CAR T cell therapy for lymphomas

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1 CAR T cell therapy for lymphomas Sattva S. Neelapu, MD Associate Professor and Deputy Chair ad interim Department of Lymphoma and Myeloma UT MD Anderson Cancer Center, Houston, TX

2 CAR T cell therapy What are CAR T cells? Do they work for lymphomas? How do they work and what are the side effects? What is the future?

3 Chimeric Antigen Receptor (CAR) Modified T cells Normal T cell CAR T cell Genetically engineered T cells altered to express an artificial receptor, CAR CD19 Adapted from Hinrichs & Restifo. Nat Biotech 2013

4 Development of CAR T cell therapy Cytotoxicity Proliferation + ++ Cytokine secretion + ++ In vivo persistence + ++ Adapted from Maus et al. Blood 2014;123:

5 2 nd generation CD19 CAR T cells in clinic MSKCC/Fred Hutch NCI U Penn MDACC CD19 Ab CD28/4-1BB CD3z Gene transfer Retrovirus Retrovirus Lentivirus Sleeping beauty Juno Therapeutics Kite Pharma Novartis Ziopharm

6 CAR T cell therapy What are CAR T cells? Do they work for lymphomas? How do they work and what are the side effects? What is the future?

7 General Treatment Schema 2-4 wks manufacturing Apheresis / Blood draw Days -5 to -3 Day 0 Conditioning chemotherapy Cyclophosphamide Fludarabine CAR T cells ( million cells)

8 NCI Study CD19 CAR in refractory B-cell lymphomas - CD19/CD3z/CD28 Lymphoma subtype n ORR CR PR DLBCL/PMBCL 17 65% 35% 30% CLL 7 86% 57% 29% Indolent NHL 5 100% 25% 75% Total 29 76% 38% 38% 16 patients still in response; 12 ongoing > 1 year None of the CRs have relapsed 3 patients were re-treated after progression and all 3 responded Kochenderfer, et al, J Clin Oncol, 2014 Kochenderfer, et al, ASH, 2014 Bot et al, ASCO, 2015

9 U Penn Study CD19 CAR in relapsed or refractory B-cell lymphomas - CD19/CD3z/4-1BB Lymphoma subtype n ORR CR PR DLBCL 15 47% 40% 7% FL 11 73% 64% 9% MCL 2 50% 50% - Total 28 57% 51% 6% None of the CRs have relapsed Schuster et al, ASH 2015, Abstract # 183

10 FHCRC Study CD19 CAR in relapsed or refractory B-cell lymphomas CD19/CD3z/CD28 Lymphoma subtype n ORR CR PR DLBCL/tNHL 18 50% 22% 28% FL 6 67% 33% 33% MCL 4 25% - 25% CLL 6 67% 50% 17% Total 34 52% 26% 26% CAR T cells reach higher peaks and persist longer with Cy/Flu conditioning regimen compared with Cy regimen Turtle et al, ASH 2015, Abstract # 184

11 Resolution of liver and spleen masses PMBCL DLBCL Kochenderfer, et al, J Clin Oncol, 2014

12 CAR T cell therapy What are CAR T cells? Does it work for lymphomas? How do they work and what are the side effects? What is the future?

13 CAR T cell response to antigen CAR T cell CD19 Proliferate Make cytokines Kill the target cells

14 CAR T-cell expansion after infusion Peak day 7-17 Kochenderfer, et al, J Clin Oncol, 2014

15 Summary of Toxicities Cytokine release syndrome (CRS) Fever, hypotension, hypoxia Generally resolves within 1-3 weeks Managed using IL-6 receptor blockade (tocilizumab) Neurotoxicity (reversible) aphasia/dysphasia, confusion, somnolence, tremors, seizures Low blood counts and infection (from conditioning chemo) Tumor lysis syndrome (manageable) Hypogammaglobulinemia and infections -- Late toxicity due to B-cell depletion

16 CAR T cell therapy What are CAR T cells? Does it work for lymphomas? How does it work and what are the side effects? What is the future? Can the CAR T cells be centrally manufactured and shipped to treatment facilities? Can it be made into an off-the shelf product? Will it be effective for other lymphomas? How can the efficacy be improved? How can the toxicity be lowered?

17 Other targets for CAR T cell therapy Lymphoma subtype Targets Phase of development B-cell lymphomas and leukemias (DLBCL, BL, FL, MCL, MZL, CLL, ALL) CD19, CD22 Phase II/Registration Hodgkin lymphoma CD30 Preclinical / Phase I T-cell lymphomas CD5, CD30 Preclinical / Phase I Multiple myeloma CD19, BCMA, CS1/SLAMF7 Preclinical / Phase I AML CD123 Preclinical

18 Other CAR T Cell Trials Target Institution / Sponsor N Histology Disease setting Efficacy Ref CD30 Baylor 9 HL ALCL Relapsed/ Refractory 1CR 1PR 4SD ASH 2015, Abst 185 BCMA NCI 11 MM Relapsed / Refractory 1CR 3 PR ASH 2015, Abst LBA-1 CD19 Cellectis (Off-the shelf) 1 ALL Refractory CR ASH 2015, Abst 2046

19 Summary Highly effective in patients with MRD or bulky disease in aggressive (DLBCL, PMBCL, DHL, THL, Burkitt s) and indolent B-NHL, CLL, ALL, HL, and MM Appears to be safe in refractory patients as well as after autologous- or allogeneic-sct Cytokine release syndrome (CRS) and neurotoxicity are the major toxicities but are reversible Efficacy and toxicity appear to be comparable between the various 2 nd generation CAR T cell products Multicenter phase 2 registration trials are ongoing in lymphomas Off-the shelf allogeneic CAR T cells are entering clinical trials Combination strategies are being tested in preclinical studies

20 Acknowledgements Patients Physicians Scientists Nurses Clinical research staff Laboratory research staff Funding agencies Sponsors Kite Pharma Novartis Juno Therapeutics