Contents

Search

chimeric antigen-receptor (CAR) T-cell therapy; tisagenlecleucel; CTL019 (Kymriah)

Indications: - hematopoietic malignancies - refractory acute lymphoblastic leukemia* FDA-approved 8/2017) [7,13] - refractory large B-cell lymphoma (FDA-approved Oct 2017) [12,13] - multiple myeloma targeting BCMA [10] - relapsed or refractory T-cell acute lymphoblastic leukemia [17] - investigational treatment of refractory systemic lupus erythematosus [18] - investigational treatment of aging through removal of senescent cells targeting cell-surface uPAR [20] * B-cell precursor acute lymphoblastic leukemia Contraindications: - only 26% of patients with relapsed/refractory CLL respond [11] * CLL = chronic lymphocytic leukemia Procedure: - a tumor-binding element is introduced into a patient's T-cells using viral vectors - these T-cells are cultured to produce large numbers of such cells, then reinfused into the patient - modified T-cells attack leukemia cells with CD19 antigen (B-cells) or CD7 antigen (T-cells) - BCMA target in multiple myeloma [10] * - vaccinations - CAR T-cell therapy directed against B-cell antigens (CD19/BCMA) [21] - patients should not receive influenza vaccine & COVID-19 vaccine < 3 months after completing therapy - non-live vaccines should not be given < 6 months after completing therapy Monitor: - neurologic assessment every 8 hours Adverse effects: - cytokine release syndrome (cytokine storm)* most common - CAR T-cell-related encephalopathy (CRES) 2nd most common - may result in fatal cerebral edema [4] - may result from reactivation of herpesvirus 6B [19] * boxed warning Laboratory: - daily starting day of infusion - complete blood count QD - chemistry 14 panel - PT, aPTT, INR - serum C-reactive protein - serum ferritin Clinical trials: - relapsed B-cell acute lymphoblastic leukemia (ALL) - median survival with CAR T-cell therapy = 12.9 months - subgroup with low disease burden = 20 months [9] - relapsed or refractory T-cell acute lymphoblastic leukemia - complete response in 90% of patients in phase 1 trial [17] Notes: - Medicare announces coverage for CAR T-cell therapy Aug 2019 [15]

Specific

afamitresgene autoleucel (Tecelra) axicabtagene ciloleucel (Yescarta) brexucabtagene autoleucel (Tecartus, Zynteglo) ciltacabtagene autoleucel (Carvykti) idecabtagene vicleucel (Abecma) lifileucel (Amtagvi) lisocabtagene maraleuce (BREYANZI) tisagenlecleucel (Kymria)

General

cancer immunotherapy

References

  1. Komaroff AL Immunotherapy to Fight Cancer Begins to Work. NEJM Journal Watch. June 16, 2015 Massachusetts Medical Society (subscription needed) http://www.jwatch.org
  2. Gever J FDA Approves CAR T-Cell Therapy for Leukemia. 'First gene therapy available in the United States,' says agency. MedPage Today. August 30, 2017 https://www.medpagetoday.com/HematologyOncology/Leukemia/67615 - FDA News Release. Aug 30, 2017 FDA approval brings first gene therapy to the United States. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm
  3. Court E Novartis' CAR-T gene therapy, the first approved by FDA, to cost $475,000 MarketWatch. Aug 31, 2017 http://www.marketwatch.com/story/novartis-car-t-gene-therapy-the-first-approved-by-fda-to-be-priced-based-on-cancer-patients-outcomes-2017-08-30
  4. Anello J, Feinberg B, Heinegg J et. al. New Guidelines and Recommendations, October 2017 Medscape - Oct 06, 2017 http://reference.medscape.com/viewarticle/886616_5
  5. Kuehn B The Promise and Challenges of CAR-T Gene Therapy. JAMA. Published online November 22, 2017 PMID: 29167891 https://jamanetwork.com/journals/jama/fullarticle/2664338
  6. Wikipedia: Tisagenlecleucel https://en.wikipedia.org/wiki/Tisagenlecleucel
  7. Schuster SJ, Svoboda J, Chong EA Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med. Dec 10, 2017 PMID: 29226764 http://www.nejm.org/doi/full/10.1056/NEJMoa1708566 - Tran E, Longo DL, Urba WJ A Milestone for CAR T Cells N Engl J Med. Dec 10, 2017 PMID: 29226781 http://www.nejm.org/doi/full/10.1056/NEJMe1714680
  8. Young K, Fairchild DG, Di Francesco L. Physician's First Watch, Jan 31, 2018 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org - American Society of Clinical Oncology, News Release Jan 30, 2018 CAR T-Cell Immunotherapy Named Advance of the Year in Annual ASCO Report. Cancer Progress Report Highlights Life-Saving Potential of Immunotherapy, Critical Role of Federal Funding. https://www.asco.org/about-asco/press-center/news-releases/car-t-cell-immunotherapy-named-advance-year-annual-asco-report - American Society of Clinical Oncology Clinical Cancer Advances 2018 ASCO's 13th Annual Report on Progress Against Cancer. https://www.asco.org/research-progress/reports-studies/clinical-cancer-advances-2018
  9. Park JH, Riviere I, Gonen M et al Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. N Engl J Med 2018; 378:449-459. Feb 1, 2018 PMID: 29385376 http://www.nejm.org/doi/full/10.1056/NEJMoa1709919
  10. Fuerst ML CAR T-Cell Therapy Shows Durable Activity in Heavily Pretreated Multiple Myeloma. B-cell maturation antigen most promising myeloma target for CAR T-cell therapy. MedPage Today. ASCO Reading Room. Feb 1, 2018 https://www.medpagetoday.com/reading-room/asco/immunotherapy/70885 - Cohen AD, Garfall AL, Stadtmauer EA et al 505 Safety and Efficacy of B-Cell Maturation Antigen (BCMA)- Specific Chimeric Antigen Receptor T Cells (CART-BCMA) with Cyclophosphamide Conditioning for Refractory Multiple Myeloma (MM). ASH 59th Annual Meeting. Dec 9-12, 2017 https://ash.confex.com/ash/2017/webprogram/Paper106279.html
  11. Nelson R T-Cell Biomarker Predicts Response to CAR T-Cell Therapy in Patients With CLL Medscape - May 07, 2018. https://www.medscape.com/viewarticle/896261 - Fraietta JA, Lacey SF, Orlando EJ et al Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nature Medicine. April 30, 2018 PMID: 29713085 https://www.nature.com/articles/s41591-018-0010-1.epdf
  12. Schuster SJ, Bishop MR, Tam CS et al Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. Dec 1, 2018 PMID: 30501490 https://www.nejm.org/doi/full/10.1056/NEJMoa1804980?query=featured_home
  13. Bankhead C CAR T-Cell Responses Prove Durable in ALL, DLBCL. Two studies demonstrate long-term control in relapsed/refractory disease. MedPage Today. Dec 1, 2018 https://www.medpagetoday.com/meetingcoverage/ashhematology/76644 - Grupp SA, et al Updated analysis of the efficacy and sasfety of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia. American Society of Hematology (ASH) 2018; Abstract 895. - Schuster SJ, et al Sustained disease control for adult patients with relapsed or refractory diffuse large B-cell lymphomas: An updated analysis of JULIET, a global pivotal phase II trial of tisagenlecleucel. American Society of Hematology (ASH) 2018; Abstract 1684.
  14. Jacobson C, Emmert A, Rosenthal MB CAR T-Cell TherapyA Microcosm for the Challenges Ahead in Medicare. JAMA. Published online July 29, 2019. PMID: 31355862 https://jamanetwork.com/journals/jama/fullarticle/2744409
  15. Young YD Medicare Announces Coverage for CAR T-Cell Therapy Medscape - Aug 08, 2019. https://www.medscape.com/viewarticle/916604
  16. Liu E, Marin D, Banerjee P et al Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med 2020; 382:545-553. Feb 6. PMID: 32023374 https://www.nejm.org/doi/full/10.1056/NEJMoa1910607
  17. Bankhead C Anti-CD7 CAR-T Therapy Yields High Response Rate in Acute Leukemia. Complete responses in 18 of 20 patients with relapsed/refractory T-cell ALL. MedPage Today August 4, 2021 https://www.medpagetoday.com/hematologyoncology/leukemia/93902 - Pan J, Tan Y, Wang G et al Donor-derived CD7 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia: First-in-human, phase I trial. J Clin Oncol. 2021. Jul 29 PMID: 34324392 https://ascopubs.org/doi/abs/10.1200/JCO.21.00389
  18. Mackensen A et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 2022 Oct; 28:2124. PMID: 36109639 https://www.nature.com/articles/s41591-022-02017-5
  19. Lareau CA, Yin Y, Maurer K et al. Latent human herpesvirus 6 is reactivated in CAR T cells. Nature 2023 Nov; 623:608 PMID: 37938768 https://www.nature.com/articles/s41586-023-06704-2
  20. Amor C, Fernandez-Maestre I, Chowdhury S et al Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction. Nat Aging. 2024 Jan 24. PMID: 38267706 https://www.nature.com/articles/s43587-023-00560-5
  21. Brooks M ASCO Releases Vaccination Guidelines for Adults With Cancer MDedge/Internal Medicine. March 28, 2024 https://www.mdedge.com/internalmedicine/article/268479/preventive-care/asco-releases-vaccination-guidelines-adults-cancer