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Personalized Cancer Vaccines Demonstrate Potential in Melanoma Studies

NEW YORK (GenomeWeb) – A pair of new studies is pointing to the potential of personalized anti-cancer vaccine strategies in individuals with advanced melanoma.

For one of the studies, appearing online today in Nature, a German-led team that included investigators from the biotechnology company BioNTech used a combination of comparative exome sequencing and RNA sequencing to profile mutation patterns and predict neoantigens in tumor samples from more than a dozen individuals with stage III or stage IV melanoma. Using its pipeline for mutation detection, neo-epitope prediction, and prioritization, the group translated the results into personalized vaccines targeting a subset of each individual's tumor mutations.

With these so-called mutanome vaccines, they saw a range of T cell-mediated responses in the melanoma patients — including a significant dip in metastases and complete response in a small subset of patients treated with vaccination alone or in combination with checkpoint blockade chemotherapy.

The eight individuals who did have detectable tumor lesions at the time of vaccination did not experience disease recurrence over one to two years of follow up, the researchers reported. For the five patients with relapsed metastatic disease at vaccination, meanwhile, they saw objective responses in two individuals, while another patient responded to a combination of neo-epitope vaccination and anti-PD-1 checkpoint blockade immunotherapy.

"Our observations indicate that neo-epitope vaccines alone may prevent recurrent disease in high-risk patients," co-senior authors Özlem Türeci from the Cluster for Individualized Immunointervention and Carmen Loquai, with the Johannes Gutenberg University, both in Mainz, and their co-authors wrote. "Moreover, they provide a rationale for combining the vaccine with PD-1/PD-L1 blockade."

For the other neo-antigen vaccine paper, investigators from the Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, and elsewhere outlined the approach they used to uncover as many as 20 targetable neo-antigen targets per person in half a dozen vaccinated individuals with melanoma.

"We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoral balance in favor of enhanced tumor control," senior author Catherine Wu, a medical oncology researcher at Dana-Farber, and her co-authors wrote.

Members of that team began by doing exome sequencing on tumor and matched normal samples from 10 melanoma patients, verifying and investigating the expression of apparent somatic mutations in these data with tumor-specific RNA sequencing.

After taking predicted immune binding patterns and other factors into account, the researchers narrowed in on 97 neo-antigens for vaccine-based targeting in six of the melanoma cases, who were vaccinated in the weeks or months after surgery. Tumor samples from two other individuals did not show the enhanced mutation rate that is typical of melanomas, they noted, while two more individuals were not vaccinated despite the availability of personalized immunizing long peptides.

Based on stimulated T cell assays, the team estimated that patients' CD4+ T cells subsequently tackled some 60 percent of those personalized neo-antigens, while CD8+ T cells showed signs of activity against 16 percent of the neo-antigen set.

Over more than two years of follow up, the team reported, four of the six vaccinated individuals continued to be recurrence-free. The remaining two individuals had tumor recurrence that was effectively treated with pembrolizumab, a checkpoint blockade drug targeting PD-1.

Based on their results so far, the authors of that study suggested that neo-antigen vaccines may prove useful for not only targeting tumor tissue selectively, but also for tackling tumor heterogeneity.

"Future neo-antigen vaccine trials will take advantage of improved methods for predicting antigen presentation to increase the fraction of neo-antigens inducing tumor-reactive T cells," they wrote, "and will test for synergy with checkpoint blockade and other immunotherapies."

Wu and other investigators involved in that study have founded an immuno-oncology company called Neon Therapeutics that is working to develop neo-antigen-based cancer vaccines.

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