Clinical translation of PeptiCRAd-1: Interim clinical evaluation of a modular oncolytic adenovirus vaccine platform targeting NY-ESO-1 and MAGE-A3 in advanced solid tumors.

Abstract

2604 Background: Oncolytic viruses can convert poorly immunogenic tumors into inflamed, immune-responsive lesions, but clinical benefit is often limited by insufficient induction of tumor antigen–specific T cells. PeptiCRAd-1 is a novel peptide-guided oncolytic adenoviral immunotherapy designed to deliver tumor antigens while providing intrinsic immune stimulation. It consists of a conditionally replicating adenovirus expressing CD40L and OX40L and coated with NY-ESO-1 and MAGE-A3 peptides to enhance priming of antigen-specific adaptive immunity. Methods: VALO-001 (NCT05492682) is an ongoing, open-label, non-randomized phase 1 trial enrolling adults with injectable advanced solid tumors expressing NY-ESO-1 and/or MAGE-A3, including melanoma, TNBC, NSCLC, sarcomas, and colorectal cancer. Treatment includes low-dose cyclophosphamide followed by intratumoral PeptiCRAd-1 prime/boost injections combined with pembrolizumab. Primary objectives are safety and tolerability; secondary/exploratory endpoints assess innate and adaptive immune activation: antigen-specific T-cell induction, tumor-infiltrating lymphocyte (TIL) density, viral shedding, and preliminary antitumor activity. Immune monitoring includes cytokine profiling, ELISpot for NY-ESO-1/MAGE-A3 responses, and paired biopsies for multiparametric immunophenotyping. Results: Seven patients have been enrolled and treated in the START Phase 1 evaluation of PeptiCRAd-1: five in the intratumoral (i.t.) cohort and two in the combined intratumoral plus subcutaneous (i.t. + s.c.) cohort. Across both groups, study treatment has been feasible and well tolerated, with no dose-limiting toxicities, treatment-related serious adverse events, or unexpected safety signals reported to date. In the i.t. cohort, innate immune activation occurred in 3/5 patients; NY-ESO-1/MAGE-A3-specific T-cell responses in 3/5; and increased TILs in 4/5. Clinical responses were observed in 2/5, with disease control in 3/5 patients. Early i.t. + s.c. data show markedly stronger peptide-specific T-cell responses than i.t. alone, supporting combined local–systemic immunization. This cohort remains open, with eight additional patients required. Across evaluable patients, biopsies demonstrated increased TIL density, and early antitumor activity—including partial responses and durable stable disease—was observed across multiple tumor types. Conclusions: PeptiCRAd-1 shows a favorable safety profile and induces coordinated systemic and intratumoral immune activation in advanced solid tumors. Robust antigen-specific T-cell responses and enhanced TIL infiltration support its potential to strengthen antitumor immunity and justify continued evaluation, including combination with PD-1 blockade. Clinical trial information: NCT05492682 .