Chimeric Antigen Receptors (CAR)

Transcription

1 CAR Therapy In CLL

2 Chimeric Antigen Receptors (CAR) 4-1BB (CD137) Costimulatory Domains: PENN: 4-1BB MSKCC: CD28 USCD: CD28

3 Porter, D.L. et al Sci Trans Med 7:1-12, 2015 CD19 CAR T Cell Therapy For CLL Patients At U Penn Characteristics Number Number of Patients Treated 14 Median Age at Infusion (range) 66 (51-78) Male 12 (85% of total) Median Number Prior Therapies (range) 5 (1-11) Cases With del(17p) 6 (43% of total) Cases with Unmutated IGHV 4 (29%)

4 CD19+ve Heme Malignancy Eligibility Tumor Restaging 6 months post infusion Monthly observation / monitoring 6 months post infusion Observation / monitoring Quarterly Lentiviral observation/monitoring vector safety assessments to year annually 2 Roll over to destination protocol for 15 year f/u for monitoring for delayed AEs related to gene transfer CART-19 T Cells Manufacture / Cryopreservation PBMC PBMC Baseline Assays Endpoint Assays FDA Approved Therapy Monitor for recurrence Wk - 4 ChemoRx ~d -4 CART-19 Infusions -19 Infusion Day 0,1,2 (split dose) Day 11 (full dose if available) Wk + 4 Apheresis #1 (10-15L) Assess Response Apheresis #2 (2L) Incurable with standard therapies

5 Treatment Of CLL Patients With CD19 CAR at U Penn ID Total T cells Infused x 10 8 CAR T cells Infused x 10 8 Peak CAR T Expansion (%CD3) Best Overall Response F/U or Relapse (mo) N/A CR N/A CR N/A PR PR NR NR CR CR PR <0.1 NR NR NR PR NR 3 Porter, D.L. et al Sci Trans Med 7:1-12, 2015

6 CD19 CAR T cell Expansion In 1 st Year Porter, D.L. et al Sci Trans Med 7:1-12, 2015

7 No acute infusion toxicities Toxicities Most patients experience delayed, grade IV cytokine release syndrome (CRS) High fevers Nausea Myalgias Capillary leak syndrome Hypoxemia Hypotension Tocilizumab (anti-il-6r) can be used for grade IV CRS causing lifethreatening hemodynamic/respiratory instability Porter DL, et al. Blood 122:873 ASH Proceedings 2013, 2012

8 Progression Free Survival S/P CD19 CAR T Cell Therapy In CLL At U Penn Porter, D.L. et al Sci Trans Med 7:1-12, 2015 Median PFS 6 months

9 Persistence of CD19 CAR T cells In Patients Who Achieved CR at U Penn Porter, D.L. et al Sci Trans Med 7:1-12, 2015

10 Outcome Of CD19 CAR T-cells In CLL Overall response rates 40% Patients with CR had no minimal residual disease (MRD) Responding patients had persistence of CAR T cells more than several months post-rx Patients with persistence of CAR T cells had Persistent absence of normal B cells Profound hypogammaglobuinemia IgM and IgA levels of 0 Required maintenance therapy with IVIg Porter DL, et al. Blood 122:873 ASH Proceedings 2013, 2012

11 Forest Plot Of Response Rates And CI In Patients with CLL Or Lymphomas In Other CD19 CAR T cell Therapy Trials CLL ES (95% CI) Other Lymphomas ORR 60% for CLL ORR 40% Adapted From Zhang T, et al. Oncotarget 2015 Overall Response Rate

12 Some patients vaccinated with autologous CLL cells made anti- autoantibodies Is expressed on CLL cells but not normal adult cells except for hematogones provides a growth/survival advantage for CLL cells in vitro and in vivo Some, but not all, patients with anti- autoantibodies made anti- with functional activity Fukuda, T, et al Blood, 2004,104 (11): 772 Fukuda T, et al Proc Natl Acad Sci USA, 2008, 105: Broome HE, Leuk Res. 2011,35(10): Widhopf, G, et al PNAS 111:793, 2014

13 Is Expressed During Embryogenesis Receptor tyrosine kinase-like orphan receptor 1 Evolutionarily conserved, type-i membrane protein Has a tyrosine-kinase-like and Ser/Thr-rich domains Expressed primarily during embryogenesis Green JL, et al. Trends Cell Biol. 2008,18: Matsuda T, et al. Mech Dev. 2001,105:153-6.

14 Is Not Expressed By Normal Post-Partum Tissues Hematogones CD10 + CD19 + CD34 - However, is expressed on hematogones: Rare subpopulation of precursor B cells CD45 -dim CD10 + CD19 + blasts similar to pre-b ALL 0.25% of normal marrow Increased in pediatric marrow S/P myeloablative Rx Fukuda, T, et al Blood, 2004,104 (11): 772 Fukuda T, et al Proc Natl Acad Sci USA, 2008, 105: Broome HE, Leuk Res. 2011,35(10):1390-4

15 Restricted Expression Of On CLL B-cells 2004 ASH Annual Meeting. Blood, 2004,104 (11): , PNAS, 105(8): Is expressed on CLL cells but not on normal B-cells

16 Confidential Chimeric Anti- T-cell Receptors Anti- mab CLL cell

17 Confidential Sustained Numberic Expansion Of -specific CAR+ T cells on aapc Deniger, D.C. et al PLoS One June 2015

18 Confidential Cytolytic Specificity of Anti- CD19 or Anti- CAR T cells CD19-/+ CD19 CD19+/ + CD19 CD19-/- CD19+/- CD19 CD19 Deniger, D.C. et al PLoS One 2015

19 Confidential In Vivo Clearance Of + Tumor Cells By -Specific CAR+ T cells Deniger, D.C. et al PLoS One June 2015