Chi Lin, MD, PhD, on Immunotherapy and Chemoradiation in Pancreatic Cancer

Immunotherapy can be said to have revolutionized the treatment landscape of various malignancies, but less so in pancreatic cancer. The majority of the initial clinical trials in pancreatic cancer patients used single-agent immunotherapy and showed no efficacy. However, these trials included only a small number of patients and the majority of patients were heavily pretreated with current standard-of-care treatments.

A study presented at the 2020 Gastrointestinal Cancers Symposium analyzed National Cancer Database data of 252,280 patients with pancreatic adenocarcinoma and found that immunotherapy combined with treatments such as chemotherapy and chemoradiation significantly improved median overall survival (OS) rates.

In the following interview, Chi Lin, MD, PhD, professor and vice chair of research in the department of radiation oncology at the University of Nebraska Medical Center in Omaha, elaborated on the team's research.

What does your study add to the literature about the role of immunotherapy in pancreatic cancer?

Lin: Our findings, uniquely combining immunotherapy with chemoradiation, have not been reported before. Some of our findings are in agreement with the early results of the few small phase I clinical trials of immunotherapy combined with chemotherapy. The findings of our study together with the encouraging early findings of these clinical trials warrant future clinical trials of combining immunotherapy with chemotherapy and chemoradiation in patients who receive or do not receive the definitive surgery of the tumor.

What are the highlights of the study? Were there any surprises?

Lin: Combining immunotherapy with chemoradiation significantly improved OS in pancreatic adenocarcinoma patients with surgery or no surgery compared with chemoradiation alone. Surprisingly, combining immunotherapy with chemotherapy significantly improved OS only in patients who did not receive definitive surgery compared with chemotherapy alone.

When would you recommend immunotherapy in the course of treatment?

Lin: Adding immunotherapy to adjuvant chemotherapy can significantly improve OS compared with only adjuvant chemotherapy, which supports the use of immunotherapy adjuvantly. Studies have demonstrated that neoadjuvant chemotherapy and/or chemoradiation may convert at least one-third of patients who initially have borderline resectable pancreatic adenocarcinoma to a resectable tumor. Combining immunotherapy with neoadjuvant chemotherapy and/or chemoradiation therapy could further enhance the conversion of borderline resectable tumor to resectable tumor because chemotherapy and radiation cause the release of neoantigens from the tumor and upregulation of inflammatory cytokines. This promotes the presentation of the neoantigens in the tumor microenvironment, thereby increasing the immunogenicity of the tumor cells making them better targets for immunotherapy. The irradiated tumor cells may also release cellular danger-associated molecular patterns and cytokines that enhance the traffic of immune cells leading to the elimination of the tumor cells.

Why does the addition of immunotherapy to chemoradiation lead to significantly improved survival?

Lin: The improved OS with the addition of immunotherapy to standard treatments may be additive or synergistic. Chemotherapy and radiation therapy cause the release of neoantigens and upregulation of inflammatory cytokines, which promote the presentation of the neoantigens in the tumor microenvironment and thereby increase the immunogenicity of the tumor cells making them better targets for immunotherapy. Chemotherapy and radiation therapy also induce immunogenic cell death, which can help T cells activated by immunotherapy attack the cancer cells. Chemotherapy, especially gemcitabine, has been associated with an increase in tumor-specific T-cell infiltration, a decrease in Treg cells, and the suppression of myeloid-derived suppressor cells in preclinical and clinical studies, all of which will optimize the efficacy of immunotherapy. Through this mechanism, chemoimmunotherapy can improve the effectiveness of the abscopal phenomenon in eradicating the local and distant tumor cells and improve local control and OS.

What is the next step in this research?

Lin: Future large clinical trials of immunotherapy combined with chemotherapy and chemoradiation in both patients who receive surgery and who do not receive surgery are warranted. One focus should also be on the appropriate timing of immunotherapy with chemotherapy and chemoradiation and with surgery.

You can read the abstract of the study here and read a critique about the clinical implications here.