Looking at the Future of CAR T-Cell Therapy: Combinations and Beyond. David G. Maloney, MD, PhD

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2 Looking at the Future of CAR T-Cell Therapy: Combinations and Beyond David G. Maloney, MD, PhD

3 Novel Approaches to CAR T-Cell Therapy: Combinations and Beyond Fred Hutch Cancer Research Center David G. Maloney, MD, PhD Member-FHCRC, Professor-University of Washington Medical Director Bezos Family Immunotherapy Clinic Norma and Leonard Klorfine Endowed Chair for Clinical Research

4 Disclosures Juno Therapeutics/Celgene: research funding Advisory board participation Celgene/Juno Roche/Genentech Kite Pharma/Gilead Novartis

5 CD19 Directed CAR T-Cell Therapy: Current Paradigm Collection of cells by resting state leukapheresis T cells from patients often compromised in number or subsets Cell manufacture (2-4 weeks) May include isolation of T-cell subsets T-cell stimulation Transduction with viral vector (gamma or lentivirus containing the CAR) Cell growth to target numbers (generally 1-2 million/kg) Pass release criteria for safety and FDA specifications Lymphodepletion chemotherapy Given to deplete endogenous T cells and increase engraftment of CAR-T Generally with cyclophosphamide and fludarabine CAR T-cell infusion (usually cryopreserved and contain low level DMSO) Monitoring for CRS and neurotoxicity

6 Current CD19 CAR-T Toxicity: CRS and Neurotoxicity Cytokine release syndrome (CRS) Early hemodynamic changes associated with capillary leak High fever, hypotension, tachycardia, decrease in protein/albumin, weight gain Coagulopathy and increased transfusion requirements Increased risk of hepatic and renal dysfunction Elevated AST, ALT, bilirubin, alkaline phosphatase, creatinine Cardiac arrhythmias Elevated serum cytokines (IL-6 and many others) Elevated serum CRP and ferritin Usually responds to tocilizumab ± dexamethasone Neurotoxicity Often presents with word finding difficulties and can progress to coma May be associated with cerebral edema or seizures Often onset 2-4 days after CRS Generally reversible, but may be fatal Not clear if treatments are effective (usually treated with steroids)

7 How to Improve Outcome? Smarter, controllable CAR-T cells Current CAR-T cells + additional agents Checkpoint blockade with PD-1 or PD-L1 antibodies Ibrutinib Universal CAR-T cells off the shelf UCART19 Other CAR constructs NK-T CAR

8 Smarter, Controllable CAR-T cells

9 Chimeric Antigen Receptor Design and Evolution Fesnak AD, June CH, Levine BL, Nature Reviews, 2016

10 New Chimeric Antigen Receptor Models and Concepts Fesnak AD, June CH, Levine BL, Nature Reviews, 2016

11 New Chimeric Antigen Receptor Models and Concepts, cont. Fesnak AD, June CH, Levine BL, Nature Reviews, 2016

12 Controlling CARs by Boolean Logic Circuits Chang ZL and YY Chen, Trends in Mol Med, 2018

13 Controllable CAR: SUPRA CAR Cho, JH et al, Cell, 2018

14 Controllable CAR: SUPRA CAR, cont. Cho, JH et al, Cell, 2018

15 Controllable CAR: SUPRA CAR, cont. Cho, JH et al, Cell, 2018

16 Controllable CAR: SUPRA CAR, cont. Cho, JH et al, Cell, 2018

17 Controllable CAR: SUPRA CAR, cont. Cho, JH et al, Cell, 2018

18 CAR-T cell Combinations

19 ZUMA-1: Preliminary Analysis of B-Cell and Immune-Related Molecules at Progression by Central Review Progression Biopsies N=21 CD19 (n=21) CD19+ 14/21 (67) CD19-7/21 (33) PD-L1 (n=19) PD-L1+ 9/14 (64) PD-L1 4/14 (29) PD-L1 N/E 1/14 (7) PD-L1+ 4/7 (57) PD-L1-2/7 (29) PD-L1 N/E 1/7 (14) Post-progression tumor biopsies (21 evaluable patients) - 33% were CD19- by central review - 62% were PD-L1+ by central review Baseline and post-progression samples were not obtained from the same lesions. CD19 H-score of 0 was determined negativity. H-scores 1 were considered positive. H-score was calculated as a product of IHC intensity (scale 1-3) multiplied by the percentage of tumor cells at a given intensity (0%-100%). PD-L1 status was determined by the percentage of tumor cells with any membrane staining above background or by the percentage of tumor-associated immune cells with staining at any intensity above background. IHC, immunohistochemistry; N/E, not evaluable; PD-L1, programmed cell death-ligand 1. Neelapu et al, ASH 2017, Abstract 578

20 ZUMA-1: Representative Immunohistochemistry of B-Cell and Immune-Related Molecules Patient Summary CD19 at Baseline CD19 at PD PD-L1 at PD BOR: PR BL: CD19+ PD: CD19 PD-L1+ BOR: PR BL: CD19+ PD: CD19+ PD-L1+ All images at 40 magnification. Scale bar indicates 60 µm. BL, baseline; BOR, best objective response; PD, progressive disease; PD-L1, programmed cell death-ligand 1. Neelapu et al, ASH 2017, Abstract 578

21 JCAR017 Re-expansion and Tumor Regression Following Incisional Tumor Biopsy Case Report 68-yo woman with refractory DLBCL Flu/Cy lymphodepletion JCAR017 CD19 specific CAR-T cell infusion no CRS or NT 1 month PET negative CR, including brain mass 3 month extra cranial PD Incisional biopsy Re-expansion of CAR-T and remission Pre CAR-T 1 mo post CAR-T, CR 3 mo post CAR-T, PD Post-incisional Bx, CR Abramson J et al, NEJM, 2017

22 Improving CD19 CAR T-Cell Therapy Decrease tumor escape mechanisms CD19 negative relapse Target additional tumor associated antigens Multiple CAR-T products Cells with multiple CAR-receptors Block PD-1/PD-L1 signaling Combine CAR-T with PD-1 or PD-L1 mabs Knock out PD-1 in the CAR-T cells (armored CARS)

23 CAR-T Cell Combinations: Checkpoint Inhibitor mabs PD-L1 tumor expression Case Report 35-yo man with refractory PMBCL Cy x 6 doses for lymphodepletion CART x 10 6 /kg Day 26 PD with symptoms, increased mass Rx: Pembrolizumab 2 mg/kg Activation of CAR-T cells and tumor reduction Chong EA, Schuster SJ, Blood, 2017

24 Ongoing Clinical Trials of Anti CD19 CAR-T and Checkpoint mabs Multiple ongoing clinical trials (few highlighted here) Axicabtagene ciloleucel and atezolizumab (anti-pd-l1) Full dose mab evaluated from day 21 to day 1 post CAR-T in phase 1 (3 x 3 design, n=9) mab q 3 weeks x 4 doses Well tolerated, no obvious increase CRS or NT (ASH 2017) Phase 2 enrolling JCAR014 and durvalumab (FHCRC #9457) Evaluating post-treatment durvalumab (q month) Evaluating pre-treatment (d -1) durvalumab followed by posttreatment durvalumab for up to 1 year JCAR017 and durvalumab (enrolling)

25 Ibrutinib May Improve CAR-T Cell Function and Decrease CRS Pts with CLL have defective T cells from CLL exposure Ibrutinib treated patients have Improved CAR-T generation and expansion Better T-cell function Less CRS Better clinical activity from CAR-T? Ibrutinib improves CAR-T expansion Fraietta JA et al. Blood 2016;127:

26 Ibrutinib Potentiates CTL019 Cell Expansion and Engraftment, Which Correlates With Clinical Response Fraietta JA et al. Blood 2016;127:

27 Universal CAR-T? Autologous CAR-T Approach Patient specific therapy Pts have compromised T cells Autologous leukaphereses Requires 3-4 weeks for production Less immune rejection No risk of GVHD Cells may persist a long time Universal CAR-T Off the shelf universal donor/cell line Cells with no prior exposure to cytotoxins Off the shelf Off the shelf, could be pre-shipped to center Immune rejection requires additional engineering Risk of GVHD requires additional engineering Shorter persistence

28 Engineered Off the Shelf CAR-T Cells CS1 o r UCART Attributes TALEN CAR expression to redirect T-cells to tumor antigens Suicide gene (RQR8) for safety Inactivation of the TCRa constant gene (TRAC) eliminates the TCR and minimizes risk of GvHD Donor blood cells TALEN mediated gene editing to enable an allogenic approach Product Additional gene editing to Facilitate continued lymphodepletion (CD52,dCK) Prevent CAR-T cell cross-reactivity (CS1/SLAMF7) To checkpoint pathways inhibition (PD1,Lag3, ) To delay rejection by T-cells (MCH-I inactivation)

29 UCART19* Initial Proof of Concept in ALL 1 st patient dosed in June 2015 (compassionate) Phase 1 trials (US/EU) started in June 2016 Tumor cell 4 recruiting centers (EU and US) 14 patients treated disclosed (7 adults and 7 pediatric)** Results in line with early autologous CAR-T phase 1 results published in past years UCART19 Patients failed >5 lines of treatment, including autologous CAR-T Ph1b expansion at U Penn and MD Anderson * UCART19 is exclusively licensed to Servier and under a joint clinical development program between Servier and Pfizer ** Including compassionate

30 Phase 1 pediatric B-cell ALL trial UCART19 Clinical Trial Results Used as a bridge to allogeneic HCT (MRD negative remission) N=6, age 3.75 y (range y) 5 patients had < 10% BM blasts Flu/Cy/alemtuzumab lymphodepletion Toxicity CRS in all patients, ( 1 grade 1, 4 grade 2, 1 grade 3) NT, 2 grade 1, 1 grade 2 3 prolonged cytopenia 1 grade 1 cutaneous GVHD 5 had viral infections (adeno, CMV, metapneumo, BK) 5/6 MRD negative (flow), 3/6 PCR (d28-42) and 5 received allogenic HCT (d49-62) Conditioning Flu/TBI ± Cy/ATG and all received rituximab 3/5 alive (2 PD and 1 TRM [infections]) 2 in MRD negative remission (10 and 11 months) Veys P, abstract/presentation at EBMT, 2018

31 Universal CD19 CAR-T: FT819 Manufactured from an induced pluripotent stem cell Unlimited self renewal CAR construct introduced into the TRAK locus in single pluripotent cell Lacks endogenous TCR Uniform CAR expression Better elimination of tumor (mouse) c/w conventional CAR-T Second targeting receptor containing CD16 Fc Binds to mabs coating tumor cells providing additional activity through ADCC May help prevent antigen negative escape Valamehr B et al, AACR, 2018

32 Cord Blood Derived CD19 Specific NK-T CAR NK-T cells derived from cord blood Universal donor, no HLA matching Multiple products per cord, off the shelf Genetically engineered to express CD19 CAR with CD28 costimulatory domain Secrete IL-15 (promotes NK cell proliferation and survival) icasp9 Initial clinical trial results encouraging NK-T cell engraftment and expansion in vivo CRS Tumor responses in NHL and ALL Rezvani K and Shpall EJ, MD Anderson

33 CAR NK Cells in Patients With Relapsed/Refractory B-lymphoid Malignancies (CLL, NHL, ALL) PI: Katy Rezvani MD, PhD; MD Anderson Cancer Center NK cells derived from CB NK NK NK NK NK NK NK Transduction of NK cells with retroviral vectors NK NK NK NK NK NK NK NK NK NK NK NK NK NK NK NK NK NK NK NK NK NK NK NK NK NK NK NK NK NK Antigen Specific CAR+ NK cells Expansion of CAR NK cells Cyclophosphamide, 300 mg/m 2 Fludarabine 30 mg/m2 3 dose levels. Patient receive one infusion at: 1x10e5/kg, 1x10e6/kg, 1x10e7/kg, Cell Infusion Day -14 Day -12 Day -10 Day -4 Day -3 Day -2 Day 0 Banked umbilical cord blood Courtesy K. Rezvani Approved by IRB and FDA (IND 17321)

34 Patient 5- CLL With Richter s Transformation Achieved Complete Response in Lymph Nodes Pre-admission Day 30 post CAR NK Courtesy K. Rezvani

35 Future Approaches to CAR-T Therapy: Conclusions CAR-T cell design will allow endless possibilities Controllable CAR expression Logic driven CAR expression and killing Mitigation of toxicity Enhanced proliferation, killing and resistance to inhibition Combinations will likely improve outcome Checkpoint mabs Ibrutinib? Universal CAR-T (or NK-T) approaches Improve delivery of an off the shelf product Reduce cost (??) May be challenging to get new approaches approved in current era

36 Immunotherapy is changing the way cancer is treated! BEZOS FAMILY IMMUNOTHERAPY CLINIC