Chimeric Antigen Receptor T Cell Immunotherapy: What You Need to Know #393

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 nonhematologic 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 discusses 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 antitumor effects. Patients who receive CAR T cell therapy have a recovery/monitoring period of approximately three to six months. During this period, patients are evaluated for side effects and treatment response. Care is usually limited to specialty referral centers. Although CAR T cell therapy is being studied widely in solid tumors, such as prostate, breast, lung, and colorectal cancer, the following are Food and Drug Administration (FDA)-approved indications for CAR T cell therapy:

Tisagenlecleucel: children or adults 25 years or younger with relapsed or refractory acute lymphoblastic leukemia.

Response Rates and Durable Remissions

Compared with 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, whereas 71% of patients in the follicular lymphoma cohort had a complete response. These remissions were durable, with 60% of patients being relapse free at four 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. Although 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:

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 and copays. 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.