Engineered T Cells That Target a Recurrent ATM Mutation in Cancer Cells
This technology is a human T cell engineered with a T cell receptor (TCR) that recognizes a mutated form of the DNA-repair protein ATM, presented on the HLA A*03:01 immune molecule. It offers a way to direct a patient’s own immune cells toward cancer cells that carry this mutation, while sparing cells with normal ATM.
Description
ATM is a protein that helps cells repair broken DNA. A subset of tumors carry a mutation at position 2695 of ATM, where the normal glycine is replaced by valine, alanine, cysteine or serine. Because this change exists only in tumor cells, a short fragment of the mutated protein displayed on the cell surface (by HLA A*03:01) can act as a tumor-specific marker for the immune system.The invention is a defined T cell receptor, made of an alpha chain and a beta chain with specified recognition regions, that binds this mutated fragment. T cells are modified to express the receptor, using nucleic acid delivered by a vector such as a viral vector. In T cells the natural TCR genes can be downregulated so the engineered receptor predominates. The resulting cells can be made from a patient’s own T cells and given back to the patient for cancer treatment.
Applications
- Autologous T cell therapy for cancers carrying ATM position 2695 mutations- Personalized or genotype-guided oncology, pairing HLA and ATM mutation screening with treatment
- Companion diagnostic development to identify eligible patients
- Viral-vector or nucleic-acid delivery platforms for TCR-based therapeutics
- Combination regimens with other cancer immunotherapies
Advantages
- Targets a mutation-specific peptide, with reactivity to mutant ATM and none observed against wild-type ATM in vitro- Recognizes several mutant forms at position 2695 (valine, alanine, cysteine, serine)
- Uses a defined receptor sequence that can be introduced by standard nucleic acid and vector approaches
- Supports use of the patient’s own cells (autologous)
- Allows downregulation of endogenous TCR chains, so the introduced receptor predominates