Project Term
–
Project Summary
On the basis that T-cell acute lymphoblastic leukemia (T-ALL) cells overexpress IL-7 receptor (IL7R), which promotes chemotherapy resistance and relapse, we developed IL7R-targeted chimeric antigen receptor (CAR) T cells with low- and high-affinity single-chain variable fragments (scFvs). Following extensive investigation, we established the antitumor efficacy of low-affinity IL7R CAR against T-ALL cells in vitro, in vivo and against patients’ T-ALL blasts using their own T cells transduced with IL7R CAR. With data establishing tumor specificity and antitumor efficacy, and a novel manufacturing method of ‘natural selection’ to seamlessly manufacture a large number of IL7R CAR T cells from patients with T-ALL, we are now proceeding with Investigational New Drug studies to initiate a phase I clinical trial in 2025 Q4.
Lay Abstract
T-ALL is an aggressive cancer, accounting for 10-15% of children and 20-25% of adults with ALL. More than 50% of adults and up to 10% of children with T-ALL experience recurrent disease after their initial treatment, highlighting an unmet clinical need. Since T-ALL cancer cells have high levels of IL7 receptor (IL7R), which is linked to chemotherapy resistance and disease relapse, we developed a specialized immune cell therapy called chimeric antigen receptor (CAR) T cells targeting IL7R, and showed that they can effectively eradicate cancer cells. Based on this promising result, we now propose to conduct a phase I clinical trial with IL7R CARs to treat children and adults with T-ALL.
Although an antibody targeting the IL-7/IL7R axis may be beneficial, these antibodies don’t specifically target cancer cells and can cause harmful side effects, which led us to develop IL7R CAR T cells. However, since IL-7 receptor is also found on healthy T cells and plays a key role in their survival, we were initially concerned whether we can successfully manufacture IL7R CAR T cells that are effective against patients’ cancerous T-ALL cells. Our extensive data to date, testing various versions of CAR T cells using multiple donor and patient T cells, shows that a low-affinity IL7R CAR minimizes the risk of attacking healthy T cells (fratricide) and can be reliably manufactured for clinical trials. To further enhance safety, we created a built-in control mechanism that allows us to turn off or adjust IL7R CAR T cells if needed. In our lab studies, this safety switch was able to fine-tune the activity of CAR T cells and their cancer-fighting ability, ensuring better control over treatment.
Furthermore, our convincing data supporting the use of IL7R CARs in clinical trials (manuscript draft ready to be submitted along with final application) was reviewed by our institution’s scientific and clinical reviewers, and we were awarded an MSK Technology Development Award along with other funds to complete IND (Investigational New Drug) studies (~$1M). This peer review and the support facilitated by the institution attests to the strength of our data, and the IND process which is already in progress to initiate the trial.
The clinical trial plasmid construction is completed, IND studies are initiated, and a clinical trial protocol is being written by the Principal investigator (PI) and Co-PI of this proposal, who are experts and leaders in immune effector cell therapy and T-cell malignancies in the world. We anticipate IND studies to be completed to obtain all regulatory (IRB and FDA) approval with a goal to initiate the trial in Q4 of 2025. We plan to finish the first phase of our clinical trial by 2028 while also running additional research studies from the trial to gather more insights, to move forward to a phase 2 clinical trial.
Program
