CTIM-30. INVESTIGATION OF THE COMBINATION OF D2C7-IT WITH AN FC-ENGINEERED ANTI-HUMANCD40 MONOCLONAL ANTIBODY (2141-V11) WHEN ADMINISTERED INTRATUMORALLY VIA CONVECTION-ENHANCED DELIVERY (CED) FOLLOWED BY CERVICAL PERILYMPHATIC INJECTIONS (CPLIS) OF

Abstract BACKGROUND When administered via CED in glioma models, D2C7-IT, an antibody toxin conjugate, combined with an anti-mouseCD40 generates robust antitumor immunity by killing tumor cells, activating microglia, reversing glioma-associated microglia and macrophage (GAMM)-mediated immune suppression, and empowering polyfunctional tumor antigen-specific CD8 T cells. In addition to reprogramming GAMMs, anti-CD40 also activates dendritic cells and induces glioma-specific T cell responses in tumor-draining lymph nodes. After evaluating the safety and efficacy of D2C7-IT CED monotherapy in rGBM (NCT02303678), we initiated an assessment of the safety and efficacy of the combination of D2C7-IT+2141-V11 CED followed by repeated subcutaneous CPLIs of 2141-V11 ipsilateral to the tumor in rGBM (NCT04547777). METHODS Eligibility included adult patients with solitary supratentorial rGBM, IDH wild-type; ≥ 4weeks after chemotherapy, bevacizumab, or investigational agent; adequate organ function; and KPS ≥70%. Patients were treated with D2C7-IT (166μg) and 2141-V11 (3mg), both infused via CED, followed by CPLI of 2141-V11 at 2mg at weeks 2 and 4 post-D2C7-IT+2141-V11 CED, followed by every 3 weeks for 1 year and then every 4-6 weeks. RESULTS A total of 27 rGBM patients (median age: 61) enrolled on trial and were treated with D2C7-IT+2141-V11 CED followed by CPLIs of 2141-V11. As of May 28, 2025, patients have received an average of 12 CPLIs of 2141-V11 (range 3-27). No study-related grade 4 or 5 adverse events (AEs) were observed. Grade 3 AEs related to D2C7-IT and/or 2141-V11 include one each of seizure and cerebral edema. AEs related exclusively to CPLIs of 2141-V11 consist of grade 1 injection site reactions. The combination therapy demonstrated a survival of 16.4 months compared to 8 months for D2C7-IT CED monotherapy (p=0.0034). CONCLUSIONS The addition of CPLIs of 2141-V11 post CED of D2C7-IT+2141-V11 is feasible, shows an acceptable toxicity profile, and has a survival advantage compared to D2C7-IT monotherapy.