Both STING agonist and LADD-based immunotherapies induce tumor-specific T cells and can be effectively combined with anti-CTLA4 Meredith L Leong1, Weiwen Deng1, Victor Lira1, Anthony L Desbien1, Kelsey Sivick Gauthier1, Gabrielle Reiner1, Brian Francica1, Paul Vink2, Laura Hix Glickman3, Natalie Surh1, William G Hanson1, Joost Kreijtz2, Chudi O Ndubaku, Hans van Eenennaam2, Thomas W Dubensky Jr4, Peter Lauer1, Sarah M McWhirter1, Andrea van Elsas1,2 1Aduro Biotech, Inc.; 2Aduro Biotech Europe; 3Actym Therapeutics; 4Tempest Therapeutics
Development of effective and durable antitumor immunity requires activation, expansion and maintenance of functional tumor antigen-specific effector T cells. Approvals of anti-CTLA4 and anti-PD1 to treat patients diagnosed with highly infiltrated tumors, such as melanoma, highlight the power of checkpoint modulation as well as the importance of tumor-specific T cells in the tumor microenvironment (TME). In addition to a novel humanized anti-CTLA4 antibody, Aduro Biotech is developing other immunotherapies, including a synthetic cyclic dinucleotide agonist of STING (ADU-S100) and neoantigen expressing live attenuated double deleted Listeria monocytogenes (personalized LADD or pLADD), with a goal to induce tumor-specific T cells and to repolarize the TME. In multiple mouse models, intratumoral administration of ADU-S100 results in maturation of APCs in draining lymph nodes, activation and expansion of tumor-specific T cells, and durable anti-tumor activity. Preclinical efficacy with ADU-S100 can be enhanced by combination with anti-CTLA4. LADD-based immunotherapy induces antigen-specific CD8+ T cells, repolarization of the TME and significant therapeutic benefit in syngeneic mouse models, and combination with anti-CTLA4 further improved efficacy in these models. Taken together, these preclinical studies demonstrate that combinations of Aduro's proprietary immune-based therapies, including anti-CTLA4, LADD, and ADU-S100, alter the immune system and TME in diverse ways and can work in together to maximize efficacy, warranting further exploration of these promising combinations.
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