Work

1068 Innate and adaptive immune responses and antitumor activity associated with ARV-6723, a PROTAC HPK1 degrader, in exhausted/post-immune checkpoint inhibitor (ICI) preclinical settings

Year: 2026

Type: conference-abstract

Abstract: Background Patients with ICI resistance often exhibit an immunosuppressive, exhausted tumor microenvironment (TME), highlighting the need for therapies that reprogram the TME and restore antitumor immunity. ARV-6723 potently degrades hematopoietic progenitor kinase 1 (HPK1), a negative regulator of T-cell activation, promoter of T-cell exhaustion, and immunosuppressive modulator of multiple immune cell types through kinase-dependent and scaffolding functions. We have shown that ARV-6723 reversed T-cell exhaustion and suppression in vitro and demonstrated superior antitumor activity versus ICI therapy or an investigational HPK1 inhibitor in multiple ICI-resistant mouse models.1–3Methods To further assess activity in ICI-resistant models, ARV-6723 (30 mg/kg orally once daily) was compared with an anti-programmed death-1 (PD-1) antibody ± anti-cytotoxic T-lymphocyte-associated-4 (CTLA-4) antibody (each 10 mg/kg intraperitoneally twice weekly) in a syngeneic mouse model (LLC1-IFNγ) generated through chronic interferon (IFN)-γ exposure to induce T-cell dysfunction/exhaustion. 4 ARV-6723 was also evaluated in a CD34+ humanized mouse implanted with a melanoma patient-derived xenograft collected at ICI progression. Tumors were analyzed by multiplex immunofluorescence and RNA-sequencing. Banked patient peripheral blood mononuclear cells (PBMCs) collected pre- and post-ICI were treated ex vivo and evaluated by cytokine and transcriptomic analyses.Results In the LLC1-IFNγ model, ARV-6723 induced significant tumor growth inhibition (TGI 64%; P < 0.0001), whereas anti-PD-1 ± anti-CTLA-4 antibody showed no effect. Transcriptomic analysis demonstrated reversal of the chronic IFN-γ-induced ‘Terminally Exhausted CD8’ signature. ARV-6723 uniquely increased inferred innate immune populations and significantly increased the IFN-γ response gene to IFN-stimulated gene resistance signature (IFNG.GS/ISG.RS) ratio (P < 0.005),5 indicating a shift toward productive IFN signaling. Multiplex immunofluorescence revealed marked ARV-6723-induced increases in T-cell aggregates.In the humanized model, anti-PD-1 antibody exhibited no antitumor activity, whereas ARV-6723 achieved 57% TGI (P < 0.0001). Transcriptomic analyses demonstrated increases in inferred activated dendritic cells, M1 macrophages, and memory/activated T-cells, with enhanced antigen presentation and IFNG.GS/ISG.RS ratio (P < 0.05).Transcriptomic profiling of patient-matched PBMCs revealed enrichment of antigen presentation, IFN-γ, and IFN regulatory factor pathways among genes differentially expressed after ICI treatment versus baseline, with ex vivo ARV-6723 (100 nM) further augmenting these immune-related signatures. Under stimulation conditions, ARV-6723 increased IFN-γ and interleukin-2 in 3 sets of PBMC samples, supporting transcriptomic findings.Conclusions ARV-6723 demonstrated significant TGI in mouse- and human-derived models of ICI resistance. Differentiated antitumor activity was associated with robust remodeling of both innate and adaptive immune compartments, supporting the potential of ARV-6723 to overcome multiple ICI resistance mechanisms and warranting evaluation in patients with disease progression on ICIs.References Corwin WL, DeBerardinis AM, Conrad R, Scopel M, Morgan P, Chakraborty S, Frenette J, Wilson R, Corradi J, Davenport K, Cadelina G, Pizzano J, Van Acker A, Ishchenko A, Araujo E, Hornberger KR, Cacace A, Juncadella IJ. Preclinical antitumor activity of potent and orally bioavailable PROTAC HPK1 degraders as monotherapy or combined with an anti-PD-1 antibody. Poster 1158 presented at: Society for Immunotherapy of Cancer (SITC) 2025 Annual Meeting; 2025 Nov;5–9; National Harbor, MD, USA.Van Acker AC, Corwin WL, DeBerardinis A, Rousseau E, Conrad R, Scopel M, Kuhlberg C, Cadelina G, Davenport K, Wu W, Corradi J, Pizzano J, Hornberger KR, Cacace AM, Landrette S, Wang X(J), Juncadella IJ. Antitumor and immunomodulatory activity of ARV-6723, a PROTAC HPK1 degrader, across high- and low-immunogenic solid tumors. Poster C041 presented at: AACR Immuno-Oncology Conference; 2026 Feb;18–21; Los Angeles, CA, USA.Van Acker AC, Corwin WL, DeBerardinis A, Rousseau E, Conrad R, Scopel M, Kuhlberg C, Cadelina G, Davenport K, Wu W, Corradi J, Pizzano J, Hornberger KR, Cacace AC, Juncadella IJ, Landrette S, Wang X(J). Preclinical antitumor and immunomodulatory activity of ARV-6723, a PROTAC HPK1 degrader, versus ICIs. Poster 4309 presented at: American Association for Cancer Research (AACR) Annual Meeting; 2026 Apr;17–22; San Diego, CA, USA.Memon D, Correa de Sampaio P, et al. Adaptive interferon signaling reshapes the tumor microenvironment and drives immune checkpoint inhibitor resistance. Cancer Cell. 2024;42(2):209–224.e9. doi:10.1016/j.ccell.2023.12.011. PMID: 38215748Benci JL, Johnson LR, et al. Opposing functions of interferon coordinate adaptive and innate immune responses to cancer immune checkpoint blockade. Cell. 2019 Aug 8;178(4):933–948.e14. doi: 10.1016/j.cell.2019.07.019.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.1068