Characterizing and harnessing tumor-reactive T cells in the brain (CENTRIC-BRAIN)

Personalized tumor immunotherapy - vaccines and T cell therapies - requires the selection of few immunogenic epitopes recognized by tumor-reactive T cell receptors (TCRs) from thousands of potential tumor antigens in each tumor.

This selection is a huge challenge, particularly in brain tumors, where access to tumor tissue is limited and tumor-infiltrating T cells (TILs) are sparse.

CENTRIC-BRAIN will reverse this epitope-centric approach by directly harnessing tumor-reactive orphan TCRs from TILs for personalized brain tumor immunotherapy.

Using human brain tumor tissue we have developed and experimentally validated predicTCR, a novel approach using machine learning and explainable AI to derive a classifier that predicts tumor-reactivity of such orphan TCRs based on the expression of signature genes with > 90% accuracy across multiple tumour entities.

CENTRIC-BRAIN will employ predicTCR to develop a personalized adoptive cell therapy using transgenic T cells with tumor-specific TCRs and improved function. �CENTRIC-BRAIN hypothesizes that the signature genes underlying predicTCR determine the phenotypic and functional properties of tumor-reactive T cells and that predicted tumor-reactive orphan TCRs can be employed for adoptive therapy with personalized TCR-transgenic T cells.

Aim 1 will refine predicTCR by characterizing the transcriptional programs and spatial distribution of tumor-reactive T cells in human brain tumor samples.

Aim 2 will define the functional relevance of transcriptional programs for tumor-reactive T cells in syngeneic humanized and patient-derived xenograft brain tumor models.

Aim 3 will validate the predicted tumor-reactive orphan TCRs by adoptive transfer of T cells genetically engineered to express predicted tumor-reactive TCRs.

CENTRIC-BRAIN will thus revolutionize precise and efficient implementation of personalized adoptive cell therapy for brain tumors using T cells expressing tumor-reactive patient-derived orphan TCRs.