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-CD19 CAR-T cell

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.

Engineered Autologous T Cell Therapy: 2 Forms

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

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: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:10.1038/nrclinonc.2013.46

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)

CD19-specific scFv Co-stimulatory domain: CD28 Essential signaling domain: CD3

z

of TCR

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)

CD19-specific scFv Co-stimulatory domain: CD28 Essential signaling domain: CD3

z

of TCR

Streamlined Manufacturing Process for anti-CD19 CAR T Cells

Apheresis product shipped to CMO Lymphocyte enrichment

• Efficient T cell stimulation and growth

without anti-CD3 / anti CD28 beads T cell activation with anti-CD3 Ab

• Simple, largely closed system production, amenable to cGMP operations

Retroviral vector transduction of CAR gene

• Transportation logistics arranged for multi-center trials

T cell expansion Harvest , cryopreserve product Ship product; ready for bedside use

Anti-Tumor Activity Across Relapsed/Refractory B-cell Malignancies • 32 patients enrolled (29 evaluable), including largest dataset of anti-CD19 CAR in lymphoma

Tumor Type (n evaluable)

Any (29) DLBCL/PMBCL (17) CLL (7) Indolent NHL (5)

Overall Response Rate

76% 65% 86% 100%

Complete Response Rate

38% 35% 57% 25% • 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

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

Anti-CD19 Treatment Achieves Complete Responses in Heavily Pretreated Patients with ALL: NCI experience 78.8%

Intention-to-Treat Analysis

Complete Response MRD negative Complete Response Allogeneic Transplant Relapse Post Allogeneic Transplant

ALL (N=20)

14 (70%) 12 (60%) 10 (50%) 0 (0%) 51.6% Median follow up = 10 mo Lee et al Lancet 2015

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

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: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: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) 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) 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

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) Phase 1 DLBCL, PMBCL, TFL 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