Vidutolimod monotherapy had an ORR of 20.0%, with a median DOR of 5.6 months. Based on the efficacy data presented in Table 1, vidutolimod polysorbate 20 (PS20) A was selected for further development as this formulation in combination with pembrolizumab had a best objective response rate (ORR RECIST v1.1) of 23.5%, with a median duration of response (DOR) of 25.2 months. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 37.1% of patients treated with vidutolimod + pembrolizumab and in 22.5% of patients treated with vidutolimod monotherapy. Most patients had PD as their last response to prior anti–PD-1 therapy (Part 1, 93.1% Part 2, 80.0%). The median age was 64 years in Part 1 (range, 30-90) and 68 years in Part 2 (range, 30-89). Key objectives included assessment of safety and clinical activity, and exploratory analyses were performed on available tumor biopsies using immunohistochemistry and RNAseq.Īt data cutoff (August 17, 2021), 159 patients had enrolled in Part 1 and 40 patients in Part 2.
Part 1 evaluated vidutolimod + pembrolizumab and Part 2 evaluated vidutolimod monotherapy. This two-part, open-label, multicenter, phase 1b study ( NCT02680184 ) enrolled adults with histologically confirmed metastatic or unresectable cutaneous melanoma who had stable disease after ≥12 weeks or PD on anti−PD-1 treatment, measurable disease per RECIST v1.1, ECOG PS 0/1, and ≥1 lesion accessible for intratumoral injection.
This phase 1b study evaluated the safety and clinical activity of intratumoral vidutolimod with and without pembrolizumab in patients with refractory melanoma. Vidutolimod (CMP-001) is a first-in-class, immunostimulatory virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist. There are limited therapeutic options for patients with progressive disease (PD) on or after PD-1–blocking antibody therapy. Our approach to focus on preclinical tumor models with similar genetic background but different sensitivity to anti-PD-1 therapy would contribute to illustrating the potential mechanism of anti-PD-1 response and to generating a novel concept to synergize current anti-PD-1 therapies for cancer patients. Further pathway analyses enable us to propose a hypothesis that Wnt pathway could be one of the major factors to differentiate CT-26 from Colon 26 model and link to anti-PD-1 response. By characterizing the mouse cells lines and tumor-immune context in the tumor tissues with comprehensive analysis approaches, we found that CT-26 showed “hot tumor” profile with more infiltrated immune cells than Colon 26. Genomic/transcriptomic analyses highlighted thatWnt pathway was one of the potential differences between CT-26 and Colon 26, showing Wnt activity was higher in Colon 26 than CT-26.ĬT-26 and Colon 26 syngeneic tumor models showed different sensitivity to anti-PD-1 therapy, although both tumor cells are murine colorectal carcinoma cell lines from BALB/c strain.
Immune-profiling showed that CT-26 tumor tissue was infiltrated with more immune cells than Colon 26.
CT-26 tumor mice were more sensitive to the anti-PD-1 antibody than Colon 26, while both models show similarly sensitivity to anti-CTLA4 antibody. We performed in vivo screening for anti-PD-1 therapy across 23 syngeneic tumor models and found that CT-26 and Colon 26, which are murine colorectal carcinoma derived from BALB/c mice, showed different sensitivity to anti-PD-1. We performed tumor-immune profiling of the two models to identify the potential mechanism for anti-PD-1 response. In order to delineate the mechanisms of anti-tumor activity of ICB in preclinical syngeneic tumor models, we selected two syngeneic murine colorectal cancer models based on in vivo screening for sensitivity with anti-PD-1 therapy. Harnessing preclinical tumor models is one way to understand the mechanism of treatment response. Despite many preclinical and clinical studies to understand the mechanism of anti-tumor efficacy of ICB, the mechanism is not completely understood. However, anti-tumor response of the ICB is insufficient for many patients and limited to specific tumor types. Immune checkpoint blockade (ICB) therapies have changed the paradigm of cancer therapies.