Conociendo la inmunoterapia

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1. Conociendo la nueva inmunoterapia del cáncer 2. Mauricio Lema Medina MD Clínica de Oncología Astorga / Clínica SOMA Medellín Inspirado en: Michael Bierut, 2013,…
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  • 1. Conociendo la nueva inmunoterapia del cáncer
  • 2. Mauricio Lema Medina MD Clínica de Oncología Astorga / Clínica SOMA Medellín Inspirado en: Michael Bierut, 2013, Logo para Mohawk Fine Papers
  • 3. 3 Conflicts of interest for this talk Mauricio Lema Medina @Onconerd
  • 4. @Onconerd
  • 5. 2018
  • 6. Cancer incidence affected by… Immunosuppressed Patients receiving immunosuppressive agents Tumor infiltrating lymphocytes
  • 7. Immunoediting Elimination Equilibrium Escape Complete destruction of cancer cells Cancer growth stalled Cancer growth unhindered Disis ML, Semin Oncol, 2014
  • 8. The goal of cancer immunotherapy is to boost or restore the ability of the immune system to detect and destroy cancer cells by overcoming the mechanisms by which tumors evade and suppress the immune response, Disis ML, Semin Oncol, 2014
  • 9. The goal of cancer immunotherapy is to boost or restore the ability of the immune system to detect and destroy cancer cells by overcoming the mechanisms by which tumors evade and suppress the immune response, Disis ML, Semin Oncol, 2014
  • 10. Immunoediting Elimination Equilibrium Escape Complete destruction of cancer cells Cancer growth unhindered Disis ML, Semin Oncol, 2014 Immunotherapy
  • 11. Cell mediated immunity
  • 12. IL-2 discovery 1976 Gallo (Science) 10,000 mouse T- cells 300,000 mouse T-cellsMurine IL-2 (Rosenberg) recombinant IL-2 + LAK Destroyed Linda Taylor’s melanoma 1984 (Rosenberg) NEJM (Rosenberg)
  • 13. T-Cell activation
  • 14. Discovery of the T-Cell Receptor 1984 (Nature) A Cure Within, Neil Canavan, 2018
  • 15. Antigen recognition site CD3-domains T-Cell receptor CD3-domains
  • 16. Major Histocompatibility Complex II
  • 17. James Allison Co-stimulatory signal CD28 - B7 Ralph Steinmann Dendritic cells
  • 18. James Allison Co-stimulatory signal CD28 - B7 Accelerator Ralph Steinmann Dendritic cells
  • 19. Célula tumoral Célula Dendrítica Antígeno tumoral Linfocito T CD8+/Citotóxico
  • 20. Célula tumoral Célula Dendrítica Antígeno tumoral Linfocito T CD8+/Citotóxico Receptor de célula T (TCR) MHC II y antígeno MHC II: Major histocompatibility complex
  • 21. Activación de célula T Célula tumoral Célula Dendrítica Linfocito T CD8+/Citotóxico Co-estimuladora CD28 Co-estimuladora B7.1/B7.2 (CD80/86)
  • 22. La activación del linfocito T (cebamiento o priming) reqiere de las dos sinapsis CO- ESTIMULATORIAS: MHCII-TCR (con presentación de antígeno) y CD80 (u CD86)- CD28
  • 23. James Allison Ralph Steinmann Dendritic cells
  • 24. CTLA-4 is NOT produced by resting T-Cells… but only in T-Cells that had been activated …CTLA-4 appeared to bind the same LIGANDS as CD28
  • 25. James Allison Co-inhibitory signal CTLA4 - B7 Ralph Steinmann Dendritic cells
  • 26. Célula tumoral Célula Dendrítica Linfocito T CD8+/Citotóxico CTLA-4 Co-estimuladoras B7.1/B7.2 (CD80/86) Freno de las células T
  • 27. The primary role of immune checkpoints is to protect tissues from damage when the immune system is responding to pathogens and to maintain tolerance to self-antigens (ie, prevent autoimmunity). This is primarily achieved by downregulating T-cell activation or effector functions Disis ML, Semin Oncol, 2014
  • 28. The primary role of immune checkpoints is to protect tissues from damage when the immune system is responding to pathogens and to maintain tolerance to self-antigens (ie, prevent autoimmunity). This is primarily achieved by downregulating T-cell activation or effector functions Disis ML, Semin Oncol, 2014
  • 29. James Allison Professor, Chair of Immunology M.D. Anderson Cancer Center Houston, Texas Nobel Prize Medicine and Physiology - 2018 CTLA-4 was a brake Protein structure of the T-Cell receptor (M.D. Anderson) Born 1948, Alice, Tx Co-stimulatory signal CD28 CTLA-4 and CD28 shared the same ligands (B7-1, B7-2 in dendritic cells) “((in cancer))… this all starts a negative program as well by inducing thE CLKA-4 gene, and that’s what’s going to eventually turn the system off.” “I proposed treating cancer by ignoring it.”
  • 30. CTLA-4 wild type CTLA-4 -/-
  • 31. Slide uploaded by J Gulley
  • 32. Hippilimumab
  • 33. Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Célula Dendrítica Linfocito T CD8+/Citotóxico CTLA-4 Co-estimuladora B7.1 T-Cell brake Anti-CTLA-4
  • 34. James Allison Professor, Chair of Immunology M.D. Anderson Cancer Center Houston, Texas Nobel Prize Medicine and Physiology - 2018 Search for a biotech company interested in an anti-CTLA-4 in cancer Born 1948, Alice, Tx Medarex synthesis of Ipilimumab “medarex thought that mdx-010 was an activating molecule”
  • 35. Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Célula Dendrítica Linfocito T CD8+/Citotóxico CTLA-4 Co-estimuladora B7.1 Restablishes T-Cell functionality Anti-CTLA-4
  • 36. Célula dendrític a Célula T MHC TCR B7 CD28 CTLA-4 Célula T Células Dendrítica s Interacción de Células Presentadoras de antígeno – Células T Anti- CTLA-4 Bloqueo del CTLA-4 Los anticuerpos anti CTLA-4 restablecen la respuesta antitumoral de linfocitos T Ipilimumab Tremelimumab
  • 37. James Allison Professor, Chair of Immunology M.D. Anderson Cancer Center Houston, Texas Nobel Prize Medicine and Physiology - 2018 Clinical Trials Melanoma Search for a biotech company interested in an anti-CTLA-4 in cancer Born 1948, Alice, Tx Medarex synthesis of Ipilimumab Phase I trial of Ipi: 3 objective responses
  • 38. Jedd Wolchok First clinical trials with Ipilimumab by MSKCC/Medarex Worked in immunology with Dr. Houghton (MSKCC) Born 1965, Staten Island, NY Heard about Allison’s anti-CTLA-4 ab
  • 39. Jedd Wolchok Chief, Melanoma and Immunotherapeutics Service Memorial Sloan Kettering Cancer Center New York, New York First clinical trials with Ipilimumab by MSKCC/Medarex Worked in immunology with Dr. Houghton (MSKCC) Born 1965, Staten Island, NY Heard about Allison’s anti-CTLA-4 ab Despite the bad test results, the patient said he felt better Initial studies looked for Response Rates using RECIST One patient with melanoma had progressed, by RECIST, but said “I feel better” That same patient came back with LESS disease
  • 40. Jedd Wolchok Chief, Melanoma and Immunotherapeutics Service Memorial Sloan Kettering Cancer Center New York, New York Born 1965, Staten Island, NY Despite the bad test results, the patient said he felt better For Phase III trial the CHOSEN primary endpoint was Overall Survival, not PFS Precedent: Another anti-CTLA-4 (tremelimumab) chose PFS as the primary endpoint, and the trial was negative
  • 41. Clinical Trials Melanoma Search for a biotech company interested in an anti-CTLA-4 in cancer James Allison, MD Anderson/MSKCC Medarex synthesis of Ipililimumab Phase I trial of Ipi: 3 objective responses Jedd Wolchok, MSKCC Axel Hoos, BMS
  • 42. 48 INFOGRAPHICS | TEMPLATE IPILIMUMABMELANOMA Phase III DTIC Metastatic Melanoma Ipilimumab Hodi SF, NEJM, 2010 R Anti-CTLA4
  • 43. Clinical Trials Melanoma Search for a biotech company interested in an anti-CTLA-4 in cancer James Allison, MD Anderson/MSKCC Medarex synthesis of Ipililimumab Phase I trial of Ipi: 3 objective responses FDA approval of Ipilimumab in Metastatic Melanoma (2011) Jedd Wolchok, MSKCC Axel Hoos, BMS
  • 44. T-Cell/Drugs Ligands Where Action CTLA-4 B7.1 (CD80) APC Immune response inhibited CTLA-4 B7.2 (CD86) APC Immune response inhibited Ipilimumab anti-CTLA-4 T-Cells Immune response restored Tremelimumab anti-CTLA-4 T-Cells Immune response restored
  • 45. Effector T-Cells
  • 46. Célula tumoral MHC clase I + Ag
  • 47. Célula tumoral CD8+ Célula T MHC clase I + Ag TCR +++
  • 48. Activación de la célula T efectora Célula tumoral CD8+ Célula T MHC clase I + Ag TCR +++
  • 49. Tasuku Honjo Professor, Department of Immunology and Genomic Medicine Kyoto University Kyoto, Japan PD-1Worked in AICDA Born 1942, Kyoto, Japan Looking for thymic Selection mechanisms Curiosity, a challenge, and courage… patience Knock-out (PD-1) mice Unlike CTLA-4 mice, PD-1 mice did survive After a while… PD-1 mice developed diseases… 2002 1994 PD1 is broadly expressed: T-Cells, B-Cells, NK-Cells
  • 50. Célula tumoral Linfocito T CD8+/Citotóxico IFN-γ IFN-γR PD-1 +++
  • 51. El PD-L1 (PD-L2) se expresa en las células bajo el influjo continuo de interferón gamma Célula tumoral Linfocito T CD8+/Citotóxico IFN-γ IFN-γR PD-L1 PD-1 - - - La sinapsis PD1/PD-L1 Inhibe al linfocito T citotóxico
  • 52. Célula tumoral Linfocito T CD8+/Citotóxico PD-L1 PD-1 - - - Anti-PD1
  • 53. Célula tumoral Linfocito T CD8+/Citotóxico PD-L1 PD-1 +++ Anti-PD1 Restituye la actividad antitumoral del linfocito T
  • 54. Célula tumoral Linfocito T CD8+/Citotóxico PD-L1 PD-1 - - - Anti-PD-L1
  • 55. Célula tumoral Linfocito T CD8+/Citotóxico PD-L1 PD-1 +++ Anti-PD-L1 Restituye la actividad antitumoral del linfocito T
  • 56. Droga Mecanismo de acción Pembrolizumab Anti-PD1 Nivolumab Anti-PD1 Avelumab Anti-PD-L1 Durvalumab Anti-PD-L1 Atezolizumab Anti-PD-L1 Célula T Célula tumoral MHCTCR PD-1 PD-L1 Cancer cell T-cell
  • 57. T-Cell/Drugs Ligands Where (Ligands) Action CTLA-4 B7.1 (CD80) APC Immune response inhibited CTLA-4 B7.2 (CD86) APC Immune response inhibited Ipilimumab anti-CTLA-4 T-Cells Immune response restored Tremelimumab anti-CTLA-4 T-Cells Immune response restored PD1 PD-L1 Tumor cells Immune response inhibited PD1 PD-L2 Tumor cells Immune response inhibited Nivolumab PD1 T-Cell Immune response restored Pembrolizumab PD1 T-Cell Immune response restored Atezolizumab PD-L1 Tumor cells… Immune response restored Avelumab PD-L1 Tumor cells Immun response restored Durvalumab PD-L1 Tumor cells Immune response restored
  • 58. Inspirado en: Saul Bass, 1955,, The Man With the Golden Arm
  • 59. Inspirado en: Saul Bass, 1955,, The Man With the Golden Arm
  • 60. Algunos ejemplos Inspirado en: Saul Bass, 1955,, The Man With the Golden Arm
  • 61. Inspirado en: Saul Bass, 1955,, The Man With the Golden Arm
  • 62. Inspirado en: Saul Bass, 1955,, The Man With the Golden Arm
  • 63. Inspirado en: Saul Bass, 1955,, The Man With the Golden Arm
  • 64. Inspirado en: Saul Bass, 1955,, The Man With the Golden Arm
  • 65. Inspirado en: Saul Bass, 1955,, The Man With the Golden Arm
  • 66. Ipilimumab -Melanoma-
  • 67. IPILIMUMABMELANOMA Phase III DTIC Metastatic Melanoma Ipilimumab Hodi SF, NEJM, 2010 R Anti-CTLA4
  • 68. Survival Time Modified from Ribas A, et al. Clin Cancer Res. 2012;18:336-341. Survival Pattern with Chemotherapy and Immune checkpoint blockade Chemotherapy
  • 69. Survival Time Modified from Ribas A, et al. Clin Cancer Res. 2012;18:336-341. Survival Pattern with Chemotherapy ICI Chemotherapy ICI: Immune checkpoint inhibitor
  • 70. Rivas https://www.nobelprize.org/uploads/2018/10/allison-lecture.pdf
  • 71. Schadendorf, JCO, 2015https://www.nobelprize.org/uploads/2018/10/allison-lecture.pdf
  • 72. Anti-PD(L)1…
  • 73. Key Eligibility Criteria Untreated stage IV NSCLC No sensitizing EGFR or ALK alteration ECOG PS 0 or 1 PD-L1 ≥ 50% No symptomatic brain metastases No significant glucocorticoid or immunosuppressive therapy Platinum-based chemotherapy Q3W for 4 x 6 cycles Pembrolizumab 200 mg Q3W for 35 cycles Pemetrexed maintenance, allowed Pembrolizumab 200 mg Q3W for up to 35 cycles R 1:1 On PD Reck M, NEJM, 2016 KEYNOTE-024
  • 74. Reck M, JCO, 2018
  • 75. Key Eligibility Criteria Untreated stage IV nonsquamous NSCLC No sensitizing EGFR or ALK alteration ECOG PS 0 or 1 Provision of a sample for PD-L1 assessment No symptomatic brain metastases No pneumonatisi requiring systemic steroids Placebo (normal saline) + Pemetrexed 500 mg/m2 + Carboplatin AUC 5 OR Cisplatin 75 mg/m2 Q3W for 4 cycles Pembrolizumab 200 mg + Pemetrexed 500 mg/m2 + Carboplatin AUC 5 OR Cisplatin 75 mg/m2 Q3W for 4 cycles Pembrolizumab 200 mg Q3W for up to 31 cycles + Pemetrexed 500 mg/m2 Q3W Placebo (normal saline) for up to 31 cycles + Pemetrexed 500 mg/m2 Q3W Pembrolizumab 200 mg Q3W for up to 35 cycles R 2:1 On PD Gandhi, AACR, 2018 KEYNOTE-189
  • 76. Gandhi, AACR, 2018
  • 77. Arm B Atezolizumab + Carboplatin + Paclitaxel + Bevacizumab 4 or 6 cycles Atezolizumab + Bevacizumab Arm C (control) Carboplatin + Paclitaxel + Bevacizumab 4 or 6 cycles Bevacizumab Key Eligibility Criteria Untreated stage IV or recurrent non- squamous NSCLC Chemotherapy-naïve ECOG PS 0 or 1 Provision of a sample for PD-L1 and biomarker assessment R 1:1:1 Reck, ESMO, 2017 IMpower150
  • 78. Reck, NEJM, 2018 Only wild-type
  • 79. Nivolumab in Pretreated Advanced NSCLC: Randomized Late-StageTrials CheckMate 017 CheckMate 057 Nonsquamo us SIIIB/IV (N = 582) Nivolumab Docetaxel Squamous SIIIB/IV (N = 272) Nivolumab Docetaxel
  • 80. LT OS & Impact of Early Response/Disease Control With Nivolumab in 2L+ NSCLC Figure 2. OS with nivolumab vs docetaxel in CheckMate 017/ 057a Nivolumab (n = 427) Docetaxel (n = 427) Median OS (95% CI), mo 11.1 (9.2, 13.1) 8.1 (7.2, 9.2) 427 264 145 84 45 34 1957 26 11 1 0 100 0 40 60 80 20 34% 14% 8% 5% 14%17% 48% 27% 427 280 205 150 84 70 55113 64 37 9 0 Nivolumab Docetaxel No. at risk Nivolumab Docetaxel Months 0 6 18 24 30 42 48 6012 36 54 66 OS(%) aIn the nivolumab and docetaxel arms, 4.0% (17/427) and 10.1% (43/427) of patients, respectively, received subsequent immunotherapy (includes 23 patients who crossed over from the docetaxel arm to the nivolumab arm); 5 of 19 patients (26.3%) originally randomized to docetaxel and still alive at database lock received immunotherapy as subsequent therapy.
  • 81. 90 163 73105 52 38 27 1518 12 9 5 0 PD-L1 expression < 1% 100 0 40 60 80 20 Months 153 5095 31 20 13 910 6 3 1 0 OS(%) 0 126 18 24 30 4236 48 54 60 66 34% 13% 7% 4% 9% 12% 45% 24% Nivolumab Docetaxel No. at risk Nivolumab Docetaxel PD-L1 expression ≥ 1% Months Nivolumab Docetaxel OS(%) 100 0 40 60 80 20 0 126 18 24 30 4236 48 54 60 66 34% 15% 10% 21% 4% 20% 54% 32% 185 99123 76 58 42 3638 33 20 4 0 179 61112 36 27 23 1017 8 5 0 0 No. at risk Nivolumab Docetaxel Figure 3. OS with nivolumab vs docetaxel by tumor PD-L1 expression in CheckMate 017/ 057a Nivolumab (n = 185) Docetaxel (n = 179) Median OS (95% CI), mo 13.4 (10.0, 17.7) 8.5 (7.0, 9.3) Nivolumab (n = 163) Docetaxel (n = 153) Median OS (95% CI), mo 9.7 (7.6 13.3) 7.8 (6.7, 10.5) aIn all randomized patients from CheckMate 017 and 057 with evaluable PD-L1 expression.
  • 82. IMpassion130 Study Design Presented By Peter Schmid at 2019 ASCO Annual Meeting
  • 83. OS in PD-L1+ Population Presented By Peter Schmid at 2019 ASCO Annual Meeting
  • 84. Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Younes A, Lancet Oncol, 2016
  • 85. Ipilimumab + Nivolumab (IO-IO combinations)
  • 86. Advanced Melanoma 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Larkin J, NEJM, 2015
  • 87. CheckMate 204 Study Design Presented By Hussein Tawbi at 2019 ASCO Annual Meeting
  • 88. Progression-Free Survival – Asymptomatic Patients Presented By Hussein Tawbi at 2019 ASCO Annual Meeting
  • 89. Intracranial Tumor Burden Change and Characteristics of Intracranial Response – Asymptomatic Patients Presented By Hussein Tawbi at 2019 ASCO Annual Meeting
  • 90. CM 214: Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma Motzer R, NEJM, 2018 1096 patients were assigned to receive nivolumab plus ipilimumab or sunitinib
  • 91. Survival Time Modified from Ribas A, et al. Clin Cancer Res. 2012;18:336-341. Survival Pattern with Chemotherapy, ICI and IO-IO ICI Chemotherapy ICI: Immune checkpoint inhibitor IO-IO: Combination ICIs IO-IO
  • 92. Immune Checkpoint Inhibitors Main Clinical Indications
  • 93. Metastatic melanoma NSCLC Stage III melanomaUrothelial cancer Renal-cell carcinomaHNCa
  • 94. Gastroesophageal cancer Breast cancer (TNBC) Hodgkin’s lymphomaMerkel-cell carcinoma Microsatellite-instability (tumor agnostic) SCLC NHL ThyroidHCC
  • 95. Mauricio Lema Medina MD Clínica de Oncología Astorga / Clínica SOMA Medellín Inspirado en: Michael Bierut, 2013, Logo para Mohawk Fine Papers @Onconerd
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