Cancer Neoantigen Vaccine R&D Contributes to Personalized Medicine

Vaccines have traditionally been used to prevent infectious diseases, whose ability to induce and amplify antigen-specific immune responses has long been considered a potentially valuable tool for the treatment of cancer. Early therapeutic vaccination strategies focused on the abnormally expressed or over-expressed self-antigens in tumors, tumor-associated antigens (TAA). However, this strategy is basically unsuccessful in clinical practice because TAA-specific T cells are affected by central and/or peripheral tolerance. In addition, such TAAs are also expressed to a certain extent in non-malignant tissues, which increases the risk of vaccine-induced autoimmune toxicity.

Mutations in tumor cells can produce new self-antigen epitopes, called neoepitopes or neoantigens. Vaccines based on neoantigens rather than traditional TAAs have several advantages. First, neoantigens are only expressed by tumor cells, so they can trigger a true tumor-specific T cell response, thereby preventing off-target damage to non-tumor tissues. Second, neoantigens are new epitopes derived from somatic mutations, which may bypass the central tolerance of T cells to their own epitopes, thereby inducing immune responses to tumors. In addition, the neoantigen-specific T cell response enhanced by such vaccines persists and enhances immune memory after treatment, making the long-term prevention of disease recurrence possible.

Clinical progress of neoantigen vaccines

At present, there are several personalized neoantigen vaccines in progress of clinical trials. These preliminary studies provide important clues for the immunogenicity and therapeutic potential of personalized neoantigen cancer vaccines.

• GEN-009 is a personalized neoantigen vaccine, containing 4-20 synthetic long peptides selected using the ATLAS epitope discovery platform, using poly-ICLC preparations.
• RO7198457 is a personalized RNA-lipoplex neoantigen vaccine that encodes up to 20 new antigens.
• mRNA-4157 is another lipid-encapsulated RNA neoantigen vaccine that has been tested as a monotherapy in 13 patients with high-risk resectable solid tumors, and combined with pembrolizumab in the treatment of 20 patients with unresectable advanced solid tumors, the latter including 12 patients with disease progression before immune checkpoint inhibitors (ICI) treatment.

Challenges of neoantigen vaccines

Although some preliminary clinical trial data of neoantigen vaccines showed strong immunogenicity and evidence of targeted tumor cell killing, a relatively large proportion of vaccine neoepitopes did not stimulate T cell responses. The primary challenge in the field of cancer vaccine research is to improve inducing T cell responses, especially the maximum activation and expansion of CD8+ T cells.

To achieve this goal, complementary therapies that promote APC function and optimal activation of T cells in lymph nodes may be required, such as ICIs, costimulatory receptor agonists (such as CD40), TLR agonists, and growth factors that support DC development and/or function (such as GM-CSF), and Fms-related tyrosine kinase 3 ligands (FLT3L).

Another challenge is to determine the optimal vaccine delivery system so that the vaccine can be produced quickly, cost-effectively, and deployed in promptly. Different vaccine formats, including peptides, RNA, DNA, viral structures, or DCs, have their individual advantages and disadvantages. However, there is a lack of head-to-head comparisons of these different methods in patients.

The timing of ICI administration and therapeutic vaccination is another important factor to be considered. Combining ICIs with therapeutic vaccination regimens may be beneficial, but careful consideration should be taken into account of the most appropriate component therapy regimen.

The progress in quickly and comprehensively identifying tumor-specific mutations provides a tumor-specific target that has been difficult to find for a long time. Preliminary studies have shown that personalized neoantigen vaccines can bring significant clinical benefits to cancer patients, but still face many challenges. The ultimate goal is to develop a stable, safe, and capable strategy of maximizing T cell responses. Currently, many studies using different vaccine delivery platforms and combination therapies are underway, and the results are worth looking forward to.