RESEARCH

Tumor Microenvironment

The tumor immune environment can be thought of as an ecosystem-like network of interacting cells, signaling molecules, extracellular matrix, and mechanical cues that can support tumor growth, protect the tumor from host immunity, foster therapeutic resistance, and support metastases.

The Cancer Vaccine Institute is focused on immune modulation strategies to create “danger” or “rejection” signals that make the tumor appear more dangerous to the immune system and transform the tumor-immune environment from tumor protecting to tumor killing. Our group is actively evaluating multiple immumodulatory approaches that could be used alone or in combination with vaccination and T-cell therapy to remodel the tumor immune environment and stimulate an effective anti-tumor immune response. These strategies include the activation of antigen presenting cells via stimulation of toll like receptors (TLRs) and elimination of immune suppressive cell populations (Tregs and MDSC), leading to enhanced local cytokine production and a Th1-polarized microenvironment that favors tumor cell killing by cytotoxic T lymphocytes.

The activity of the gut microbiome has been linked to the development of cancer. It has been shown that the particular make-up of one’s microbiome can influence the success of certain immunotherapies. Our group has made a novel discovery that an immune response to some gut bacteria may be suppressing immunity to cancer cells, and currently we are looking at how changing the make-up of the gut bacteria using ‘probiotics’ might be able to bypass this suppression of the immune system and make our vaccines more effective.

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Active Modulation of the Tumor Microenvironment

  • Depleting T regulatory cells: We have shown that depletion of Tregs using ONTAK, a fusion protein of IL-2 and diphtheria toxin, can significantly inhibit tumor growth in a mouse model of breast cancer. This finding has been translated into a clinical trial in breast and ovarian cancer patients.

  • Topical Imiquimod for breast cancer chest wall metastasis: Recurrent chest wall disease occurs in up to 35% of breast cancer patients and has few treatment options. Using a mouse model of breast cancer, we showed that topical treatment with imiquimod cream can inhibit tumor growth. This finding has been translated into a clinical trial by our group.

  • TLR8 agonist to enhance NK cell function and ADCC: We have characterized VTX-2337as a novel TLR8 agonist that selectively activates myeloid DC and induces high levels of TNF-a and IL-12. VTX-2337 also enhances NK cell function and augments antibody-dependent cell-mediated cytotoxicity (ADCC). This finding has led to a clinical trial in head and neck cancer patients testing the combination of VTX-2337 with cetuximab mAb therapy.

  • Natural products to enhance anti-tumor immunity: We have found that protein-bound polysaccharide (PSK), a hot water extract from Trametes Versicolor, has potent TLR2 agonist activity. PSK inhibits tumor growth in a CD8 T cell and NK cell-dependent manner. PSK also enhanced human NK cell function and augments HER2-targeted monoclonal antibody therapy. This finding is being translated into an upcoming clinical trial in breast cancer patients testing the combination of PSK , trastuzumab, and HER2-targeted CD4 peptide vaccine.