• Biotherapeutics

    Science Saturday: A new understanding of the inner workings of CAR-T cell therapy

T-cell engineering lab

Mayo Clinic researchers have biomanufactured chimeric antigen receptor-T cell therapy  (CAR-T cell therapy) in a new way to track the cells' cancer fighting journey and predict toxic side effects. This Mayo Clinic breakthrough, published in Cancer Immunology Research, also could unravel the mystery of how to unleash CAR-T cell therapy to destroy solid tumors.

Saad Kenderian, M.B., Ch. B.

"This new technology allows us to image CAR-T cells after they are given to patients and study their fate," says Saad Kenderian, M.B., Ch.B., a Mayo Clinic hematologist and researcher, and lead author. "This allows us to investigate strategies that could improve CAR-T cell trafficking and penetration into the tumor cells, and thus can improve tumor killing."

The research

Mayo Clinic researchers engineered CAR-T cells to express a sodium iodide symporter protein that could be imaged by a positron emission tomography (PET) scan in preclinical models. Investigators monitored in real time, tracking precisely how CAR-T cells multiplied and targeted cancer for destruction. This new imaging lays the foundation for strategies that could use CAR-T cell therapy to fight more types of disease.

"Until now, we have not had a clinically relevant imaging platform to monitor cell expansion and trafficking to tumor sites," says Dr. Kenderian. "We can show in mouse models that imaging by PET scans shows how CAR-T cells move, and when they increase in number and cause side effects. This new understanding may help us expand CAR-T cell therapy to more cancers so more patients can benefit."

A new type of regenerative immunotherapy

Immunotherapies unlock the body’s defense mechanisms to fight bacteria, viruses and diseases, including cancer. CAR-T cell therapy is a new type of regenerative immunotherapy that harnesses the body's defense system by genetically modifying cells, equipping them to go on search-and-destroy missions to kill cancer. These synthetic cells become a living drug that mobilizes through the body, continually tapping the immune system to attack disease.

CAR-T cell therapy has shown promise of therapeutic benefit in blood cancers

CAR-T cell therapy has shown promise of therapeutic benefit in blood cancers, and the Food and Drug Administration approved it for use in lymphoma, leukemia and most recently multiple myeloma patients. However, severe side effects and poor understanding of how CAR-T cell therapy can be effective on solid tumors are hurdles to overcome.

Mayo Clinic's Center for Regenerative Medicine and Center for Individualized Medicine are at the forefront of research and practice that seek to expand regenerative immunotherapy options to more types of cancers, and potentially neurological and autoimmune disorders.

"We have seen unprecedented therapeutic efficacy in clinical trials of CAR-T cell therapy in patients with some blood cancers, including B-cell acute lymphoblastic leukemia, B-cell non-Hodgkin lymphoma, B-cell chronic lymphoblastic leukemia, and multiple myeloma," says Dr. Kenderian. "However, wider adoption of CAR-T cell therapy is limited due to minimal activity in solid tumors and development of life-threatening toxicities."

Cytokine release syndrome is a potentially devastating side effect of immunotherapies such as CAR-T cell therapy. It may cause severe reactions, including nausea, rapid heartbeat, low blood pressure, problems breathing and, in some cases, can be fatal.

While this new discovery in CAR-T cell imaging may help overcome hurdles of toxic side effects and limited efficacy in malignancies beyond blood cancers, additional study is needed to verify these findings. The next step is to test this platform in phase 1 clinical trials of CAR-T cells to monitor their movement and expansion in patients to understand how cells fail.

Reona Sakemura, M.D., Ph.D., a Mayo Clinic hematology researcher, is first author of this study. This study was conducted in collaboration with Stephen Russell, M.D., Ph.D., and Kah Whye Peng, Ph.D., who have developed and studied the use of sodium iodide symporter protein in clinical trials using oncolytic viruses and gene therapy.