Dual effects of a targeted small-molecule inhibitor (cabozantinib) on immune-mediated killing of tumor cells and immune tumor microenvironment permissiveness when combined with a cancer vaccine.
BACKGROUND
Growing awareness of the complexity of carcinogenesis has made multimodal therapies for cancer increasingly compelling and relevant. In recent years, immunotherapy has gained acceptance as an active therapeutic approach to cancer treatment, even though cancer is widely considered an immunosuppressive disease. Combining immunotherapy with targeted agents that have immunomodulatory capabilities could significantly improve its efficacy.


METHODS
We evaluated the ability of cabozantinib, a receptor tyrosine kinase inhibitor, to modulate the immune system in vivo as well as alter the phenotype of tumor cells in vitro in order to determine if this inhibitor could act synergistically with a cancer vaccine.


RESULTS
Our studies indicated that cabozantinib altered the phenotype of MC38-CEA murine tumor cells, rendering them more sensitive to immune-mediated killing. Cabozantinib also altered the frequency of immune sub-populations in the periphery as well as in the tumor microenvironment, which generated a more permissive immune environment. When cabozantinib was combined with a poxviral-based cancer vaccine targeting a self-antigen, the combination significantly reduced the function of regulatory T cells and increased cytokine production from effector T cells in response to the antigen. These alterations to the immune landscape, along with direct modification of tumor cells, led to markedly improved antitumor efficacy.


CONCLUSIONS
These studies support the clinical combination of cabozantinib with immunotherapy for the treatment of cancer.
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive; Room 8B13, Bethesda, MD, 20892, USA. anna.kwilas@nih.gov.
Anna R
AR
Kwilas
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive; Room 8B13, Bethesda, MD, 20892, USA. smith.andressa.a@gmail.com.
Andressa
A
Ardiani
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive; Room 8B13, Bethesda, MD, 20892, USA. renee.donahue@nih.gov.
Renee N
RN
Donahue
Exelixis, Inc., South San Francisco, CA, USA. daftab@exelixis.com.
Dana T
DT
Aftab
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive; Room 8B13, Bethesda, MD, 20892, USA. jh241d@nih.gov.
James W
JW
Hodge
D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D007167:Immunotherapy; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D010641:Phenotype; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects
D000813:Anilides; D014408:Biomarkers, Tumor; D019496:Cancer Vaccines; D011725:Pyridines; D054852:Small Molecule Libraries; C558660:cabozantinib