Immunotherapy for Rare Cancers: New Horizons and New Hope

Rare cancers are more common than many realize.

Collectively, they account for nearly one in four cases globally, more than any other single type of cancer. And while cures for most remain elusive, the immunotherapy and genomic revolutions have us on the verge of starting to change that.

There are hundreds of rare cancers—the National Cancer Institute’s definition covers those that affect fewer than 40,000 people per year in the U.S., while Foundation Medicine estimates far fewer U.S. residents are affected each year with ultra-rare cancers that affect one in five U.S. residents—and surely some we still don’t know about. Some are well-known and well-studied, like esophageal cancer and pediatric leukemia. Others are nearly unknown, like Wilms tumors in the kidney, fibrolamellar carcinomas in the liver, and chordomas in the spine.

Though the collective impact of rare cancers is large, the scarcity and variety of rare cancers make widespread clinical progress challenging, but not impossible. According to Cancer Research Institute CEO and Director of Scientific Affairs Jill O’Donnell-Tormey, PhD, immunotherapy can be an effective

As so few people have rare cancers, there are few oncologists that specialize in treating them. Many clinicians lack experience in diagnosing or treating rare cancers effectively. Compounding this problem is fierce competition for patient enrollment in clinical trials, which is already a challenge even for patients with the more common types of cancer.

Enter immunotherapy.

Over the last decade, checkpoint inhibitor immunotherapies have improved survival in certain types of advanced cancers, including esophageal cancer, now approved as first-line therapy. Earlier this month our ASCO22 coverage highlighted the benefits of PD-L1 immunotherapy in combination with chemotherapy in the TOPAZ-1 trial for advanced biliary tract cancer. These and other clinical studies demonstrate the potential for checkpoint blockade therapy to benefit some patients with rare cancers.

Scientists are making progress on learning how to make immunotherapy even more effective in more patients. When given alone as cancer treatment, checkpoint blockade immunotherapy works in roughly 20 percent of cancer patients. CRI-funded research scientists are working to understand why more patients don’t benefit from this type of immunotherapy. Finding answers to that question appears today to rely in part on the identification of diagnostic and predictive biomarkers. Biomarkers provide clues into a patient’s disease and can help predict who is likely to respond to immunotherapy.

Biomarkers have helped expand immunotherapy’s benefit to patients with rare cancers, too.

In 2017, the FDA issued its first tumor-agnostic approval, based on a biomarker called high microsatellite instability (MSI-high). This decision enabled all those with MSI-high solid tumors to receive PD-1 checkpoint immunotherapy if they had no alternative treatment options, no matter how rare their cancer was or where it developed. A similar approval also covers patients whose solid cancers have high tumor mutational burden, or TMB.

While very powerful, MSI-high is itself a rare biomarker, found in only 3 to 4 percent of all people with cancer.

The expression of PD-L1 is another immunotherapy biomarker that has been incorporated into several regulatory agency approvals. While the power of PD-L1 expression to predict who will respond to immunotherapy does not appear overall to be as strong a signal as the MSI-high biomarker, the approval opened immunotherapy options up to more cancer patients.

Biomarker identification and validation as diagnostic and therapeutically predictive signals remains a primary objective across academic and industry research. The future of cancer care, however, will involve comprehensive screens of multiple biomarkers that, together, describe what precisely is going on at the site of tumors, how the immune system is responding, and how to nudge it to eliminate cancer.

Several recent studies have uncovered biomarkers linked to improved immunotherapy outcomes in people with sarcomas, a family of rare cancers. Of note, patients whose so-called “hot” tumors that already had the immune system’s attention were more likely to respond to treatment. Also responding better to immunotherapy were patients with certain types of bacteria present in their feces. This discovery can help scientists engineer healthier microbiomes in people to reduce their risk of developing certain cancers.

Another promising treatment approach for people with rare cancers involves cellular therapies like CAR T cell therapy, T cell receptor (TCR) therapy, and other cell therapies. These treatments boost individual patient immune responses against cancer. They are designed to recognize threats in the form of irregular or dangerous proteins, carbohydrates, and fat molecules present around, on, and within cancer cells.

Immunotherapy holds the promise to treat all cancer patients effectively, including those patients with rare or ultrarare cancers.

To learn more about cutting-edge cell therapy strategies and how breakthroughs in sarcoma might apply to other cancers including rare cancers, check out our interview with Dr. Cassian Yee, a CRI-Chordoma Foundation CLIP Investigator at the University of Texas MD Anderson Cancer Center.