CAR T cell therapy is a revolutionary new approach to cancer treatment that harnesses the power of the immune system to fight cancer. CARs are engineered synthetic receptors that function to redirect lymphocytes, most commonly T cells, to recognize and eliminate cells expressing a specific target antigen. (1). These modified T cells then target and destroy cancer cells, offering a potentially curative treatment option for patients with certain types of cancer.

Indications for CAR T therapy include certain types of leukemia and lymphoma that have not responded to other treatments, such as chemotherapy or stem cell transplantation. In particular, CAR T therapy has shown promising results in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). (2-4) and multiple myeloma (5)

However, CAR T therapy is not without its complications. The most common side effect of CAR T therapy is cytokine release syndrome (CRS). Clinically, the CRS can present with fevers, myalgias, hypotension and hypoxia. CRS occurs when the infused T cells activate the immune system, leading to the release of cytokines that can cause systemic inflammation. They can be mild and self-limiting, or progress in severity to high-grade fevers, hemodynamic compromise requiring vasopressor support, capillary leak, and severe hypoxia requiring ventilator support and multiple organ failure. (6) CRS median time of onset following CART infusion of 2–3 days. (7-9)

Another common, challenging side effect associated with CAR T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS), which can manifest as confusion, seizures, or other neurological symptoms. It is thought to be caused by the activation of T cells in the central nervous system, leading to inflammation and damage to brain cells.(10)

CRS can mimic other medical conditions such as sepsis, infection, or adrenal insufficiency, it would be important of A&E physician to raise our awareness. The treatment of CRS from CART depends on the severity of symptoms and can range from supportive care to more aggressive interventions. The use of antibiotics, steroid and tocilizumab (11) a monoclonal antibody that blocks the action of IL-6 are the mainstay treatment for severe case. Other medications that may be used include anakinra,(12) which blocks the action of IL-1, and siltuximab, (13) which blocks the action of IL-6.

Overall, CAR T therapy is a promising new treatment option for certain types of cancer, but it is important to be aware of the potential complications and to carefully monitor patients undergoing this treatment. As AED physician, we may encounter the complications of CART Therapy. We should resuscitate the patient as treatment of sepsis with cardiovascular support. The early use of immunotherapies, IL blocker would be considered with discussion with oncologists and ICU doctors.

Reference:

1. Sadelain, M., Brentjens, R. & Rivière, I. The basic principles of chimeric antigen receptor design. Cancer Discov. 3, 388–398 (2013).

2. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia. New Engl J Med (2011) 365:725–33.

3. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al.. Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia. New Engl J Med (2013) 368:1509–18.

4. Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, et al.. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. New Engl J Med (2017) 377:2545–54.

5. 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):1726–1737

6. Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014;20(2):119–122.

7. Novartis Pharmaceuticals corporation. Kymriah (tisagenlecleucel) [package insert]. U.S. Food and Drug Administration website. Available from: https://www.fda.gov/media/107296/download Revised March 28, 2019. Accessed October 2019.

8. Kite Pharma, Incorporated. Yescarta (axicabtagene ciloleucel) [package insert]. U.S. Food and Drug Administration website. Available from: https://www.fda.gov/media/108377/download Revised February 20, 2018. Accessed October 2019.

9. Kite Pharma, Incorporated. Yescarta (axicabtagene ciloleucel) [package insert- list of adverse reactions]. U.S. Food and Drug Administration website

10. Hayden PJ, Roddie C, Bader P, Basak GW, Bonig H, Bonini C, et al. Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA). Ann Oncol. (2022) 33:259–75.

11. Si S, Teachey DT. Spotlight on Tocilizumab in the Treatment of CAR-T-Cell-Induced Cytokine Release Syndrome: Clinical Evidence to Date. Ther Clin Risk Manag. 2020 Aug 4;16:705-714.

12. Strati P, Ahmed S, Kebriaei P, Nastoupil LJ, Claussen CM, Watson G, Horowitz SB, Brown ART, Do B, Rodriguez MA, Nair R, Shpall EJ, Green MR, Neelapu SS, Westin JR. Clinical efficacy of anakinra to mitigate CAR T-cell therapy-associated toxicity in large B-cell lymphoma. Blood Adv. 2020 Jul 14;4(13):3123-3127.

13. Lipe BC, Renaud T. Siltuximab as a primary treatment for cytokine release syndrome in a patient receiving a bispecific antibody in a clinical trial setting. J Oncol Pharm Pract. 2023 Jun;29(4):1006-1010.