Bacterial and neoantigen strategies for developing cancer vaccines

Abstract

Cancer is a group of disorders characterized by aberrant cell proliferation and the ability to infiltrate or migrate to different regions of the body. These uncontrollably aberrant cells, if not eliminated by the body, may aggregate to create a bulk of tissue termed a tumor. The tumor then develops, and cancer cells escape from the tumor and travel via the circulatory or lymph system to distant regions of the organism included the lungs, liver, intestines, etc., forming additional tumors, which is known as metastasis. Although advances in cancer treatment and diagnosis, cancer remains a serious public health issue and one of the top reasons for mortality globally. The future of cancer immunotherapy may depend on combination treatments combining checkpoint inhibitors with customized cancer vaccines and innovative targeted therapeutics against the immunosuppressive tumor milieu.

Tumors that have metastasized to other organs are the leading cause of mortality in cancer patients. Hindering invasive and migratory capabilities of cancer cells can offer new approaches to treat patients with malignant cancer. In our previous study, engineered Salmonella Typhimurium strains were shown to potently inhibit the metastasis of multiple mouse tumors. Here, we demonstrate that sera from Salmonella -treated mice impair the migration ability of breast cancer cell line 4T1 in vitro. Our findings indicate that the PI3K-AKT pathway is involved in this inhibitory function. Further results show that 4T1 cells cocultured with Salmonella-treated mice serum down-regulate vimentin and N-cadherin expression. Likewise, the Salmonella-treated mice sera also showed similar inhibition of migration of human breast cancer cells, including MDA-MB-231, 1937, and BT459 cells.

In my studies, efforts are also made to develop a rational design platform for neoantigen-based cancer vaccine therapy and evaluate the antitumor immunological effect of peptide-based prototype vaccines in a mouse bladder tumor model. Using our platform, we discover newly generated tumor-specific antigens by identifying somatic point mutations in MB49 bladder cancer cell lines. The following T-cell immunogenicity test demonstrates that our prediction platform is capable of accurately identifying safe and effective neoantigens from exome and transcriptome data. Furthermore, our results show that these neoantigens from druggable "mutanome" can elicit significant protective immunity against bladder tumor growth in a subcutaneous model, and have a strong therapeutic efficacy in an orthotopic tumor model.

Taken as a whole, since cancer is a multifactorial illness, no individual therapy is totally efficient. Additional scientific and clinical studies are expected to combine the greatest strengths of bacterial therapy and neoantigen-based vaccine, as well as other therapies, as a tremendous weapon in the battle against cancer and metastases.