Alt-neoantigens

Two studies tap a new vein of cancer neoantigens via alternative splicing

Neoantigens derived from alternative splicing could broaden the target space for cancer vaccines and T cell therapies, according to two studies published this month. While questions remain about whether they are sufficiently immunogenic to create potent drugs, the findings feed into a growing body of research looking beyond point mutations for ways to differentiate tumor antigens from those in normal tissue.

To attack tumors and protect normal tissues, immuno-oncologists are developing therapies against neoantigens -- tumor-specific peptides that the immune system regards as non-self.

At least 14 companies are developing therapeutic vaccines against tumor neoantigens. The process involves sequencing a patient’s tumor and normal tissues, predicting which tumor mutations are likely to present as peptides on his or her HLA alleles, and then vaccinating with DNA, RNA or peptide versions of those tumor-specific neoantigens (see “Neo Wave”).

The approach is also guiding development of cell therapies, with at least two companies, Neon Therapeutics Inc. and Pact Pharma Inc., developing personalized T cell therapies against individual patient neoantigens (see “Highly Personal”).

Also, on Aug. 23, neoantigen vaccine company Gritstone Oncology Inc. announced a partnership with bluebird bio Inc. to develop tumor-targeted T cell therapies.

Most neoantigen identification strategies have focused on comparisons between tumor and normal DNA, looking for point mutations and relying on RNA sequencing to identify which ones are actually expressed.

But alternative splicing -- in which a gene’s exons and introns are carved up differently to produce mRNA -- offers a different source of diversity from point mutations.

The new studies, led by researchers at ETH Zurich and Dana-Farber Cancer Institute, used RNA

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