CAR T-Cell Therapy: Efficacy, Treatment, Access Michael I. - PowerPoint PPT Presentation

CAR T-Cell Therapy: Efficacy, Treatment, Access Michael I. Nishimura, Ph.D. Professor of Surgery and Vice Chair for Surgery Research Stritch School of Medicine Tumor Immunology & Immunotherapy Program Cardinal Bernardin Cancer Center Loyola University Chicago

Disclosures  Basic, Translational, Pre-clinical and Clinical  Basic, Translational and Pre-clinical studies studies supported in total or in part by following supported in part by the following NIH grants: Department of Defense grant:  R01 CA90873 (MN, inactive)  Idea Development Award 110036 - W81XWH-  R01 CA102280 (MN, inactive) 12-1-0185 (ICL, inactive)  R01 CA107947 (MN, inactive)  Pre-clinical studies supported in part by a  R01 CA107947 S1, ARRA Supplement (MN, inactive) grant from the Falk Foundation:  P01 CA154778 (MN, inactive)  Catalyst Research Program Award (MN,  R21 CA153789 (MN, inactive) inactive)  R21 AR056624 (SM, inactive)  Transformtional Research Award (MN, active)  R01 CA138930 (SM, inactive)  R01 AR054749 (ICL, inactive)  rhIL-15 and other cytokines for the  R01 AR057643 (ICL, inactive) preclinical studies and clinical trials  R01 AI129563 (BB & MN MPI, active) generously provided by the Biological  Lentivirus vector development studies supported Resources Branch, DCTD, NCI by subcontracts from the Lentigen Corp.  Conflict of Interest  R43 CA126461 (BD, inactive)  Consulted for Sanofi S.A.  R44 CA126461 (BD, inactive)  Chair SAB for T-Cure  CD19 CAR studies supported by a generous gift  SAB for Moderna Therapeutics from the Leukemia Research Foundation  SAB for Anocca, AB

Acknowledgements Nishimura Lab Loyola University Northwestern Univ. Colorado Denver Glenda Callender Medical Center University Hugo Rosen Timothy Clay Lucy Golden-Mason Jose Geuvara I. Caroline Le Poole David Cole Rachel Leistikow Phong Le Emilia Dellacecca Mary Custer Rachel H. McMahan Jonathan Eby Clinical Team Annika Dalheim Jared Klarquist Joseph Clark Lentigen Corporation Matthew DeJong Jeffrey Mosenson Constantine Godellas Telma da Palma Boro Dropulic Nasheed Hossain Erica Fleming-Trujillo Heather Embree Med. Univ. South Carolina Kelli Hutchens Kendra Foley Rimas Orentas Shikhar Mehrotra Ann Lau Clark Elizabeth Grindstaff Amir Al Khami Karen Pilman BRB, NCI, NIH Elizabeth He Wood Diane Palmer Navtej Kaur Barbara Kaplan Jason Yovandich Pravin Kesarwani Mala Parthasarathy Aaron Lesher Stephen Creekmore Osama Naga Courtney Wagner Mingli Li Jodi Seiser Gretchen Lyons Shahid Hussain University of Utah Patrick Stiff Mark McKee Keisuke Shirai Brian Evavold Tamson Moore Earle Chile Research Elizabeth Garrett-Mayer Elizabeth Motunrayo Kolawole Kelly Moxley Institute David Murray University of Notre Dame Brendan Curti Hakan Norell Karolinska Institute Brian Baker Christopher Fountain Jeffrey Roszkowski Rolf Kiessling Fernando Huyke Pablo Sanez-Lopez Larrocha Bernard Fox Yuneng Mao Lance Hellman Gina Scurti Tarsem Moudgil Eiji Miyahara Nishant Singh Thomas Smith Walter Urba Yuan Wang Timothy Spear NHLBI, NIH Natalie Spivey Mallory Thomas Richard Childs David Yu Adriana Byrnes Siao-Yi Wang Elena Cherkasova Rosa Nadal Rios

Objectives 1) Brief History and Rationale for Adoptive T-Cell Therapy for Cancer 1. Overview of Cancer Immunotherapy 2. Adoptive Cell Transfer Therapy a) Stem Cell Transplantation b) Tumor Infiltrating Lymphocytes (TIL) 3. Lymphodepletion 2) Reasons for Using Genetically Modifying T Cells 1. Altering Antigen Specificity a) Types of receptors used for gene therapy b) Chimeric Antigen Receptors i. Evolution/Generations of CAR ii. Targets for CAR Therapy iii. Why CD19? iv. Clinical Outcomes c) T Cell Receptors i. Targets ii. Clinical Outcomes 3) Gene Modified T Cells – Loyola Experience 1) Manufacture, purification, and tracking of transduced T cells in humans 2) Clinical trial Design 3) TCR gene modified T cell clinical trial results

Immunotherapy For Cancer – The immune system has evolved to enable us to fight various pathogens (virus, bacteria, fungus, etc.) – The immune system must first know what is “normal self” before it can know what should be attacked – Since cancer is derived from normal cells, with few exceptions, the immune system is not very efficient at recognizing and eliminating cancer cells naturally.

Immunotherapy For Cancer Goal: To boost the host anti-tumor immune response leading to regression of widely disseminated disease and prevention of recurrent disease. Approaches: 1) Cytokines (IL-2, IFN-g, GM-CSF, and others) 2) Vaccines (Peptide, recombinant protein, whole cell, cell extract, dendritic cell, recombinant virus, and others) 3) Monoclonal antibodies a) Therapeutic b) Blocking 4) Adoptive cell transfer 1) LAK 2) T cells 3) NK cells 4) Stem cell transplantation (autologous, allogeneic, cord blood)

Immunotherapy For Cancer

Allogeneic Stem Cell Transplant Rezvani et al. Bone Marrow Transplant. 2015 From Winthrop P. Rockefeller Cancer Institute Web Site

TIL Therapy Tumor Infiltrating Lymphocytes: – T cells are chemotactic and can migrate to sources of antigen – Tumor-reactive T cells can accumulate in tumor lesions – TIL cultures can recognize many HLA matched tumors or only the autologous tumor – TIL can be expanded from some tumors to therapeutic numbers Rosenberg et. al., J Natl Cancer Inst ;85:622-632, 1993

TIL Therapy Total number Objective response rate Treatment of patients CR PR CR + PR IL-2 134 9 14 23 (17%) TIL + IL-2 86 5 24 29 (34%) Prior IL-2 28 1 8 9 (32%) No prior IL-2 58 4 16 20 (34%) Rosenberg et al., JNCI 86:1159-1166, 1994

Lymphodepletion/Homeostatic Proliferation Homeostasis: 1) The hematopoietic system regulates the number of each cell type in the blood, lymphoid organs, and bone marrow. 2) Depletion of one or more of these hematopoietic cell types leads to mobilization of the progenitors to restore the population to normal. Lymphodepletion: 1) Chemotherapy and/or total body irradiation can destroy the hematopoietic system leading to homeostatic proliferation of the depleted cell types.

Lymphodepletion Prior to T Cell Infusion Advantages: 1) The cytokines and other factors that drive the hematopoietic system to regenerate also favor the expansion of the adoptively transferred T cells, both normal and gene modified. 2) Suppressor cells derived from the hematopoietic system (Treg, myeloid derived suppressor cells, etc.) are eliminated. Disadvantages: 1) Chemotherapy and/or total body irradiation leads to immune suppression. 2) Chemotherapy and/or total body irradiation has toxicities.

Adoptive Cell Therapy TIL with Prior Lymphodepletion Rx CR NMA 21/43 (49%) +2Gy 13/25 (52%) +12 Gy 18/25 (72%) Rosenberg et al, Clin Can Res, 2011

Common Hurdle for Adoptive Cell Therapy Facts: 1) Tumor reactive T cells can be difficult to obtain from all patients. 2) TIL therapy requires a resectable tumor. 3) Expansion of T cells to therapeutic numbers takes time. 4) Many cancers progress rapidly such that in many cases the patient can be too sick for adoptive T cell therapy. Conclusions: 1) Despite the effectiveness of adoptive T cell transfer, this approach is only practical for some patients.

Gene Modified T Cell Therapy Altering Antigen Specificity Antigenic Peptide Surface Antigen β 2 M MHC Class I α β TCR CD3 Tumor cell T-cell

Gene Modified T Cell Therapy Altering Antigen Specificity

Gene Modified T Cell Therapy Altering Antigen Specificity – The Receptors Chimeric Chimeric Activating Immunoglobulin Chimeric Single Chain Ligand T Cell Receptor Receptor Receptor Antibody Receptor L H CD3 a b V NKG2D-CD3 z IL-13-CD3 z scFv-Fc g scFv-CD3 z e e g z z d C

Gene Modified T Cell Therapy Advantages and Disadvantages of CAR Therapy Advantages Disadvantages 1) CAR T cells can be generated for 1) CAR T cells can only recognize any patient that has T cells in a antigens expressed on the target short period of time (~10-20 days) cell surface 2) Recognizes antigens in an MHC- 2) Associated with serious side unrestricted fashion effects, such as targeting normal cells expressing the target antigen 3) Supersensitive, requires very low antigen expression 3) Risk of Cytokine Release Syndrome (CRS) 4) Can target non-protein antigens 5) Can engineer functional CD4 + and CD8 + T cells and non-T cells.

Gene Modified T Cell Therapy Altering Antigen Specificity - CAR α β TCR V L V H CD3 CAR CD3ζ pA T-cell V L V H CD3ζ LTR LTR y + Linker

Gene Modified T Cell Therapy Altering Antigen Specificity - CAR Antigenic Peptide Surface Antigen β 2 M MHC Class I α β TCR CD3 Tumor cell CAR T-cell

Gene Modified T Cell Therapy Altering Antigen Specificity - CAR Antigenic Peptide Surface Antigen β 2 M MHC Class I α β TCR Tumor cell CD3 T-cell

Gene Modified Cell Therapy Evolution of CAR α β TCR CD3 OX40 CD28 CD28 4-1BB z chain ICOS OX40 T-cell z chain 4-1BB ICOS z chain Third generation First generation Second generation CAR CAR CAR