Background: Immunotherapy using one’s own T-cells that are genetically engineered to express a chimeric antigen receptor (CAR) is an emerging therapy for hematologic and non-hematologic cancer. CAR-T cell therapy has induced rapid and durable clinical responses in otherwise fatal cancers, but is associated with unique, possibly severe, toxicities. This Fast Fact will discuss the basics of CAR-T cell therapy for clinicians, approved indications, and toxicities.
CAR-T Cell Therapy: CAR T-cell therapy alters the function of a patient’s own T cells or those of a healthy donor, to recognize and kill cancer cells (1). These tumor-targeted T cells are engineered in the laboratory, expanded to large numbers and infused back into the patient a few weeks after harvest. Once infused, the CAR-T cells divide and multiply, bypassing the barriers and incremental kinetics of active immunization, exerting both immediate and long-term anti-tumor effects. Patients who receive CAR T-cell therapy have a recovery/monitoring period of approximately 3-6 months. During this period, patients are evaluated for side effects and treatment response. Care is usually limited to specialty referral centers. While CAR T-cell therapy is being studied widely in solid tumors, such as prostate, breast, lung and colorectal cancer, the following are FDA-approved indications for CAR T-cell therapy:
- Tisagenlecleucel – children or adults 25 or younger with relapsed or refractory acute lymphoblastic leukemia.
- Axicabtageneciloleucel – Relapsed/Refractory large B-cell lymphoma despite ≥ 2 systemic therapies.
- CAR T-cells in the treatment of multiple myeloma were granted fast track designation by the FDA.
Response Rates and Durable Remissions: Compared to historical controls, objective and complete response rates have been impressive in patients who have progressed on other treatments. Of 24 patients enrolled in a single institution trial of tisagenlecleucel, 46% of patients in the diffuse large b-cell cohort had a complete remission, while 71% of patients in the follicular lymphoma cohort had a complete response. These remissions were durable, with 60% of patients being relapse-free at 4 years (2). For comparative purposes, prognosis in this cohort of patients is poor, with a median overall survival of 4.4 months and 1 year overall survival rate of 23%(3).
Safety and Toxicity of CAR-T Cell Therapy: Unlike chemotherapy-associated side effects, many of the CAR-T cell toxicities resolve only when cells are done expanding, eradicating, or become exhausted. While toxicities are usually manageable and reversible, national data suggest 5-10% of patients have lethal side-effects within the first three months. There is little data about the long-term side effects of CAR-T cell therapy. Safety concerns include:
- Immune-mediated rejection of normal tissues that express the targeted antigen: also known as “on-target, off-tumor” response (6). For example, a B-cell aplasia induced by CD-19 targeted CARs.
- Cytokine release syndrome (CRS): high fevers, hypotension, hypoxia, and toxicity of any organ that usually occurs within the first week after CAR-T infusion (8). It is likely due to intense anti-tumor responses by activated T cells. While CRS can bring one to the brink of critical illness, it is usually fully reversible. CRS is common, with rates between 37-93%. Most patients who experience a durable response from CAR-T therapy exhibit at least some degree of CRS, so its presence is interpreted as a good prognostic sign. Patients at high risk of severe CRS include those with bulky tumor burden, comorbidities, and those who develop CRS within 3 days of cell infusion (4). The rates of severe CRS are 1-23% for patients with lymphoma and 23-46% for patients with ALL, with nearly half of those enrolled in the early CAR-T trials requiring intensive care management (5). Management of severe CRS remains challenging, given the delicate balance of mitigating uncontrolled inflammation without dampening antitumor efficacy. While oncologists may try to avoid corticosteroids to preserve antitumor efficacy, they may be necessary for severe cases as may vasopressors and specialized medications such as tocilizumab or anakinra (6).
- CAR-T-cell related immune effector cell-associated neurotoxicity syndrome (ICANS) is characterized by global encephalopathy, aphasia, seizure/seizure-like activity, obtundation, tremor/myoclonus, and hallucinations (6). Rates of severe ICANS are 12–30% for patients with lymphoma and 13–42% for patients with leukemia. Clinical factors impacting the risk of ICANS include marrow disease, higher CAR T-cell dose, prior severe CRS, and pre-existing neurologic comorbidities. While ICANS is often reversible, permanent neurologic side-effects and fatalities have resulted from ICANS.
Cost: The price of CAR T-cell therapy approximates $500,000 (7). This does not include the cost of inpatient monitoring and toxicity management, which can add hundreds of thousand dollars. Insurance coverage for the treatment varies with many payers making coverage decisions on a case-by-case basis. Even when payers cover the cost of treatment, however, patients often are responsible for expenses such as travel, copays, etc. From a national health care perspective, CAR-T costs have been manageable because the eligible population for CAR-T remains small. If CAR-T demonstrates benefit across a broader range of malignancies, it might be used in millions, raising cost concerns for health systems (7).
Prognostic Uncertainty: Although treatment carries quality of life, morbidity, and mortality risks, many patients face almost certain death without CAR-T. Also, it can be challenging to identify which patients will/will not have durable responses. Advance care planning is therefore nuanced given the prognostic uncertainty, and the unique nature of a binary outcome. This differs from our traditional understanding of disease trajectory for advanced malignancies. It is important to balance the hope for a good response, with the realization that good outcomes are not guaranteed and rapid trajectory to end-of-life is possible.
1. Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol. 2018;15(1):31-46.
2. Chong EA, Svoboda J, Nasta SD, et al. CD19‐directed car t cell therapy (CTL019) for relapsed/refractory diffuse large B‐cell and follicular lymphomas: four year outcomes. Hematol Oncol. 2019;37(suppl S2):137-138. doi: 10.1002/hon.96_2629.
3. Van den Neste E, Schmitz N, Mounier N, Gill D, Linch D, Trneny M, et al. Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study. Bone Marrow Transplantation. 2016;51(1):51-7.
4. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-17.
5. Santomasso B, Bachier C, Westin J, Rezvani K, Shpall EJ. The Other Side of CAR T-Cell Therapy: Cytokine Release Syndrome, Neurologic Toxicity, and Financial Burden. Am Soc Clin Oncol Educ Book. 2019;39:433-44.
6. Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy – assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47-62.
7. Green AK, Saltz LB. Can We Afford That CAR? Confronting the Effect of Novel Immunotherapies on Future Health Care Costs. Journal of Clinical Oncology. 2018;36(13):1381-2.
Authors’ Affiliations: Johns Hopkins Medicine, Baltimore, MD; Massachusetts General Hospital, Boston, MA.
Conflicts of Interest: The authors declare that they have no conflict of interest.
Version History: First electronically published in March 2020. Originally edited by Sean Marks MD.
Fast Facts and Concepts are edited by Sean Marks MD (Medical College of Wisconsin) and associate editor Drew A Rosielle MD (University of Minnesota Medical School), with the generous support of a volunteer peer-review editorial board, and are made available online by the Palliative Care Network of Wisconsin (PCNOW); the authors of each individual Fast Fact are solely responsible for that Fast Fact’s content. The full set of Fast Facts are available at Palliative Care Network of Wisconsin with contact information, and how to reference Fast Facts.
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