The Hunt for Effective Anticancer Vaccines

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Researchers are hotly pursuing 2 distinct biological paths that show remarkable promise in the hunt for an effective anticancer vaccine.
Researchers are hotly pursuing 2 distinct biological paths that show remarkable promise in the hunt for an effective anticancer vaccine.

Researchers are hotly pursuing 2 distinct biological paths that show remarkable promise in the hunt for an effective anticancer vaccine.

One uses neoantigens produced by the cancer itself to create personalized immunotherapies and was shown to reduce tumor size and prevent relapse.

The second, thus far tested only in mouse models, employs the immunogenic properties of induced pluripotent stem cells to create a vaccine that not only reduces metastatic tumor load, but may be a truly preventative vaccine — an inoculation capable of blocking the development of future malignancies even in those who have never had cancer.

Last summer, 2 separate teams — one from the United States and the other Germany — published papers focusing on the neoantigen approach.

The American study involved only 6 participants with previously untreated melanoma, but, the authors wrote, “4 had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells.”1

To create the vaccine, the researchers conducted whole-exome sequencing of tumorous and normal-cell DNA from each patient, ran RNA sequencing of their tumors, and synthesized peptides targeting as many as 20 neoantigens per patient that would stimulate production of a repertoire of T cells. The immunogenic T cells, the authors noted, “discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour.”

Therefore, they concluded: “[o]n the basis of the observed induction of de novo T-cell clones that detect multiple individual-specific neoantigens and recognize endogenously processed antigens and autologous tumour cells, our vaccine is likely to target a diversity of malignant clones per patient, thus addressing tumour heterogeneity as well as minimizing the chance of tumour escape by loss of antigen.”

The German team also used exome sequencing to develop personalized vaccines for 13 patients with melanoma. But they used RNA molecules to deliver the vaccine and trigger the participants' immune systems. Nine of the participants, 8 given just the vaccine and 1 given the vaccine plus a checkpoint inhibitor, remained cancer-free 12 to 23 months later.3

The study built on results the researchers previously found in murine tests with skin, breast, and colon cancer tumors. In that earlier study, they discovered that “a considerable fraction of non-synonymous cancer mutations is immunogenic and that, unexpectedly, the majority of the immunogenic mutanome is recognized by CD4+ T cells.”

Based on that, they identified mutations that could be targeted with synthetic poly-neo-epitope messenger RNA vaccines. The vaccinations, they wrote, induced “tumour control and complete rejection of established aggressively growing tumours in mice.”3

They realized, however, that “the vast majority of mutations are unique to the individual patient. Hence, mutanome vaccines need to be individually tailored and rapidly manufactured on-demand.”

The authors solved that problem through a predictive algorithm and existing RNA vaccine technology. The result, they wrote, “may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo-epitope target repertoire of cancers, enabling the effective targeting of every patient's tumour with vaccines produced ‘just in time'.”

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