CAR-T Cell Therapy Researcher Aims to Help Leukemia Patients Avoid Relapse

Precursor B-cell acute lymphoblastic leukemia (pre-B-ALL) is the most common pediatric malignancy with a survival rate of over 90%, thanks to updated modern chemotherapy regimens and prognostication.

Still, there is a subset of pediatric patients who either relapse or don’t respond to chemotherapy. Historically, their only option has been a hematopoietic stem cell transplant, which can lead to significant morbidity and mortality. Chimeric antigen receptor (CAR) T cell therapy has transformed therapeutic options for patients with relapsed/refractory pre-B-ALL. However, despite initial response, an estimated 40% to 50% of responders relapse after CAR-T cell therapy.

Vanessa Ann Fabrizio, MD, MS, a Children’s Hospital Colorado bone marrow transplant and cell therapy physician, is a leading researcher investigating ways to improve these outcomes.

Dr. Fabrizio and her team are researching ways to improve the persistence of CAR-T cells by characterizing the T cell phenotype at the time of T cell collection in the heterogenous, real-world setting. Her team was recently awarded a grant to further this work from Hyundai Hope on Wheels, a program sponsored by the car manufacturer, which supports innovative childhood cancer research projects.

In CAR-T cell therapy, a patient's T cells are engineered to target a protein called CD19 on the leukemia cells. The researchers suspect that more "naive" and less "exhausted" T cells will be more effective because these cells can multiply better, live longer and fight cancer cells more efficiently. “We believe that in order for patients to maintain remission, the CAR-T cells must persist to provide long-term immune surveillance against cancer recurrence,” says Dr. Fabrizio.

Naive T cells can also become memory cells that help protect against future occurrences of the disease. “Our hypothesis is based on prior research studies that have demonstrated that naive T cell subsets enhance persistence in vivo with adoptive transfer and persistence is inversely linked to exhaustion,” says Dr. Fabrizio.

Relapse after CAR-T cell therapy

According to Dr. Fabrizio, there are several different mechanisms that are thought to lead to cancer relapse post-CAR-T cell therapy:

• Antigen loss: The tumor cells no longer express the CAR-T cell target antigen that recognizes and kills the cancer cells.
• Limited Persistence: CAR-T cells can experience limited persistence or exhaustion where they are still able to recognize the cancer cells but do not persist long enough to continue surveillance and eradicate any new leukemic cells that arise.

Using a technology called CyTOF (an advanced flow cytometry technique), the researchers will analyze T cells from patients' blood samples at the time of leukapheresis to identify specific phenotypes and correlate this with clinical outcomes.

Dr. Fabrizio’s research focuses on real-world patients, not just clinical trial participants, aiming to benefit children with pre-B-ALL who have limited treatment options after relapse. The researchers anticipate direct translation, with plans to integrate findings of how to design the most potent, persistent T cell subsets into the next generation of CAR-T cell trials. “We hope researchers who are studying CAR-T cells in the lab and are creating new generations of this therapy will be able to benefit from this knowledge by creating CAR-T cell products that are enriched for the most potent, persistent T cell subsets,” says Dr. Fabrizio.