CAR-T cells: New HOPE FOR CANCER PATIENTS CBMTG: BMT 101 Natasha Kekre, MD, MPH, FRCPC Hematologist, Blood and Marrow Transplant Program, TOH Clinical Lead, BioCanRx CAR-T cell initiative Associate Scientist, Ottawa Hospital Research Institute Assistant Professor Of Medicine, University Of Ottawa June 6, 2018

Advisory board for Kite/Gilead Advisory board for Jazz Pharmaceuticals Conflicts of Interest Advisory board for Kite/Gilead Advisory board for Jazz Pharmaceuticals Advisory board for Sanofi

Background Patients with relapsed or refractory ALL or NHL have a very poor prognosis with currently available therapies Refractory or relapsed non-Hodgkin’s lymphoma: Adult ALL at first relapse: Crump, M., et al. Blood, abstract blood-2017-03-769620. Oriol A, et al. Haematologica. 2010;95(4):589-596.

New cancer therapies have arrived… Bispecific T-cell engagers (BiTEs) Antibodies Immunotherapy CAR-T cells Checkpoint inhibitors http://www.genscript.com/immune-checkpoint-inhibitors.html Wu J, et al. J Hematol Oncol. 2015;8:104.

What are CAR-T cells? T-cells that are taken from a patient and genetically modified to target cancer cells This creates “super T-cells” which can target tumour specific antigens, then activate and kill the tumour cells Cytotoxicity CD3 Costim domain receptor CAR T-cell CD19 Cancer cell

How are CAR-T cells made? Step 1: Collect T cells from the patient

How are CAR-T cells made? Step 2: CAR-T cell production and expansion CD19 vector in retro or lentivirus Anti-CD19 + = http://www.nature.com/nri/journal/v2/n8/fig_tab/nri859_F3.html

How are CAR-T cells made? Step 3: Conditioning Chemo and Administer CAR-T cells

Emily’s story In May 2010, 5 year old Emily Whitehead was diagnosed with ALL and started aggressive chemotherapy In October 2011, she relapsed and received more chemo 2 weeks before her scheduled HSCT, she relapsed again and the transplant was cancelled Her family was told there was no more therapy available and she had weeks to months to live In April 2012, she was enrolled into the phase I clinical trial of CAR-T cells Emily Whitehead was the first patient treated with CAR-T cells at U Penn She had a difficult course… In May 2012, bone marrow showed she was in complete remission Maude, SL et al. N Engl J Med 2014; 371:1507-1517

Clinical evidence for cAR-T cells N Engl J Med 2014; 371:1507-1517

Results - outcomes Complete remission was achieved in 27 patients (90%) 6-month event-free survival rate was 67% 6-month overall survival rate was 78%

Results - Toxicity

CONFIDENTIAL Hartmann J, et al. EMBO Mol Med. 2017 Sep;9(9):1183-1197.

Pivotal FDA Approvals for Anti-CD19 CAR-T cells ELIANA TRIAL (N= 75) ZUMA TRIAL (N=101) Patient population Pediatric/young adult patients with relapsed or refractory CD19+ ALL Median age was 12 years (3-23) Median follow-up 13.1 months Adult patients with DLBCL, PMBCL or transformed FL Median age was 58 years (23-76) Median follow-up was 15.4 months Product Tisagenlecleucel Lentivirus; 4-1BB co-stim domain Axicabtagene Ciloleucel Gamma-retrovirus; CD28 co-stim domain CAR-T cell therapy Fludarabine 30 mg/m2 daily x 4 Cylophosphamide 500 mg/m2 daily x 2  CTL019 (median 3.1×106 cells/kg) Maximum 2.0 ×108 total cells Fludarabine 30 mg/m2 daily x 3 Cyclophosphamide 500 mg/m2 daily x 3  Axi-cel (target 2.0×106 cells/kg) Efficacy ORR: 81% at 3 months EFS: 50% at 12 months OS: 76% at 12 months ORR: 82% at 6 months PFS: 44% at 12 months OS: 59% at 12 months Toxicity Grade 3 or 4 AEs: 73% CRS: 77% (48% received tocilizumab) Neurotoxicity: 40% (managed with supportive care) Grade 3 or 4 AEs: 95% CRS: 93% (13% grade 3 or 4, all resolved except one) Neurotoxicity: 64% (28% grade 3 or 4, all resolved except one) Gamma-retrovirus FMC63 CD28 Maude et al. N Engl J Med 2018; 378:439-448 Neelapu SS, et al. NEJM 2017;377:2531-2544.

Systematic Review: Overall Response Disease Type Study name Event rate and 95% CI Event Lower Upper rate limit ALL Brentjens 2011 0.111 0.015 0.500 Brentjens 2013 0.917 0.378 0.995 Davila 2014 0.857 0.573 0.964 Maude 2014 0.900 0.732 0.967 Dai 2015 0.667 0.333 0.889 Lee 2015 0.447 0.832 Kebriaei 2016 0.091 0.013 0.439 Prudent 2016 0.167 0.010 0.806 Turtle 2016.A 0.983 0.783 0.999 Zhu 2016 Chen 2017 0.833 0.369 0.977 Gardner 2017 0.930 0.805 Pan 2017 0.882 0.762 0.946 Qasim 2017 0.194 0.990 Rossig 2017 0.143 0.020 0.581 ALL OVERALL 0.691 0.489 0.840 CLL Kalos 2011 0.875 0.266 0.993 Cruz 2013.i 0.250 0.063 0.623 Brudno 2016 0.400 0.214 0.620 CLL OVERALL 0.418 0.188 0.690 MPL Gardner 2016 MPL OVERALL NHL Kochenderfer 2012 0.750 0.377 0.937 Kochenderfer 2013 0.300 0.100 0.624 Locke 2016 0.714 0.327 0.928 Turtle 2016.B 0.633 0.451 0.784 Wang 2016 0.571 0.230 0.856 Kochenderfer 2017 0.727 0.511 0.872 Neelapu 2017 0.815 0.723 Schuster 2017 0.387 0.738 NHL OVERALL 0.662 0.539 0.766 OVERALL 0.643 0.546 0.730 0.00 0.50 1.00 Statistics for each study

Safety considerations with Car-T cells Bonifant CL, et al. Mol Ther Oncolytics. 2016 Apr 20;3:16011.

Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2017.148 Neelapu, S. S. et al. (2017) Chimeric antigen receptor T‑cell therapy — assessment and management of toxicities Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2017.148

Cytokine Release Syndrome with CAR-T cells Lalu, M et al. Unpublished Work by Emma Grigor

Treatment of Cytokine release syndrome Lee et al. Blood 2014 124:188-195

Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2017.148 Neurotoxicity Neelapu, S. S. et al. (2017) Chimeric antigen receptor T‑cell therapy — assessment and management of toxicities Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2017.148

Neurotoxicity with CAR-T cells Lalu, M et al. Unpublished Work by Emma Grigor

CAR-T cell THERAPIES ARE GROWING Hartmann J, et al. EMBO Mol Med. 2017 Sep;9(9):1183-1197.

When Will CAR-T cells come to Canada? Both FDA approved products are being submitted for approval with Health Canada Pending CADTH review, these therapies can then be given in Canadian centers Canadian clinical trials with CAR-T cells are slowly opening and running Therapy remains very expensive – how will this fit into standard of care?

Future of CAR-T cells Add BRAKES: Suicide gene inserts Change the DRIVER: New vectors New viruses Current CAR-T cell trials: Anti-CD22 for ALL and Lymphoma Anti-CD30 for Lymphoma Anti-BCMA for Myeloma Anti-CD138 for Myeloma Anti-CD33 for AML Anti-HER2 for breast and other Anti-GPC3 for HCC Anti-Eph2 for malignant glioma Improve TOXICITY: Treatment of CRS/neurotox Predictors of CRS Change the ROAD: New antigens New tumours