Early induction of cytokines, specifically elevated serum interleukin-2 (IL-2) within the first days following CAR T-cell therapy infusion, is strongly associated with subsequent rapid and robust CAR T-cell expansion in patients with leukemia or lymphoma treated with axicabtagene ciloleucel (axi-cel; Yescarta) or brexucabtagene autoleucel (brexu-cel; Tecartus). This finding, from a multi-study analysis presented at the 2024 SITC Annual Meeting, suggests that early IL-2 levels could serve as a predictive biomarker for CAR T-cell activity.
Other cytokines, including interferon gamma (IFN-γ) and GM-CSF, also showed predictive capabilities, but linear modeling indicated that early IL-2 was the strongest predictor of CAR T-cell expansion. Notably, IL-2 maintained a strong connection to expansion even at day 7 post-infusion.
Biomarker Potential of IL-2
According to Chad Williams, PhD, senior scientist at Kite Pharma and first author of the study, monitoring serum IL-2 could facilitate early detection of CAR T-cell expansion and acute clinical activity. This is particularly relevant because detecting CAR T cells early post-infusion is challenging, often requiring sufficient immune cell counts in peripheral blood via PCR or flow cytometry.
The study authors emphasized the importance of establishing a reliable biomarker for early detection of CAR T-cell expansion to improve real-time monitoring of CAR activity. Using serum cytokines or product phenotype leverages knowledge of product attributes or non–cell-based measurements post–CAR T-cell infusion to predict CAR expansion before it occurs in the patient.
Study Details and Findings
The analysis included data from over 700 patients treated with axi-cel or brexu-cel across multiple clinical trials, including ZUMA-1, ZUMA-2, ZUMA-3, ZUMA-5, ZUMA-7, and ZUMA-12. Researchers assessed serum levels of 27 cytokines within the first week of CAR T-cell therapy and used linear regression modeling to identify cytokines associated with CAR T-cell expansion at peak and day 7.
Cross-study linear modeling revealed that CAR T-cell product phenotypes associated with expansion were less predictive than serum cytokines. While less-differentiated CCR7-positive and CCR7+CD45RA-positive T cells showed positive associations with CAR T-cell expansion, these associations were weaker than those of serum cytokine levels following CAR T-cell infusion. Furthermore, less differentiated CCR7-positive or naive CD4-positive T cells were best associated with high levels of IL-2 at days 1 and 3. Product phenotype was more strongly associated with early levels of in vivo cytokines than CAR T-cell expansion.
LASSO modeling of day 7 CAR T-cell expansion, using product phenotype and serum cytokines, validated the linear modeling results, confirming the strong association between early IL-2 and IFN-γ levels and CAR T-cell expansion. Although CAR T-cell product features, such as the number of CCR7-positive T cells, were consistently associated with CAR T-cell expansion, the levels were lower than those observed in patients with early cytokine levels.
Implications for CAR T-Cell Therapy
The study highlights the complexity of factors mediating robust CAR T-cell expansion, suggesting that biomarkers closer to the expansion event, like early IL-2, are better predictors than product phenotype. These findings could refine monitoring strategies and potentially guide interventions to optimize CAR T-cell therapy outcomes.
