Vaccinating against cancer: getting to prime time

Abstract

Immunotherapies, such as immune checkpoint inhibitors, cellular therapies, and T-cell engagers, have fundamentally changed our approach to treating cancer. However, successes with cancer vaccines have been more difficult to realize. While vaccines against specific viruses have been widely adopted to prevent the development of cancer, only two vaccines can improve survival in advanced disease: sipuleucel-T and talimogene laherparepvec. These represent the two approaches that have the most traction: vaccinating against cognate antigen and priming responses using tumors in situ. Here, we review the challenges and opportunities researchers face in developing therapeutic vaccines for cancer.

Keywords: Adjuvants, Immunologic; Antigens, Neoplasm; Immunity; Vaccination.

Figure 1

Therapeutic cancer vaccines correct defective antitumor immunity. (A) Defective antigen presentation or biased endogenous immunity toward non-relevant truncal mutations compromises the activation of naïve T cells by dendritic cells (DC). Inadequate priming results in suppressed T-cell activation. Activated T cells differentiate into memory T cells and eventually effector T cells which encounter an immunosuppressive tumor microenvironment that leads only to partial tumor killing or equilibrium of tumor mass. Activated T cells also lead to the differentiation of terminally exhausted T cells which express high exhaustion markers, low proliferative potential, and low cytotoxicity. Permanent exhaustion of antigen-primed T cells leads to tumor escape. (B) Cancer vaccines can elicit more effective antigen presentation and force presentation or more relevant truncal mutations or differentiation antigens by DCs. Immune agonistic properties of vaccines lead to more robust T-cell priming and activation. The regeneration of non-exhausted cytotoxic effector T cells leads to more effective tumor killing.

Figure 2

Stepwise design of cancer vaccines. Step 1: Selection of antigens which may be cognate tumor-associated antigens or tumor-specific antigens such as oncoviral-associated antigens, non-cognate tumor-specific antigens, or personalized neoantigens. Step 2: Encoding tumor antigens using either DNA, RNA, or peptides. Step 3: Packaging tumor antigens into delivery systems such as nanoparticles, autologous immune cells, oncolytic viruses, viral vectors, or tumor-cell lysates. Downstream immunological efficacy is measured by accurate antigen selection, effective immune priming, antigenic spreading, antigen-specific T-cell activation, and durable immunity.

Figure 3

Cancer vaccine combination strategies for early-stage cancer. Conventional modalities (chemotherapy, surgery, radiotherapy (RT), tyrosine kinase inhibitors (TKI), cell therapy) of treatment according to tumor volume are illustrated by the red graph (top half). Introducing tumor vaccines combined with other modalities in the adjuvant, neoadjuvant, and prevention stages of cancer is illustrated in the green graph (bottom half). IO, immune modulators; MRD, minimal residual disease; ACT, adoptive cell therapy; dMMR, deficiency in mismatch repair; MSI, microsatellite instability.