Chimeric antigen receptor (CAR) T-cell therapy has proved to be a valuable treatment option for patients with lymphoma in whom other therapies have failed. In clinical trials, the cellular immunotherapy was shown to provide durable remissions for nearly 40% of patients with large B-cell lymphoma. Despite its success, CAR T-cell therapy may not be the best option for all patients due to their cancer prognosis and the risk for developing severe toxicities or treatment-related death.
In a new study published in Clinical Cancer Research, Faramand et al identified several possible factors that could help physicians know if patients are at higher risk for severe adverse events before they receive CAR T-cell therapy.
The development of immune-mediated toxicities, such as cytokine-release syndrome and neurotoxicity, remains a common challenge of CAR T-cell therapy. The immune boost associated with the treatment can also cause large amounts of cytokines to be released into the blood, which can cause a patient to develop a fever, increased heart rate, difficulty breathing, or low blood pressure.
“Identifying which [patients treated with] CAR T-cell therapy may be more susceptible to those severe toxicities before therapy could allow us to better tailor their care to mediate or reduce those adverse reactions,” said corresponding study author Marco Davila, MD, PhD, Associate Member of the Blood and Marrow Transplant and Cellular Immunotherapy Department and Medical Director of Cell Therapies at the H. Lee Moffitt Cancer Center & Research Institute.
Methodology
To better understand what may put a patient at higher risk for toxicities, researchers followed 75 patients with large B-cell lymphoma who were treated with the CAR T-cell product axicabtagene ciloleucel as the standard of care. Levels of serum cytokine and catecholamine, a type of neurotransmitter, were measured before receiving lymphodepleting chemotherapy prior to treatment, on the day of their CAR T-cell infusion, and daily thereafter during their hospitalization. Tumor biopsies were also performed before treatment to analyze gene expression of the tumor and its microenvironment.
KEY POINTS
- Patients with increased pretreatment levels of interleukin-6, an inflammatory molecule, had a higher risk for neurotoxicity and cytokine release syndrome from CAR T-cell therapy.
- The interaction between infused CAR T cells and the recipient's immune cells may determine the severity of the toxicities and suggest further studies on reducing inflammation and targeting the tumor microenvironment prior to therapy.
Results
The researchers found that patients with increased pretreatment levels of interleukin-6, an inflammatory molecule, had a higher risk for neurotoxicity and cytokine-release syndrome from CAR T-cell therapy. This group also had an elevated risk of death from the treatment.
“These patients experienced significant toxicities despite management with early cytokine blockade and steroids,” said first study author Rawan Faramand, MD, Assistant Member of the Blood and Marrow Transplant and Cellular Immunotherapy Department at Moffitt.
Tumor gene-expression data showed myeloid cells and regulatory T cells may also play an important role in the development of neurotoxicity and cytokine release syndrome. The researchers believe the interaction between infused CAR T cells and the recipient’s immune cells may determine the severity of the toxicities and suggest further studies on reducing inflammation and targeting the tumor microenvironment prior to therapy.
They concluded, “These results suggest that a pro-inflammatory state and an unfavorable tumor microenvironment preemptively put patients at risk for toxicity after CAR T-cell therapy. Tailoring toxicity management strategies to patient risk may reduce morbidity and mortality.”
Disclosure: This study was supported by a grant from the National Cancer Institute. For full disclosures of the study authors, visit clincancerres.aacrjournals.org.
