Louis Chesler, MD, PhD

Pediatric oncologist, Louis Chesler, MD, PhD, wants to treat childhood cancer using methods to reduce side effects that accompany high-dose treatments. The Oxford-Harrington Rare Disease Center Scholar and his co-investigator John Anderson, PhD, are equipping chimeric antigen receptor (CAR) T cells with molecular on/off switches that are sensitive to and compatible with other cancer drugs. The collaborators are testing molecular toggles, called iTags, activated by ImIDs (immunomodulatory drugs currently used in cancer therapy) to stop tumor growth.

The CAR T target is the B7H3 (CD276) cell-surface receptor, expressed on both adult and childhood cancer cells, which plays a key role in cancer development as an immune checkpoint. Because B7H3 has little to no expression on normal tissues, the approach minimizes side effects and allows normal physical growth in the children. To counter relapse and T cell exhaustion that occur with immunotherapies given to children with solid and brain tumors, the inventors are building in CAR T rest and recovery phases. The technology also enables specific targeting of CAR T to each tumor type, broadening the range of cancers that could be treated to include solid and brain tumors.

“Immunotherapies such as CAR T are showing real promise in the clinic,” Dr. Chesler says. “We are designing CAR T that could work optimally together with other effective drugs in order to maximize the effectiveness of immunotherapy.”

Although the approach using ImIDs and iTags to counter CAR T exhaustion is in the theoretical stage, Dr. Chesler and Dr. Anderson are continuing to experiment while awaiting critical data that will determine next steps.

“The ability to precisely control CAR T lifespan and prevent their exhaustion is a key tool for the use of cellular immunotherapies to effectively treat solid and brain cancers. We hope that our technological advances make CAR T therapy safer, more durable and effective to help move these exciting treatments forward more rapidly,” Dr. Anderson says.

“Our current work is on the right track to improving cancer survivability.”