gough_crittenden_2009As principle investigators of two R01 Research Project grants from the National Cancer Institute, Michael J. Gough, Ph.D.,  and Marka R. Crittenden, M.D., Ph.D.,  are examining the combination of highly targeted radiation therapy with novel immunotherapies for cancer. Together, they lead the Integrated Therapies Laboratory with the goal of developing more effective therapies for patients with cancer. Their research encompasses basic science, preclinical therapy models and translational research through a multidisciplinary team of scientists, clinicians and physician-scientists. 

Radiation vs Listeria vaccination

The role of radiation therapy as an immunotherapeutic agent is a subject of ongoing research. Preclinical studies indicate high-dose radiation therapy is effective in mediating cancer regression when paired with immunotherapy. 

In the prevailing theory, radiation therapy eradicates cancer cells, which are processed by the immune system, prompting an influx of cancer-killing CD8 T cells to the tumor site. Checkpoint immunotherapies counteract the immune-suppressing forces of the tumor microenvironment, which enables the elimination of residual cancer cells that survive radiation. Drs. Gough and Crittenden tested this concept, and their findings may guide how these therapies are combined when treating patients with cancer.

In a preclinical pancreatic cancer model, Drs. Gough and Crittenden compared high-dose radiation therapy and a Listeria monocytogenes vaccine platform. They analyzed the ability of both agents to generate anti-cancer immune responses when combined with an anti-PD-1 antibody, a type of checkpoint immunotherapy. They observed Listeria vaccination prompted a greater increase in the number of tumor-reactive T cells than radiation. However, the vaccine failed to provide an advantage over radiation in controlling tumor growth. 

“In our experiments, generating large numbers of tumor-reactive T cells by Listeria vaccination did not substitute for the efficacy of radiation and an anti-PD-1 antibody,” says Dr. Gough. “This leads us to question whether the main driver of radiotherapeutic efficacy is to increase the number of CD8 T cells, and provides guidance for future investigations.” 

Innate and Adaptive Immunity

In other experiments, Drs. Gough and Crittenden are using Listeria vaccination to study innate and adaptive immune responses to cancer. Whereas the innate immune system initiates immune responses, an adaptive immune response can provide long-term immunity.

In a preclinical model, their lab evaluated an approach to amplify the inflammatory immune response to Listeria by modifying expression of suppressor of cytokine signaling 1, or SOCS1, a protein known to suppress inflammation. They reasoned loss of the SOCS1 protein in dendritic cells, a cell that links innate and adaptive immune responses, would boost immune activation and increase T-cell responses.

By testing the Listeria vaccine in dendritic cells engineered to lack SOCS1, they compared results from in vitro experiments with those performed in living organisms, known as in vivo experiments. Contrary to their expectations, they observed a decrease in CD8 T-cell responses. As reported in the Journal of Immunology, dendritic cells lacking SOCS1 expression were functional, but failed to generate an efficient adaptive immune response. When the innate immune response increased, the adaptive immune response decreased.

“We demonstrated for the first time that cell-specific loss of SOCS1 in dendritic cells in vivo redirects the immune response following Listeria vaccination away from an adaptive response and toward an innate response,” says Dr. Crittenden. “Strategies that aim to generate cancer immunity by means of CD8 T-cell meditation may need to avoid over-activation of cross-presenting dendritic cells to optimize the adaptive immune response.”

Their discovery is yielding new directions of research. Drs. Gough and Crittenden have applied these insights to other areas of investigation in their laboratory with the hope of improving therapies for patients with cancer.

Personalized Immunosurgical Therapy 

Research_TestTubeIn collaboration with R. Bryan Bell, M.D., D.D.S., FACS, and Rom S. Leidner, M.D., co-medical directors, Providence Head and Neck Cancer Program, Drs. Gough and Crittenden are investigating a surgical approach to deliver immunotherapy treatments to patients’ tumors at the site of surgical resection. Using a biomaterial gel, they administer stimulator of interferon genes ligands, known as STING ligands at the site of partial tumor resection as a means to prevent local recurrence of head and neck squamous cell carcinoma. Activation of STING ligands in the tumor microenvironment has been shown to prompt anticancer immune responses in preclinical models.  

As reported in Cancer Research, Drs. Gough and Crittenden demonstrate that although control-treated tumors recur locally, tumors treated with STING-loaded biomaterials are cured. The mechanism of tumor control required activation of STING and induction of type I interferons in host cells, not cancer cells, and resulted in CD8 T-cell-mediated cure of residual cancer cells. 

Additionally, they used a novel tumor explant assay to screen individual murine and human tumor responses to therapies ex vivo. This information enabled them to personalize the biomaterial and immunotherapy applied to previously unresponsive murine tumors. Their research showed explant assays identify the diversity of tumor-specific responses to STING ligands and establish the utility of the explant assay to personalize immunotherapies according to the local response.