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

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

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

7. Schematic of how the Immune System works

8. Schematic of the Immune system

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

10. Lymph nodes modulate the immune system

11. The Ying and Yang of the Immune System

12. 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

13. Targets for Immunotherapy are on the cell surface

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

15. Immune responses often require both B and T Lymphocytes

16. How T-cells can kill cancer

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

18. 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

19. DISCLAIMER / FORWARD LOOKING STATEMENTS
I am neither an employee nor representative of Kite Pharma, Inc. (“Kite”).  Any statements made by me during this presentation are mine alone, have not been authorized or otherwise endorsed by Kite and are not to be attributed to Kite.  As a courtesy as the trial sponsor of KTE-C19-101, Kite has provided publicly available information for my presentation.

20. Engineered Autologous T Cell Therapy: 2 Forms

21. 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

22. Figure 1 Chimeric antigen receptors
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: /nrclinonc

23. 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
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: /nrclinonc

24. Kite/NCI Study of anti-CD19 CAR in Relapsed/Refractory B-Cell Malignancies
Phase 1/2 study investigating safety, feasibility, and efficacy
Refractory/recurrent disease incurable by standard therapy
Evolving treatment protocol (conditioning/dosing) VH VL
CD19-specific scFv
Co-stimulatory domain: CD28
Essential signaling domain: CD3z of TCR

25. Kite/NCI Study of anti-CD19 CAR in Relapsed/Refractory B-Cell Malignancies
Phase 1/2 study investigating safety, feasibility, and efficacy
Refractory/recurrent disease incurable by standard therapy
Evolving treatment protocol (conditioning/dosing) VH VL
CD19-specific scFv
Co-stimulatory domain: CD28
Essential signaling domain: CD3z of TCR

26. 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
T cell activation with anti-CD3 Ab
Retroviral vector transduction of CAR gene
T cell expansion
6-8 day process
Harvest , cryopreserve product
Ship product; ready for bedside use

27. 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 ( months)
Tumor Type
(n evaluable)
Overall Response Rate
Complete Response Rate
Any (29)
76%
38%
DLBCL/PMBCL (17)
65%
35%
CLL (7)
86%
57%
Indolent NHL (5)
100%
25%
Source: S:\CD19\Clinical Development\data\30NOV2014\derived
Kochenderfer Blood 2012; Kochenderfer JCO 2015; Kochenderfer ASH 2014

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

29. Intention-to-Treat Analysis
Anti-CD19 Treatment Achieves Complete Responses in Heavily Pretreated Patients with ALL: NCI experience
78.8%
51.6%
Median follow up = 10 mo
Intention-to-Treat Analysis
ALL (N=20)
Complete Response
14 (70%)
MRD negative Complete Response
12 (60%)
Allogeneic Transplant
10 (50%)
Relapse Post Allogeneic Transplant
0 (0%)
Lee et al Lancet 2015

30. 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

31. Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46
Table 2 Summary of the first patients treated on the NCI adult autologous anti‑CD19 CAR trial
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: /nrclinonc

32. 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)
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: /nrclinonc

33. 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)
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: /nrclinonc

34. 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)
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: /nrclinonc

35. 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 1stH2015
Total of approximately 120 pts
Multi-center study (approximately 25 sites)
Phase 1
Phase 2
DLBCL, PMBCL, TFL
Cohort 1: DLBCL
(n=72)
Cohort 2: PMBCL and TFL
(n=40)
DLBCL=Diffuse Large B-cell Lymphoma
PMBCL=Primary Mediastinal B-cell Lymphoma
TFL=Transformed Follicular Lymphoma
ASCT=autologous stem cell transplant