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An Introduction to Chimeric Antigen Receptor T-Cell (CAR-T) Therapy

26 Sep 2019 1:16 PM | Mandy Garion (Administrator)

Author: Christopher Clayton, PharmD
Preceptor: Jacob Kettle, PharmD, BCOP

Learning Objectives

  1. Describe the general principles of CAR T-cell therapy
  2. Summarize literature supporting CAR T-therapy for diffuse large B-cell lymphoma and acute lymphocytic leukemia
  3. Describe the common adverse effects of CAR T-cell treatment and their management
  4. Discuss the current state and future directions of CAR T-therapy

Introduction

The human immune system possesses essential and sophisticated mechanisms capable of recognizing, attacking, and ultimately causing lysis of tumor cells.1,2 The efficacy of these processes is unfortunately limited due to insufficient numbers of T-cells specific for tumor antigens, blunted T-cell activation resulting from immune checkpoints, and an immunosuppressive tumor microenvironment.3 The principle theory behind CAR-T (chimeric antigen receptor T-cell) therapy is to overcome the shortcomings of the human immune system through the laboratory design and development of immune cells which specifically target cancer in sufficient abundance to yield a tumor response.4

CAR-T therapy is produced through a complex manufacturing process that generally takes several weeks to complete. The process begins with T-cell extraction from the patient through leukapheresis. A CAR is then introduced ex vivo to the T-cells via viral transfer vector.3,5 The CAR T-cells then undergo expansion to produce enough cells to provide an adequate dose before they can be administered to the patient. Following administration, the modified T-cells will presumably recognize the target on tumor cells and initiate an immune cascade to destroy the malignant cells.3,6,7 Due to the length of time needed to both develop a therapy and for the immune system to illicit a response after administration, the use of conventional cytotoxic chemotherapy is a necessary component of CAR-T therapy.5

Access to CAR-T is currently limited to a relatively small number of institutions owing to the complexity of CAR T-cell manufacture and administration. Further, the immense financial burden (up to $475,000 for the drug cost alone) creates additional logistical barriers to implementation.

Overview of Evidence                                    



While CAR-T only has FDA approval for DLBCL and ALL, researchers are actively striving to identify more uses for CARs in other types of malignancy as research is underway in numerous solid tumors and hematological malignancies.14,15,16 For instance, CARs have been designed to target B-cell maturation antigen (BCMA) for treatment of multiple myeloma, type 1 insulin-like growth factor receptor (IGF1R) and receptor tyrosine kinase-like orphan receptor (ROR1) for sarcoma, and the L1-cell adhesion molecule (L1-CAM) for ovarian cancer.14,15 The greatest challenge in developing new therapy appears to be establishing targets on the cancer cells that are not routinely expressed on normal tissue.14

Adverse Effects

Treatment with CAR-T is associated with considerable risks. The most common serious complication of CAR-T therapy is cytokine release syndrome (CRS), a phenomenon caused by the rapid release of inflammatory cytokines and chemokines.17 CRS generally occurs 2-3 days following administration and is characterized by fever, hypotension, hypoxia, tachycardia, and cardiac, renal, or hepatic dysfunction.16 Reported frequency of CRS ranges from 57% to 93% of patients with many experiencing a severe and potentially life-threatening reaction.10,11,13 Management of CRS revolves around initiation of immune suppression (i.e. corticosteroids) and supportive care measures to support end organ function.16 Tocilizumab, an anti-IL-6 monoclonal antibody, is also an effective component of proper management.17,18 Beyond CRS, neurotoxicity is also a common and severe adverse effect of CAR-T. As many as 40% of patients will experience neurologic symptoms, including encephalopathy, headache, tremor, dizziness, aphasia, delirium, insomnia, anxiety, autonomic neuropathy, agitation, and psychosis.13,17 Symptoms tend to occur 4-10 days following treatment and persist for up to two weeks or longer.13,17 Seizures and life-threatening cerebral edema may also occur.17 Likewise, it is recommended to initiate one month of seizure prophylaxis beginning on the day of treatment.17 Less severe and more persistent chronic side effects of CAR-T therapy include infections, blood dyscrasias, acute kidney injury, and increased hepatic enzyme levels among others.6,7 Many of these effects could occur for up to 8 weeks following treatment.


Conclusion

CAR-T therapy has demonstrated efficacy in the treatment of patients with relapsed or refractory DLBCL or ALL, both of which are historically challenging disease states. Further, the potential for customization suggests CAR-T may become an important treatment modality in additional tumor types in the future. Despite the promise, CAR-T is associated with frequent and potentially life-threatening adverse events as well as financial and logistical barriers due to the complexity of this type of therapy. Assuming the current trajectory holds and use of CAR-T becomes more widespread in the future, it will become increasingly more important for pharmacists in all practice settings to become familiar with this emerging cancer treatment. 

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References

  1. Yang Y. Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest. 2015;125:3335-3337.
  2. Khalil DN, Smith EL, Brentjens RJ, et al. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol. 2016;13:273-290.
  3. Roberts ZJ, Better M, Bot A, Roberts MR, Ribas A. Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL. Leuk Lymphoma. 2018;59(8):1785-96.
  4. Sadelain M, Brentjens RJ, Riviere I. The promise and potential pitfalls of chimeric antigen receptors. Curr Opin Immunol. 2009;21:215-23.
  5. Davila ML, Brentjens R, Wang X, Riviere I, Sadelain M. How do CARs work? Early insights from recent clinical studies targeting CD19. OncoImmunology. 2012;1(9):1577-1583.
  6. Kymriah (tisagenlecleucel) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; May 2018.
  7. Yescarta (axicabtagene ciloleucel) [prescribing information]. Santa Monica, CA: Kite Pharma, Inc; received May 2019.
  8. Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomized controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7:379-91.
  9. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28:4184-90.
  10. Neelapu SS, Locke FL, Bartlett LJ, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-44.
  11. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545-54.
  12. Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-47.
  13. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-48.
  14. Yong CSM, Dardalhon V, Devaud C, et al. CAR T-cell therapy of solid tumors. Immunol Cell Biol. 2017;95:356-63.
  15. Hamieh M, Sadelain M. Insights into chimeric antigen receptor therapy for chronic lymphoblastic leukemia. Trends Mol Med. 2018;24(9):729-31.
  16. Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380(18)1726-37.
  17. National Comprehensive Cancer Network. Management of Immunotherapy-Related Toxicities (Version 2.2019). http://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed June 5, 2019.
  18. Actemra (tocilizumab) [product information]. South San Francisco, CA: Genentech Inc; April 2019.

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