Biomarker analysis and studies of pharmacokinetics, pharmacodynamics, and T-cell composition show certain T-cell characteristics are linked with outcomes and toxicity with axicabtagene ciloleucel in large B-cell lymphoma.
Analysis of product features of axicabtagene ciloleucel (axi-cel; Yescarta) in patients with relapsed/refractory large B-cell lymphoma from the phase 3 ZUMA-7 trial (NCT03391466) revealed that T-cell attributes were closely linked with tumor burden, efficacy outcomes, peak levels of proinflammatory cytokines, and toxicities such as neurologic events (NEs) and cytokine release syndrome (CRS), according to data presented during the American Association for Cancer Research (AACR) 2022 Annual Meeting.1
Specifically, CCR7-positive/CD45RA-positive T cells that expressed CD27 and CD28 were associated with all efficacy metrics, including durability or response. Products with central memory T cells, defined as CCR7 positive and CD45RA negative, were linked with higher levels of proinflammatory cytokines and CRS of grade 2 or greater. Finally, CCR7-negative/CD45RA- negative, or differentiated, T cells were negatively associated with efficacy and were further linked to higher peak levels of additional proinflammatory serum molecules and high levels of grade 3 or greater neurologic events.
“The quality of the T cells appears to matter more than the quantity in the ZUMA-7 clinical trial,” Jason Westin, MD, director of the Lymphoma Clinical Research and section chief of Aggressive Lymphoma in the Department of Lymphoma/Myeloma, Division of Cancer Medicine of The University of Texas MD Anderson Cancer Center in Houston, said in a presentation of the data. “We found that optimizing the product composition towards the juvenile T-cell phenotype to find a CCR7-positive, CD45RA-positive, CD27-positive, and CD28-positive [product] may improve the axi-cel therapeutic index.”
Axi-cel is an autologous anti-CD19 CAR T-cell that was investigated in the phase 1/2 ZUMA-1 trial (NCT02348216), which examined axi-cel as therapy in adults with aggressive refractory non-Hodgkin lymphoma. In the trial, CAR T-cell peak expansion was associated with overall response rate, durability of response, and NEs. These findings also revealed associations of CCR7/CD45RA positivity with efficacy and toxicity outcomes, prompting investigators to further investigate these attributes in ZUMA-7.
Outcomes of ZUMA-7 showed event-free survival (EFS) improvement in 60% of patients with relapsed/refractory LBCL who were being treated with axi-cel as second-line treatment vs standard of care (HR, 0.398; 95% CI, 0.308-0.514; P <.0001)2 and led to recent approval of the therapy in this setting. Notably, the rates of toxicities in ZUMA-7 were much lower compared with ZUMA-1, specifically NEs of grade 3 or greater (21% vs 32%, respectively) and CRS of grade 3 or greater (6% vs 11%, respectively). Samples from a total of 170 patients were used for biomarker analyses and pharmacokinetic (PK), pharmacodynamic (PD), and T-cell composition studies were performed.
The PK profile between the 2 studies were consistent, with peak CAR T-cell expansion occurring around 7 days following infusion with a rapid decline thereafter. Peak levels of CAR T-cells were slightly higher in ZUMA-1 at 38.3 cells/μl (IQR, 14.7-83.0) vs 25.84 cells/μl (IQR, 8.15-57.93) in ZUMA-7, but time to peak was 8 days in both studies.
Notably, tumor regression was associated with peak CAR T-cell expansion, but this did not necessarily translate to durability or response in the second-line setting. “What that means is patients who had any response vs no response had a much higher peak CAR T-cell level. However, [when comparing] those with a durable or ongoing response vs those who have progression after initial response, we unfortunately do not see any difference in the CAR T-cell levels. Therefore, the peak levels do not predict for durability of response,” Westin explained.
Looking at toxicities associated with CAR T-cell therapy, grade 3 or greater CRS was not statistically significantly associated with higher levels of peak CAR T-cell expansion, although Westin pointed out that these results could be unreliable due to a small patient sample. Conversely, grade 3 or greater NEs were significantly associate with higher peak levels of CAR T cells.
Serum PD analytes of chemokines and cytokines within the blood revealed associations with CRS and NEs in both ZUMA-1 and ZUMA-7, namely that more differentiated cells tended to have a positive association with more toxicities. CCR7-positive/CD45RA-negative, or central memory T cells, were positively associated with the toxicities with the higher Spearman R. Additionally, CCR7-negative T-effector memory cells and T-effector cells were also correlated with increased toxicity.
Products enriched with CCR7-positive/CD45RA-positive naïve T cell were significantly associated with durable response (P = .0408). Patients with a higher proportion of naïve T cells also had improved EFS (P = .0264), although Westin pointed out that axi-cel was favorable vs chemotherapy regardless of this biomarker (P <.0001).
Poor responses could be characterized by T-cell products exhibiting pronounced effector phenotypes with exhaustion markers. Lower levels of CD27/CD28-negative, PD-1/TIM-3/CD8-positive, or exhausted T cells, were linked with better EFS (P = .0156). On the other hand, high levels of CD27/CD28/PD-1/TIM-3/CD8-positive T cells, or juvenile phenotypes, were correlated with better EFS (P = .0127).
“When we look at the T cells within the axi-cel product, we find that CAR-positive and CAR-negative naïve T cells were associated with improved outcomes and more differentiated and exhausted T cells were associated with worse outcomes,” Westin concluded.