Neoadjuvant Chemotherapy May Render Advanced Ovarian Cancers Responsive to Immunotherapy
Although most patients with advanced ovarian cancer initially respond to platinum-based chemotherapy, they usually relapse. According to a study by Frances R. Balkwill, PhD, Professor of Cancer Biology at Barts Cancer Institute, Queen Mary University of London, United Kingdom, and colleagues published in Clinical Cancer Research, neoadjuvant chemotherapy seemed to alter the immune cells in the tumors of patients with stage III/IV high-grade serous ovarian cancer. The results suggest that the effects of immunotherapy might be enhanced if given after chemotherapy, possibly improving disease control. If these results are confirmed in additional studies, the incorporation of immunotherapy into postchemotherapy treatment options may also benefit patients with other types of cancer.
The researchers obtained pre- and post-treatment omental biopsies and blood samples from a total of 54 women with stage IIIC and stage IV tubo-ovarian high-grade serous carcinoma undergoing platinum-based neoadjuvant chemotherapy and 6 patients undergoing primary debulking surgery. They then measured T-cell density and phenotype, immune activation, and markers of cancer-related inflammation using immunohistochemistry, flow cytometry, electrochemiluminescence assays, and RNA sequencing and related their findings to histopathologic treatment response.
Progression-free survival was calculated from the date of the first neoadjuvant chemotherapy to disease progression or death, whichever came first, using GCIG CA-125 criteria for biochemical disease progression. Overall survival was calculated from the date of the first neoadjuvant chemotherapy to death from the cancer. Survival functions were estimated using the Kaplan-Meier method, and the log-rank test was applied.
The researchers found evidence of T-cell activation in omental biopsies after neoadjuvant chemotherapy: CD4+ T cells showed enhanced interferon-gamma production, and antitumor Th1 gene signatures were increased. T-cell activation was more pronounced with good response to neoadjuvant chemotherapy. The CD8+ T-cell and CD45RO+ memory cell density in the tumor microenvironment was unchanged after neoadjuvant chemotherapy, but biopsies showing a good therapeutic response had significantly fewer FoxP3+ T regulatory (Treg) cells. This finding was supported by a reduction in a Treg cell gene signature in post- vs pre–neoadjuvant chemotherapy samples, which was more pronounced in good responders.
Plasma levels of proinflammatory cytokines decreased in all patients after neoadjuvant chemotherapy. However, a high proportion of T cells in biopsies expressed immune checkpoint molecules PD-1 (programmed cell death protein 1) and CTLA4 (cytotoxic T-lymphocyte–associated protein 4), and PD-L1 (programmed cell death ligand 1) levels were significantly increased after neoadjuvant chemotherapy.
“Our study showed that chemotherapy altered the immune cells…that are found in metastatic ovarian cancer samples in a way that suggested they were better able to fight the cancer after the treatment,” said Dr. Balkwill, in a statement. “Our research provides evidence that immunotherapy may be more effective if given straight after chemotherapy. Although we found that chemotherapy activated the T cells, the levels of the protein PD-L1 remained the same or increased. However, immune checkpoint blockade therapies can stop this from happening, so we suggest that immune checkpoint blockade might be a suitable form of immunotherapy to give to ovarian cancer patients after chemotherapy.”
According to Dr. Balkwill, a major limitation of the study was the small sample size, which also prevented the researchers from analyzing pre- and post-chemotherapy samples from the same patient, in some cases because there was not enough material.
Funding for this study was provided by the Swiss Cancer League, the European Research Council, Cancer Research UK, the Barts Cancer Institute, and the London Charity. ■