Investigating Tumor Growth After Immunotherapy

Anish Thomas, MD, the Roswell Park Professor of Hematology and Oncology, was senior author of the study. — Anish Thomas, MD, the Roswell Park Professor of Hematology and Oncology. was senior author of the study.

A new Northwestern Medicine study has uncovered a biological mechanism that may explain why a subset of tumors unexpectedly grows at an accelerated rate after being treated with certain immunotherapies, according to findings published in the journal Cancer Discovery.

The findings could help physicians improve precision therapy strategies for select cancer patients, said Anish Thomas, MD, the Roswell Park Professor of Hematology and Oncology and senior author of the study.

In the study, investigators led by Thomas examined outcomes from a clinical trial testing bintrafusp alfa, an experimental therapy that simultaneously blocks the immune checkpoint protein PD-L1 and the signaling molecule TGF-beta in patients with relapsed small cell lung cancer and related neuroendocrine cancers.

They found that while some patients experienced a favorable response to treatment, others developed hyperprogressive disease, a phenomenon in which tumors grow faster after treatment begins. Among 34 patients evaluated in the study, 18 percent experienced significant tumor shrinkage, while 38 percent of patients experienced hyperprogressive disease.

The team found that the risk appears tied to TGF-beta signaling within the tumor: In a subset of tumors, TGF-beta acts as a growth suppressor in advanced cancer. Blocking that pathway, Thomas said, can remove a critical brake on tumor growth, allowing cancer cells to multiply rapidly.

“The main takeaway is that blocking more immunosuppressive pathways is not necessarily better,” said Thomas, who recently joined Northwestern Medicine from the National Cancer Institute, where he was a tenured senior investigator and served as deputy chief of the Developmental Therapeutics Branch and led the clinical trial on which the study is based. “In some tumors, those same pathways may also be restraining cancer growth, so context matters.”

Immune checkpoint inhibitors have transformed treatment for many cancers by helping immune cells recognize and attack tumors. Investigators have increasingly explored combining checkpoint blockade with therapies targeting additional immune-suppressive mechanisms, including TGF-beta; bintrafusp alfa was designed to do both simultaneously.

Instead, the study revealed that some tumors TGF-beta signaling may help keep cancer-cell growth in check. Analyses of patient tumor biopsies, blood immune cells and circulating tumor DNA showed that tumors of patients who developed hyperprogressive disease had elevated TGF-beta signaling before treatment.

Next, the scientists validated their findings in cultured cells. In small cell lung cancer cell lines with intact TGF-beta signaling, blocking the pathway triggered accelerated growth. Cell lines lacking a functional TGF-beta response did not show the same effect, according to the study.

“What we found is that some of these same pathways that suppress the immune response can also restrain the cancer cells themselves,” said Thomas, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “When you block them, you may remove that restraint and allow the tumor to grow more rapidly.” Additionally, the research team found that higher TGF-beta signaling was associated with increased inflammatory signaling and poorer survival outcomes for patients.

The investigators also analyzed data from hundreds of patients enrolled in other bintrafusp alfa clinical trials involving cervical cancer, nasopharyngeal cancer and non-small cell lung cancer. They found evidence that hyperprogressive disease occurred across multiple tumor types, though at different frequencies, suggesting that their findings have implications beyond small cell lung cancer.

“There are some cancers in which TGF-beta appears to help restrain tumor growth,” Thomas said. “Our findings suggest that those tumors may not be good candidates for therapies that block the TGF-beta pathway.” The study highlights the importance of understanding the biology of individual tumors before selecting treatment, Thomas said.

“The implications go beyond this particular drug,” Thomas said. “Several therapies that target TGF-beta are currently being tested in clinical trials. Our findings suggest that it will be important to identify tumors in which TGF-beta is actually helping restrain cancer growth, because blocking the pathway in those tumors could have unintended consequences.” Thomas said the research also demonstrates the value of deeply analyzing patient samples collected during clinical trials, even when the treatment does not perform as expected.

“Although this was a relatively small cohort, the patient samples gave us an opportunity to understand why some patients did poorly,” Thomas said. “By going back to the clinical specimens, we were able to identify a biological hypothesis that can now be tested prospectively and used to inform the design of future trials targeting TGF-beta.”

Thomas and his collaborators are now working to identify biomarkers of TGF-beta-responsive small cell lung cancer and determine which treatment strategies may be most effective for this subset of patients.

The Center for Cancer Research, an Intramural Program of the National Cancer Institute, supported the study under grant ZIA BC 011793.

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