Abstract B117: Phase 1 study of CM24 in combination with nivolumab in patients with advanced pancreatic cancer - Survival, potential biomarker and effect on neutrophil extracellular traps (NETs)
Authors: Borazanci Erkut , Pant Shubham , Perets Ruth , Golan Talia , Al Hallak Mohammed Najeeb , Cecchini Michael , Maierson Tomer , David Hava Ben , Schickler Michael , Reuveni Hadas 
Published: January 2024

Abstract
Background: The monoclonal antibody CM24 blocks the activity of carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), which is known to have several important roles in cancer progression, immune evasion, and metastasis. The homophilic interaction of CEACAM1 on tumor cells and tumor infiltrating lymphocytes (TILs) silences the anti-tumor immunity. Additionally, CEACAM1 is part of the neutrophil extracellular trap (NET) complex. NETs are regarded as an important component in the tumor microenvironment, which contribute to metastasis and immune evasion. Previously we have demonstrated direct binding of CM24 to NETs and inhibition of NET-induced cancer cell migration and tumor metastasis by the antibody. Here, we present the results from the dose escalation part of a Phase 1/2 study of CM24 and nivolumab (NCT 04731467) and the findings of exploratory studies that were conducted as part of this trial. Methods: In the dose escalation part of the study, 11 pancreatic ductal adenocarcinoma (PDAC) patients who received 2 prior lines of therapy were administered CM24 at 10, 15 and 20mg/kg q2w and nivolumab at 480mg q4w. Levels of CEACAM1 and myeloperoxidase (MPO) were measured in serum by ELISA. Pretreatment biopsies from 8 evaluable PDAC patients were analyzed, along with pretreatment and on treatment serum samples. Quantitative multiplex IF and immunohistochemistry (IHC) were used to evaluate CEACAM1, PDL1, TIM3 and CEACAM1-positive TILs in patient biopsies. Results: Nine PDAC patients were evaluable for exploratory efficacy assessment with a median OS of 4.5 (95% CI 2.0-11.1) months, including 1 confirmed PR and 2 pts with SD for a disease control rate of 33%. Percentage of CEACAM1+TILs in patient biopsies ranged between 0% and 10%, and a cutoff rate to define low (0-5%) vs. high (&gt; 5%) expression was used to stratify the patient survival data. High CEACAM1+TILs (median of 10%) were measured in 3/8 PDAC patients with median survival of 11.1 months (range: 9.6-14.6 months) compared to 5/8 patients with low CEACAM1+TILs (median 2%) who exhibited shorter survival (range: 2-4.5 months), suggesting positive association (p=0.017). IHC analysis of CEACAM1 further revealed CEACAM1-positive NETs in the biopsies of all PDAC patients. In serum, enhanced levels of the NET biomarker MPO were detected in PDAC patients (n=10) as compared to healthy volunteers (n=30), demonstrating a 3-fold difference in the mean value (p&lt;0.01). Interestingly, MPO levels decreased by an average of 40% (p&lt;0.05) across all dose levels within 2 weeks of CM24 therapy. Additional findings will be presented at the conference. Conclusions: CM24 in combination with nivolumab shows promising initial activity results and a favorable safety profile in PDAC patients who have progressed after second-line therapy. The positive association between the level of CEACAM1+TILs and OS as well as CM24 effects on NETs, advocate for the role of CM24 in controlling immune evasion. These 2 potential biomarkers are being investigated in the ongoing randomized Phase 2 study.
Citation Format: Erkut Borazanci, Shubham Pant, Ruth Perets, Talia Golan, Mohammed Najeeb Al Hallak, Michael Cecchini, Tomer Maierson, Hava Ben David, Michael Schickler, Hadas Reuveni. Phase 1 study of CM24 in combination with nivolumab in patients with advanced pancreatic cancer - Survival, potential biomarker and effect on neutrophil extracellular traps (NETs) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B117.