Personalized T cell-mediated cancer immunotherapy: progress and challenges

- Patient-specific mutated neoantigens are important targets of anti-tumor immunity.
- Personalized immunotherapies that target neoantigens may be safer and more effective.
- Personalizing T cell-mediated immunotherapies will require efficient platforms for neoantigen and T cell receptor discovery.
- TCR repertoire analysis may be an inroad for identifying targets of immunity against low mutational burden cancers.
- Personalized immunotherapies present novel regulatory and logistical challenges.

Immunotherapies are yielding effective treatments for several previously untreatable cancers. Until recently, vaccines and adoptive cell therapies have been designed to target public tumor antigens common to multiple patients rather than private antigens specific to a single patient. Due to the difficulty of identifying public antigens that are expressed exclusively on tumor cells, these studies have yielded both clinical successes and serious immune-related adverse events. Multiple avenues of research now underscore the centrality of tumor-specific mutated private antigens to endogenous anti-tumor immunity. Immunotherapies that target these neoantigens may enable safer and more durable tumor regression, but personalized targeting presents a number of challenges. Foremost among these is to develop processes that accelerate advancement from neoantigen discovery to use of these neoantigens as vaccines or as targets for adoptive cell therapies. Exome sequencing has facilitated discovery of neoantigens for melanoma and other highly mutated cancers. New technologies - possibly proceeding from T cell receptor repertoire sequencing - are needed to identify antigens for cancers with low mutational burden and few neoantigens. In this review, we discuss progress toward personalizing T cell-mediated immunotherapy for cancer as well as challenges going forward.

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