Advances in the development of personalized neoantigen-based therapeutic cancer vaccines

Abstract

Within the past decade, the field of immunotherapy has revolutionized the treatment of many cancers with the development and regulatory approval of various immune-checkpoint inhibitors and chimeric antigen receptor T cell therapies in diverse indications. Another promising approach to cancer immunotherapy involves the use of personalized vaccines designed to trigger de novo T cell responses against neoantigens, which are highly specific to tumours of individual patients, in order to amplify and broaden the endogenous repertoire of tumour-specific T cells. Results from initial clinical studies of personalized neoantigen-based vaccines, enabled by the availability of rapid and cost-effective sequencing and bioinformatics technologies, have demonstrated robust tumour-specific immunogenicity and preliminary evidence of antitumour activity in patients with melanoma and other cancers. Herein, we provide an overview of the complex process that is necessary to generate a personalized neoantigen vaccine, review the types of vaccine-induced T cells that are found within tumours and outline strategies to enhance the T cell responses. In addition, we discuss the current status of clinical studies testing personalized neoantigen vaccines in patients with cancer and considerations for future clinical investigation of this novel, individualized approach to immunotherapy.

Abstract

Personalized neoantigen-based therapeutic vaccines hold promise as cancer immunotherapies. This Review provides an overview of the complex personalized neoantigen vaccine production process, vaccine-induced T cell responses and strategies to enhance these responses. Completed and ongoing clinical studies testing such vaccines are discussed, and considerations for future clinical investigation of this novel, individualized form of immunotherapy are outlined.

Key points

• Personalized therapeutic cancer vaccines predicated on neoantigens have been shown to be feasible, safe and immunogenic in patients with melanoma and glioblastoma.

• Different vaccine formats and delivery strategies are currently being tested in clinical studies involving patients with various tumour types.

• Deeper evaluation of the phenotypes, functionality and long-lasting memory potential of vaccine-induced neoantigen-specific CD4 ⁺ and CD8 ⁺ T cells is warranted to improve understanding of their therapeutic activity and optimize vaccination strategies.

• Neoantigen target discovery is continually being advanced to improve the identification of immunogenic neoepitopes that can be recognized by CD8 ⁺ T cells; algorithms for the more challenging task of predicting CD4 ⁺ T cell neoepitopes are also emerging.

• Innovative vaccine delivery platforms and the most effective timing of combinatorial therapies should be further explored to reduce costs and time delays and increase clinical efficacy.