Donor T Cells May Enhance Immunotherapy

A new study suggests that T cells from healthy donors recognize many neoantigens—mutant peptides on the surface of tumor cells, formed as a result of DNA damage–that are often neglected by a patient's own immune system (Science 2016;352:1337–41). As such, it may be possible to “outsource” neoantigen-induced immune reactivity to donor T cells, and thereby enhance patients' response to immunotherapy.

In a healthy immune system, the T-cell receptor (TCR) of each T cell has the capacity to recognize a different peptide, explains co–senior author Ton Schumacher, PhD, of the Netherlands Cancer Institute in Amsterdam: The body's own peptides are overlooked, while foreign or mutated peptides trigger T cells to proliferate and mount an attack. However, in the weakened immune system of a patient with cancer, endogenous T cells may lose their ability to recognize tumor-expressed neoantigens as foreign. In this setting, according to this proof-of-principle study, outfitting patient T cells with TCRs from healthy donor T cells that recognize specific neoantigens on their tumors could be a feasible strategy.

Schumacher and his colleagues used whole-exome and RNA sequencing to map all possible neoantigens on tumor cells from a patient with melanoma. They found 126 candidates, only two of which were recognized by the patient's own tumor-infiltrating T cells. However, in T cells cultivated from a healthy donor, they were able to induce immune reactivity to five of these neoantigens.

Similarly, of 154 neoantigens mapped by the researchers in another patient with melanoma, none were detected by the patient's T cells, but immune responses to six were induced among T cells from four healthy donors.

The investigators then sequenced TCRs on the most immune-reactive T cells from three donors, reconstructed these TCRs, and expressed them in healthy peripheral blood T cells. Through this TCR gene transfer approach, the team successfully redirected the specificity of peripheral blood T cells to recognize melanoma cells harboring the relevant neoantigens.

This study reveals “a neglected repertoire of neoantigens on human tumors that can potentially be seen by T cells,” Schumacher says. “The moment we are able to induce T-cell recognition of these antigens, we can expect to boost the reactivity of the currently used immunotherapies.”

The findings may help in the development of antigen-specific adoptive T-cell therapies, notes Cassian Yee, MD, a melanoma specialist at The University of Texas MD Anderson Cancer Center in Houston.

“Outsourcing immune responses to a donor would mean we are no longer limited to trying to validate or identify immune-reactive T cells in cancer patients, who often lack sufficient T cells capable of recognizing neoantigens,” says Yee. “That can be a major barrier to developing these new therapies.”

Developing an efficient gene delivery system is the next step for researchers before the outsourcing principle can be tested in humans, says Schumacher.

“The current gene transfer methods are generally lentivirus- or retrovirus-based, and production of these vector systems is slow and costly,” he says. “We need an efficient and relatively low-cost system in order to deliver donor TCRs into patients' T cells.” –Janet Colwell

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