Can Immunotherapy Work in Ovarian Cancer?

June 2019, Vol 10, No 3

San Francisco, CA—Patients with ovarian cancer can respond to immunotherapy, but rationally designed synergistic combinations will be necessary to enhance upfront efficacy and to sustain durability, said Daniel J. Powell Jr, PhD, Scientific Director of Immunotherapy, Division of Gynecologic Oncology, Center for Cellular Immunotherapy, University of Pennsylvania, Philadelphia, at the 2019 ASCO-SITC Clinical Immuno-Oncology Symposium.

So far, the only immunotherapy approved for ovarian cancer is bevacizu­mab (Avastin), which targets the VEGF receptor–signaling pathway. The pau­city of approved immunotherapies for ovarian cancer results from a common misconception that ovarian cancer is not immune-responsive, said Dr Powell.

The defining role of immune cells that control tumor progression was first elucidated in ovarian cancer, he pointed out, in which dense accumulation of T-cells within the tumor was shown to predict survival. An early experiment showed a reduction in CA125 levels and a reduction in tumor size with a strategy of vaccination using a GM-CS modified whole tumor vaccine in combination with ipilimumab (Yervoy) in patients with recurrent ovarian cancer.

This observation led to clinical trials of different checkpoint inhibitors in the context of recurrent ovarian cancer. The KEYNOTE-100 clinical trial, with pembrolizumab (Keytruda) reported data from a set of 100 patients, and showed an overall response rate of just 9%, with a higher overall response rate in patients with PD-L1 expression (14% with combined positive score ≥1 and 25% with a score of ≥10). The overall response rate in KEYNOTE-100 was consistent with findings in other studies of single checkpoint inhibition in ovarian cancer, Dr Powell said.

“Unlike other cancers, such as melanoma and lung cancer,…ovarian cancer is a disease of gene amplification and homologous recombination deficiency. It does not have a high tumor mutational burden. So I think we need to think about ovarian cancer as a different type of disease—one that could be immune responsive but doesn’t fit within the paradigm of neoantigen recognition,” Dr Powell said.

Targeting CTLA-4 and PD-1 on T-Cells

CD137-positive T-cells are tumor-­reactive T-cells that are enriched within the tumor microenvironment and, once isolated, produce proinflammatory cytokines in response to autologous tumor cells, whereas CD137-negative cells do not. CD137-positive tumor reactive cells express high levels of PD-1 and CTLA-4, as well as other negative immunoregulatory molecules at the global level, Dr Powell explained.

Recent research shows that within the tumor reactive tumor-infiltrating lymphocyte subset are 4 phenotypic metaclusters. The distribution of these subtypes skews toward exhausted T-cells, with far fewer effector T-cells. Effector T-cells express very high levels of CTLA-4, whereas exhausted T-cells have high levels of PD-1 and also express high levels of CD28, a co-stimulatory molecule required for cell proliferation.

“We know that CTLA-4 is required during the priming phase, while PD-1 is induced during the effector phase,” said Dr Powell. “So we rationalize that ovarian cancer could be treated better with a combination of [drugs] targeting these 2 molecules.”

In patients with persistent or recurrent ovarian cancer, a phase 2 randomized clinical trial of nivolumab (Opdivo) with or without ipilimumab, each followed by maintenance nivolumab, demonstrated a 3 times higher rate of response within 6 months in the nivolu­mab-ipilimumab arm compared with single-agent nivolumab (31.4% vs 12.2%, respectively). The complete response rate, however, was nearly identical in the 2 arms—5.9% versus 6.1%, respectively. The median progression-­free survival (3.9 months vs 2.0 months, respectively; P = .041) was also significantly superior with the combination, with a nonsignificant trend toward improved overall survival (28.1 months vs 21.8 months; P = .43), although the study was underpowered to detect a clinically important difference in overall survival, said Dr Powell.

Similar to renal-cell carcinoma, an increased likelihood of response was observed in the subset with clear-cell cancer.

The responses were independent of age, performance status, and number of previous cytotoxic regimens, which would suggest that these T-cells are recognizing cancer or are recruiting new T-cells, or perhaps the T-cells are resistant to the effects of chemotherapy effects, he said.

“It raises questions of whether this therapy should be brought upfront immediately after surgical debulking and chemotherapy,” Dr Powell said. The potential to synergize immunotherapy with a vaccine that bolsters the endogenous immune response is warranted by the results.

Although ovarian cancer has naturally occurring tumor reactive T-cells, not all patients with ovarian cancer have them. Tumor-intrinsic factors can limit response, such as loss of class I or loss of antigen-processing machinery. Synthetic biology provides a possible solution by engineering tumor reactive T-cells that can recognize cancer, according to Dr Powell.

Alpha Folate Receptor and Cellular Therapy

One target that has been analyzed in the context of cellular therapy is alpha folate receptor (aFR). Its surface GPI-anchored protein transports folate, internalizes it, and allows DNA synthesis and other transcriptional activity, which renders a growth advantage for cancer cells by promoting proliferation, migration, and loss of adhesion. aFR is an ideal target in ovarian cancer, Dr Powell said, because 90% of ovarian cancers express high levels of target antigen.

Toxicity has not been reported with any aFR-targeted therapy—an anti-aFR antibody, an antibody-drug conjugate, or bispecific antibodies. Overall response rates with the latter 2 approaches have been approximately 25%.

The first chimeric antigen receptor (CAR) T-cell therapy targeting aFR did not produce any responses and caused toxicity related to the high-dose interleukin-2 that was co-administered. Failure was blamed on poor transgene expression and lack of persistence of T-cells. To overcome the problem of poor T-cell persistence, CD137 has been incorporated into CAR T-cells as a co-stimulatory domain.

“These cells that are outfitted with co-stimulatory domains have a capacity to persist in vivo,” Dr Powell said. Based on potent antitumor effects observed in a xenograph model, a clinical trial to target aFR has been opened to patients with persistent or recurrent stage IV high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.

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