Car rates

Axi-cel’s T cell attributes correlate with large B-cell lymphoma outcomes

According to an analysis of the ZUMA-7 clinical trial, CCR7-positive and CD45RA-positive T cells that expressed CD27 and CD28 appear to be associated with all measures of efficacy, including durability or response.

In the ZUMA-7 Phase 3 clinical trial (NCT03391466), researchers analyzed product characteristics in patients with relapsed/refractory large B-cell lymphoma and showed that T-cell attributes were closely related to tumor burden, efficacy outcomes, peak levels of pro-inflammatory cytokines and toxicities such as neurological events (EN) and cytokine release syndrome (CRS).1

According to data presented at the 2022 AACR Annual Meeting, CCR7-positive/CD45RA-positive T cells that expressed CD27 and CD28 were specifically associated with all measures of efficacy, including durability or response. Products containing central memory T cells, defined as CCR7 positive and CD45RA negative, were associated with higher levels of pro-inflammatory cytokines and grade 2 or higher CRS. Finally, CCR7-negative/CD45RA-negative or differentiated T cells were negatively associated with efficacy and were further linked to higher peak levels of additional serum pro-inflammatory molecules and higher levels of grade neurological events. 3 or more.

“The quality of T cells appears to matter more than quantity in the ZUMA-7 clinical trial,” said Jason Westin, MD, director of clinical lymphoma research and aggressive lymphoma section chief at the Department of lymphoma/myeloma, division of Cancer Medicine at the University of Texas MD Anderson Cancer Center in Houston, said in a presentation of the data. “We found that optimizing the composition of the product 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 studied in the Phase 1/2 ZUMA-1 trial (NCT02348216), which investigated axi-cel as a treatment in adults with aggressive refractory non-Hodgkin’s lymphoma. In the trial, maximal CAR T cell expansion was associated with overall response rate, response durability, and NE. These results also revealed associations between CCR7/CD45RA positivity and efficacy and toxicity outcomes, prompting researchers to further investigate these attributes in ZUMA-7.

ZUMA-7 results showed improved event-free survival (EFS) in 60% of patients with relapsed/refractory LBCL who were treated with axi-cel as second-line therapy compared to standard therapy (HR , 0.398, 95% CI, 0.308-0.514; P <.0001>2 and led to the therapy’s recent approval in this setting. Notably, toxicity rates in ZUMA-7 were much lower compared to ZUMA-1, particularly EN grade 3 or greater (21% versus 32%, respectively) and CRS grade 3 or greater (6% versus 11%, respectively). ). Samples from a total of 170 patients were used for biomarker analyzes and pharmacokinetic (PK), pharmacodynamic (PD) and T cell composition studies were performed.

The PK profile between the 2 studies was consistent, with a peak in CAR T cell expansion occurring approximately 7 days after 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) versus 25.84 cells/μl (IQR, 8.15-57.93 ) in ZUMA-7, but the time to peak was 8 days in both studies.

Notably, tumor regression was associated with maximum CAR T cell expansion, but this did not necessarily translate to durability or response in the second-line setting. “This means that patients who had a response versus no response had a much higher peak level of CAR T cells. However, [when comparing] those with a durable or continued response versus those with progression after the initial response, unfortunately we see no difference in CAR T cell levels. Therefore, peak levels do not predict response durability” , Westin explained.

Regarding toxicities associated with CAR T-cell therapy, CRS grade 3 or higher was not statistically significantly associated with higher levels of maximum CAR T-cell expansion, although Westin pointed out that these results may not be reliable due to a small sample of patients. Conversely, grade 3 or higher ENs were significantly associated with higher peak levels of CAR T cells.

Serum PD analytes of chemokines and blood cytokines revealed associations with CRS and NEs in ZUMA-1 and ZUMA-7, namely, 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 toxicities with the higher Spearman R.

CCR7-positive/CD45RA-positive naïve T-cell enriched products were significantly associated with a durable response (P = 0.0408). Patients with a higher proportion of naïve T cells also had improved SES (P = 0.0264), although Westin pointed out that axi-cel was supportive of 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 depleted T cells were associated with better SES (P = 0.0156). On the other hand, high levels of CD27/CD28/PD-1/TIM-3/CD8 positive T cells, or juvenile phenotypes, were correlated with better SES (P = 0.0127).

“When we look at the T cells in the axi-cel product, we find that naïve CAR-positive and CAR-negative T cells were associated with better outcomes and more differentiated and exhausted T cells were associated with poorer outcomes. “, concluded Westin.

Reference

1. Filosto S, Vardhanabhuti S, Canales M, et al. Axicabtagene ciloleucel (axi-cel) product attributes differentially associated with efficacy and toxicity in second-line large B-cell lymphoma. Presented at the 2022 American Association for Cancer Research (AACR) Annual Meeting; April 8-13, 2022; Abstract CT004.

2. Locke F, Miklos DB, Jacobson CA, et al. Primary Analysis of ZUMA-7: A Randomized Phase 3 Trial Comparing Axicabtagene Ciloleucel (axi-cel) to Standard of Care in Patients With Relapsed/Refractory Large B-Cell Lymphoma. Blood. 2021;138(supplement 1):2. doi:10.1182/sang-2021-148039