Chimeric Antigen Receptor T-Cell Therapy for Cancer and Heart: JACC Council Perspectives

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has significantly advanced the treatment of patients with relapsed and refractory hematologic malignancies and is increasingly investigated as a therapeutic option of other malignancies. The main adverse effect of CAR T-cell therapy is potentially life-threatening cytokine release syndrome (CRS). Clinical cardiovascular (CV) manifestations of CRS include tachycardia, hypotension, troponin elevation, reduced left ventricular ejection fraction, pulmonary edema, and cardiogenic shock. Although insults related to CRS toxicity might be transient and reversible in most instances in patients with adequate CV reserve, they can be particularly challenging in higher-risk, often elderly patients with pre-existing CV disease. As the use of CAR T-cell therapy expands to include a wider patient population, careful patient selection, pre-treatment cardiac evaluation, and CV risk stratification should be considered within the CAR T-cell treatment protocol. Early diagnosis and management of CV complications in patients with CRS require awareness and multidisciplinary collaboration.

Keywords: cardiotoxicity; chimeric antigen receptor T-cell therapy; cytokine release syndrome.

Figure 1.. Mechanism of CAR T-cell therapy and Cytokine Release Syndrome

This figure illustrates stepwise mechanism of CAR T-cell therapy and related CRS. 1. White blood cells are drawn from the patient via leukapheresis. T cells are then separated in the Lab. 2. T cells are genetically modified or “engineered” with viral or nonviral vector inserting a gene encoding a chimeric antigen receptor into the T cells. 3. Engineered T cells, now known as CAR T cells, can recognize and attach to the specific antigen on the cancer cells. 4. CAR T cells are grown and multiplied in the bioreactor to create millions of copies. 5. Before the CAR T cells are administered, the patient receives preconditioning chemotherapy to lower the cell count to allow space for the incoming CAR T cells. 6. CAR T cells are infused back into the patient’s blood where they proliferate, detect and destroy the tumor cells. 7. CRS occurs as a result of the supraphysiologic levels of inflammatory cytokines released by the activated CAR T-cells and other immune cells such as macrophages. Abbreviations: Ang-2: Angiopoetin 2; CAR: chimeric antigen receptor; IL: interleukin; IFN-γ: interferon gamma; MCP1: Monocyte chemoattractant protein 1; TNF-α: tumor necrosis factor alpha; vWF: von Willebrand factor.

Central Illustration.. Cardiovascular Evaluation of Patients Planned for CAR T-cell Therapy

Proposed algorithm for cardiovascular evaluation prior to CAR T-cell therapy. Abbreviations: CAR: chimeric antigen receptor; CAD: coronary artery disease; CRS: cytokine release syndrome; CV: cardiovascular; CVD: cardiovascular disease; ECG: electrocardiogram; GDMT: guideline directed medical therapy; HF: heart failure