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.

Fig. 1. Personalized neoantigen-based vaccination has the potential to induce long-lasting tumour-specific memory T cell populations.

Following vaccination, both neoantigen-specific CD4⁺ T cells and CD8⁺ T cells are induced either de novo or through boosting of existing neoantigen-specific T cell responses. These T cells proliferate and kill tumour cells expressing the neoantigen. As tumour cells are eliminated, the release of tumour antigens might contribute to epitope spreading and thus an increased breadth of the tumour-specific T cell response. Following tumour eradication, the responding T cell populations contract, although subpopulations persist as components of the memory T cell pool. Indeed, vaccine-induced neoantigen-specific T cells have the potential to generate long-lived central memory T (T_CM) cells and effector memory T (T_EM) cells. Whether neoantigen-based vaccination can generate tissue-resident memory T (T_RM) cells or peripheral memory T (T_PM) cells remains unknown.

Fig. 2. Roles of neoantigen-specific CD4⁺ T cells following therapeutic vaccination.

CD4⁺ T cells have many roles in the vaccine-induced antitumour immune response. By interacting with dendritic cells and enhancing antigen cross-presentation, CD4⁺ T cells perform the well-described roles of providing ‘help’ in the generation of the antitumour cytotoxic CD8⁺ T cell responses. CD4⁺ T cells can also produce many cytokines, including IFNγ and TNF, that stimulate and modulate immune responses. In addition, other types of immune cell with potential antitumour activity, such as macrophages, can be recruited as a result of CD4⁺ T cell-related responses. Interestingly, cytotoxic gene-expression signatures have been observed in neoantigen-specific CD4⁺ T cells induced following therapeutic vaccination, which indicates that these cells might contribute to the elimination of tumours with upregulation of MHC class II (MHC II) proteins (dashed arrow); however, whether vaccine-induced neoantigen-specific CD4⁺ T cells do indeed have this capacity needs to be investigated further.

Fig. 3. Considerations relating to therapeutic neoantigen vaccine regimens.

Various factors should be considered during the design of therapeutic vaccination regimens. Following sample collection, the time required to generate the personalized vaccine is a crucial factor, particularly in the metastatic disease setting. The manufacturing time is dependent on the choice of vaccine platform, as indicated for the various platforms listed along the red arrow. However, while the personalized vaccine is being designed and manufactured, combinatorial therapies can be administered to the patient with the aim of fostering a favourable immunological milieu. Adjunctive therapies can also be given either at the time of or following vaccination to enhance the immune response. Additional variables include the route of administration of the vaccine and any combination therapies, as well as the number of booster vaccinations. In the case of disease recurrence, tumour DNA sequencing can be repeated (for example, to understand why the vaccine was ineffective for long-term tumour control and/or to identify potential alternative neoantigens), and vaccine-induced T cell responses can be evaluated using both blood and tumour samples to inform decisions regarding subsequent therapy. FLT3L, Fms-related tyrosine kinase 3 ligand; GM-CSF, granulocyte–macrophage colony-stimulating factor.

Fig. 4. Algorithm-based identification of neoantigens for use in therapeutic vaccines.

Many areas of advancement might improve the efficacy of personalized vaccines, as indicated in this figure. For example, the identification of targetable neoantigens could be improved through development of better prediction algorithms. Various vaccine modalities and dosing schedules could be explored to generate maximally effective antitumour immune responses. Importantly, detailed assessments of the characteristics of the immune responses induced by vaccination could be used to inform iterative improvements in the approach to vaccine design and administration. These include evaluating the magnitude of neoantigen-specific responses (by ELISpot) and in-depth phenotyping via single-cell RNA sequencing (scRNA-seq) analyses. MHC II, MHC class II; MS, mass spectrometry; scTCR, single-cell T cell receptor; SFC, spot-forming cell; SNV, single-nucleotide variant.