Preclinical antitumor and immunomodulatory activity of ARV-6723, a PROTAC hematopoietic progenitor kinase 1 (HPK1) degrader, versus immune checkpoint inhibitors (ICIs)

Although ICIs have demonstrated robust and durable responses in several solid tumor types, most patients display primary or secondary resistance, often attributed to an immunosuppressive microenvironment and/or T-cell exhaustion. Thus, there is a high unmet need for agents that can overcome ICI resistance to improve patient outcomes. HPK1 negatively regulates T-cell activation/proliferation, promotes T-cell exhaustion, and modulates activation of other immune cell types through kinase and less well-defined scaffolding activity. Degradation of HPK1 by ARV-6723, a potent, oral PROteolysis TArgeting Chimera (PROTAC), has the potential to induce broad immunomodulatory changes and overcome multiple mechanisms of ICI resistance, restoring T-cell activation and attenuating T-cell exhaustion. ARV-6723 (5 or 30 mg/kg orally once daily) was compared with an anti-programmed death-1 (PD-1) antibody (10 mg/kg intravenously [IV] twice weekly [BIW]) alone or combined with an anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody (10 mg/kg IV BIW) in syngeneic mouse tumor models of ICI resistance (a murine-derived lung cancer cell line chronically treated in vitro with interferon-gamma [LLC1-IFNgamma] to model T-cell dysfunction/exhaustion and Kras LSL-G12D/+ ;Trp53 LSL-R172H/+ ;Pdx1-Cre;Rosa26 YFP/YFP [KPCY] to model T-cell exclusion/low T-cell infiltration). Immunomodulatory activity was characterized by multicolor flow cytometry and by whole transcriptome and peripheral cytokine analyses. In the LLC1-IFNgamma model, ARV-6723 (5 and 30 mg/kg) induced significant tumor growth inhibition (TGI) of 27% ( P <0.01) and 57% ( P <0.001), respectively, whereas anti-PD-1 antibody alone or combined with anti-CTLA-4 antibody did not yield significant TGI (2% and 13%, respectively). In the KPCY model, ARV-6723 (30 mg/kg) induced TGI of 89% ( P <0.01), comparable to the anti-PD-1/anti-CTLA-4 antibody combination (83%; P <0.05) and superior to anti-PD-1 antibody alone (28%). Preliminary mechanistic analysis revealed differential immunomodulatory effects in the periphery with ARV-6723 that were not seen with anti-PD-1 antibody alone or combined with anti-CTLA-4 antibody, eg, increased effector/memory T cells, increased natural killer (NK) cells, and correlative cytokine changes (decreased immunosuppressive cytokine interleukin [IL]-10 and increased proinflammatory cytokines IL-5 and keratinocyte-derived chemokine). ARV-6723 demonstrated greater antitumor activity and proinflammatory, immunomodulatory effects (including increased NK and T cell populations) than single-agent or combination ICI in preclinical models of ICI resistance. These data highlight the potential for ARV-6723 to overcome ICI resistance, supporting its future investigation alone or in combination with ICIs in patients with solid tumors.