cannon

Professor Department of Microbiology & Immunology 

Research Interest:  Viral and tumor immunology
Ph.D., University of London
Postdoctoral:  MRC National Institute for Medical Research, London, and the Scripps Research Institute, La Jolla
Phone: (501) 296-1254 
Fax: 
(501) 686-5359

E-mail

Research Description

Dendritic cell vaccination for ovarian cancer

The finding that Th17 infiltration correlates with markedly prolonged overall survival among ovarian cancer patients offers a counterpoint to the known association of Treg infiltration with poor clinical outcomes, and prompts the question of whether Th17 cells could be induced or expanded to therapeutic advantage. We have shown that treatment of ovarian tumor antigen-loaded, cytokine-matured DC with a combination of IL-15 and a p38 MAPK inhibitor (DCIL-15/p38inhib) offers potent synergy in antagonism of Treg induction and redirection toward Th17 responses that correlate with strong CD8+ CTL activation, thus affording the opportunity for clinical trials of DC vaccination that promotes Th1/Th17 immunity.

We have recently initiated a Phase I clinical trial of DCIL-15/p38inhib vaccination for stage IIIC–IV ovarian cancer patients following initial surgery and chemotherapy (ClinicalTrials.gov identifier NCT02111941). The target antigen is folate receptor alpha (FRa), based on epitopes recognized by T cells and antibodies from women with breast or ovarian cancer. This is a multi-institute consortium led by Matthew S Block, MD, PhD (Mayo Clinic, Rochester, MN), Keith L Knutson, PhD (Vaccine & Gene Therapy Institute, Port St. Lucie, FL) and Martin J Cannon, PhD (UAMS).

The development of DC vaccination strategies to boost Th17 immunity in ovarian cancer patients represents a significant step forward, but there remains the question of whether DC vaccination alone would be sufficient to provide clinical benefit in the face of continuing local immune suppression in the tumor microenvironment. Functional analysis of ovarian tumor-infiltrating leukocytes has shown that tumor-associated CD14+ cells are abundant in vivo, are chemo-attractive for Th1/Th17 effector CD4+ T cells, and are uniquely immunosuppressive for DC-driven tumor antigen-specific T cell responses by mechanisms involving IL-10 and indoleamine 2,3-dioxygenase. Current research is focused on elucidation of the signaling pathways that drive myeloid cell-mediated immune suppression and on development of adjuvant treatments for DC vaccination against ovarian cancer.

References

Nounamo, B., Liem, J., Blair, S., Cannon, M.J., Liu, J. 2017. Replicating myxomavirus optimizes cisplatin for the treatment of ovarian cancer in vitro and metastatic tumor in vivo. In press, Molec. TherapyNounamo, B., Liem, J., Blair, S., Cannon, M.J., Liu, J. 2017. Replicating myxomavirus optimizes cisplatin for the treatment of ovarian cancer in vitro and metastatic tumor in vivo. In press, Molec. Therapy

Lamichhane, P., Karyampudi, L., Shreeder, B., Krempski, J., Bahr, D., Daum, J., Kalli, K.R., Goode, E.L., Block, M.S., Cannon, M.J., Knutson, K.L.. 2017. IL-10 release upon PD-1 blockade sustains immunosuppression in ovarian cancer. In press, Cancer Res.

Goyne, H, Stone, P.J.B., Cannon, M.J. Editorial: combinatorial strategies for alleviation of tumor-associated immune suppression and therapeutic vaccination against ovarian cancer. Immunotherapy 3:805-807, 2011.

Cannon, M.J., Goyne, H., Stone, P.J.B., MacDonald, L.J., James, L.E., Cobos, E., Chiriva-Internati, M. 2013. Modulation of p38 MAPK signaling enhances dendritic cell activation of human CD4+ Th17 responses to ovarian tumor antigen. Cancer Immunol. Immunother. 62:839-849.

Goyne, H.E., Cannon, M.J. Dendritic cell vaccination, immune regulation and clinical outcomes in ovarian cancer. Frontiers in Immunology, 4:382, published online 18 November 2013.

Goyne, H.E., Stone P.J.B., Burnett, A.F., Cannon, M.J. 2014. Ovarian tumor ascites CD14+ cells promote CD4+ T cell migration and suppress tumor antigen-specific CD4+ T cell responses through IL-10 secretion and indoleamine 2,3-dioxygenase. J. Immunotherapy 37:163-169.

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