Osteosarcoma is a type of cancer that originates in the bone, most commonly affecting adolescents and young adults, though it can also occur in older adults. It is considered the most common primary malignant bone tumor. While traditional treatments like surgery and chemotherapy have improved survival rates for localized osteosarcoma to over 70%, the prognosis for recurrent or metastatic disease, especially when it spreads to the lungs, remains challenging. Immunotherapy offers a newer approach that aims to leverage the body’s natural defenses to combat this aggressive cancer.
Understanding Immunotherapy
Immunotherapy represents a distinct approach to cancer treatment compared to conventional methods like chemotherapy and radiation. While chemotherapy uses drugs that attack rapidly dividing cells and radiation therapy destroys cancer cells in a localized area, immunotherapy stimulates the patient’s own immune system to recognize and eliminate cancer cells.
The immune system naturally protects the body from abnormal cells. However, cancer cells often evade detection by exploiting “immune checkpoints,” molecules on immune cells that regulate the immune response. Cancer cells can upregulate molecules like PD-L1, which bind to receptors like PD-1 on T cells, effectively “putting the brakes” on the immune response. Immunotherapy aims to overcome these evasion mechanisms, allowing the immune system to attack the tumor.
Immunotherapy Approaches for Osteosarcoma
Different immunotherapy strategies are being explored for osteosarcoma, each with a unique mechanism to engage the immune system. These approaches aim to enhance the immune system’s ability to identify and destroy cancer cells.
Immune checkpoint inhibitors (ICIs) are a class of immunotherapy drugs that block interactions between immune checkpoints like PD-1 on T-cells and PD-L1 on tumor cells. This action “releases the brakes” on the immune system, allowing T-cells to reactivate and mount an anti-tumor response. While ICIs have shown success in other cancers, their effectiveness as single agents in osteosarcoma has been less consistent. However, combining PD-1/PD-L1 inhibitors with CTLA-4 inhibitors may improve therapeutic effects, showing promise in mouse models of metastatic osteosarcoma.
Chimeric Antigen Receptor (CAR) T-cell therapy involves genetically modifying a patient’s T-cells to express a specialized receptor, enabling them to recognize and target specific markers on cancer cells. These engineered T-cells are then expanded in a laboratory and infused back into the patient. While successful in blood cancers, its application in solid tumors like osteosarcoma faces challenges. These include the difficulty of CAR T-cells effectively reaching and infiltrating solid tumors, the hostile tumor microenvironment, and the need to identify specific antigens. Researchers are working to improve CAR T-cell homing to tumors and enhancing their persistence and function within the tumor microenvironment.
Oncolytic viruses are naturally occurring or engineered viruses that selectively infect and destroy cancer cells while leaving healthy cells unharmed. As these viruses replicate within and lyse tumor cells, they release tumor antigens and other molecules that can stimulate a broader anti-cancer immune response. Various oncolytic viruses, including adenovirus, herpes simplex virus (HSV), and measles virus, have demonstrated effectiveness in preclinical models of osteosarcoma. Some strains, like modified HSV-1, have progressed to early-phase clinical studies for osteosarcoma patients, and their efficacy is often enhanced when combined with other treatments.
Cancer vaccines aim to prime the body’s immune system to recognize and attack osteosarcoma cells. These vaccines expose the immune system to specific tumor antigens, derived from whole cells, lysates, DNA, RNA, peptides, or proteins, to generate a targeted immune response. Early studies using autologous tumor lysates as vaccines showed increased overall survival in osteosarcoma patients. Dendritic cell (DC) vaccines, which involve isolating and loading a patient’s immune cells with tumor antigens before re-injecting them, have also shown promise in reducing immunosuppression caused by cancer cells. Recent research also explores RNA-based vaccines to enhance CAR T-cell activity against osteosarcoma by activating the tumor microenvironment and promoting CAR T-cell migration and persistence.
Other emerging therapies for osteosarcoma include adoptive cell therapies beyond CAR T-cells, such as the use of gamma-delta T-cells (gdT cells). These gdT cells, which can be sourced from healthy donors, are engineered to release tumor-targeting antibodies and immune-stimulating cytokines directly into the tumor. Preclinical studies have shown that these engineered gdT cells can outperform conventional immunotherapy in controlling osteosarcoma growth, particularly when combined with bone-sensitizing drugs. Cytokine therapies, which involve using immune-modulating proteins like interferons and interleukins, are also being investigated to enhance anti-tumor immunity, though challenges remain in optimizing their therapeutic application and managing side effects.
Clinical Trials and Evolving Therapies
Immunotherapy for osteosarcoma is an active area of research, with many promising treatments currently in various stages of clinical trials. While traditional treatments like surgery and chemotherapy remain standard, particularly for localized disease, the high rates of recurrence and metastasis in osteosarcoma patients underscore the urgent need for new therapies. Immunotherapy is not yet a standard frontline treatment for all osteosarcoma cases, but ongoing research is continuously expanding its role.
Clinical trials are fundamental to the development of new cancer treatments, evaluating their safety and effectiveness. For osteosarcoma, many immunotherapy agents are being tested in Phase I, II, or III trials, focusing on patients with recurrent or metastatic disease. Some trials explore combinations of immune checkpoint inhibitors like nivolumab and ipilimumab for metastatic sarcoma, including osteosarcoma, with reports indicating tumor remission or stabilization. A listeria-based immunotherapy (OST-HER2) for lung metastatic osteosarcoma recently completed a Phase 2b clinical trial, demonstrating improved one-year event-free survival. The company anticipates submitting a Biologics Licensing Application to the FDA in 2025.
Identifying which patients will respond best to immunotherapy is a significant area of research. This involves studying biomarkers, measurable indicators that can predict treatment response or disease progression. For osteosarcoma, research is ongoing to identify specific biomarkers, such as PD-L1 expression or tumor mutational burden, that could help select patients most likely to benefit. Liquid biopsies, analyzing tumor components in blood, represent a less invasive method for identifying these biomarkers and monitoring treatment response.
Combination therapies are a major trend in osteosarcoma research, aiming to enhance immunotherapy’s effectiveness by combining it with traditional treatments or other targeted agents. These combinations might include immunotherapy with chemotherapy, radiation therapy, or molecularly targeted drugs. The rationale is that different treatments can work synergistically to overcome osteosarcoma cells’ complex defense mechanisms and the immunosuppressive tumor microenvironment. This integrative approach offers hope for more effective and personalized treatment strategies, as research continues to uncover new ways to harness the immune system against this challenging bone cancer.