Extremely Rapid Method to Isolate Neoantigen Reactive T Cell Receptors (TCRs)

Adoptive cell transfer (ACT) uses tumor infiltrating lymphocytes (TILs) that recognize unique antigens expressed by cancer cells (“neoantigens”). Neoantigen specific TIL administration in patients has resulted in long term regression of certain metastatic cancers. However, one of the challenges of ACT and engineered T cell receptor (TCR) therapies more broadly, is the identification and isolation of these mutation specific TILs and TCRs. Only a fraction of TILs in a given patient is known to be tumor reactive, while the majority are not useful for cell therapy. The current procedures for isolating neoantigen reactive TILs and TCRs are time consuming, labor-intensive, and lack sensitivity and specificity. 

Researchers at the National Cancer Institute (NCI) have developed a novel method to identify neoantigen reactive T cells and TCRs, isolated from fresh tumors of common epithelial cancers. This method does not require tumor cells to be grown or propagated in vitro. By using a single cell, transcriptome-based approach and barcoded antibodies (CITE-seq), neoantigen reactive T cells can be clustered within tSNE (t-Distributed Stochastic Neighbor Embedding) plots. Using genetic markers that are highly expressed in such clusters, a transcriptomic gene signature, called “NeoTCR Signature”, has been developed. This NeoTCR Signature can be used to identify a very high frequency of previously unknown T-cell clones and TCRs that recognize neoantigens from the autologous tumor. Critically, identification and isolation of the neoantigen-reactive TCR can now occur in a few days, in stark contrast to the 6-8 weeks required for current methods. This rapid determination of the neoantigen reactive TCR sequences can be useful for translating this information into TCR-engineered T-cell populations for immunotherapy. This technique can also identify T-cells with specificities for new neoantigens not presently identifiable by conventional screening methods. 

NCI seeks commercial partners to co-develop and/or license this technology.