Introduction
Chimeric Antigen Receptor (CAR) T-cell immunotherapy is a cancer therapy designed to redirect T-cell specificity to tumor-associated antigens.^1-4 CAR T-cells have been shown to induce remission in patients with high-risk cancers refractory to other forms of cancer therapies.^2,3 The first line of Food and Drug Administration (FDA) approved CAR T-cell therapies has been CD19-directed (axicabtagene, brexucabtagene, tisagenlecleucel) for the treatment of children with acute lymphocytic leukemia and adults with advanced B-cell lymphoma. The indications for CAR T-cells are expected to expand because numerous CAR T-cell products for the treatment of hematologic malignancies and solid tumors are in development. However, life-threatening events with hemodynamic instability and cardiogenic shock have been attributed to CRS associated with CAR T-cell therapy. As such, CV specialists play an important role in the multidisciplinary care of patients receiving CAR T-cell therapy. This article summarizes the CV manifestations of CRS with practical guidance on CV assessment and management during CAR T-cell therapy.

Mechanism of CAR T-Cells
 CARs are engineered receptors that graft a defined specificity onto an immune effector cell—typically a T-cell—and augment T-cell function.¹ Briefly, the normal T-cells of a patient with cancer are extracted and infected with a modified virus that transfers cancer-targeting genetic information into the T-cell genome, directing newly synthesized CAR protein expression on the altered T-cell's surface. After ex vivo expansion of the modified T-cell population, these CAR T-cells are reinfused into the patient, who has undergone cytotoxic lymphodepletion. The altered CAR T-cell engraft and proliferate in the patient, causing targeted cancer cell apoptosis,⁵ and may promote immune surveillance to prevent cancer recurrence in the long term.^1,4

Cytokine Release Syndrome
Major adverse events of CAR T-cell immunotherapy include CRS and neurological toxicity, both of which have prompted an FDA black box warning.^6,7 CRS is a clinical syndrome of fever, hypotension, and acute hypoxia caused by supraphysiologic levels of inflammatory cytokines released by the activated CAR T-cells and other immune cells such as macrophages. It is a systemic inflammatory disorder with multiorgan involvement, ranging in severity from mild to severe. Elevated cytokines noted during CRS include IL-6, TNF-α, IL-10, and IFN-Υ.1 The current consensus grading scale uses fever, hypotension, and hypoxia as components of the severity assessment (Table 1).⁸ The severity of CRS coincides with the disease burden and higher infused CAR T-cell dose.¹

Table 1: American Society for Transplantation and Cellular Therapy Grading System for CRS⁸

	Grade 1	Grade 2	Grade 3	Grade 4
Fever Temperature ≥38°C With or without constitutional symptoms	+	+	+	+
With
Hypotension	–	+ Without need for vasopressors	+ Requiring one vasopressor without vasopressin	+ Requiring multiple vasopressors (excluding vasopressin)
And/or
Hypoxia	–	+ Requiring nasal cannula <6 L/min	+ Requiring supplemental oxygen >6 L/min without positive pressure	+ Requiring positive pressure ventilation

CV Effects
CAR T-cell therapy-associated CV effects have been reported mostly in the context of CRS. MACE associated with CRS include de novo arrythmia, cardiomyopathy, HF, and cardiac death.^9,10 Although the pathophysiology of CAR T-cell therapy-induced CV adverse events is not fully understood, it is thought to be similar to cardiomyopathy associated with sepsis and stress likely through IL-6, which has been implicated as a mediator of myocardial depression in infectious and inflammatory states.¹¹ Another mechanism of CAR T-cell therapy-induced adverse CV events involves direct cardiotoxicity due to potential cross-reactivity with unrelated peptides expressed by normal tissue. Two patients developed fever and progressive cardiogenic shock with death after receiving T-cells targeting MAGE-A3, which was attributed to autoimmunity with off-target cross-reactivity of T-cell receptors against the striated muscle-specific protein titin.¹³ Such case reports highlight the need for improved methods to define specificity of engineered T-cell receptors and strategies to mitigate the risk of off-target toxicity.

Based on registry cohorts, the median time to CRS was 5-6 days, and the median time to MACE was 11-21 days after CAR T-cell infusion.^9,10 In one registry cohort, all adverse CV events took place in patients experiencing ≥2 CRS.⁹ CV death occurred in 6%, new arrythmias occurred in 12%, and new onset HF occurred in 11% of CAR T-cell recipients with CRS grade ≥2. Those with grade ≥3 CRS experienced a fivefold higher MACE rate, including a sevenfold higher incidence of cardiomyopathy compared to patients with lower CRS grade. Troponin elevation was noted in more than half of the patients undergoing CART T-cell therapy and was associated with subsequent CV events.⁹ A recent retrospective study showed that the incidence of cardiomyopathy, defined as a reduction of left ventricular ejection fraction >10% from baseline to <50%, in the context of high-grade CRS may be close to 10% among patients receiving CAR T-cell infusion. Patients who developed cardiomyopathy were older and had a higher prevalence of CV risk factors at baseline. Although left ventricular ejection fraction often recovered, many patients demonstrated persistent cardiac dysfunction.¹²

CV Assessment and Management
Given the MACE associated CAR T-cell therapy, a detailed CV history and physical should be performed prior to initiation of therapy. Echocardiographic evaluation should be strongly considered among patients with known cardiac disease or a prior exposure to anthracyclines. In some institutions, an echocardiogram is obtained as part of standard practice to assess biventricular systolic function and exclude significant valvular disease. For patients with known cardiac disease or active cardiac symptoms, risk stratification and optimization of CV status are indicated. Imaging stress test can be considered in patients with pre-existing coronary artery disease (CAD) or multiple CV risk factors to rule out occult obstructive CAD and assess ischemic burden. Patients with a history of HF, regardless of the cause, are likely to be at risk for HF exacerbation due to volume shifts; recommendations for volume status monitoring and HF management should be provided prior to initiating CAR T-cell therapy. Patients with obstructive CAD or significant aortic stenosis may be at risk of MACE such as HF, myocardial infarction, cardiogenic shock, and death in the setting of CRS-induced hypotension. Such cases require multidisciplinary discussion with patient involvement to weigh the risks and benefits of the CAR T-cell therapy and compare with alternative treatment options.

Cardiac monitoring during therapy includes frequent vital sign assessment and telemetry. Hypotension and shock are common adverse effects related to CRS, which are mostly vasodilatory in nature. First-line treatment for hypotension includes volume resuscitation with intravenous fluid. For hypotension not responsive to fluid boluses, vasopressor should be initiated, and other causes should be considered such as infection, pulmonary embolism, or primary cardiac events. Signs and symptoms of high-grade CRS should prompt further cardiac evaluation including electrocardiogram, troponin, brain natriuretic peptide, and echocardiogram, and consideration for initiation of tocilizumab.

Tocilizumab is an anti-IL-6-receptor antagonist that is FDA approved to manage severe CRS and may also mitigate CV toxicity of CAR T-cells.¹ In a registry of 137 CD-19-targeting CAR T-cell recipients, the CV event risk increased 1.7-fold with each 12-hour delay to tocilizumab.⁹ Although timing of tocilizumab initiation with respect to CRS severity varies among different institutions, it is often given with grade 2 or higher. Of note, 95% of cardiac events were noted in patients who had a troponin elevation; therefore, troponin elevation may help identify candidates experiencing CRS for early tocilizumab treatment.⁹ Further investigation with randomized controlled trials is needed to delineate the optimal treatment strategy for CAR T-cell-related cardiotoxicity.

Conclusions
CAR T-cell immunotherapy is an exciting breakthrough cancer treatment with expanding indications that will include a wider population at risk. CV specialists will be seeing an increasing number of patients with cancer receiving CAR T-cell immunotherapy. Best preventive strategies to minimize CV complications remain undefined. For now, a practical approach for the management of patients undergoing CAR T-cell therapy includes careful assessment of CV symptoms with selective use of serum biomarkers and imaging indices for early detection of cardiotoxicity and prompt initiation of supportive treatment as needed. Data on CAR T-cell-related cardiotoxicity is presently limited to retrospective registry cohorts; further investigation is needed to inform evidence-based practice guidelines for effective treatment with CAR T-cells while optimizing CV outcome.

References

1. June CH, Sadelain M. Chimeric Antigen Receptor Therapy. N Engl J Med 2018;379:64-73.
2. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med 2017;377:2531-44.
3. Park JH, Rivière I, Gonen M, et al. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. N Engl J Med 2018;378:449-59.
4. Ganatra S, Carver JR, Hayek SS, et al. Chimeric Antigen Receptor T-Cell Therapy for Cancer and Heart: JACC Council Perspectives. J Am Coll Cardiol 2019;74:3153-63.
5. Davenport AJ, Jenkins MR, Cross RS, et al. CAR-T Cells Inflict Sequential Killing of Multiple Tumor Target Cells. Cancer Immunol Res 2015;3:483-94.
6. KYMRIAH™ (tisagenlecleucel) (FDA.gov website). May 2018. Available at https://www.fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/Package-Insert---KYMRIAH.pdf. Accessed September 25, 2020.
7. YESCARTA™ (axicabtagene ciloleucel) (FDA.gov website). May 2020. Available at https://www.fda.gov/media/108377/download. Accessed September 25, 2020.
8. Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant 2019;25:625-38.
9. Alvi RM, Frigault MJ, Fradley MG, et al. Cardiovascular Events Among Adults Treated With Chimeric Antigen Receptor T-Cells (CAR-T). J Am Coll Cardiol 2019;74:3099-108.
10. Lefebvre B, Kang Y, Smith AM, Frey NV, Carver JR, Scherrer-Crosbie M. Cardiovascular Effects of CAR T Cell Therapy: A Retrospective Study. JACC CardioOncol 2020;2:193-203.
11. Pathan N, Hemingway CA, Alizadeh AA, et al. Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock. Lancet 2004;363:203-9.
12. Ganatra S, Redd R, Hayek SS, et al. Chimeric Antigen Receptor T-Cell Therapy-Associated Cardiomyopathy in Patients With Refractory or Relapsed Non-Hodgkin Lymphoma. Circulation 2020;142:1687-90.
13. Linette GP, Stadtmauer EA, Maus MV, et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 2013;122:863-71

Clinical Topics: Cardio-Oncology, Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Cardio-oncology, Cardiotoxicity, Immunotherapy, Adoptive, Troponin, Connectin, Natriuretic Peptide, Brain, Exercise Test, Interleukin-6, Anthracyclines, Shock, Cardiogenic, Cytokines, Retrospective Studies

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