Abstract 309: Adding nadunolimab to chemotherapy or antibody drug-conjugates (ADCs) may improve antitumor efficacy and counteract peripheral neuropathy

Abstract Background: Nadunolimab, a fully humanized ADCC-enhanced, monoclonal IgG1 antibody targets IL-1 receptor accessory protein (IL1RAP) and blocks IL-1 signaling. In pts, nadunolimab with standard chemotherapies showed good safety and promising efficacy. In 73 advanced pancreatic ductal carcinoma (PDAC) pts, combination with nab-paclitaxel and gemcitabine showed 33% ORR and 13.2mo OS, with 48% ORR and 14.2mo OS in the IL1RAP-high subgroup. In 40 1st or 2nd line non-small cell lung cancer pts, combination with platinum-doublet showed 55% ORR and 13.7mo OS, with 91% ORR and 26.7mo OS in the 2nd line non-squamous subgroup. Interestingly, in addition to promising anti-tumor effects, a significantly delayed onset and reduced incidence of nab-paclitaxel/gemcitabine-related chemotherapy-induced peripheral neuropathy (CIPN) were observed in pts receiving higher doses of nadunolimab compared to lower doses (36% vs 60%). CIPN is a neuroinflammatory side effect driven by immune activation and cytokine release such as IL-1 that limits treatment and severely impairs quality of life. Building on these promising findings, our aim was to further investigate nadunolimab’s additional potential in mitigating neuropathies associated with chemotherapy and ADCs. Methods: The potential neuroprotective effect of nadunolimab was analyzed in two clinical trials: one involving 14 pts with 8 different cancer indications treated with FOLFOX and nadunolimab at 1 mg/kg (n=7) or 0.5 mg/kg (n=7), and another involving 18 PDAC pts treated with FOLFIRINOX and nadunolimab at doses of 0.5 mg/kg (n=8), 1 mg/kg (n=3), 1.5 mg/kg (n=4), and 2.5 mg/kg (n=3). In mice, neuropathy was induced by vincristine, nab-paclitaxel, nab-paclitaxel plus gemcitabine, or ADC payloads. The effects of nadunolimab surrogate antibody (10 mg/kg) on neuropathy were evaluated using electronic von Frey apparatus, parallel rod floor apparatus, and grip strength meter. Tissue samples were analyzed for inflammatory markers and immune cell infiltration. Results: We observed a lower incidence of any-grade FOLFOX-induced CIPN in the 1 mg/kg nadunolimab dose group compared to the 0.5 mg/kg dose group (43% vs 100%) and a significantly longer time to onset (median not estimable vs 4 days; HR=0.15, p=0.0004). Similar trends were observed for FOLFIRINOX-induced CIPN in PDAC pts. In mice, CIPN was linked to infiltration of myeloid cells and inflammatory cytokines in dorsal root ganglia. Co-administration of the nadunolimab surrogate completely abrogated CIPN. Ongoing studies aim to confirm the effects of the nadunolimab surrogate on ADC payload-induced neuropathy. Conclusion: Overall, our current findings in conjunction with previous results, suggest that nadunolimab may not only offer anti-tumor benefits but also protection against the neuro-inflammatory component driving chemotherapy- and ADC-induced neuropathy. Citation Format: Samuel Le Sourd, Rocio Garcia-Carbonero, Sandrine Hiret, Elin Jaensson Gyllenback, Camilla Rydberg Millrud, Lars Thorsson, Svetlana Shatunova, Irina Vetter, Hana Starobova, David Liberg. Adding nadunolimab to chemotherapy or antibody drug-conjugates (ADCs) may improve antitumor efficacy and counteract peripheral neuropathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 309.