Tumor-specific Cryptigen-derived peptides presented on MHC molecules (Cryptigens)

Tumor-specific Cryptigen-derived peptides presented on MHC molecules are a novel class of immunotherapy targets derived from the non-canonical or dark matter regions of the genome. Unlike traditional neoantigens that arise from mutations in protein-coding exons, Cryptigens originate from sequences previously thought to be non-coding, such as introns, retrotransposons, and alternative reading frames (Gritstone bio, 2024; Nature Biotechnology, 2018). These peptides are processed and presented on the cell surface by Major Histocompatibility Complex (MHC) molecules, where they can be recognized by the T-cell receptor (TCR) of CD8+ cytotoxic T cells. In the context of oncology, these antigens are highly attractive because they are often shared across patients with the same tumor type or are highly specific to the malignancy, providing a broader target repertoire than individualized neoantigens. Companies like Gritstone bio utilize proprietary artificial intelligence platforms, such as EDGE, to identify these cryptic epitopes using mass spectrometry and deep learning (Nature, 2021). Therapeutic interventions, including personalized (GRANITE) and off-the-shelf (SLATE) vaccines, aim to elicit a robust and durable immune response against these targets to treat various solid tumors, including colorectal and lung cancers.

Other names

Non-canonical tumor antigensDark matter antigensCryptic tumor antigensTS-CryptigensNon-coding region derived antigens

Therapeutic vaccines (viral vectors or mRNA) deliver genetic sequences encoding these tumor-specific peptides to stimulate the expansion of CD8+ cytotoxic T cells that recognize and eliminate tumor cells presenting the Cryptigen-MHC complex (Gritstone bio, 2024).