Tumor immunotherapy across MHC barriers using allogeneic T-cell precursors

JL Zakrzewski, D Suh, JC Markley, OM Smith… - Nature …, 2008 - nature.com
JL Zakrzewski, D Suh, JC Markley, OM Smith, C King, GL Goldberg, R Jenq, AM Holland…
Nature biotechnology, 2008nature.com
We present a strategy for adoptive immunotherapy using T-lineage committed lymphoid
precursor cells generated by Notch1-based culture. We found that allogeneic T-cell
precursors can be transferred to irradiated individuals irrespective of major histocompatibility
complex (MHC) disparities and give rise to host-MHC restricted and host-tolerant functional
allogeneic T cells, improving survival in irradiated recipients as well as enhancing anti-tumor
responses. T-cell precursors transduced to express a chimeric receptor targeting hCD19 …
Abstract
We present a strategy for adoptive immunotherapy using T-lineage committed lymphoid precursor cells generated by Notch1-based culture. We found that allogeneic T-cell precursors can be transferred to irradiated individuals irrespective of major histocompatibility complex (MHC) disparities and give rise to host-MHC restricted and host-tolerant functional allogeneic T cells, improving survival in irradiated recipients as well as enhancing anti-tumor responses. T-cell precursors transduced to express a chimeric receptor targeting hCD19 resulted in significant additional anti-tumor activity, demonstrating the feasibility of genetic engineering of these cells. We conclude that ex vivo generated MHC-disparate T-cell precursors from any donor can be used universally for 'off-the-shelf' immunotherapy, and can be further enhanced by genetic engineering for targeted immunotherapy.
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