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NHL immunotherapy

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NHL immunotherapy. FB Hagemeister.

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NHL immunotherapy

  1. 1. Immunotherapy for Lymphoma: Finally? F B Hagemeister, MD Professor of Medicine Department of Lymphoma and Myeloma M D Anderson Cancer Center Bangkok 29 August 2015
  2. 2. Chimeric Antigen Receptor-T Cell Therapy for Lymphomas • Development of CAR-Ts • Studies in Adults with B-Cell Lymphomas • Identification and Management of Toxicities
  3. 3. ASCT for Relapsed DLBCL: Pre-Rituximab Era (PARMA study)  7 year EFS was 41% vs 13% in for ASCT vs the chemo alone arm EFS (months) Survival(%) DHAP x 6 (n = 54) DHAP x2 + ASCT (BEAC) (n = 55) p = 0.002 41% 13% 100 90 80 70 60 50 40 30 20 10 0 0 30 60 90 120 150 Results are only for those in PR/CR after 2 DHAP Only CRs to initial chemotherapy were enrolled
  4. 4. EFS (induction ITT) OS (induction ITT) R-ICE/ASCT vs R-DHAP/ASCT for Rel/Ref DLBCL: EFS and OS by Induction Survivalprobability 0.0 0.2 0.4 0.6 0.8 1.0 0 12 24 36 48 60 72 OS (months) Survivalprobability EFS (months) 0.0 0.2 0.4 0.6 0.8 1.0 0 12 24 36 48 60 72 p = 0.2672 p = 0.3380 R-ICE R-DHAP R-ICE R-DHAP Gisselbrecht et al. JCO 28:4184–4190, 2010. Includes all patients! Note: Not much improvement in 20 years of research!
  5. 5. The Limited Benefit of ASCT for Relapsed DLBCL 300 patients DLBCL 200 Cured with RCHOP 100 Relapse Or refractory 50 Transplant candidate 50 Transplant ineligible 25 Chemo-refractory 25 Respond and ASCT Friedberg 2011 ASH Educational Session 210 Cured 90 receive Palliation. Most likely die from DLBCL 15 patients relapse 10 Cured after ASCT
  6. 6. Mechanisms of T-Cell Anergy in Therapy of Cancer • T-cell response to antigens requires: – Recognition of antigen – Activation of the T cell – Persistence of T-cell function • T-cell anergy is caused by: – Inhibition or lack of activating signals – Loss of antigen presentation – Activation of suppressive cells – Presence of suppressive ligands Gotsman et al Circulation Res 109: 1220-1231, 2008. Scott et al. Nature Rev Cancer 14: 517-534, 2014.
  7. 7. Design of CAR-T Cells for Cancer Immunotherapy • Basic Design: Two Fundamental Domains – Antigen binding portion • A single chain variable fragment (scFv) derived from a monoclonal antibody – One or more intracellular T-cell signaling domains • CAR-Ts must expand, persist, exhibit enduring antitumor cytotoxicity, withstand an immunosuppressive microenvironment, and overcome tumor antigen escape
  8. 8. CAR-T Cells Recognize Antigen But Must Be Activated and Persist • The tumor specific portion recognizing the tumor antigen can come from two sources – A T cell that is naturally occurring or from a transgenic mouse – A tumor specific antibody found on normal B cells • Activation requires modification of the T cell by adding a naturally occurring protein (CD3zeta, 1st generation) • Persistence induced by stimulation via other proteins (CD28, 2nd generation) or costimulants (4- 1BB or OX40 or other, 3rd generation) Kershaw et al. Nature Rev Cancer 13: 525-541, 2013. Cassuri et al. J Cancer 2: 378-382, 2011>
  9. 9. Development of CARs for Therapy of Cancer Components of an Artificial TCR 1st, 2nd, and 3rd Generation CARs Resultant CAR can be inserted into T Cells by transfection with viruses of other means
  10. 10. CD19 as an Antigenic Target in Lymphoma and Myeloma An Ideal Antigen? Lymphoma Myeloma Expressed on Most Tumor Cells Yes No Expressed on Cell Surface Yes Yes Essential for Tumor Growth Unknown Unknown Expressed on Clonogenic Cells Probably Unknown Not Expressed on Normal Cells or Target Toxicity Acceptable B-Cell Depletion Acceptable B-Cell depletion Acceptable Kochenderfer er al. Blood 119: 2709-2720, 2014.
  11. 11. Importance of the Microenvironment in Limitation of CAR-T Effectiveness • Endogenous immunosuppressive cells – CD4 regulatory T cells – Myeloid-derived suppressor cells – Plasmacytoid dendritic cells – Tumor-associated macrophages • Immune checkpoint inhibitors • Immunosuppressive soluble ligands and cytokines – Interleukin (IL)-10 – Transforming growth factor (TGF)-beta
  12. 12. Variables Potentially Affecting Results in CAR-T Trials Variables Implications Antigen Efficacy Safety (Off Tumor/On Target Toxicity) CAR Construct Type CD28 (MSKCC) 4-BB (U Penn) Comparisons of Efficacy and Persistence Unknown Delivery Vector Lentivirus, Other Retrovirus CD3 Beads, Cytokines Efficiency Unknown Effect on Efficacy T Cells (Bulk vs Subsets) Lymphodepleting Therapy Impact Always Significant Control of Immune Function Tumor Volume May Be Important
  13. 13. Chimeric Antigen Receptor-T Cell Therapy for Lymphomas • Development of CAR-Ts • Studies in Adults with B-Cell Lymphomas • Identification and Management of Adverse Events
  14. 14. Phase I 19-28z CAR-T After ASCT for Rel/Ref Aggressive B-NHL • 11 patients with disease chemosensitive to relapse therapy • Eligibility – PET positive disease after > 2 cycles of relapse therapy, but PR by other criteria – Marrow involvement at time of relapse or refractory disease and not an allo candidate • Phase I Study: Generate CAR using CD28 for persistence, attached to activated scFv-C3zeta chain (19-28z CAR) • Retrovirus used to insert CAR into T cell Sauter et al. ASCO 2015, Abst 8515.
  15. 15. Potential Advantages of 19-28z CAR-T Cells Post-Ablative Chemotherapy and ASCT • After expansion of resultant CAR-Ts (weeks), cells are infused following AutoSCT into eligible patients • Potential advantages of this sequence – Modulation of a hostile immunosuppressive tumor microenvironment • Elimination of regulatory T cells • Elimination of myeloid suppressor cells – Elimination of cytokine “sinks” for optimized proliferative expansion of 19-28z CAR-T cells Sauter et al. ASCO 2015, Abst 8515.
  16. 16. Phase I 19-28z CAR-T After ASCT for Rel/Ref Aggressive B-NHL Sauter et al. ASCO 2015, Abst 8515. Salvage Chemo Leukapheresis Generation of CAR-Ts -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +10 Hospital BEAM Pegfilgrastim ASCT Infusion 19-28z CAR-Ts Anticipated Engraftment Dose Levels -1 2 x 106 + 1 5 x 106 +2 1 x 107 + 3 2 x 107
  17. 17. Phase I CAR-Ts After ASCT for Rel/Ref Agg B-NHL: Patients and Results • 11 patients enrolled, med age: 61 (34-75 years) • Pathology: DLBCL-5; tFL/MZL/CLL-4; BL-1; Blastoid MCL-1. • Status prior to ASCT: 10 PR (2 with BM involved), 1 PET CR but with leukemic phase • Median prior therapies: 2 (range 2-4) • CAR-T doses: 10 receive 5 x 106 /kg, 1 receives 10/kg • Toxicity: 7/11 have CRS/CNS toxicity, 1 dies at 1 mo • Response (10 eval): CR – 6 patients; 2 CRs have PD • PFS: 10 eval, 4 CRs still in CR at 13, 15, 20, 21 mo Sauter et al. ASCO 2015, Abst 8515.
  18. 18. CAR-T Cells for Relapsed/Refractory CD19 Positive NHLs • CTL019 engineered T cells contain: • Chimeric antigen receptor (CAR) specific for CD19. • Activation and signaling via a CD3-zeta domain. • Costimulatory signaling via a CD137 (4- 1BB) domain. • Other chimeric antigen receptor-modified T cell therapy against CD19 has been effective in treating relapsed and refractory ALL and CLL. Maude et al. N Engl J Med 2014; 371:1507-17. Grupp et al. N Engl J Med 2013; 368:1509-18. Porter et al. N Engl J Med 2011; 365:725-33. Chimeric Antigen Receptor (CAR) CD19 CD3-ζ Schuster et al. ASCO 2015, Abst 8516.
  19. 19. CAR-T Cells for Relapsed/Refractory CD19 Positive NHLs: Criteria for Entry DLBCL • Progression after ASCT or ineligible for ASCT • Transformation from CLL/SLL or FL allowed FL • > 2 prior regimens • Progression < 2 years after last therapy MCL • Progression after ASCT • Any relapse or progression and ineligible for ASCT or AlloSCT Schuster et al. ASCO 2015, Abst 8516.
  20. 20. Month +3 response assessment CAR-T Cells for Rel/Ref CD19 Positive NHLs: Treatment Schema CD19+ Lymphoma •Eligibility determination •Enrollment Apheresis •Baseline immune assays Restaging and Lymphodepleting Chemotherapy CT Scans and Bone Marrow. Therapy Physician Choice. Ends 1-4 Days before CTL019 infusion CTL019 Infusion, Monitoring and Response Assessments Day 0 Month +1 Month +2 and +3 evaluations Quarterly f/u x 2 yr F/U 15 years Adverse event monitoring CTL019 infusion = Clinical evaluation; immune/CTL019 assays Day -1 Schuster et al. ASCO 2015, Abst 8516.
  21. 21. CAR-T Cells for Rel/Ref CD19 Positive NHLs: Patient Features Feature DLBCL (N=19) FL (N=8) MCL (N=3) Med age, Yr (range) 56 (25 - 77) 61 (43-71) 55 Med # prior Txs (range) 4 (1 - 8) 6 (4-8) 4 (3-6) Prior SCT, N (%) 7 (37) 2 (25) 1 (33) Stage III-IV, N (%) 12 (63) 7 (88) 3 (100) High LDH, N (%) 14 (74) 5 (63) 2 (66) > 1 ENS, N (%) 6 (32) 1 (13) 3 (100) Med PS (range) 1 (0 - 1) 0 (0-1) 1 (0-1) Schuster et al. ASCO 2015, Abst 8516.
  22. 22. DLBCL: ORR at 3 Mo 50% (N = 13) Best Response 50% (N = 13) - CR: 2 - PR: 4 - PD: 6 - Response not yet assessed: 1 - CR: 5 - PR: 1 - PD: 6 - Response not yet assessed: 1 • 3 PR at 3 mo converted to CR at 6; 1 PR at 3 mo had PD at 6 CAR-T Cells for CD19 Positive NHLs: Response Rates for DLBCL and FL FL: ORR at 3 Mo 100% (N = 7) Best Response 100% (N = 7) - CR: 3 - PR: 4 - CR: 6 - PR: 1 • 3 PR at 3 mo converted to CR by 6 mo; 1 PR at 9 mo had PD at 12 Schuster et al. ASCO 2015, Abst 8516.
  23. 23. CAR-T Cells for Rel/Rel CD19 Positive NHLs: PFS Results for DLBCLs N = 13 Median PFS 90 days 1.00 0.75 0.50 0.25 0.00 0 100 200 300 400 Days Schuster et al. ASCO 2015, Abst 8516.
  24. 24. CAR-T Cells for Rel/Ref CD19 Positive NHLs: PFS Results for FLs N = 7 Median not reached Median follow-up 290 days 1.00 0.75 0.50 0.25 0.00 0 100 200 300 400 Days Schuster et al. ASCO 2015, Abst 8516.
  25. 25. AE G3 G4 AE G3 G4 Renal 2 Infections 2 Anemia 1 Hypophosphatemia 3 1 CRS 1 1 Hypotension 1 1 Delirium 1 Leukopenia 3 2 Fever 1 Lymphopenia 10 8 Hypertension 2 Neutropenia 3 6 Hypocalcemia 1 Thrombocytopenia 1 Hypokalemia 1 Transaminitis 1 Hyponatremia 1 CAR-Ts for Rel/Ref NHLs: Grade 3-4 AEs in > 2 Patients Regardless of Cause Schuster et al. ASCO 2015, Abst 8516.
  26. 26. Current CAR Studies for Lymphomas or Myelomas (2015) • Seven centers have trials targeting CD19 – NCI (Bethesda) – MSKCC (New York) – Fred Hutchinson (Seattle) – U Penn (Philadelphia) – City of Hope (Los Angeles) – Baylor (Houston) – MDACC (Houston) • Multicenter Trials – Kite – Novartis • One study targeting CD22 at NCI
  27. 27. Chimeric Antigen Receptor-T Cell Therapy for Lymphomas • Development of CAR-Ts • Studies in Adults with B-Cell Lymphomas • Identification and Management of Adverse Events
  28. 28. Classic Toxicity Associated with CAR- T Cell Therapy • Cytokine Release Syndrome (CRS) – High fevers, hypotension, hypoxia – Mild Coagulopathy (Elevated D-Dimer, Low Fibrinogen, C-Reactive Protein) – Hepatosplenomegaly, mild transaminitis – Elevated cytokines: IL-6, TNF • Macrophase Activation Syndrome – High Ferritin levels – Moderate marrow hemophagocytosis (HLH)
  29. 29. Neurologic Symptoms Observed in CD19 CAR-T Trials • Mental status changes associated with hypotension and fevers – Classically confusion; obtundation when severe – Occasionally mild, with focal neurologic changes, including aphasia and myoclonus – Easiest identification: handwriting – Most resolve in days to weeks • Exact cause unknown – Associated with larger tumor burden, marrow involvement – Also thought to be off target toxicity, CARs found in CSF
  30. 30. Unmet Needs in CAR-T Research • Improve Efficacy – Improve antigens or combinations – Improve CAR-T effector function and persistence. – Decrease immunosuppression in microenvironment (better conditioning, humanization of scFv) • Improve Safety – Better understand causes/prevention of CRS and neurotoxicity – Include safeguards (suicide genes) in next CAR-Ts • Integrate into Standard Care and Improve Feasibility – Develop combination therapies – Study applicability beyond specialized centers
  31. 31. Chimeric Antigen Receptor-T Cell Therapy for Lymphomas • Development of CAR-Ts • Studies in Adults with B-Cell Lymphomas • Identification and Management of Adverse Events
  32. 32. Immunotherapy for Lymphoma: Finally? F B Hagemeister, MD Professor of Medicine Department of Lymphoma and Myeloma M D Anderson Cancer Center Bangkok 29 August 2015

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