Dual-antigen recognition could improve cancer immunotherapy

Creating T cells that recognize two different antigens on the surface of a tumor cell rather than just one could make the targeting of immunotherapy more precise and spare more normal cells.

In adoptive cell transfer, a person's own immune-system T cells are genetically modified to recognize a certain antigen on the surface of a cancer cell. Once the T cells are infused back into the patient, they attack the cancer cells.

Adoptive cell therapies have been effective in the treatment of melanoma and indolent B-cell malignancies, but their broad applicability is limited by a lack of truly tumor-specific target antigens, explained Michel Sadelain, MD, PhD, and colleagues in Nature Biotechnology (2012;31[1]:71-76). Yet there are very few antigens, if any, that are found only on cancer cells.

“We are getting better at working these T cells and enhancing them so that we can get a powerful immunological response against cancer,” commented Sadelain in a separate statement issued by Memorial Sloan-Kettering Cancer Center, New York, New York, where he is director of the Center for Cell Engineering. “The dilemma now is that we are concerned with limiting these responses and making them as targeted as possible to avoid potentially harmful side effects.”

In an effort to better train T cells to specifically attack cancer cells without damaging healthy tissue, Sadelain's group is exploring the concept of creating T cells that recognize two different antigens found on a tumor cell. This signature would be unique to a given type of cancer, and the T cells would attack only those cells that express both antigens.

The new technique makes use of two types of receptors: Chimeric antigen receptors (CARs) allow T cells to target antigens on the surface of a tumor cell, and chimeric costimulatory receptors (CCRs) are used by T cells to recognize a second antigen. The investigators created T cells that carried a CAR and a CCR for two antigens found on prostate cancer cells, and infused the engineered T cells into mice with prostate cancer. The T cells attacked only tumors that carried both antigens.

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