An obscure, decades-old antibiotic is showing promise for both reducing the toxicity and enhancing the efficacy of dual immune checkpoint blockade therapy, according to Houston Methodist Hospital research that could extend the revolutionary treatment to more patients.

Using an illuminating drug screening strategy that looked at more than 3,000 FDA-approved drugs, the team found that clofazimine maximized the benefits of anti-PD-1 and CTLA-4 therapy, a potent combination that works in a subset of patients but also can cause treatment-limiting side effects.

"This is a much-needed potential breakthrough for the many cancer patients who haven't been able to take full advantage of immunotherapy due to the severity of the side effects," said Houston Methodist Associate Professor Dr. Maen Abdelrahim, one of the study leaders. "It could represent a new way forward with robust but manageable cancer treatment options that could extend life expectancy and improve quality of life."

In what team members called remarkable, clofazimine not only outperformed steroid treatment or a reduction in checkpoint blockade dosages — standard responses to immune-related adverse events (irAEs) — in reversing side effects, it also potentiated curative responses. By contrast, steroids has a detrimental effect on antitumor efficacy.

The discovery, published in the peer-reviewed journal Cancer Cell and described in an accompanying editorial as "having your cake and eating it too," highlights clofazimine's potential to overcome a longstanding hurdle in cancer immunotherapy: balancing treatment potency with patient safety.

"It's a basic law of the universe that nothing comes without a price," said Dr. Abdelrahim, a gastrointestinal oncologist, translational pharmacologist and co-author of the study. "In dual immunotherapy, we're unleashing the power of the immune system to its fullest, which is great for attacking tumor cells, but it significantly raises the toxicity of the treatment and the risk of severe, life-threatening, or even fatal, complications."

In patients receiving a combination PD-1 and CTLA-4 blockade, the incidence of severe irAEs ranges from 30% in lung cancers to 70% in melanoma.

When adverse events impact a patient's colon, heart, liver, kidney or other essential organs, typically the treating physicians will hold or interrupt the treatment, add an effectiveness-reducing steroid or immunosuppressant, or discontinue treatment altogether.

In search of a better alternative, the Houston Methodist research team looked for one that could help limit irAEs without compromising the cancer-fighting power of the therapy.

Clofazimine, originally approved to treat leprosy, emerged as an ideal candidate because it not only reduced side effects in laboratory models, but also appeared to amplify the immune system's ability to recognize and attack cancer cells.

"We wanted to identify a drug that could potentially leave the effectiveness of dual ICB therapy intact, but this drug actually enhanced it," said Dr. Abdelrahim.

The results were validated in a variety of models, including melanoma organoids derived from patient tissue samples, as well as in murine, colorectal, melanoma and lung cancer models.

• Mechanistically, the antibiotic operates through a dual action: it activates the E2F1 pathway in CD8+ T cells, enabling the immune system's "killer cells" to better recognize and respond to tumors.
• It also reduces pathogenic, Th17 cells, which are commonly linked to irAEs.

The "uncoupling" of efficacy and toxicity of this dual ICB therapy allows oncologists to administer high-impact treatments with far fewer complications, allowing for implications in clinical practice that are profound.

Dr. Abdelrahim, who is leading the upcoming Phase 1 Clinical Trial for clofazimine in human cancer patients, is optimistic about its application.

"It's rare to find an agent that enhances immunotherapy without significant drawbacks," Dr. Abdelrahim said.

If successful, clofazimine could become a valuable addition to dual ICB therapies for cancers like melanoma, colorectal, liver and non-small-cell lung cancers, where the treatment regimen is already FDA-approved but often interrupted or modified due to irAEs.

The team will initiate phase 1/2a clinical trials in early 2025. If successful, clofazimine could become a valuable addition to dual ICB therapies for cancers like melanoma, colorectal, liver and non-small-cell lung cancers, where the treatment regimen is already FDA-approved but often interrupted or modified due to irAEs.

Other leaders on the study were Dr. Yong Lu, an assistant professor of Immunology at Houston Methodist, and Dr. Gang Xue of Wake Forest University.