Dr Hassel on the Rationale for Combining IO102-IO103 with Pembrolizumab in Treatment-Naive Advanced Melanoma

“IO102-IO103 is an immune modulatory off-the-shelf vaccine, and it consists of 2 peptides: IDO1 and PD-L1. It is administered subcutaneously, after which the peptides are taken up by antigen-presenting cells that process and present them to T cells, leading to the activation and expansion of T cells reactive against IDO1 and PD-L1.”

Jessica C. Hassel, MD, a professor in the Department of Dermatology at Heidelberg University, discussed the rationale for combining the investigational immune-modulatory therapeutic cancer vaccine IO102-IO103 with pembrolizumab (Keytruda) in patients with treatment-naive advanced melanoma. During the 2025 ESMO Congress, investigators presented findings from the phase 3 IOB-013/KN-D18 trial (NCT05155254), which is comparing IO102-IO103 plus pembrolizumab with pembrolizumab alone to determine whether the combination can enhance antitumor immunity and overcome immune resistance mechanisms in this population.

IO102-IO103 is an off-the-shelf, subcutaneously administered peptide vaccine composed of 2 immunogenic peptides targeting indoleamine 2,3-dioxygenase (IDO) and programmed death ligand 1 (PD-L1), Hassel explained. Once injected, the peptides are internalized by antigen-presenting cells, processed, and presented to T cells. This activates and expands T-cell populations capable of recognizing and destroying IDO- and PD-L1–expressing cells within the tumor microenvironment. These targets include not only tumor cells but also immunosuppressive myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells, which contribute to immune evasion and tumor progression.

By eliminating these suppressive cell populations, IO102-IO103 is designed to reprogram the tumor microenvironment and facilitate the activation and infiltration of tumor-reactive T cells. Hassel noted that this mechanism complements that of pembrolizumab, which prevents PD-1–mediated T-cell exhaustion. Together, the 2 agents may work synergistically to enhance and sustain immune-mediated tumor clearance compared with PD-1 blockade alone.

IOB-013/KN-D18 is a randomized, double-blind, placebo-controlled study enrolling patients with previously untreated, unresectable, or metastatic melanoma. The primary end point is progression-free survival, with secondary end points including overall survival, overall response rate, and duration of response.

Hassel emphasized that the study seeks to address a key limitation of immune checkpoint inhibitor monotherapy—persistent immunosuppression within the tumor microenvironment that contributes to both primary and acquired resistance. If the combination demonstrates superior efficacy without compromising safety, IO102-IO103 plus pembrolizumab could represent a novel first-line strategy for the treatment of patients with advanced melanoma, providing a biologically rational approach to enhance the depth and durability of immune checkpoint responses in this patient population.