T-cell Immunotherapies Show Promise Amid Cardiotoxicity and Operational Challenges

Cancer treatment has evolved over time with recent advances expanding the options, including innovative approaches such as targeted therapies and immunotherapies. Immunotherapy now offers multiple modalities, including immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapies and T-cell engagers, providing more precise and personalized alternatives for many patients.

Chimeric antigen receptor (CAR) T cell therapy is an expanding class of cellular immunotherapy that uses adoptive transfer of genetically engineered T cells to augment efficient antitumour responses. Other T cell therapies — bispecific antibodies, tumour-infiltrating lymphocytes and T cell receptor-engineered T cells — can also cause cardiotoxicity, but the mechanisms and inflammatory pathways are distinct for each therapy.

Several T-cell engager therapies are currently approved in Canada, including Tarlatamab, Teclistamab, Glofitamab, Elranatamab and Talquetamab. These agents have created meaningful new options for patients with hematologic malignancies, particularly multiple myeloma and B-cell lymphomas and are now expanding into solid tumours, including small-cell lung cancer.

T cell immunotherapies, particularly CAR T cell therapy, carry a risk of cardiovascular toxicity, primarily driven by systemic inflammation and cytokine release syndrome (CRS). T cell activation can lead to massive cytokine release and excessive inflammation. Like other inflammatory syndromes, CRS can lead to cardiovascular complications, including arrhythmias, myocardial infarction and heart failure, with an incidence of cardiovascular events as high as 20% among patients who develop high-grade CRS.

CRS involves systemic inflammation including fever, low blood pressure, organ dysfunction and immune effector cell-associated neurotoxicity syndrome (ICANS) can manifest as confusion, seizures or tremors which can significantly impact the wellbeing and safety of patients. Data indicate the central role of IL-6 in the pathophysiology of CAR T cell-related adverse events, and IL-6 blockade with tocilizumab has been used to prevent and treat severe CRS.

A multidisciplinary team from William Osler Health System (Osler) recently shared findings from a retrospective evaluation examining the real-world use of T-cell engager therapy, with a focus on cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and the operational impact on care delivery. The evaluation reviewed outcomes for 30 patients treated within Osler's oncology program. CRS was the most common adverse event, occurring in 77 per cent of patients, often within 12 to 24 hours of the first dose. While most cases were manageable with supportive care and the administration of tocilizumab, an inflammation treatment drug, the team emphasized that early recognition and close monitoring remain essential.

CRS severity seems to be the strongest predictor of cardiotoxicity, and strategies aimed at preventing high-grade CRS could be key to lowering the risk of cardiovascular complications. T cell therapies have no cardiovascular contraindications, and pretherapy cardiovascular evaluation is highly individualized, including assessment of cardiovascular risk factors, pre-existing cardiovascular disease and previous exposure to cardiotoxic therapies.

Beyond clinical management, the findings highlighted a substantial need for hospital and clinical resources. Patients receiving T-cell engager therapy experienced an average inpatient length of stay of 11.4 days, impacting staffing, bed capacity, and system resources. These insights are particularly relevant as cancer programs explore the possibility of outpatient administration models and what that means for patient care. The question remains as to how to safely support patients that experience stronger adverse effects of treatment, both during regular hours and after hours with an outpatient model.

The work reinforced the importance of investing time and resources into preparation. The team used all the resources available including iHuddle boards to educate staff and created protocols to make sure education, monitoring, and escalation pathways were in place.

Overall, this real-world evaluation underscores that advancing innovative cancer therapies requires more than clinical efficacy alone. Safe and sustainable delivery depends on coordinated planning across clinical teams, pharmacy, nursing, operations, and research.