Radiation therapy, the immune system and what’s ahead

Radiation therapy is often thought of as a treatment for localized cancer that hasn’t spread. But when paired with other therapies, it can be an effective option for patients with metastatic disease.

“It has long been recognized that there are opportunities to use drugs to make radiation therapy even more effective,” says Benjamin Schrank, M.D., Ph.D., a resident physician in Radiation Oncology and a member of the Wen Jiang Laboratory. Well-established examples include cisplatin for patients with head and neck or gynecologic cancers, 5-fluorouracil for patients with gastrointestinal cancers and temozolomide for patients with glioblastoma.

New research being presented by Schrank at the 2024 American Society for Radiation Oncology (ASTRO) Annual Meeting is offering a new pathway for immunotherapy-driven cancer treatment.

“We’re moving beyond this notion of radiation as a local therapy to the idea that radiation can cause an immune response that then can synergize with other kinds of drugs to treat cancer,” Schrank says.

Radiation therapy combinations help exploit DNA damage

A chemotherapy drug like a cytotoxic agent works well with radiation therapy because radiation introduces DNA damage to cancer cells, making them weak. Both therapies lead to DNA damage, so when used in combination, the effect is amplified.

“We’re tipping the scales so much that the cancer cells can’t survive,” Schrank says.

In some situations, radiation therapy can further exploit cancer cells’ unique characteristics, such as DNA repair mutations. “We’re able to leverage those specific tumor mutations and use radiation plus a drug to more effectively target DNA repair,” Schrank says. This is seen in certain glioblastoma patients when DNA repair mutations are treated with radiation therapy and temozolomide.

The immune-activating potential of radiation therapy

However, the benefit of these combinations isn’t solely driven by the medications being paired with radiation therapy. “Multiple studies in both preclinical and clinical settings have shown radiation therapy can modulate immune response, and when delivered properly, it can actually help the immunogenicity of tumors and allow the immune system to better recognize tumor cells,” says Wen Jiang, M.D., Ph.D.

Radiation can cause immune signaling that can drive a systemic anti-tumor response. “We've increasingly realized that radiation itself is almost like a drug. When delivered at very high doses, it becomes immunogenic,” Schrank says.

This benefit has been studied and advanced by researchers at MD Anderson in several cancer types, including lung cancer when stereotactic body radiation therapy is combined with immunotherapy.

“We are actively studying how tumors respond to radiation and immunotherapy to make the benefit of combination therapy a reality for every patient,” Schrank says.

Antibody-drug conjugate designed to trigger an immune response

While radiation can stimulate the immune system, Schrank’s recent research on a first-in-class antibody-drug conjugate (ADC) offers a complementary immune-driven strategy. This work is being presented at the 2024 American Society for Radiation Oncology Annual Meeting.

The ADC works by targeting CD47, a protein that tumors use to evade the immune system following radiation. By binding to CD47, the drug helps immune cells engulf cancer cells. Once the cancer cell is destroyed, the immune cell becomes activated.

This approach represents a significant shift in how ADCs have been used to treat cancer. “The drug’s main function is to help the immune cells better recognize the tumor cells. Once they do, they engulf the cancer cells and serve as a bridge to other components of the immune system,” Jiang says. Ultimately, the intent is to have the drug trigger an adaptive immune response to help eliminate the tumor.

The antibody-drug conjugate activates immune cells using a bacterial toxin that stimulates the release of tumor DNA and other tumor cell components, which help train the immune system to recognize the cancer.  Because it doesn’t deliver a chemotherapy drug, it doesn’t have the side effects seen with other ADCs.

The future of antibody-drug conjugate design

Jiang and Schrank see the novel antibody-drug conjugate as having the potential to alter how ADCs are designed to treat cancer.

“I hope this opens a new avenue of research that expands ADCs from just being focused on destroying tumor cells. A live tumor cell can be a great opportunity to train the immune system,” Jiang says.

Schrank echoes this sentiment and sees the work as just the beginning. “We’re not just looking to kill cancer cells. We want to train the immune system to recognize tumors so it can continue fighting the cancer even after treatment,” says Schrank.

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