By Ayako Wakatsuki Pedersen, SVP of Translational Research at IO Biotech
Since their introduction centuries ago, vaccines have drastically improved public health and increased life expectancy by preventing the spread of deadly infectious diseases. For decades, scientists have also studied the potential for developing vaccines that can be used to treat diseases such as cancer, but clinical trial results to date have mostly delivered disappointing results.1 Only three cancer vaccines have been approved by the Food and Drug Administration (FDA) since the first approval in 1990.1-3
Promising scientific advances and preclinical study results have led to a resurgence of cancer vaccine development, with more than 350 clinical trials currently ongoing.2,4,5 Oncologists and their patients are eagerly watching, hopeful that the newest cancer vaccines will be more powerful against cancer with minimal toxicity for the patient.
Many of the past failures with cancer vaccines were at least partly due to the lack of basic knowledge about the interactions between the immune system and tumor biology.1,2 Now, we know that cancer evades treatments with a variety of escape mechanisms, including by making the immune system ignore the tumor, and that it’s possible to disrupt those escape plans on a molecular level.
One approach that may overcome that issue is with vaccines that train the immune system to recognize and attack cancer cells. Some of these vaccines are personalized for each patient, designed to attack certain targets called antigens that are unique to a patient’s tumor.2,3 The process for making this type of vaccine requires extracting a tumor sample from a patient, identifying the antigens unique to the patient’s tumor, and incorporating these antigens into a vaccine: a time-consuming process that delays treatment while the patient’s disease potentially progresses.
Scientists can also develop “off-the-shelf” vaccines to target common antigens shared by many patients with a specific type of cancer, making the vaccines easier to produce and store for future use as well as shortening the time to treatment for patients.2
Perhaps the most formidable barrier to cancer vaccines is that tumors circumvent attacks by creating a microenvironment that suppresses the immune system.6 For example, tumors can trick immune cells and direct them to suppress the body’s ability to fight cancer. The enhanced immune suppressive activity in the tumor microenvironment helps the tumor grow, while making the cancer harder to treat.
Consequently, new treatments have been designed to reactivate the immune system’s attack against cancer. A novel class of immune-modulating cancer vaccines have dual functionality: They train the immune system to kill both tumor cells and immune-suppressive cells in the tumor microenvironment.1
Immune-modulating vaccines can also start a therapeutic chain reaction. Once the tumor microenvironment is remodeled from cancer-friendly to cancer-hostile,7 tumor-killing immune system cells can attack the tumor.1 As the tumor cells die, more antigens are released, enabling the immune system to recognize and kill more tumor cells. This makes the initial attack on the tumor stronger, potentially last longer and can enhance the efficacy of other immunotherapies.
Our lead immune-modulating cancer vaccine candidate at IO Biotech, IO102-IO103, targets cells that express IDO and PD-L1, targeting both tumor and immune cells that are contributing to the main immune resistance mechanisms in cancer patients. In a Phase 1/2 trial, IO102-IO103 combined with an immune checkpoint inhibitor (ICI) showed promising results in patients with metastatic melanoma while demonstrating a safety profile similar to that of ICI therapies targeting the PD-1 antigen alone, with no additional systemic toxicity observed.8,9 Pending results from an ongoing Phase 3 clinical trial, this therapy could become available to patients in the United States as early as 2025.10
Vaccines designed to overcome the immune-suppressive tumor microenvironment barrier are an exciting and promising treatment modality. Generating off-the-shelf drug candidates may transform cancer treatment and have applications beyond cancer for other difficult-to-treat diseases, bringing hope to patients.
References
1. Strum S, Andersen MH, Svane IM, Siu LL, Weber JS. State-Of-The-Art Advancements on Cancer Vaccines and Biomarkers. Am Soc Clin Oncol Educ Book. 2024;44(3):e438592.
2. Lin MJ, Svensson-Arvelund J, Lubitz GS, et al. Cancer vaccines: the next immunotherapy frontier. Nat Cancer. 2022;3(8):911-926.
3. Hargrave, A., Mustafa, A.S.,Hanif, A., Tunio, J.H., Hanif, S.N.M. Recent Advances in Cancer Immunotherapy with a Focus on FDA-Approved Vaccines and Neoantigen-Based Vaccines. Vaccines 2023, 11, 1633.
4. Janes ME, Gottlieb AP, Park KS, Zhao Z, Mitragotri S. Cancer vaccines in the clinic. Bioeng Transl Med. 2024; 9(1):e10588.
5. Drew L. Cancer vaccines: reasons for optimism. Nature. 2024; 627:S33.
6. Rostamizadeh L, Molavi O, Rashid M, et al. Recent advances in cancer immunotherapy: Modulation of tumor microenvironment by Toll-like receptor ligands. Bioimpacts. 2022;12(3):261-290.
7. Dey S, Sutanto-Ward E, Kopp KL, et al. Peptide vaccination directed against IDO1-expressing immune cells elicits CD8+ and CD4+ T-cell-mediated antitumor immunity and enhanced anti-PD1 responses. J Immunother Cancer. 2020;8(2):e000605.
8. 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 2021; 127: 2212–2223
9. Lorentzen CL, Kjeldsen JW, Ehrnrooth E, Andersen MH, Marie Svane I. Long-term follow-up of anti-PD-1 naïve patients with metastatic melanoma treated with IDO/PD-L1 targeting peptide vaccine and nivolumab. J Immunother Cancer. 2023;11(5):e006755.