CAR T and Other Advances in Immunotherapy. Kathleen Dorritie, MD June 12, 2018

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1 CAR T and Other Advances in Immunotherapy Kathleen Dorritie, MD June 12,

2 Fourth Modality of Cancer Treatment Has Arrived Surgery Radiation Chemotherapy Immunotherapy 2

3 Nature Rev Cancer. 2009;9: : Coley s Toxin

4 The Immune System Is Capable of Eliminating Tumor Cells 2 Cancer antigen presentation (dendritic cells/apcs) 1 Release of cancer cell antigens (cancer death cell) 3 Priming and activation (APCs and T cells) Trafficking of T cells to tumors (CTLs) Lymph BUT TUMORS ARE SMART.THEY node FIND WAYS TO Blood vessel EVADE THE IMMUNE SYSTEM! 5 Infiltration of T cells into tumors GOAL OF IMMUNOTHERAPY IS TO WAKE UP THE (CTLs, endothelial cells) IMMUNE SYSTEM. 4 Recognition of cancer cells by T cells (CTLs, cancer cells) 6 4 APC=antigen presenting cells; CTL=cytotoxic T lymphocytes Chen DS et al. Immunity. 2013;39(1):1-10. Killing of cancer cells (immune and cancer cells) 7

5 Therapies to Drive an Immune Response Vaccines Adoptive T-cell therapies CAR-T TIL therapy Cytokines TLR agonists Agonist antibodies (4-1BB, OX-40) Checkpoint blockade (Abs blocking CTLA4, PD-1, PD- Yervoy Keytruda Opdivo

6 Immune Therapy in Melanoma Prior to Immune therapy, median overall survival for patients with stage IV melanoma was less than 1 year 5-year survival rate was 10% 6

7 Hodi FS et al. N Engl J Med 2010;363: Ipilimumab

8 Survival in Metastatic Melanoma with Nivolumab Published in: Suzanne L. Topalian; Mario Sznol; David F. McDermott; Harriet M. Kluger; Richard D. Carvajal; William H. Sharfman; Julie R. Brahmer; Donald P. Lawrence; Michael B. Atkins; John D. Powderly; Philip D. Leming; Evan J. Lipson; Igor Puzanov; David C. Smith; Janis M. Taube; Jon M. Wigginton; Georgia D. Kollia; Ashok Gupta; Drew M. Pardoll; Jeffrey A. Sosman; F. Stephen Hodi; JCO 2014, 32, DOI: /JCO Copyright 2014

9 Ipi plus Nivo 9 Wolchok JD, et al. N Engl J Med Oct 5; 377(14):

10 U.S. FDA Approved Immune-Checkpoint Inhibitors Squamous Cell Head & Neck Cancer 1L nivolumab after platinum chemotherapy 1L pembrolizumab after platinum chemotherapy Malignant Melanoma Adj./1L ipilimumab 1L nivolumab ± ipilimumab Adj. nivolumab 1L pembrolizumab Merkel Cell Carcinoma 2L avelumab Hepatocellular Carcinoma 2L nivolumab after sorafenib Adv. Renal Cell Carcinoma 1L nivolumab plus ipilimumab 2L nivolumab after anti-angiogenic therapy Locally Adv. or Met. Urothelial Cancer 1L nivolumab after platinum chemotherapy 1L pembrolizumab after platinum chemotherapy or in platinum-ineligible patients 1/L atezolizumab after platinum chemotherapy 1L avelumab after platinum chemotherapy 1L durvalumab after platinum chemotherapy Non-Small Cell Lung Cancer 1L pembrolizumab TPS 50% 1L pembrolizumab + pemetrexed/carboplatin in non-squamous NSCLC 2L pembrolizumab TPS 1% 2L nivolumab 2L atezolizumab NSCLC Maintenance durvalumab after chemoradiation Gastric & GEJ Carcinoma 3L pembrolizumab after fluoropyrimidine- and platinum-chemotherapy +/- HER2 therapy & CPS 1 Classical Hodkin Lymphoma 4L pembrolizumab 3L nivolumab after auto-hsct and BV 4L nivolumab and after auto-hsct MSI-H or dmmr Cancers 2L nivolumab in CRC after FOLFOXIRI 2L pembrolizumab in CRC after FOLFOXIRI 2L pembrolizumab in any MSI-H/dMMR cancer 1 Prescribing information pembrolizumab (Keytruda ), revised: 11/ Prescribing information durvalumab (Imfinzi ), revised: 05/ Prescribing information nivolumab (Opdivo ), revised: 04/ Prescribing information ipilimumab (Yervoy ), revised: 04/ Prescribing information atezolizumab (Tecentriq ), revised: 04/ Prescribing information avelumab (Bavencio ), revised: 10/2017 Updated on 23-Apr medi-paper.com Copyright Photo: 7activestudio / 123RF Stock Photo

11 Cellular Therapies Tumor Infiltrating Lymphocytes (TILs)!being investigated in solid tumors T Cell Receptor Therapy (TCR) Chimeric Antigen Receptor (CAR) T Therapy 11

12 What are Chimeric Antigen Receptor (CAR) T cells (aka gene therapy)? 1. What are T-cells aka T Lymphocytes? Immune cells that mature in the thymus gland There are many subtypes of T cells Some work by releasing chemical messages (cytokines) to upregulate or downregulate the immune response Others have more direct killing effect 12

13 What are Chimeric Antigen Receptor (CAR) T cells? What is an antigen and antigen receptor? Antigens are foreign substances that cause the immune response Antigen receptors are proteins found on B- and T- cells When a protein binds to its receptor, a cascade of chemical signaling occurs inside the cell 13

14 What are Chimeric Antigen Receptor (CAR) T cells? T cells genetically engineered to express an artificial T cell receptor through which they target specific populations of cells 14

15 How CAR T-cells are Made Roughly 2-3 weeks Chemo is typically fludarabine + cyclophosphamide (Cytoxan) making space for CAR T- cells Mikkilineni L, Blood

16 Cell Infusion Prior to infusion, you receive conditioning or lymphodepleting chemotherapy to make room for the T-cells (3 days) Rest x 2-4 days Cell infusion (inpatient or outpatient depending on center or clinical trial) CLOSE monitoring (potential for severe side effects) 16

17 CAR T-cells for Acute Lymphoblastic Lymphoma: ELIANA trial (Novartis/UPenn) Open-label, single-arm multicenter global study (Pivotal registration trial) CTL019 (Kymriah, tisagenlecleucel) Relapsed/Refractory ALL in pediatric/young adult population (Very difficult population to treat, survival in months at best) Buechner, J. EHA, June 24, 2017, Abstract S476

18 CAR-T cells for ALL: ELIANA trial N=63 (all with at least 3 mo follow-up) Complete response/cri (complete response but did not fully recover counts) RFS (relapse free survival) probability at 6 mo OS (overall survival) probability at 6 mo OS probability at 12 mo 52 (83%) 75% (57%-87%) 89% (77%-94%) 79% (63%-89%)

19 Maude, SL. NEJM, Survival

20 Maude, SL. NEJM, Duration of Remission

21 21 Kymriah was the first CAR T therapy to be approved by the FDA in August 2017 for Acute Lymphoblastic Leukemia in children and young adults May 2018 approved for Diffuse Large B cell Lymphoma

22 22 DLBCL ZUMA-1 (NIH/Kite Pharma)

23 Results At min 6 mo f/u Historical control ORR to salvage 20% (P<0.001) Median time to response: 1 mo ( mo) Neelapu, S.S. et al, NEJM, 377;26.

24 eelapu, S.S. et al, NEJM, 377;26. Duration of response Take Away: Responses are holding!

25 25 Yescarta approved in October 2017 Third product for lymphoma, JCAR (Juno Therapeutics) anticipated later this year

26 Fig 2. Complete remissions (CRs) of chemotherapy-refractory large-cell lymphomas in patients receiving anti-cd19 chimeric antigen receptor T cells. (A) Positron emission tomography (PET)/computed tomography (CT) scans show CR of chemotherapy-refractory primary mediastinal B-cell lymphoma (PMBCL) in patient No. 2. (B) PET/CT scans demonstrate CR of lymphoma in patient No. 8 who had chemotherapy-refractory PMBCL with extensive liver involvement. (C) PET/CT images show CR of diffuse large B-cell lymphoma, not otherwise specified, in patient No. 14, who had extensive splenic lymphoma. Published in: James N. Kochenderfer; Mark E. Dudley; Sadik H. Kassim; Robert P.T. Somerville; Robert O. Carpenter; Maryalice Stetler-Stevenson; James C. Yang; Giao Q. Phan; Marybeth S. Hughes; Richard M. Sherry; Mark Raffeld; Steven Feldman; Lily Lu; Yong F. Li; Lien T. Ngo; Andre Goy; Tatyana Feldman; David E. Spaner; Michael L. Wang; Clara C. Chen; Sarah M. Kranick; Avindra Nath; Debbie-Ann N. Nathan; Kathleen E. Morton; Mary Ann Toomey; Steven A. Rosenberg; JCO 2015, 33, DOI: /JCO Copyright 2014

27 Response to Therapy: Patient with Heavily Treated Follicular Lymphoma James N. Kochenderfer et al. Blood 2010;116: by American Society of Hematology

28 Ali, Blood BCMA CAR Myeloma

29 CAR T Therapy Being Investigated in Lymphomas Leukemias (Acute and Chronic) Multiple Myeloma Solid Tumors 29

30 Things to Consider CAR T therapy is expensive (hundreds of thousands per infusion), need to look at the big picture Insurance companies scrambling to figure out coverage Medicare working to incorporate coverage Some companies have assistance programs Clinical trials also provide access Early cost-effectiveness analysis suggests the benefit might be worth the cost (QALY) 30

31 Other Things to Consider Only specialized centers can administer! limits access, but necessary for safety Requires team effort to ensure safety! must have trained nurses, various physicians all working together 31

32 Future of CAR T Continued modification of the cells themselves Move CAR T to earlier line of therapy? Enhance therapeutic benefit Target multiple antigens at one time Combine with other immune therapies Application to solid tumors 32

33 Concluding Thoughts Immunotherapy is changing the way we treat cancer It is starting to be incorporated earlier in cancer treatment More patients are achieving durable responses There is great promise in combining immunotherapy and other targeted agents 33

34 The promise of immunotherapy: The Kaplan-Meier curve tail Survival (%) Time Chemotherapy Genomically targeted therapy Immune checkpoint therapy Combination with genomically targeted agent and immune checkpoint therapy Sharma P & Allison JP. Cell 2015

35 UPMC Hillman Cancer Center Patient-centered and Research-driven Thank you!!! Bridging Laboratory to Clinic to Community