Tom Dubensky, Aduro Biotech

Insights from Listeria monocytogenes for the Development of Effective Cancer Immunotherapy Strategies

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.  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.