Tumor microenvironment markers forecast immunotherapy response in rare cancers

A new study in Cell Reports Medicine from researchers at The University of Texas MD Anderson Cancer Center identified key features that may help predict which types of rare cancers are likely to respond to immunotherapy.

In a Phase 2 study of 154 patients with rare cancers, led by Aung Naing, M.D., professor of Investigational Cancer Therapeutics, the immunotherapy pembrolizumab had a modest overall response rate of 14.8% and a clinical benefit rate of 26.8%. However, researchers found that certain other features of the tumor microenvironment may serve as predictive markers of response beyond what can currently be provided by genomic analysis.

This is an important finding because it is difficult to generate data on rare cancers. What we show in this study is that, beyond the conventional genomic markers of response, several features within the tumor microenvironment may provide new insight into what types of rare cancers might respond to immunotherapy."

Aung Naing, M.D., Professor of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center 

Why is this finding important in rare cancers?

Rare cancers are defined as those with fewer than 15 cases per 100,000 people per year, but collectively they make up about a quarter of all cancer deaths each year in the United States. This makes treating rare cancers an urgent need, but one with significant hurdles.

Despite the challenges of conducting trials on rare cancers, the investigators successfully enrolled 154 patients, representing one of the larger immunotherapy studies in this space. A key strength of the trial was the collection of biopsies before and during treatment from the same disease site, allowing investigators to study precisely how tumors and the immune system changed in response to therapy.

There are some biomarkers used currently to determine which rare cancers may be likely to respond to immunotherapy, such as microsatellite instability, high mutational burden or high PD-L1 expression. In this trial, however, a significant number of patients with strong responses did not have tumors with these markers.

This demonstrates a need to find additional predictive biomarkers. Immunotherapy can improve outcomes for many patients, but identifying those patients, especially with rare cancers, has been a significant challenge.

What are tumor microenvironment features and which ones were identified?

Researchers are quickly learning how physical properties in and around tumors may be as important as their genomic profile in determining treatment plans. Examples of these can include how many immune cells are already present or the densities of those cells in certain areas.

By integrating tools that can map and analyze the tumor microenvironment, the team found three new potential markers to identify patients with rare cancers most likely to respond to immunotherapy. These include pre-existing infiltration of immune cells – particularly CD3 and CD8 T cells – active T cell signaling, and the ability of some tumors with moderate levels of immune cells to recruit additional immune cells during treatment.

What does this mean for rare cancer patients?

This study demonstrates that genomic markers may not identify all patients who could benefit from immunotherapy, but an approach that also utilizes analysis of the tumor microenvironment may help physicians improve treatment selection for these patients.

According to Naing, more studies are needed to continue to validate these findings, but this trial highlights the importance of profiling the tumor microenvironment.

"These types of trials are difficult, but also critically important to help us learn more about rare cancers as a group," Naing said. "While each tumor may be rare, we're getting better at figuring out which properties they have in common that can inform treatment and help us get patients on the right therapies faster."