IMT-009（IMT）在晚期癌症中的首次人体剂量递增（DE）和生物标志物队列扩展（BCE），以及IMT与fruquintinib（F）联合治疗微卫星稳定型结直肠癌（MSS CRC）的1b期（Ph1b）研究

Background: CD161 is a C-type lectin receptor on NK cells and memory T cells found in cancers and associated with treatment resistance. CD161 binds to CLEC2D resulting in T/NK inhibition. CLEC2D is highly expressed on germinal center B cells in tertiary lymphoid structures (TLS), as well as some cancer cells and other immune cells. IMT is a human, Fc-attenuated, IgG1 mAb that binds CD161 and blocks interaction with CLEC2D. IMT increased human NK cell degranulation, cytokine production, and cellular killing of CLEC2D+ tumor cell targets by T cells. It inhibited tumor growth in humanized mouse model of CLEC2D+ cells supporting development of IMT as a novel cancer immunotherapy. Methods: NCT05565417 is a Phase 1 DE and BCE trial of IMT in pts with solid tumors or lymphoma, and a Ph1b of IMT with F in 2nd - 4th line MSS CRC. The primary objective was safety (CTCAEv5); other objectives included PK, PD, response (RECIST v1.1), and translational biomarkers. The BCE and Ph1b required pre-treatment tissue demonstrating CD161+ cells using a validated, central IHC assay. BCE enrollment was restricted to MSS CRC, NSCLC, HNSCC, esophageal cancer, and lymphoma. Results: As of Jan 30, 2026, 22 pts (6F, 16M, med age 63, range 30-78, med 4 prior Tx) received IMT in DE at fixed doses ranging from 6 to 1600 mg IV every 3 weeks. In the BCE, 26 pts (11F, 15M, med age 60.5, range 28-80, med 3 prior Tx) were enrolled at 240, 800, and 1600 mg dose levels. IMT exposure increased in a dose proportional manner and RO appeared saturated by the 240 mg dose. The highest treatment-related AE was Gr2 and the most common TRAEs (n>=3 pts) were arthralgia (4), nausea (4), fatigue (3), vomiting (3). 34 pts had MSS CRC, 32 of which were treated at 240 mg or higher. One patient with a liver met and pelvic mass had a cPR and the pre-treatment tumor had a high CD161 immune infiltrate. Another patient was treated for 14 months with SD. In Ph1b, 19 patients with MSS CRC (9F, 10M; med age 54, range 32-78, med 2 prior Tx) were treated with IMT at 240, 800, or 1600mg in combination with F, which was given according to the USPI. The most common treatment emergent AEs were fatigue, abd pain, anorexia, HTN, hypothyroid, and nausea, and 1 Gr4 and no Gr5 AEs reported. 1 patient had a cPR and 3 additional patients were on treatment for > 6 months. Multiplexed imaging of pretreatment tissue suggested that the presence and number of CLEC2D/CD161+ TLS and CXCL13 may be associated with clinical benefit. Conclusions: IMT was well-tolerated as monotherapy and in combination with F. Evidence of anti-tumor activity was observed, and translational data support the hypothesis that CD161⁺ T cells may be suppressed by CLEC2D in TLS. Pre-treatment selection of patients with TLS may enrich for clinical benefit to IMT, and CXCL13 may be a relevant pre-treatment selection marker to identify potential TLS in future trials.