The technology is designed to prevent AlloCAR T cells from being recognized by host T cells without triggering substantial natural killer (NK) cell rejection and while preserving CAR T cell function. The findings were presented today during a poster session at the 37th Annual Meeting of the
The development of 'off-the-shelf' (allogeneic) CAR T products that utilize cells from healthy donors have the potential to make CAR T therapies scalable and accessible to more patients. The effectiveness of allogeneic CAR T cells requires controlling immune rejection of allogeneic CAR T cells by the patient's immune cells, namely T and NK cells. Allogene is currently developing ALLO-647, a lymphodepletion agent which targets host immune cells but not AlloCAR T cells, to enhance the window of CAR T engraftment, but is also investigating several novel strategies that may enhance the performance of allogeneic CAR T products by controlling immune rejection. This preclinical study evaluated an alternative approach to immune evasion by selectively targeting NLRC5 and RFX5, transcriptional regulators that control expression of HLA molecules. NLRC5 knockout avoids CD8 T cell mediated rejection and RFX5 knockout avoids rejection by both CD8 and CD4 T cells, allowing the possibility to avoid a broader spectrum of T cell-mediated rejection with just one edit, in contrast to alternative approaches that require two edits.
'We believe that novel approaches to cloaking may further increase the efficacy of off-the-shelf CAR T products through avoidance of immune rejection,' said
In the study, the survival of 'cloaked' cells was assessed in mixed lymphocyte reaction assays with T cells, NK cells, or a combined assay with T and NK cells. The knockout of NLRC5 or RFX5 in allogeneic CAR T cells enhanced survival in the presence of host T cells and elicited only minor NK cell reactivity, thereby effectively mitigating rejection. Importantly, the inactivation of NLRC5 or RFX5 did not impact CAR T cell phenotype or cytotoxic activity. The NLRC5 or RFX5 edited CAR T cells also demonstrated superior persistence and anti-tumor efficacy compared to un-edited CAR T cells or B2M edited CAR T cells in a stringent syngeneic model in vivo. These modifications would be designed to be part of an overall editing and gene expression platform to avoid CAR T rejection.
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Cautionary Note on Forward-Looking Statements
This press release contains forward-looking statements for purposes of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. The press release may, in some cases, use terms such as 'predicts,' 'believes,' 'potential,' 'proposed,' 'continue,' 'estimates,' 'anticipates,' 'expects,' 'plans,' 'intends,' 'may,' 'could,' 'might,' 'will,' 'should' or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. Forward-looking statements include statements regarding intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things: the ability to research and develop technologies to protect AlloCAR T cells from rapid host rejection; the ability of NLRC5 or RFX5 edited CAR T cells to demonstrate persistence and antitumor efficacy and the potential benefits of ALLO-647 and AlloCAR T products. Various factors may cause differences between Allogene's expectations and actual results as discussed in greater detail in Allogene's filings with the
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