Abstract
Disruption of FasL-induced apoptosis of adoptively transferred T cells enhances antitumor efficacy.
Major finding: Disruption of FasL-induced apoptosis of adoptively transferred T cells enhances antitumor efficacy.
Concept: Expression of dominant-negative Fas increases T-cell persistence and antitumor activity in vivo.
Impact: This strategy has the potential to enhance adoptive cell transfer for both solid and liquid cancers.
Although efficacy of adoptive cell transfer (ACT) has been consistently observed in hematologic lymphoid malignancies, responses to ACT in patients with solid malignancies have been relatively modest. In addition, despite high initial overall response rates in hematologic cancers, relapse represents a major obstacle to the success of ACT. Yamamoto and colleagues identified a strategy to enhance the potency of transferred T cells while limiting unregulated expansion and off-target autoimmune responses. A pan-cancer analysis of patient samples from The Cancer Genome Atlas and the Genotype-Tissue Expression normal tissues database revealed that FASLG, which encodes the apoptosis-inducing ligand FasL, is preferentially overexpressed in the majority of human tumor types independent of sensitivity to immunotherapy. Furthermore, most therapeutic T cells used for clinical adoptive immunotherapy in both hematologic and solid cancers constitutively expressed Fas, the cognate receptor for FasL. Mutation or truncation of the Fas death domain to disrupt binding to the adaptor molecule FADD resulted in dominant-negative receptors (DNR) that prevented FasL-induced apoptosis in both mouse and human T cells. Adoptive transfer of Fas-DNR–expressing T cells resulted in superior T-cell expansion and persistence and enhanced antitumor activity against solid and hematologic cancers when co-engineered to express either a T-cell receptor or chimeric antigen receptor, diminishing overall tumor burden and significantly extending survival. Despite enhanced T-cell persistence, no accumulation of abnormal CD3+B220+ lymphocytes or formation of autoantibodies was detected in mice treated with Fas-DNR–expressing T cells, indicating that these genetically engineered T cells do not proliferate uncontrollably or mediate off-target autoimmunity. Taken together, these findings provide a potentially universal strategy to augment the durability and function of adoptively transferred T cells for the treatment of a wide range of human tumors.
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