1. 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

2. 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

3. 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
Oriol A, et al. Haematologica. 2010;95(4):

4. New cancer therapies have arrived…
Bispecific T-cell engagers (BiTEs)
Antibodies
Immunotherapy
CAR-T cells
Checkpoint inhibitors
Wu J, et al. J Hematol Oncol. 2015;8:104.

5. 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

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

7. How are CAR-T cells made?
Step 2: CAR-T cell production and expansion
CD19 vector in retro or lentivirus
Anti-CD19 + =

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

9. 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:

10. Clinical evidence for cAR-T cells
N Engl J Med 2014; 371:

11. 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%

12. Results - Toxicity

13. CONFIDENTIAL
Hartmann J, et al. EMBO Mol Med Sep;9(9):

14. 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:
Neelapu SS, et al. NEJM 2017;377:

15. 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

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

17. 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: /nrclinonc

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 Unpublished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

19. Treatment of Cytokine release syndrome
Lee et al. Blood :

20. 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: /nrclinonc

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 Unpublished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

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

23. 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?

24. 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