Poster Presentation 27th Lorne Cancer Conference 2015

Redirecting immune subsets through genetic manipulation for enhancing adoptive immunotherapy. (#214)

Carmen SM Yong 1 , Jenny A Westwood 1 , Jan Schroeder 2 3 4 5 , Tony T Papenfuss 2 3 4 5 , Maria Moeller 1 , Jerry M Adams 6 , Christel Devaud 1 , Phil K Darcy 1 7 , Michael H Kershaw 1 7
  1. Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Vic, Australia
  2. Cancer Genomics Program, Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Vic, Australia
  3. Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia
  4. Department of Medical Biology, The University of Melbourne, Parkville, Vic, Australia
  5. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Vic, Australia
  6. Molecular Genetics of Cancer, The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia
  7. Department of Immunology, Monash University, Melbourne, Vic, Australia

Adoptive immunotherapy using ex vivo cultured tumour-infiltrating lymphocytes (TIL) has shown great promise as a form of cancer therapy for relatively immunogenic cancers such as melanoma. However, it is difficult to isolate TILs specific for a tumour antigen in the majority of malignancies. An alternate source of tumour-specific lymphocytes can be derived by genetic modification of autologous T lymphocytes with chimeric antigen receptors (CAR), conferring antigen specificity in a major histocompatability complex (MHC) independent manner. While CAR-expressing CD8+ T lymphocytes have shown to be effective in adoptive immunotherapy, recent evidence has suggested that a concerted effort between multiple immune subsets may enhance the anti-tumour response. However, due to current limitations in genetic modification, the ability of many leukocytes to perform anti-tumour effector functions when expressing a CAR has yet to be explored. To address this issue, we generated a novel mouse model in which the expression of a CAR specific for the Her2 antigen was driven by the pan-hematopoietic promoter, vav. In our Vav-CAR mouse model, we demonstrate that multiple immune subsets are capable of expressing 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 any prior immunisation or activation, and this tumour rejection was dependent on the presence of both Natural Killer cells and CD8+ T cells. In ongoing studies, we plan to elucidate the ability of other leukocytes to mediate anti-tumour activity when expressing a CAR, and to elucidate the optimal combination of CAR expressing leukocytes for adoptive immunotherapy.