1. The Role of Immunotherapy for the Treatment of Hematologic Malignancies Patrick Stiff MD Coleman Professor of Oncology Loyola University Medical Center 708-327-3216

2. The use of Immune therapy to fight cancer is not new Allogeneic Bone Marrow Transplantation: adoptive immunotherapy Antibodies: rituximab, brentuximab Vaccines: anti-HPV, Hepatitis B vaccines Dendritic Cell Vaccines Engineered T cells Chimeric Antigen Receptor T Cells: CAR-T

3. History of Immunotherapy for Hematologic Malignancies

4. Your Immune system is an organ in your body

5. The Bone Marrow Plays an Important Role in the Immune System

6. To invoke the immune system you need a target This is called an antigen and is usually on the surface of the cell Antigens can be targeted by antibodies or by cells or in fact by both simultaneously

7. Schematic of the Immune system

8. For cancer, T cells do most of the work in preventing and eliminating disease

9. Lymph nodes modulate the immune system

10. The Ying and Yang of the Immune System

11. Targets for Immunotherapy are on the cell surface

12. In cancer the immune system does not recognize the specific antigens on the tumor cells No response means no cancer cell killing

13. Immune responses often require both B and T Lymphocytes

14. How T-cells can kill cancer

15. Cancer Cell Dendritic Cell Stimulation doe outside the body:re-education Can the Immune Defect be Repaired: Dendritic Cell Vaccines

16. CAR-T Cell Therapies Several Platforms/strategies being developed( U Penn, MSKCC, NCI) NCI is working collaboratively with Kite Pharmaceuticals to develop therapy for lymphoma and in the future leukemia using an anti-CD19 CAR-T cell

17. Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B ‑ cell cancer with T cells expressing anti-CD19 chimeric antigen receptors Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46 Figure 5 A schematic of the current approach to anti ‑ CD19 CAR T cell therapy is shown

18. Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B ‑ cell cancer with T cells expressing anti-CD19 chimeric antigen receptors Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46 Chimeric antigen receptors: Clinically target CD19 on B cells (Lymphoma, CLL, ALL)

19. Phase 1/2 study investigating safety, feasibility, and efficacy Refractory/recurrent disease incurable by standard therapy Evolving treatment protocol (conditioning/dosing) VHVH VLVL CD19-specific scFv Co-stimulatory domain: CD28 Essential signaling domain: CD3  of TCR Kite/NCI Study of anti-CD19 CAR in Relapsed/Refractory B-Cell Malignancies

20. Streamlined Manufacturing Process for anti-CD19 CAR T Cells Efficient T cell stimulation and growth without anti-CD3 / anti- CD28 beads Simple, largely closed system production, amenable to cGMP operations Transportation logistics arranged for multi-center trials Apheresis product shipped to CMO Lymphocyte enrichment Retroviral vector transduction of CAR gene T cell expansion Harvest, cryopreserve product T cell activation with anti-CD3 Ab Ship product; ready for bedside use 6-8 day process

21. Anti-Tumor Activity Across Relapsed/Refractory B-cell Malignancies 32 patients enrolled (29 evaluable), including largest dataset of anti-CD19 CAR in lymphoma 16 patients still in response; 12 ongoing > 1 year 3 patients were re-treated after progression; all in ongoing response (17+ - 52+ months) Source: S:\CD19\Clinical Development\data\30NOV2014\derived Kochenderfer Blood 2012; Kochenderfer JCO 2015; Kochenderfer ASH 2014

22. Scans from Dr. Rosenberg NCI Before Treatment Post Treatment Ongoing Complete Response 15+ months in a patient with chemo-refractory PMBCL A patient with recurrent DLBCL post-SCT treated with anti-CD19 CAR T cells Dramatic Response with Anti-CD19 CAR

23. Anti-CD19 Treatment Achieves Complete Responses in Heavily Pretreated Patients with ALL: NCI experience Lee et al Lancet 2015 78.8% 51.6% Median follow up = 10 mo

24. Compelling Evidence of Broad Anti-Tumor Activity in B Cell Malignancies 32 patients enrolled (29 evaluable), largest dataset of anti-CD19 CAR in lymphoma Response Rate 76% overall, 65% in DLBCL/PMBCL (n=17) 16 patients with ongoing response 12 patients with ongoing response over 1 year Emerging AE profile includes: –Transient cytokine release syndrome –Reversible neurotoxicity –B cell aplasia Ongoing clinical studies to optimize cell number and conditioning regimen Kochenderfer Blood 2012; Kochenderfer JCO 2015; Kochenderfer ASH 2014

25. Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B ‑ cell cancer with T cells expressing anti-CD19 chimeric antigen receptors Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46 Figure 4 Regression of adenopathy occurred in a patient with CLL after treatment with chemotherapy followed by an infusion of anti ‑ CD19 CAR T cells and IL ‑ 2 Parts a, b and c reproduced with permission from American Society of Hematology © Blood 119, 2709–2720 (2012)

26. Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B ‑ cell cancer with T cells expressing anti-CD19 chimeric antigen receptors Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46 Figure 3 Eradication of bone marrow and blood CLL cells occurred in a patient treated with chemotherapy followed by anti-CD19 CAR T cells and IL ‑ 2 Reproduced with permission from American Society of Hematology © Kochenderfer et al. Blood 119, 2709–2720 (2012)

27. Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B ‑ cell cancer with T cells expressing anti-CD19 chimeric antigen receptors Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46 Figure 2 Eradication of bone marrow lymphoma and normal B cells occurred after anti ‑ CD19 CAR T cell infusion The CD19 and CD79a panels of part a are reproduced with permission from American Society of Hematology © Kochenderfer et al. Blood 116, 4099–4102 (2010)

28. Study at a Glance KTE-C19-101 Protocol Key Eligibility Criteria Refractory DLBCL, PMBCL, TFL Stable disease or progressive disease as best response to most recent chemotherapy containing regimen Disease progression or recurrence less than or equal to 12 months of prior autologous SCT ECOG 0-1 Primary Endpoint Objective Response Rate Operations Phase 1: First Subject Enrolled by 1 st H2015 Total of approximately 120 pts Multi-center study (approximately 25 sites) Cohort 2: PMBCL and TFL (n=40) Cohort 1: DLBCL (n=72) DLBCL=Diffuse Large B-cell Lymphoma PMBCL=Primary Mediastinal B-cell Lymphoma TFL=Transformed Follicular Lymphoma ASCT=autologous stem cell transplant Phase 2 DLBCL, PMBCL, TFL Phase 1

29. Engineered Autologous T Cell Therapy: 2 Forms CAR-T vs T-Cell receptor T cells

30. CAR & TCR Platforms Redirecting Immune Cells Against Cancer Chimeric Antigen Receptor (CAR) Products T Cell Receptor (TCR) Products Targets molecules on the cell surface Targets molecules at or below the cell surface

31. Summary We have long understood the importance of the immune system in preventing and treating cancer through BMT We are now developing methodologies where our own T-cells can kill and cure our cancers if they can be modified to do so This therapy of the future is available today and is impressively curing come patients