Novel tumor-specific Vd1/3 gd CAR T cells effectively control solid tumors

Abstract Chimeric Antigen Receptor (CAR) T cell therapy has proven to be successful in treating hematological malignancies. However, its effectiveness against solid tumors has been suboptimal so far, due to the strong immunosuppressive conditions and metabolic restrictions present in the tumor microenvironment. Furthermore, the use of autologous T cells for CAR product manufacturing has several disadvantages. Here, we demonstrate the effectiveness of a new CAR T cell platform using cord blood-derived γδ T cell subsets, which can be used allogeneically (“off-the-shelf”) and recapitulate the populations primarily found in solid tumors. As targeting motifs, we used scFv sequences specifically targeting transmembrane molecules expressed in metastatic SCLC and other tumors, but not in vital tissues, which were identified through a comprehensive proteogenomic approach. To minimize PD-1-driven inhibition and enhance metabolic re-programming, we designed a new CD3z-less CAR architecture, which is more effective than conventional second-generation CARs. Our results demonstrate that γδ T cells are natural killers independent of MHC presentation, superior to αβ T cells, allowing the generation of multiples ‘off-the-shelf’ CAR T cell products. Moreover, the new architecture demonstrated better efficiency in killing tumor cells, thus supporting a rationale for future trials aimed at rendering CAR T cells effective against the most frequent and aggressive human solid tumors.