Adoptive immunotherapy using ex vivo cultured tumour-infiltrating
lymphocytes (TIL) has shown great promise as a therapy for immunogenic
cancers. However, there are difficulties in isolating TILs in most
malignancies. Alternatively, tumour-specific lymphocytes can be generated by
genetically modifying autologous T lymphocytes with chimeric antigen receptors
(CAR), thereby conferring antigen specificity. While CAR+CD8+
T lymphocytes have shown to be effective in adoptive immunotherapy, evidence
has suggested that a concerted effort between multiple immune subsets may
enhance anti-tumour responses. However, the ability of leukocytes to perform
anti-tumour effector functions when expressing a CAR has yet to be explored. We
generated a novel mouse model whereby the expression of a CAR-specific for the
Her2 antigen is driven by the pan-hematopoietic promoter, vav. In our Vav-CAR model, we demonstrate that multiple immune
subsets express a functional CAR, and mediate antigen-specific responses
through cytokine release and cytotoxicity. Adoptive transfer of activated CAR+T
cells into tumour-bearing wild-type mice mediated significant inhibition of
established tumours. Furthermore, upon tumour challenge, naïve Vav-CAR mice are
able to mount an effective anti-tumour response upon recognition of the Her2
antigen, without prior immunisation or activation. This tumour rejection was
dependent on the presence of NK cells and CD8+ T cells. In ongoing
studies, we plan to ascertain the ability of other CAR+ leukocytes
to mediate anti-tumour activity, and to elucidate the optimal combination of
CAR expressing leukocytes for adoptive immunotherapy.