An international research team has analyzed tumor gene expression patterns from patient samples and determined that a B-cell gene expression signature and CD19 protein expression were significantly associated with improved event-free survival for patients treated with axi-cel CAR T but not standard therapy. Patients with lower tumor cell levels of CD19 had gene expression patterns associated with immune suppression.

These observations suggest that the tumor immune environment may play an important role in regulating axi-cel therapy and outcomes. In addition, biomarkers associated with improved outcomes to axi-cel therapy decreased as patients had more treatments, suggesting that receipt of axi-cel in earlier lines of treatment is essential to ensure better patient outcomes, according to the scientists who published their study “Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma” in Nature Medicine.

“The phase III ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC,” write the investigators. “B cell gene expression signature (GES) and CD19 expression associated significantly with improved event-free survival for axi-cel but not SOC. Axi-cel showed superior event-free survival over SOC irrespective of B cell GES and CD19 expression.

Inter-relation between malignant cell features and immune contexture

“Low CD19 expression in malignant cells correlated with a tumor GES consisting of immune-suppressive stromal and myeloid genes, highlighting the inter-relation between malignant cell features and immune contexture substantially impacting axi-cel outcomes. Tumor burden, lactate dehydrogenase and cell-of-origin impacted SOC more than axi-cel outcomes. T cell activation and B cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy.

“These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.”

Within the standard therapy group, the researchers discovered that patients who had a high tumor burden or elevated levels of the enzyme lactate dehydrogenase had shorter event-free survival. Additionally, patients with a nongerminal center B cell-like molecular subtype of large B-cell lymphoma had poorer outcomes with standard therapy.

In contrast, molecular subtypes were not associated with axi-cel outcomes, suggesting axi-cel may overcome some mechanisms of resistance to standard therapy.

“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,” said Frederick L. Locke, MD, chair of the blood and marrow transplant and cellular immunotherapy department at the Moffitt Cancer.

(This study was funded by Kite, a Gilead Company).

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