CMV Vectors: Exceptional Efficacy from Unconventional Cellular Immune Responses

Louis J. Picker, Oregon Health and Sciences University

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<h3>Insights from Listeria monocytogenes for the Development of Effective Cancer Immunotherapy Strategies</h3>Despite the profound clinical impact immune checkpoint inhibitors (CPIs) have on patients, it is increasingly recognized that strategies to promote infiltration of lymphocytes into the tumor microenvironment (TME) may be a necessary component of effective immunotherapy. Here we describe two approaches derived from the intracellular bacterium Listeria monocytogenes (Lm). The first is a live-attenuated Lm strain that is incapable of intracellular spread or direct infection of hepatocytes. Recombinant derivatives of this Lm strain induce a systemic pro-inflammatory cytokine profile, modify the TME to facilitate immune recognition, prime tumor associated Ag-specific CD8+ T cells, and provide evidence of clinical benefit in patients with advanced cancers. In the second therapeutic strategy, we synthesized cyclic dinucleotide (CDN) derivatives that potently activate human Stimulator of Interferon Genes (STING). This approach is based on the convergent observations of the STING-dependent induction of IFN-β expression by CDNs produced by cytosolic Lm in phagocytes, together with the STING-dependent innate recognition and T cell priming by tumor-resident dendritic cells, through CDNs produced by host cyclic GMP-AMP synthase. &nbsp;A Phase 1 clinical study to evaluate the impact of intratumoral delivery of a synthetic CDN is planned. Both Lm and CDNs potentiate antitumor efficacy of CPIs in mice, and particular combinations of these are being evaluated in humans.

Tom Dubensky, Aduro Biotech

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Immune Checkpoint Blockade in Cancer Therapy: New Insights, Opportunities, and Prospects for a CureThe existence of multiple non-redundant inhibitory pathways that limit T cell responses offers novel strategies for mobilizing the immune system to attack cancer cells. &nbsp;The best characterized of these immune checkpoints is CTLA-4, which inhibits T cell proliferation by interfering with the interaction of the costimulatory molecule CD28 with its ligands B7-1 and B7-2 on the surface of antigen presenting cells. &nbsp; &nbsp;Antibodies to CTLA-4 have proven effective against multiple tumor types in both pre-clinical and clinical studies. &nbsp;We and others have shown that CLTA-4 limits T cell proliferation by a cell intrinsic mechanism. &nbsp;However, there is also evidence that anti-CTLA-4 has to engage the target on both effector (Teff) and regulatory (Treg) T cells.PD-1, another checkpoint, recruits a phosphatase and seems to interfere with T cell antigen receptor mediated signaling. &nbsp;It has two ligands, PD-L1 and PD-L2, which are both expressed on dendritic cells. &nbsp;However, many tumor cells also express PD-L1. Emerging data suggest that T cell responses are largely directed toward neoantigens arising as a result of mutational events associated with the carcinogenesis. &nbsp;While all tumors with antigens recognizable by the immune system should be targets for checkpoint blockade, it is becoming clear that certain types of tumors with lower burdens of mutations (eg. prostate, breast, and kidney cancer) present special challenges for immune therapy. &nbsp;Strategies for effective treatment of such tumors will be discussed.

James P. Allison, Anderson Cancer Center

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Panel Discussion: Shooting the Moon- Prospects for Immunotherapies as Cures for Cancers and Infectious Diseases

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Louis J. Picker, Oregon Health and Sciences University

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