Review Highlights Progress and Potential in Immunotherapy Plus Radiotherapy for Cancer Treatment

Immunotherapy and radiotherapy have both improved survival rates for cancer, and combination therapies have potential to be even more effective and reduce recurrence. A recent review published in Frontiers in Oncology examined the mechanisms of immunotherapy and radiotherapy and how they can be combined and administered for maximum efficacy.

Radiotherapy is standard for cancerous tumors, with approximately 70% of patients with tumors being treated with it. It works by damaging the DNA of tumor cells within the irradiation field to control tumor growth. Data has increasingly shown that radiotherapy also leads to the release of myeloid-derived suppressor cells, M2-like tumor-associated macrophage, T-regulatory cells, N2 neutrophils, and immunosuppressive cytokines, promoting an immunosuppressive microenvironment.

Advances in technology have made radiotherapy more precise and effective, with proton heavy ion therapy being the most advanced option in the current treatment landscape. “With the advancement of heavy ion therapy equipment and technology, the decline of treatment costs, and the advancement of research, heavy ion therapy will gradually be popularized in various countries across the world,” study authors wrote.

Recent research has also found an abscopal effect caused by radiotherapy, further suggesting that radiotherapy affects not just the tumor site of treatment, but also the immune system.

“Many preclinical studies have shown that irradiation triggers immunogenic cell death (ICD), which promotes the release of tumor-associated antigens, changes the tumor microenvironment (TME), and activates the immune system to exert an anti-tumor immune response,” the authors wrote.

Radiation alone does not eradicate all malignant cells, though. Tumors with hypoxic cells can be resistant to radiotherapy compared with more oxygenated cells. Hypoxia can also lead to HIF signaling pathway activation, causing gene expression that can help tumors survive. A variety of other TME changes due to radiotherapy can also spur cell growth, and both short- and long-term adverse effects can occur.

Radiotherapy has seen advances in recent years, but as immunotherapy has gained traction, it has emerged as the most likely route to find a cancer cure, study authors wrote. The use of immune checkpoint inhibitors (ICIs) tumor vaccines, adoptive cell therapies, cytokine therapies, and other immunotherapies has increased in recent years.

Immunotherapy alone, however, is only used on a selection of tumor types in clinical practice and does not benefit all patients. Only approximately 10% to 30% of patients respond to single ICIs because of the complexity of cancer cell immune systems and tumor microenvironments (TMEs). Single ICIs or combination therapy is most likely to be effective in “hot” tumors, which have tumor-infiltrating lymphocytes (TILs), versus “cold’ tumors, which do not have TILs. Immunotherapy can also lead to immune-related adverse events that can happen in all organs.

Given the resistance of hypoxic cells to radiotherapy and the generally low response to single immunotherapy, the 2 methods can be complementary. Radiotherapy can release tumor neoantigens, induce ICD, and have an anti-tumor effect in vivo.

Combinations of radiotherapy and immunotherapy have been increasingly studied, although large-scale clinical data are still limited. These combinations include ICIs and radiotherapy, tumor vaccine and radiotherapy, adoptive cell therapy and radiotherapy, and cytokine therapy plus radiotherapy.

Combining radiotherapy with ICIs targeting programmed cell death receptor 1 and programmed cell death ligand 1 is one promising option that has been approved in certain advanced lung cancers and has been most effective in non-small cell lung cancer. However, many of these patients are still resistant to ICIs.

With tumor vaccines, which do not elicit tumor-eliminating immune response alone, radiotherapy may enhance immune response in vivo through several mechanisms. Various trials are underway investigating this combination.

Adoptive cell therapy, which is done by isolating immunoreactive cells from patients and reintroducing them to target antigen-specific tumor cells, is another increasingly studied treatment option that includes chimeric antigen receptor (CAR) T-cell therapy. Approximately 90% of patients experience relapse with CAR T-cell therapy, and early data show that radiotherapy may promote CAR T-cell effectiveness in solid tumors.

Cytokines, which regulate innate and adaptive immunity, have been shown to have significant anti-tumor activity but have dose-limiting severe toxicity that inhibits their efficacy. Studies are ongoing, but there may be potential for radiotherapy with adjuvant cytokine treatment or cytokine treatment followed by radiotherapy to increase effectiveness.

Study authors also highlight the development of multifunctional nanomaterials that can deliver immunomodulators and other drugs to tumors and improve the immunosuppressive environment. Multifunctional nanomaterials also have potential for use as radiosensitizers, potentially improving the effects of radiotherapy.

Overall, while some studies point to the effectiveness of combination radiotherapy and immunotherapy to improve treatment response, it is still unclear what sequence these therapies should be administered in and what the optimal timing is. The ideal radiotherapy fraction and dose selection are also questionable, as are the best immunotherapy-radiotherapy combinations for maximum anti-tumor response.

Toxicity and safety are also causes for further research, and it is still not clear which biomarkers are most useful to determine which patients may respond best to certain therapy combinations.

“If the results of more and more clinical trials are positive, it will determine how best to integrate these models and optimize synergy,” study authors wrote.

Reference

Yu S, Wang Y, He P, et al. Effective combinations of immunotherapy and radiotherapy for cancer treatment. Front Oncol. Published online February 7, 2022. doi:10.3389/fonc.2022.809304