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585 LIGHT (TNFSF14) co-stimulation enhances myeloid cell activation and anti-tumor immunity in the setting of PD-1 and TIGIT checkpoint blockade
  1. George Fromm1,
  2. Kyung Jin Yoo2,
  3. Kellsey Johannes2,
  4. Casey Shuptrine2,
  5. Zach Opheim2,
  6. Arpita Patel2,
  7. Haley Andreasen2,
  8. Jaya Miriyala2,
  9. Suresh De Silva2 and
  10. Taylor Schreiber2
  1. 1Shattuck Labs, Inc, APEX, NC, USA
  2. 2Shattuck Labs, Inc., Durham, NC, USA


Background Co-inhibition of TIGIT and PD-1/L1 improves response rates compared to monotherapy PD-1/L1 blockade in checkpoint naïve NSCLC with PD-L1 expression >50%. TIGIT mAbs with an effector competent Fc can induce myeloid cell activation, and some have also demonstrated effector T cell depletion, which carries a clinical liability of unknown significance. TIGIT antibody blockade translates to anti-tumor activity by enabling PVR signaling through CD226 (DNAM-1), which can be directly inhibited by PD-1. Further, DNAM-1 is downregulated on TIL in advanced and CPI resistant cancers. Therefore, broadening clinical responses from TIGIT blockade into PD-L1low or CPI resistant tumors, may be enhanced by immune co-stimulation that independently operates from PD-1/L1 inhibition.

Methods Mouse and human TIGIT-Fc-LIGHT molecules were generated and assessed using Octet, MSD, and cell binding assays, and function was evaluated using in vitro/in vivo activation and anti-tumor efficacy experiments; including a preclinical model engineered to mimic human CPI acquired resistance.

Results TIGIT-Fc-LIGHT was nominated using in vitro and genomic screening assays designed to identify TNF costimulatory receptors widely expressed on TIL, T stem cell memory (Tscm), and NK cells; relative to DNAM-1 expression. HVEM was prioritized, and its ligand TNFSF14 (LIGHT) also directly activates myeloid cells through binding to a second receptor, LTβR. TIGIT-Fc-LIGHT simultaneously engaged TIGIT and LIGHT receptors at low nanomolar affinities (~3.5–6.5 nM), without the requirement for an effector competent Fc. HVEM signaling overlaps with DNAM-1, and TIGIT-Fc-LIGHT activated canonical and non-canonical NFκB pathways, leading to increased tumor infiltration of antigen-specific CD8+ T and NK cells. Importantly, anti-tumor efficacy induced by monotherapy TIGIT-Fc-LIGHT was maintained in aggressive anti-PD-1 acquired resistant tumors, a model where combined PD-1 and TIGIT antibody blockade was inactive. Because HVEM lacks cytoplasmic domain homology to DNAM-1, HVEM signaling is unlikely to be regulated by PD-1. Indeed, while anti-tumor activity of TIGIT-Fc-LIGHT was enhanced by PD-1/L1 blockade, it was not dependent upon combination. TIGIT-Fc-LIGHT also directly activated myeloid cells and increased the expression of CXCL10 and CXCL11, and stimulated proinflammatory cytokines, including CCL2, CCL4, and CXCL13.

Conclusions TIGIT-Fc-LIGHT was designed to overcome the limitations of TIGIT blocking antibodies through: 1) preserved costimulation in advanced tumors, 2) direct myeloid cell activation, 3) blockade of all known TIGIT ligands, and with 4) no risk of depleting effector lymphocytes since TIGIT-Fc-LIGHT activity does not require Fc function. Pre-clinical data indicate that these goals were achieved, and further development is warranted.

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