Investigators have assessed whether specific tumor characteristics were associated with improved outcomes in patients with large B-cell lymphoma who received chimeric antigen receptor (CAR) T-cell therapy, according to a recent study published by Locke et al in Nature Medicine. The findings may help inform treatment selection in this patient population.
Background
CAR T-cell therapy has been shown to improve the treatment of certain hematologic malignancies. Initially approved for patients who didn’t respond to multiple lines of therapy, clinical trials have demonstrated that CAR T-cell therapy can be used as an earlier treatment option.
The ZUMA-7 trial compared axicabtagene ciloleucel anti-CD19 CAR T-cell therapy with standard high-dose chemotherapy followed by an autologous stem cell transplant in patients with recurrent or treatment-resistant large B-cell lymphoma. The patients who received axicabtagene ciloleucel therapy—designed to target the CD19 molecule on large B-cell lymphoma cells—experienced a 60% reduction in the risk of disease progression, the need for new therapy, or mortality compared with those who received standard therapy.
The positive findings from the trial led to the U.S. Food and Drug Administration’s approval of axicabtagene ciloleucel as second-line therapy for these patients. However, some patients who participated in the trial did not respond well to therapy or relapsed quickly after treatment.
Study Methods and Results
In the recent study, the investigators analyzed tumor gene expression patterns using the samples of patients with large B-cell lymphoma. They discovered that a B-cell gene expression signature and CD19 protein expression were significantly associated with improved event-free survival in patients treated with axicabtagene ciloleucel therapy but not in those treated with standard therapy.
The patients with lower tumor cell levels of CD19 had gene expression patterns associated with immune suppression, suggesting that the immune environment of the tumors may play an critical role in regulating axicabtagene ciloleucel therapy and outcomes. Additionally, biomarkers associated with improved outcomes to axicabtagene ciloleucel therapy decreased as the patients received more treatments. The investigators emphasized that receipt of axicabtagene ciloleucel therapy in earlier lines of treatment may be essential to ensure improved patient outcomes.
The investigators revealed that in the standard therapy group, the patients with a high tumor burden or elevated levels of the lactate dehydrogenase enzyme experienced shorter event-free survival. Further, the patients with a nongerminal center B cell–like molecular subtype of large B-cell lymphoma had poorer outcomes after receiving standard therapy. In contrast, molecular subtypes were not associated with outcomes in axicabtagene ciloleucel therapy, indicating that the treatment option may overcome some mechanisms of resistance to standard therapy.
Conclusions
“Knowledge of the immune contexture is essential for understanding mechanisms of action and likelihood of prolonged response to CAR T-cell therapy. Collectively, these data may help inform studies evaluating patient management based on tumor biology and biomarkers as well as the design of next-generation therapeutics,” concluded lead study author Frederick L. Locke, MD, Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at the Moffitt Cancer Center.
Disclosure: The research in this study was funded by Kite Pharma. For full disclosures of the study authors, visit nature.com.
