Tumor Antigens in the Age of Engineered T cell Therapies September 30 th 2016 ESMO Preceptorship Course Amsterdam Carsten Linnemann, PhD Senior Scientist Kite Pharma EU B.V. Amsterdam
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Disclosure I am an employee at Kite Pharma EU B.V. with ownership of stock and stock options in Kite Pharma, Inc. (NASDAQ: KITE) 3
Overview of content Tumor antigens: 1. Concept & therapeutic relevance 2. Targeting tumor antigens with genetically engineered T cells Take-home message: Engineered T cell therapies against tumor antigens mark a new age of cancer treatment 4
Tumor antigens Concept & therapeutic relevance
Tumor antigens make tumors visible to the immune system Definition (one of many): component generated by tumor cells that can be targeted by an immune response Types of possible immune response: innate (Macrophages, NK cells, Neutrophils, etc.), antibody-mediated or T cell mediated Immune response against tumor antigen may be naturally occurring or induced therapeutically Focus for today: tumor antigens in the context of engineered T cell therapies 6
Discovery of the first tumor antigen recognized by T cells in humans Science 1991 Van der Bruggen et al provided a conceptual basis for immunotherapy: Autologous T cells recognize a gene product found on melanoma cells The novel gene family is shared between different tumors The gene is not found in normal tissue 7 Recognition of autologous tumor lines and engineered targets by autologous T cells Van der Bruggen et al., Science 1991 Vision: T cell based therapies eradicate tumor cells with high specificity and are applicable to large patient groups
T cells recognize different classes of tumorantigens Tumor antigen class Cell Lineage antigens Example MART-1 protein in melanoma Example references Kawakami et al. Proc Natl Acad Sci USA 1994 Coulie et al. J Exp Med 1994 Overexpressed antigens WT-1 in hematological cancers Bellantuono et al. Blood 2002 Cancer/Germline antigens NY-ESO-1 expression in melanoma Jäger et al. J Exp Med 1998 Gnjatic et al. Proc Natl Acad Sci USA 2004 8 Oncogenic virus proteins HPV E6/E7 proteins expressed in cervical and H&N cancer Altered proteins arising from tumor-specific mutations Recognition of patientspecific mutations in various cancers Nakagawa et al. J Infect Dis 1997 De Jong et al. Cancer Res 2004 Lennerz et al. Proc Natl Acad Sci USA 2005 Robbins et al. Nat Med 2013
Tumor antigens can be classified by 3 parameters Ideal tumor antigen for therapy Kvistborg et al., Curr Opin Immunol 2012 9
Mobilizing patient T cells against tumor-antigens can be highly effective in advanced cancer stages Example: Treatment of metastatic melanoma with Tumorinfiltrating lymphocyte (TIL) therapy Rosenberg et al., Nat Rev Cancer 2008 10
Mobilizing patient T cells against tumor-antigens can be highly effective in advanced cancer stages Example: Treatment of metastatic melanoma with a combination therapy of anti-pd1 and anti- CTLA-4 antibodies Larkin et al., N Engl J Med 2015 11 Drake et al. Nat Rev Clin Oncol 2014
Which tumor-antigens mediate cancer regression? Example: Monitoring of T cell responses against 145 melanoma-associated T cell epitopes in patients receiving anti-ctla4 therapy 12 Kvistborg et al., Sci Transl Med 2014
Which tumor-antigens mediate cancer regression? Example: Detection of a tumor mutation-specific T cell response in a melanoma patient receiving anti-ctla4 therapy van Rooij et al. J Clin Oncol 2013 13
Which tumor-antigens mediate cancer regression? Conclusion: Tumors are immunogenic and visible for T cells (at least in a number of cases) T cell responses against different classes of tumor antigens are frequently induced by immunotherapeutic interventions Perspective: Can we learn which tumor-antigens are truly driving cancer regression to develop even more effective therapies? 14
Mobilization of endogenous tumor reactive T cells is not always effective Global manipulation Endogenous T cell compartment Possible reasons for treatment failure Anti-tumor T cell response Absence of tumorspecific T cells Dysfunction of tumor-specific T cells Side-effects too strong 15 Can we develop even better T cell therapies by engineering Designer T cell responses against tumor antigens?
Tumor antigens Targeting tumor antigens with genetically engineered T cells
Engineering T cell responses by receptor transfer Introduction of a new T cell receptor can redirect T cells against any antigen of interest Offringa Science 2006 17
Targeting solid tumors with engineered T cells Example: Treatment of metastatic melanoma using T cells engineered with a NY- ESO-1 specific TCR gene 18 Robbins et al. Clin Cancer Res 2015 Robbins et al. J Clin Oncol 2011
Natural and designer receptors allow re-direction of T cells T Cell Receptor (TCR) Intracellular Targets Chimeric Antigen Receptor (CAR) Cell surface targets 19
Targeting B cell malignancies with engineered T cells Example: Treatment of B cell Chronic lymphocytic leukemia (B-CLL) using T cells modified with anti-cd19 specific CAR Bone marrow Blood Kochenderfer& Rosenberg Nat Rev Clin Oncol 2013 Kochenderferet al. Blood 2012 20
Kite Pharma Anti-CD19-CAR therapy in ongoing clinical trials Study Phase Indication Status ZUMA-1 Phase 2 Pivotal (N=112) DLBCL PMBCL TFL Enrollment Complete Interim Data * 2016 Primary Data 2017 ZUMA-2 Phase 2 Pivotal (N=70) MCL Enrolling Data 2017 ZUMA-3 Phase 1/2 Pivotal (N=75) Adult ALL Phase 1/2 Enrolling P2 Data 2017 ZUMA-4 Phase 1/2 Pivotal (N=75) Pediatric ALL Phase 1/2 Enrolling P2 Data 2017 Additional studies in FL, CLL, earlier lines of DLBCL, and combination studies starting in 2016 21 *If supported by data, plan to file Biologics License Application based on interim data
22 4 ongoing registration studies in >40 centers in the US
KTE-C19 to be provided through a state-of-the-art manufacturing facility In-house clinical manufacturing in full operation Commercial facility in close proximity to LAX airport Capacity to produce 4,000-5,000 patient therapies per year Modular design is scalable and cost effective Site to produce KTE-C19 and all TCR products 23
The future of engineered T cell therapies has started! Thank you very much for your attention Kite Pharma at ESMO Congress 2016 Ongoing Complete Remissions in Phase 1 of ZUMA-1: A Phase 1-2 Multicenter Study Evaluating the Safety and Efficacy of KTE-C19 (Anti- CD19 CAR T Cells) in Patients with Refractory Aggressive B Cell Non- Hodgkin Lymphoma (NHL) (F. Locke) Trials in Progress: ZUMA-1: A Phase 2 Multicenter Study Evaluating KTE- C19 (Anti-CD19 CAR T Cells) In Patients with Refractory Aggressive Non- Hodgkin Lymphoma (NHL) (Neelapu) Trials in Progress: ZUMA-2: A Phase 2 Multicenter Study Evaluating the Efficacy of KTE-CD19 (Anti-CD19 CAR T Cells) in Patients with Relapsed/Refractory Mantle Cell Lymphoma (R/R MCL) (M. Wang) Trials in Progress: ZUMA-3: A Phase 1/2 Multicenter Study Evaluating the Safety and Efficacy of KTE-C19 (Anti-CD19 CAR T Cells) in Adult Patients with Relapsed/Refractory B Precursor Acute Lymphoblastic Leukemia (R/R ALL) (B. Shah) OralPresentation #3047 10/7/16: 4:00-5:30 PM Trials in Progress Poster #3222 10/8/16 1:00 2:00 PM Trials in Progress Poster #3305 10/8/16 1:00 2:00 PM Trials in Progress Poster #3713 10/8/16 1:00 2:00 PM 24