Study Reveals Actionable Findings for Improving CAR T-Cell Longevity in Patients with Acute Lymphoblastic Leukemia

Researchers uncovered that children with acute lymphoblastic leukemia (ALL) who had durable remission had more type 2 T cells, which prompt the body’s immune response to cancer. The findings, which were published in Nature, offer valuable insight that could lead to better long-term outcomes for more patients.

Background

Currently, roughly half of patients with ALL who respond to CAR T-cell therapy experience a relapse within 12 months. Because of this challenge, the researchers began investigating the molecular determinants of CAR T-cell longevity. “The initial response rates for CAR T-cell therapy for ALL were that 93% of patients had achieved a complete response, but what we’ve learned from treating more patients over the years is that not all patients have sustained remission,” says J. Joseph Melenhorst, PhD, lead researcher for the study, Director of Cell Therapy and Immuno-Engineering Program, and Vice Chair of Center for Immunotherapy and Precision Immuno-Oncology at Cleveland Clinic.

Dr. Melenhorst was part of a team that began studying CAR T cells back in 2012 while at the University of Pennsylvania. Since then, he and his colleagues have studied those patients’ immune responses to identify factors that lead to enduring remission.

Study design

To ascertain the molecular factors that led to ultralong CAR T-cell durability, the researchers generated a single-cell multi-omics atlas from 695,819 pre-infusion, CD19-directed CAR T-cell products. These cells were analyzed either at baseline or following in vitro CAR stimulations, and were derived from 82 pediatric and young adult patients with relapsed/refractory ALL who were enrolled in early CAR T-cell studies, as well as CAR T cells generated from six healthy donors. Through analysis of the expression profile of these cells, they discovered that higher type 2 functionality in the infused products was highly correlated with patients who achieved remission for [an average of] 8.4 years.

The research team further assessed the cells to better understand the mechanisms driving early immune activation. Their theory was that CAR T cells with enhanced type 2 functionality were more able to preserve central memory, making them more able to persist in the body after activation.

Key findings

The team demonstrated that CAR T cells with low type 2 can be strengthened by incorporating IL-4 during the product manufacture or by priming the cells with IL-4 prior to infusion. In preclinical models, Dr. Melenhorst's team was able to demonstrate that pre-treating CAR T cells with IL-4 resulted in higher survival rates. “We didn’t just develop and validate a novel biomarker,” says Dr. Melenhorst. “We actually found a way to make CAR T cells do their job again.”

In vivo studies proved that both methods of strengthening low type 2 CAR T-cells were notably effective in enhancing antitumor response.

The team was initially surprised by the findings. “At first we couldn’t believe that type 2 had this impact, because we tend to think of type 1 as killer cells and type 2 in terms of antibody-mediated response, so we ran a validation cohort and the results hold true,” says Dr. Melenhorst. “This was unexpected and is very exciting because it’s such an actionable finding.”

What’s next

Building on these findings, the researchers are pursuing a phase 1 trial to evaluate how restoring pathways in T cells impacts the overall response.

This work may also have positive implications for CAR T-cell therapies for other blood cancers. “Although there are differences in the signatures of diseases like ALL, there are still a lot of commonalities across ALL, chronic lymphocytic leukemia and multiple myeloma where there is a high correlation between memory cells and CAR T-cell durability,” says Dr. Melenhorst.