Tumor-activated alloreactive T cells (TAATs) suppress solid tumors with heterogeneous tumor antigen expression 4511

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Abstract Description Heterogenous tumor antigen (TA) expression is one of the key hurdles in solid tumor treatment. Eliminating TA+ cells is often insufficient to control tumor growth due to the expansion of TA- tumor cells. To address this, we propose to use alloreactive T cells from HLA-mismatched healthy donors to target all HLA+ cells within a tumor. TAATs were generated by first stimulating and expanding T cells from HLA-mismatched healthy donors with an HLA-I+ breast cancer cell line. Then, CD3ε expression by T cells was knocked out using CRISPR/Cas9 to block cell surface expression of the TCR/CD3 complex. Finally, the T cells were engrafted with a tumor-sensing mechanism, which contains a TA-specific synthetic Notch (synNotch) receptor and an expression cassette that drives the expression of an exogenous copy of CD3ε upon synNotch engagement. We hypothesize that upon recognition of TA+ tumor cells within a tumor, TAATs will restore CD3ε expression, thus alloreactivity, for long enough time to kill both TA+ tumor cells and neighboring TA- tumor cells. After migrating out of tumor, however, CD3ε expression and alloreactivity will be lost due to the absence of TA+ tumor cells. Here, we show that in subcutaneous mouse tumor models, Her2-specific TAATs suppressed the growth of tumors established with a mixture of Her2+ and Her2- cancer cells much more effectively than Her2-specific CAR T cells. Our data demonstrates the potential of TAATs to outperform CAR T cells in treating solid tumors. Funding Sources Nemours Foundation Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

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