Multiparametric Cardiac MRI in Patients Under CAR T-cell Therapy

Genetically modified chimeric antigen receptor (CAR) T cells specifically targeting CD19 or "B cell maturation antigen" (BCMA) have shown remarkable advances in the treatment of highly refractory and relapsing hematological malignancies including diffuse large B-cell lymphoma or multiple myeloma. However, this potent therapy is hampered by serious, potentially life threatening complications, which might also involve the cardiovascular system. The potential cardiotoxic profile remains poorly defined and insufficiently understood. This proposal describes a prospective, longitudinal, intraindividual cardiac magnetic resonance imaging (MRI) study in oncological patients, which are scheduled for CAR T cell therapy for cancer treatment. This explorative study is designed to evaluate and monitor acute and late effects of CAR T cell therapy on the heart muscle. Systematic cardiac MRI monitoring correlated with the clinical course and thorough immunological assessment is the next step in helping to understand the extent, pattern, and pathophysiology of CAR T cell therapy related cardiovascular adverse events.

A chimeric antigen receptor (CAR) is a recombinant fusion protein that activates T cells upon recognition of a specific antigen on the cell surface of target cells. Therapeutic success was especially noticed with CD19-specific CAR T cells in the treatment of highly refractory and relapsing hematological malignancies. CD19 is an effective target due to its expression throughout the development line of B cells and has a frequent and high-level expression on the surface of nearly all B-cell malignancies. In addition, it is not found on other normal tissue cells, including the heart, and is not shed as a soluble form. The process of manufacturing CAR T cells typically requires 3 to 4 weeks. Autologous T cells are first collected from the patient and then genetically modified ex vivo with lentiviral or retroviral vectors to reprogram the T cells to recognize tumor cells expressing a tumor associated antigen (e.g., CD19 or BCMA). The CAR T cells a multiplied in large quantities before being administered to the patient within a single infusion. Before the infusion of CAR T cells, patients undergo lymphodepleting chemotherapy, most commonly with a combination of fludarabine and cyclophosphamide. This suppresses the patient's endogenous T cell compartment and allows an in vivo expansion of the transferred CAR T cells. Although the CAR T cell therapy has clearly advanced the treatment of highly refractory or relapsing hematological malignancies, there are potentially severe drawbacks of this therapy. One especially worrisome shortcoming is the potential therapy association with the unique toxicities of a cytokine release syndrome (CRS) and neurologic toxicities.

Cardiovascular complications associated with CAR T cell therapy are less well defined but can be subclassified into autoimmune toxicities resulting from antigen-specific T cell infiltration of the heart and cytokine-mediated toxicities. Cytokine-associated cardiotoxicities have been reported especially in the setting of CRS and might be the cause for most of the observed cardiovascular side effects. In a retrospective study from Alvi et al. cardiovascular events were systematically investigated in adults treated with CAR T cell therapy. The study included 137 patients and found that up to 12% of patients had clinical apparent cardiovascular events after CAR T cell therapy initiation (median time to event 21 days). Cardiovascular events included cardiovascular death, new onset heart failure, decompensated heart failure, and new onset of arrhythmia. A decrease in left ventricular function was observed in 28% of patients while 54% of patients had an elevated troponin. Interestingly, all cardiovascular events occurred in patients with grade ≥ 2 CRS and 95% of events occurred after troponin elevation. Another retrospective study from Lefebvre et al. investigated the occurrence of major adverse cardiovascular events (MACE) in 145 adult patients treated with CAR T cell therapy. MACE included cardiovascular death, symptomatic heart failure, acute coronary syndrome, ischemic stroke, and new onset arrhythmias. In total, 31 out of 145 (21%) patients had MACE at a median time of 11 days after CAR T cell infusion. MACE was independently associated with CRS grade 3 or 4 and baseline creatinine. Overall survival after one year was 71%. Another retrospective study analyzing 116 patients with serial echocardiograms after CAR T cell therapy found that 10% of patients developed a new cardiomyopathy with a decrease of left ventricular ejection fraction (average decrease from 58% to 37%), mostly observed in patients with grade ≥ 2 CRS. Another study with a patient pool of 126, found that 10% of patients developed severe cardiac disorders after CAR T cell therapy including new onset heart failure, acute coronary syndrome, and myocardial infarction.

Cardiac MRI for assessment of acute and chronic cardiac effects in CAR T cell therapy As the impact and the pathophysiology of cardiotoxicity of CAR T cell therapies to the heart is poorly understood, it is still unclear, whether cardiotoxicity is simply an early phenomenon associated with the cytokine storm within the scope of the CRS or whether there are more direct cardiotoxic effects from the CAR T cells themselves. It has also been proposed that the observed systolic dysfunction in this setting is a sequalae of a stress induced Takotsubo syndrome. In this context, the physiological stress from the CRS could trigger the occurrence of Takotsubo syndrome. To explore the extent of cardiac injury and inflammation and the pattern of myocardial involvement related to CAR T cell therapy, cardiac MRI must be considered as the imaging modality of choice, particularly due to its inherent capabilities of advanced tissue characterization. Cardiac MRI can characterize myocardial tissue alterations, analyze involvement patterns, and give important insights into the remodeling processes. To date, no cardiac MRI studies in patients with CAR T cell therapy exist. However, in this context, multiparametric cardiac MRI can be used to detect and quantify acute diffuse myocardial tissue alterations, such as myocardial edema and fibrosis. Furthermore, alterations in myocardial function can be detected with high sensitivity by using myocardial strain analysis. Late gadolinium enhancement imaging has a very high specificity for the detection of necrotic inflammatory lesions, especially in the context of inflammatory cardiomyopathies, and could directly show inflammatory lesions associated with CAR T cell therapy. Also, cardiac MRI could reliably identify different patterns of wall motion abnormalities which are associated with Takotsubo syndrome (i.e., apical, midventricular, basal or focal types). A recent study from our group in patients under immune checkpoint inhibitors (ICI) for cancer treatment suggests that cardiac MRI is able to show subtle therapy related treatment effects and can support evidence of a specific imaging pattern of ICI-related myocarditis. Also, cardiac MRI is the imaging modality of choice to show longterm, cardiotoxic effects of chemotherapy. It is considered the reference standard for measurement of ventricular volumes and function making it ideally suited to assess adverse cardiac remodeling after termination of cancer treatment.