Tandem CAR T cells do double duty.

“Solid tumors are complex and highly heterogenous,” says Meenakshi Hegde, MD, a pediatric oncologist who conducts translational immunotherapy research at the Baylor College of Medicine Center for Cell and Gene Therapy (Houston, TX). “In any given tumor, cells can be very different from each other. Some cells might express one type of molecule while others express other types of molecules. These variants can occur in a single patient and between patients, and they’re among the reasons why it’s so difficult to successfully treat solid tumor cancers.” 

These variants also are the reason Dr. Hegde believes the fight against cancer needs to be fought across multiple battlefronts. Toward this end and with a grant from Alliance for Cancer Gene Therapy, Dr. Hegde is advancing an innovative approach to cell engineering that’s designed to expand the reach and impact of CAR T-cell therapies. 

Today’s CAR T-cell therapy standard is achieved by genetically modifying a patient’s T cells to express chimeric antigen receptors (CARs) that enable them to seek, find and destroy a specific biomarker, such as the CD19 protein antigen that’s expressed by leukemia and lymphoma cancer cells. Dr. Hegde is taking this concept a step further, exploring ways to enable T cells to recognize more than one cancer-associated molecule at a time. 

Known as bispecific tandem CAR T cells, Dr. Hegde’s modified cells are designed to identify and respond to two different molecules simultaneously – the protein HER2 and the fatty sugar GD2, two molecules that are known to be present in many different types of cancers. Dr. Hegde uses a viral vector to carry the selected CAR molecules into the T cells. There, the CARs become part of the tandem T cell DNA. When the tandem T cells replicate, the CAR molecules appear in the new T cells, prompting them to continue the HER2 and GD2 search and destroy mission. 

With their ability to thrive and perform double duty on multiple cancer cell types, Dr. Hegde’s bispecific tandem CAR T cells are expected to lend themselves to broader clinical applications. To evaluate this theory, tandem CAR T cells were tested against HER2 and GD2 in melanoma and sarcoma on the laboratory benchtop and in animal models. 

The pre-clinical results of this Alliance-funded research are promising! Tandem CAR T cells replicated more robustly and killed more tumor cells than traditional, single molecule targeted CAR T-cell therapies. This progress has not yet been published in the literature, but the conceptual groundwork that led to the Alliance-funded portion of Dr. Hegde’s research was published in The Journal of Clinical Investigation and Molecular Therapy Nucleic Acids. 

The data generated by the Alliance-funded studies is now being used to pursue additional funding and prepare an application to the U.S. Food and Drug Administration for the next step in the progression of this research — a clinical trial to test the safety of this novel approach in humans. 

“Every time I conduct a clinical trial, there is so much hope,” says Dr. Hegde. “Regardless of the outcome, the parents (of my pediatric patients) always express thanks and appreciation. Even if their child does not benefit, they are thankful that new channels are being explored and they have faith that someday cell and gene therapies will save the lives of others. 

“I believe cell and gene therapies will evolve into a standard of care. We have a lot to learn and it may take years, but we’re moving in the right direction. 

“We already have enough data to prove the safety of cell and gene therapies. What we need now is to explore more targeted treatments for cancer through more preclinical studies and more well-designed clinical trials. Ultimately, I believe we will find that it takes an individualized combination of therapies to improve survival while reducing adverse side effects.”