Immuno-Oncology and Car T
Chimeric Antigen Receptor (CAR) T-cell therapy is a revolutionary new immunotherapy with the potential to transform patient outcomes, particularly in the field of hematological oncology. The first two approvals in this space were anti-CD19 CAR T-cell products for B-cell malignancies; axicabtagene ciloleucel for relapsed/refractory diffuse large B-cell lymphoma1 and tisagenlecleucel for relapsed/refractory B-cell acute lymphoblastic leukemia2, both in the US in 2017. Targets for CAR T-cell therapy in the hemonc field, in addition to CD19, include BCMA3,4, CD75, CD1236, CD227,8, WT19, CLL1 and CD3310. A number of strategies to improve response to this therapy are also being trialled, including ‘armoured’ CAR T-cells11, and dual antigen-targeting CAR T-cells6,10.
Safety is a concern with this type of therapy, risking immune-related adverse events, including cytokine release syndrome (CRS), acute renal injury and neurotoxicity12-14. Techniques to improve the management of these toxicities, including prophylactic strategies such as tocilizumab and methods to enable the elimination of the CAR T-cells should toxicity occur, are being developed12,14-16. Another challenge to CAR T-cell therapy is the high cost17. One approach to help overcome this is the use of cells from healthy donors to create ‘off-the-shelf’ CAR T-cells5,18, which don’t have to be manufactured for individual patients.
Exciting areas for the future include the potential for further approvals, including those in the second-line setting for lymphoma19, in multiple myeloma20, in acute myeloid leukemia10, and in Europe21.
- FDA.gov [Internet]. FDA approves axicabtagene ciloleucel for large B-cell lymphoma; c2017-10 [updated 2017 Oct 25]; [cited 2018 Aug 22]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm581296.htm
- FDA.gov [Internet]. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome; c2017-08 [updated 2017 Sep 07]; [cited 2018 Aug 22]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm574154.htm
- ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2016 Jan 20. Identifier NCT02658929. Study of bb2121 in Multiple Myeloma; [cited 2018 Aug 22]. Available from: https://clinicaltrials.gov/ct2/show/NCT02658929
- VJHemOnc.com [Internet]. CAR T-cells: targeting BCMA; c2018-06; [cited 2018 Aug 22]. Available from: https://www.vjhemonc.com/video/mnto9cjxsh8-car-t-cells-targeting-bcma/
- VJHemOnc.com [Internet]. Off-the-shelf anti-CD7 CAR T-cells for T-cell malignancies; c2018-02; [cited 2018 Aug 22]. Available from: https://www.vjhemonc.com/video/slpxmgd1eec-off-the-shelf-anti-cd7-car-t-cells-for-t-cell-malignancies/
- Ruella M, Barrett DM, Kenderian SS, et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J Clin Invest. 2016 Oct 3; 126(10): 3814-3826.
- Fry TJ, Shah NN, Orentas RJ, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018 Jan; 24(1): 20-28.
- VJHemOnc.com [Internet]. New CD22 CAR T-cells for pediatric R/R B-ALL are highly effective; c2018-06; [cited 2018 Aug 22]. Available from: https://www.vjhemonc.com/video/jcrleebm9ca-new-cd22-car-t-cells-for-pediatric-rr-b-all-are-highly-effective/
- VJHemOnc.com [Internet]. Finding the right targets for CAR T-cell therapy in AML; c2018-05; [cited 2018 Aug 22]. Available from: https://www.vjhemonc.com/video/nz1a8pqhzgw-finding-the-right-targets-for-car-t-cell-therapy-in-aml/
- VJHemOnc.com [Internet]. First-in-human CLL1-CD33 compound CAR T-cells for AML; c2018-06; [cited 2018 Aug 22]. Available from: https://www.vjhemonc.com/video/zngdniwgqio-first-in-human-cll1-cd33-compound-car-t-cells-for-aml/
- ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2017 Mar 21. Identifier NCT03085173. A Trial of “Armored” CAR T Cells Targeting CD19 For Patients With Relapsed CD19+ Hematologic Malignancies; [cited 2018 Aug 22]. Available from: https://clinicaltrials.gov/ct2/show/NCT03085173
- Bonifant CL, Jackson HJ, Brentjens RJ, et al. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics. 2016 Apr 20; 3: 16011.
- Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014 Jul 10; 124(2): 188-95.
- Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014 Feb 19 ;6(224): 224ra25.
- Thomis DC, Marktel S, Bonini C, et al. A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease. Blood. 2001 Mar 1; 97(5): 1249-57.
- Tey SK, Dotti G, Rooney CM, et al. Inducible caspase 9 suicide gene to improve the safety of allodepleted T cells after haploidentical stem cell transplantation. Biol Blood Marrow Transplant. 2007 Aug; 13(8): 913-24.
- VJHemOnc.com [Internet]. Challenges for access to CAR T-cell therapy; c2018-05; [cited 2018 Aug 22]. Available from: https://www.vjhemonc.com/video/jvnj0_tkq-u-challenges-for-access-to-car-t-cell-therapy/
- Qasim W, Zhan H, Samarasinghe S, et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci Transl Med. 2017 Jan 25; 9(374).
- VJHemOnc.com [Internet]. Bringing CAR T-cells to the second-line setting; c2018-06; [cited 2018 Aug 22]. Available from: https://www.vjhemonc.com/video/76cgqy4zmbq-bringing-car-t-cells-to-the-second-line-setting/
- VJHemOnc.com [Internet]. Results from CAR T-cell bb2121 first-in-human trial for R/R MM; c2018-06; [cited 2018 Aug 22]. Available from: https://www.vjhemonc.com/video/zkburht5yto-results-from-car-t-cell-bb2121-first-in-human-trial-for-rr-mm/
- VJHemOnc.com [Internet]. Making CAR T-cells happen in Europe; c2018-06; [cited 2018 Aug 22]. Available from: https://www.vjhemonc.com/video/oax80qxsgqi-making-car-t-cells-happen-in-europe/