al. Presented at: 2014 Annual AACR Meeting; April 5-9, 2014; San Diego, CA. Presented by: Richard Kefford, ASCO 2014

  38. Overall survival based on tumor PD-L1 expression by IHC does appear to favor PD-L1+ tumors Ribas, A et al SMR 2014

  39. Conclusions: Checkpoint protein inhibition for breast cancer • Many different histologies now respond to checkpoint protein inhibitory drugs, including breast cancer! • Slow regression, progression prior to regression are common in immuno-oncology and require new response criteria to accommodate irRC responses. • Immune related adverse events are a new field for toxicity management and require a learning curve. • Prolonged duration of response and plateauing of survival curves suggest that cures are possible. • The Law of Unintended Consequences suggests that new and unexpected toxicities will occur.

  40. Clinical Development of Inhibitors of PD-1 Immune Checkpoint

  41. Abastract S1-09: Rita Nanda et al. • A phase IB study of pembrolizumab (MK-3475) in patientswithadvanced triple-negativebreastcancer. University of Chicago, IL. • Pembrolizumab (MK-3475) is a humanized IgG4, High-Affinity, Anti-PD-1 Antibody: - High affinityforthe PD-1 receptor. - Dual ligandblockade of PD-L1 and PD-L2. - No cytotoxicactivity. - PK supportsdosingevery 2 weeksorevery 3 weeks. - Demostratedclinicalactivity in multiple tumor types.

  42. KEYNOTE-012: triple-negative breast cancer cohort. • Recurrent or metastatic triple-negative BC. • ECOG PS 0 – 1. • PD-L1 tumor expression was assesed: 58% of all pts. • No systemic steroid therapy. • No autoimmune disease. • No active brain metastasis. • Response assesment every 8 weeks. • Treatment: Pembrolizumab 10 mg/kg iv Q2W.

  43. Treatment-Related Adverse Events with Incidence >5%. • Any grade: arthralgia 18.8% fatigue 18.8% myalgia 15.6% nausea 15.6% ALT/AST increased 6.3% diarrhea 6.3% erythema 6.3% headhache 6.3% . Grade 3-4: headhache 3.1%

  44. Best Overall Response (RECIST 1.1) • Overall response rate: 5 (18.5%) • Bestoverall response: - complete response 1 (3.7%) - partial response 4 (14.8%) - stabledisease 7 (25.9%) - progressivedisease 12 (44.4%) - no assesment 3 (11.1%) * 66% pts > 4 linesformetastaticdisease.

  45. Pembrolizumab: summary. • Pembrolizumab showed an acceptable safety and tolerability profile in pts with heavily pretreated, PD-L1-positive. Advanced triple-negative breast cancer. • Pembrolizumab was associated with an OOR of 18.5%. • Response was durable, with the median response duration not reached (range, 15 to 40+ weeks) and 3 of 5 responders on treatment for >11 months. • The acceptable safety and tolerability profile and promising antitumor activity support the further development of pembrolizumab in patients with advanced triple-negative breast cancer.

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