The Role of Immunotherapy for the Treatment of
- Slides: 35
The Role of Immunotherapy for the Treatment of Hematologic Malignancies Patrick Stiff MD Coleman Professor of Oncology Loyola University Medical Center 708 -327 -3216
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
History of Immunotherapy for Hematologic Malignancies
Your Immune system is an organ in your body
The Bone Marrow Plays an Important Role in the Immune System
Schematic of how the Immune System works
Schematic of the Immune system
For cancer, T cells do most of the work in preventing and eliminating disease
Lymph nodes modulate the immune system
The Ying and Yang of the Immune System
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
Targets for Immunotherapy are on the cell surface
In cancer the immune system does not recognize the specific antigens on the tumor cells No response means no cancer cell killing
Immune responses often require both B and T Lymphocytes
How T-cells can kill cancer
Can the Immune Defect be Repaired: Dendritic Cell Vaccines Dendritic Cell Stimulation doe outside the body: re-education Cancer Cell
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-CD 19 CAR-T cell
DISCLAIMER / FORWARD LOOKING STATEMENTS 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-C 19 -101, Kite has provided publicly available information for my presentation. I
Engineered Autologous T Cell Therapy: 2 Forms
CAR & TCR Platforms Redirecting Immune Cells Against Cancer Chimeric Antigen Receptor (CAR) Products Targets molecules on the cell surface T Cell Receptor (TCR) Products Targets molecules at or below the cell surface
Figure 1 Chimeric antigen receptors Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B‑cell cancer with T cells expressing anti-CD 19 chimeric antigen receptors Nat. Rev. Clin. Oncol. doi: 10. 1038/nrclinonc. 2013. 46
Figure 5 A schematic of the current approach to anti‑CD 19 CAR T cell therapy is shown Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B‑cell cancer with T cells expressing anti-CD 19 chimeric antigen receptors Nat. Rev. Clin. Oncol. doi: 10. 1038/nrclinonc. 2013. 46
Kite/NCI Study of anti-CD 19 CAR in Relapsed/Refractory B-Cell Malignancies • Phase 1/2 study investigating safety, feasibility, and efficacy • Refractory/recurrent disease incurable by standard therapy VL VH • Evolving treatment protocol (conditioning/dosing) CD 19 -specific sc. Fv Co-stimulatory domain: CD 28 Essential signaling domain: CD 3 z of TCR
Kite/NCI Study of anti-CD 19 CAR in Relapsed/Refractory B-Cell Malignancies • Phase 1/2 study investigating safety, feasibility, and efficacy • Refractory/recurrent disease incurable by standard therapy VL VH • Evolving treatment protocol (conditioning/dosing) CD 19 -specific sc. Fv Co-stimulatory domain: CD 28 Essential signaling domain: CD 3 z of TCR
Streamlined Manufacturing Process for anti-CD 19 CAR T Cells Apheresis product shipped to CMO Lymphocyte enrichment T cell activation with anti-CD 3 Ab Retroviral vector transduction of CAR gene • Efficient T cell stimulation and growth without anti-CD 3 / anti. CD 28 beads • Simple, largely closed system production, amenable to c. GMP operations • Transportation logistics arranged T cell expansion Harvest , cryopreserve product Ship product; ready for bedside use for multi-center trials 6 -8 day process
Anti-Tumor Activity Across Relapsed/Refractory B-cell Malignancies • 32 patients enrolled (29 evaluable), including largest dataset of anti -CD 19 CAR in lymphoma Tumor Type (n evaluable) Overall Response Rate Complete Response Rate Any (29) 76% 38% DLBCL/PMBCL (17) 65% 35% CLL (7) 86% 57% 100% 25% Indolent NHL (5) • 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: CD 19Clinical Developmentdata30 NOV 2014derived Kochenderfer Blood 2012; Kochenderfer JCO 2015; Kochenderfer ASH 2014
Dramatic Response with Anti-CD 19 CAR Before Treatment Post Treatment A patient with recurrent DLBCL post-SCT treated with anti-CD 19 CAR T cells Ongoing Complete Response 15+ months in a patient with chemo-refractory PMBCL Scans from Dr. Rosenberg NCI
Anti-CD 19 Treatment Achieves Complete Responses in Heavily Pretreated Patients with ALL: NCI experience Intention-to-Treat Analysis ALL (N=20) 78. 8% Complete Response 14 (70%) MRD negative Complete Response 12 (60%) Allogeneic Transplant 10 (50%) Relapse Post Allogeneic Transplant Lee et al Lancet 2015 0 (0%) 51. 6% Median follow up = 10 mo
Compelling Evidence of Broad Anti-Tumor Activity in B Cell Malignancies • 32 patients enrolled (29 evaluable), largest dataset of anti-CD 19 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
Table 2 Summary of the first patients treated on the NCI adult autologous anti‑CD 19 CAR trial Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B‑cell cancer with T cells expressing anti-CD 19 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‑CD 19 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-CD 19 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-CD 19 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-CD 19 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‑CD 19 CAR T cell infusion The CD 19 and CD 79 a 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-CD 19 chimeric antigen receptors Nat. Rev. Clin. Oncol. doi: 10. 1038/nrclinonc. 2013. 46
Study at a Glance KTE-C 19 -101 Protocol Key Eligibility Criteria • Refractory DLBCL, PMBCL, TFL Phase 1 • Stable disease or progressive disease as best response to most DLBCL, recent chemotherapy containing PMBCL, TFL 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. H 2015 • Total of approximately 120 pts • Multi-center study (approximately 25 sites) Phase 2 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
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