IO Biotech, a Copenhagen-based company, is advancing a revolutionary approach to cancer immunotherapy with its immune-modulatory vaccines that have progressed from initial skepticism to phase 3 clinical trials. Recent data presented at the American Association for Cancer Research (AACR) suggest potentially game-changing results could emerge by year's end.
The company's proprietary T-win technology represents a paradigm shift in cancer vaccine development. Unlike traditional therapeutic vaccines that target only cancer cells, IO Biotech's dual-acting vaccines activate T cells that fundamentally restructure the tumor microenvironment (TME), fighting cancer through two distinct mechanisms: directly killing tumor cells while simultaneously releasing effector T cells to create an anti-tumor, proinflammatory TME.
"It's a whole new mechanism of action," explained Mads Hald Andersen, DMSc, PhD, IO Biotech cofounder and scientific adviser, during an AACR interview. "It has been underway for 15 years. We did the first discoveries and moved slowly from phase 1 trials, and everybody was super skeptical."
Breakthrough Technology with Dual Mechanism
The T-win platform works by delivering peptide epitopes that interact with antigens to initiate dual-action immune responses. The company's lead candidate combines IO102, which targets indoleamine 2,3-dioxygenase (IDO), with IO103, targeting PD-L1. This combination, trademarked as Cylembio (imsapepimut and etimupepimut adjuvanted), has received FDA Breakthrough Therapy designation.
A phase 3 trial involving 407 patients with metastatic melanoma is evaluating Cylembio in combination with pembrolizumab (Keytruda), with results expected in the third quarter of 2025. IO Biotech anticipates filing a Biologics License Application with the FDA by the end of this year.
This development follows promising phase 1/2 data published in Nature Medicine over three years ago. In that study, 30 patients with advanced melanoma received IO102/IO103 combined with nivolumab (Opdivo). The results were impressive: an 80% objective response rate (CI, 62.7-90.5), with 43% of patients achieving complete responses (CI, 27.4-60.8). Median progression-free survival reached 26 months (CI, 15.4-69 months) and was not reached for responding patients. Overall survival at 12 months was 81.6% (CI, 61.6-92).
These outcomes significantly outperformed historical data from matched patients treated with anti-PD-1 therapy alone, who had a median progression-free survival of just 8.3 months.
Redefining Cancer Vaccine Mechanisms
Andersen explained the fundamental difference between traditional cancer vaccines and this new immune-modulatory class: "When we are generating an immune response, we are vaccinating against the whole tumor environment, so not just the cancer cells, but also the immune suppressive cells."
This approach essentially reprograms the TME to attack cancer rather than allowing tumor growth. "By vaccinating with an immune-modulatory vaccine, you can change the microenvironment from being immune hostile to immune friendly," Andersen noted.
Early skepticism centered on the vaccines' use of self-antigens—components of an organism's own cells that the immune system typically recognizes as belonging to the body and does not attack. The T-win technology specifically targets IDO and PD-L1, proteins produced within the body and expressed by immune-suppressive cells such as T regulatory cells (Tregs).
"These are there even in healthy people and are part of how the immune system is regulated," Andersen explained, adding that other companies have now adopted similar approaches.
Improved Efficacy with Reduced Toxicity
A key advantage of these immune-modulatory vaccines is their ability to achieve more durable responses than anti-PD-1 therapy alone, without the significant toxicity observed when anti-PD-1 is combined with anti-CTLA-4 therapy. While combined checkpoint inhibitors yield response rates of about 60% in advanced melanoma, approximately half of these patients develop severe adverse events.
Andersen attributes the lower toxicity profile of immune-modulatory vaccines to their selective targeting of highly immunoexpressive cells. "They do not function where these antigens are not highly expressed. And when these antigens are highly expressed, they have very immunosuppressed environment," he said. The most commonly reported adverse events are site reactions, according to Jonathan Riess, MD, MS, medical director of Thoracic Oncology at the University of California Davis Comprehensive Cancer Center.
Unlike conventional immunotherapy combinations, Andersen explained, "In the vaccine situation, you activate as part of the T cells, not because they have PD-1 on the surface, but because they recognize cells that express PD-1. They can attack them, and they can kill them."
New Data and Expanding Pipeline
At AACR, IO Biotech presented preclinical data comparing IO102/IO103's mechanism of action with checkpoint inhibitors. The research demonstrated that "vaccination against IDO1 and PD-L1 induced specific T-cell expansion in splenocytes, associated with reduced tumor growth." Importantly, the gene expression changes observed differed from the signatures of anti-PD-L1 and anti-PD1 therapies, suggesting complementary mechanisms of action.
A second abstract evaluated IO170, another IO Biotech vaccine directed at transforming growth factor (TGF)β. This candidate induces T cell activation and drives antitumor activity by modulating the TME. Using various mouse models, investigators demonstrated the vaccine's efficacy against pancreatic adenocarcinoma and in a CRISPR/Cas9-driven model of prostate cancer, confirming T cell expansion and slowed tumor progression.
Beyond the phase 3 trial, IO Biotech has completed enrollment for a phase 2 basket trial evaluating Cylembio as a neoadjuvant/adjuvant treatment for patients with resectable melanoma or head and neck cancer, with initial data expected in the second half of 2025. Additional studies are investigating IO102/IO103 in non-small cell lung cancer and metastatic urothelial cancer.
The company is also advancing IO112, another immune-modulatory therapeutic vaccine candidate targeting Arginase-1, with an Investigational New Drug Application expected this year.
"There is still a significant unmet medical need for new treatment options for patients suffering from advanced melanoma, metastatic head and neck cancer, and metastatic lung cancer," said Mai-Britt Zocca, PhD, President and CEO of IO Biotech. "The full IO Biotech team is proud to be leading the next frontier of immune-oncology with the development of therapeutic cancer vaccines for these and other difficult-to-treat cancers."
