Tumor heterogeneity presents a substantial barrier to increasing clinical responses mediated by targeted
therapies. Broadening the immune response elicited by treatments that target a single
antigen is necessary for the elimination of
tumor variants that fail to express the targeted
antigen. In this study, it is shown that adoptive transfer of T cells bearing a
chimeric antigen receptor (CAR) inhibited the growth of target-expressing and -deficient
tumor cells within ovarian and
lymphoma tumors. Mice bearing the ID8 ovarian or RMA
lymphoma tumors were treated with T cells transduced with a NKG2D-based CAR (chNKG2D). NKG2D CAR T-cell therapy protected mice from heterogeneous RMA
tumors. Moreover, adoptive transfer of chNKG2D T cells mediated
tumor protection against highly heterogeneous ovarian
tumors in which 50, 20 or only 7% of
tumor cells expressed significant amounts of NKG2D
ligands. CAR T cells did not mediate an in vivo response against
tumor cells that did not express sufficient amounts of NKG2D
ligands, and the number of
ligand-expressing
tumor cells correlated with therapeutic efficacy. In addition,
tumor-free surviving mice were protected against a
tumor re-challenge with NKG2D
ligand-negative ovarian
tumor cells. These data indicate that NKG2D CAR T-cell treatment can be an effective
therapy against heterogeneous
tumors and induce
tumor-specific immunity against
ligand-deficient
tumor cells.