By Ayako Wakatsuki Pedersen, Ph.D., Senior Vice President of Translational Research at IO Biotech
The tumor microenvironment (TME) is one of the most formidable obstacles in the fight against cancer. While therapies that target cancer cells have been revolutionary, many patients still do not respond as expected.1
The reason? The TME—an immune-suppressive barrier—shields tumors from immune system attacks.
For effective treatment, we need innovative approaches that don’t just target cancer cells but also break down the protective shield of the TME. By reprogramming this environment, we can allow immune cells to function optimally, opening the door to more effective cancer therapies.
Case in Point: Immunotherapy
Checkpoint inhibitors, such as those targeting PD-1 or CTLA-4, have transformed cancer treatment. These therapies defeat cancer cells’ ability to evade detection by the immune system cells, enabling the immune system to recognize and attack tumors.2 However, while these therapies have shown promise, they often face resistance. This resistance arises largely due to the complexity of the TME, which continues to find a way to prevent the immune cells from effectively attacking tumors. 2
To overcome this, new strategies are needed to go beyond the mere blocking of inhibitory signals to instead increase dynamic attacks on cancer at the cellular level.
IO Biotech’s Unique Approach—A Dual Action Vaccine
Unlike most cancer therapies, which focus solely on tumor cells, our therapeutic vaccine – IO102-IO103 – trains the immune system to kill both tumor cells and immune-suppressive cells in the tumor microenvironment.1
This dual-action vaccine works by activating T cells to attack cells expressing indoleamine 2,3-dioxygenase 1 (IDO1) and programmed death-ligand 1 (PD-L1), including not only tumor cells but also the immune-suppressive cells within the TME. By targeting both cancer and immune-suppressive cells, we effectively shift the balance in the TME, making it tumor-hostile and facilitate the immune attack on tumor cells.1 And unlike a checkpoint blockade approach, where selected functions of cells contributing to the immune suppressive environment in the TME are merely blocked, leaving the ‘trouble makers’ in place, our vaccine can lead to direct killing of, and/or reprogramming of, the targeted cells, resulting in dynamic changes in the TME.1
The Future of Immunotherapy—Synergizing with Immune Checkpoint Inhibitors
The possibility of transforming the TME from a cancer-supportive to cancer-hostile environment opens new possibilities for combination therapies. Immune checkpoint inhibitors, such as anti-PD-1 therapies, have been game changers in oncology, but their efficacy can be limited by the immune-suppressive nature of the TME. By reprogramming the TME, we change the rules of engagement, leading to more effective tumor killing in patients.
In clinical trials, the combination of a checkpoint inhibitor with IO102-IO103 has showed promising evidence that it could be a safe and efficacious treatment for patients with a range of cancers including metastatic melanoma, squamous cell carcinoma of head and neck (SCCHN), and non-small cell lung cancer (NSCLC). A recent Phase 2 basket trial of IO102-IO103 in combination with pembrolizumab showed encouraging results in overall response rate and other secondary endpoints in both the metastatic SCCHN and NSCLC cohorts.3 The investigators leading that study also found T-cell responses to both IO102 (targeting IDO) and IO103 (targeting PD-L1) after treatment, confirming that the vaccine-induced cytotoxicity of immune-suppressive cells in the TME enables the immune system to mount a stronger and more sustained attack on the tumors.3
This synergy highlights the future of immunotherapy, where novel therapies could be used alongside existing treatments to overcome resistance and improve patient outcomes.
Conclusion
The tumor microenvironment plays a critical role in cancer progression and resistance to treatment. Addressing this protective shield is vital for the next generation of cancer therapies. Our novel vaccine represents an innovative approach that not only targets cancer cells but also transforms the TME into a space that supports immune cell activity. Combining this vaccine with immune checkpoint inhibitors and other oncology therapeutics has the potential to improve patient outcomes in difficult-to-treat cancers and pave the way for more effective treatments.
1. Kjeldsen, J.W., Lorentzen, C.L., Martinenaite, E. et al. A phase 1/2 trial of an immune-modulatory vaccine against IDO/PD-L1 in combination with nivolumab in metastatic melanoma. Nat Med 27, 2212–2223 (2021).
2. Basudan AM. The Role of Immune Checkpoint Inhibitors in Cancer Therapy. Clin Pract. 2022 Dec 27;13(1):22-40.
3. Riess JW. A phase 2 trial of the IO102-IO103 cancer vaccine plus pembrolizumab: results from the first-line (1L) cohort of PD-L1 high metastatic non-small cell lung cancer (NSCLC). Presented at: Society for Immunotherapy of Cancer Annual Meeting; November 9, 2024; Houston, TX. Poster presentation 756. Exhibit Halls AB, George R. Brown Convention Center.