To make CAR-T therapy more accessible, it is highly desirable to develop an allogeneic adoptive transfer strategy, in which universal CAR-T cells derived from T cells from healthy donors can be applied to treat multiple patients. For this strategy to work, the αβ T-cell receptor (TCR) on allogeneic CAR-T cells needs to be eliminated to avoid graft-versus-host-disease (GVHD), and human leukocyte antigens class I (HLA-Is) on CAR-T cells need to be removed to minimize their immunogenicity. Previous studies have shown that mutation in TCRα subunit constant (TRAC) leads to loss of αβ TCR on T-cell surface2, and beta-2 microglobulin (B2M) is essential for cell-surface expression of HLA-I heterodimers3. Thus, the scientists attempted to target TRAC and B2M genes in CAR-T cells. Considering blocking programmed death-1 (PD-1) signaling can effectively treat cancers via reversing immunosuppression, we also targeted PD-1 in CAR-T cells to render them nonresponsive to PD-1 signaling.
A team of researchers from the University of Pennsylvania have received the go-ahead from a US National Institutes of Health (NIH) panel for the first test that proposes using CRISPR gene editing technology in humans to treat cancer. The NIH's Recombinant DNA Advisory Committee delivered a positive recommendation for the study, which proposes to combine gene editing and immunotherapy. If the US Food and Drug Administration (FDA) approves the trial, it will become the first to involve CRISPR–Cas9 technology in human trials. The study will be funded by the Parker Institute for Cancer Immunotherapy, established with a $250 million gift from internet billionaire Sean Parker (Nat. Biotechnol.34, 583, 2016). The institute's president and CEO Jeffrey Bluestone said that the study protocol, entitled “Phase 1 Trial of Autologous T Cells Engineered to Express NY-ESO-1 TCR and Gene Edited to Eliminate Endogenous TCR and PD-1,” will enroll 18 people with melanoma, myeloma and sarcoma at Penn's Abramson Cancer Center, MD Anderson Cancer Center in Houston, and the University of California, San Francisco. The protocol will entail removing a subject's T cells and re-infusing them a month later after genetic alterations have been made—including one that makes the cells responsive to PD-1, which some cancers use to evade the immune system. The idea is to enhance the T cells' function while reducing the risk of autoimmunity. Before enrollment can begin, the FDA must give its approval.
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To make CAR-T therapy more accessible, it is highly desirable to develop an allogeneic adoptive transfer strategy, in which universal CAR-T cells derived from T cells from healthy donors can be applied to treat multiple patients. For this strategy to work, the αβ T-cell receptor (TCR) on allogeneic CAR-T cells needs to be eliminated to avoid graft-versus-host-disease (GVHD), and human leukocyte antigens class I (HLA-Is) on CAR-T cells need to be removed to minimize their immunogenicity. Previous studies have shown that mutation in TCRα subunit constant (TRAC) leads to loss of αβ TCR on T-cell surface2, and beta-2 microglobulin (B2M) is essential for cell-surface expression of HLA-I heterodimers3. Thus, the scientists attempted to target TRAC and B2M genes in CAR-T cells. Considering blocking programmed death-1 (PD-1) signaling can effectively treat cancers via reversing immunosuppression, we also targeted PD-1 in CAR-T cells to render them nonresponsive to PD-1 signaling.