First-in-Human Chimeric antigen receptor (CAR) T cell Therapies: Promises and Challenges
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This presentation summarizes data related to the CAR-T cell technology and its potential application for cancer therapy. This oral presentation was presented at the 39th PAMM winter meeting in Roma the 8th f February 2018 by Eric Raymond
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First-in-Human Chimeric antigen receptor (CAR) T cell Therapies: Promises and Challenges
- 1. First-in-Human Chimeric antigen receptor (CAR) T cell Therapies: Promises and Challenges Prof. Eric RAYMOND MD, PhD Chair of Medical Oncology @ Groupe Hospitalier Paris Saint-Joseph – France (eraymond@hpsj.fr)
- 2. Disclosures • Pfizer • Novartis • Eli Lilly • Ipsen • Celgen • AFR-Oncology • Genoscience Pharma • SCOR
- 3. Phase I Trial of CD19-Targeted T-Cell Therapy in Adults With R/R B-Cell ALL • Patient characteristics: • 51 pts evaluable for toxicity assessment • 50 pts evaluable for response assessment with ≥ 1 mos of follow-up • Activity results: • Morphologic disease: 31/51 (61%) pts • Minimal disease: 20/51 (39%) pts • Follow-up: • Median: 8.5 mos (range: 1-54), data cutoff date of 5/2/16 • 29/50 (58%) pts with ≥ 6 mos of follow-up • 17/50 (34%) pts with ≥ 1 yr of follow-up Park JH, et al. ASCO 2016. Abstract 7003.
- 4. Various ways of directing immunity against cancer cells
- 5. Engineering of CAR-T cell receptor CAR, chimeric antigen receptor; mAb, monoclonal antibody; TAA, tumor-associated antibody; TCR, T-cell receptor. Sadelain M, et al. Nat Rev Cancer. 2003;3:35-45.
- 6. CAR gene transduction in T-cells Sadelain M, et al. Nat Rev Cancer. 2003;3:35-45. Brentjens RJ, et al. Nat Med. 2003;9:279-286.
- 7. Upgraded generations of CARs Jessica Hartmann et al. EMBO Mol Med. 2017
- 8. General processes for TCR/CAR-T cell therapy Jessica Hartmann et al. EMBO Mol Med. 2017
- 9. Theoretical benefits of CAT-T cell therapy • HLA-independent antigen recognition • Active in both CD4+ and CD8+ T-cells • Target antigens include proteins, carbohydrates, and glycolipids • Rapid generation of tumor specific T-cells • Minimal risk of autoimmunity or GVHD • A living drug, single infusion
- 10. Main companies involved in CAR-T cell therapy • JONO Therapeutics (Celgene) • KITE pharma (Gilead) • Novartis • Cellectis (Pfizer – Servier)
- 11. Overview of clinical trials using CAT-T cells Jessica Hartmann et al. EMBO Mol Med. 2017
- 12. Overview of clinical trials using CAR-T cells Jessica Hartmann et al. EMBO Mol Med. 2017
- 13. Phase I Trial of CD19-Targeted T-Cell Therapy in Adults With R/R B-Cell ALL Brentjens RJ, et al. Sci Transl Med. 2013;5:177ra38.
- 14. Phase I Trial of CD19-Targeted T-Cell Therapy in Adults With R/R B-Cell ALL • Patient characteristics: • 51 pts evaluable for toxicity assessment • 50 pts evaluable for response assessment with ≥ 1 mos of follow-up • Activity results: • Morphologic disease: 31/51 (61%) pts • Minimal disease: 20/51 (39%) pts • Follow-up: • Median: 8.5 mos (range: 1-54), data cutoff date of 5/2/16 • 29/50 (58%) pts with ≥ 6 mos of follow-up • 17/50 (34%) pts with ≥ 1 yr of follow-up Park JH, et al. ASCO 2016. Abstract 7003.
- 15. Scans from Dr. Rosenberg NCI Ongoing Complete Response 15+ months in a patient with chemo-refractory PMBCL A patient with recurrent DLBCL post-SCT treated with anti- CD19 CAR T cells Example of response under CAR-T cell therapy Before Treatment Post Treatment Kochenderfer Blood 2012; Kochenderfer JCO 2015; Kochenderfer ASH 2014
- 16. Phase I Trial of CD19-Targeted T-Cell Therapy in Adults With R/R B-Cell ALL •Post–CAR T-Cell Infusion Clinical Courses • 16 of 41 CR (39%) pts proceeded to allogeneic HSCT after achieving CR to CAR T-cells • By disease burden cohort: • 9/23 (39%) pts in morphologic disease cohort • 7/18 (39%) pts in minimal disease cohort • 15/33 MRD-CR (45%) pts relapsed • 4/15 (27%) relapses were CD19 negative/undetectable • 9/33 (27%) pts remain disease free for > 1 yr Park JH, et al. ASCO 2016. Abstract 7003.
- 17. Outcomes of CD19-Specific CAR T-Cell Therapy in Pts With B-Cell ALL Preconditioning chemo was used in all trials Jackson HJ, et al. Nat Rev Clin Oncol. 2016;13:370-383. Institution CAR Design Pt Population CR, % Toxicities NCT# MSKCC CD28, CD3ζ § n = 32 adults § R/R B-cell ALL 91 § B-cell aplasia § CRS NCT01044069 UPenn/Children’s Hospital of Philadelphia 4-1BB, CD3ζ § n = 30 children and young adults § B-cell ALL 90 § B-cell aplasia § CRS NCT01626495 NCI CD28, CD3ζ § n = 20 children and young adults § B-cell ALL 70 § B-cell aplasia § CRS NCT01593696 Fred Hutchinson Cancer Center 4-1BB, CD3ζ § n = 20 adults § B-cell ALL 83 § CRS NCT01865617
- 18. Overview of activity of CAR-T cell therapy Jessica Hartmann et al. EMBO Mol Med. 2017
- 19. Adverse events in CAR T-Cell Therapy • Often severe and require specific/hematologic resuscitation units • Cytokine release syndrome (CRS) G3/4 in 42% of patients • Fever • Hypotension • Respiratory insufficiency • Neurologic toxicity in G3/4 in 35% of patients • Delirium • Global encephalopathy • Aphasia • Seizure-like symptom/seizure • Neurologic symptoms are reversible and can occur independent of CRS • Treatment related death in about 10% of patients Park JH, et al. ASCO 2016. Abstract 7003.
- 20. Severe toxicities related to CAR-T cell therapy Jessica Hartmann et al. EMBO Mol Med. 2017
- 21. Hurdles and possible solutions for CAR T cell therapy Jessica Hartmann et al. EMBO Mol Med. 2017
- 22. Ipilimumab, marketed as Yervoy. The cost for four doses administered over 12 weeks: $120,000 US Novartis’ just-approved chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (KYMRIAH) is going to be introduced on the market at a price of $475,000 for a single infusion (total cost 1,5 millions US dollars) Cost of CAR-T cell therapy compared to other immunotherapy
- 23. Conclusions • CAR-T cell therapy is the first model where industry enters into industrial gene engineering for cell therapy using limited numbers of selected centers (for technology and safety issues) where patients have to be referred for therapy • Proof of concept has been demonstrated in CD19-expressing leukemia, also showing a high level of toxicity making this therapy restricted to a limited number of patients (at least until safety and drug-related death could be improved) • Tumor heterogeneity (variation of antigens of interest) & CAR-T cell number (dose) and distribution (how much CAR-T cell reach cancer sites) in tumor appear far more complex than expected both in leukemia (potentially explain failures) and in solid tumors (where activity seems to be lower)
- 24. Thanks for your attention http://pamm-meetings.org/