PARP Inhibitors Plus Immunotherapy May Be the Future in Ovarian Cancer

The future of treating ovarian cancer may lie in combinations of immunotherapy plus PARP inhibitors, says Samir N. Khleif, M.D.

Alternatives to chemotherapy are needed for the treatment of ovarian cancer because despite an 80 percent response to chemotherapy, recurrence is universal with few options available following recurrence. Ovarian cancer is an immune-dependent cancer; ovarian cancers with T-cell infiltration within the tumor microenvironment are associated with superior progression-free survival and overall survival.

Multiple tumor-associated antigens have been defined, from which a number of vaccines have been developed and tested. “Most have approached the vaccine as a single agent rather than as a combination agent, either in a specific antigen, either synthetic, naked DNA, RNA, bacterial or viral; whole-cell lysate, or anti-idiotype vaccine, and it is either given by itself or given in the context of a dendritic cell,” said Khleif, director of the Georgia Health Sciences Cancer Center in Augusta. Unfortunately, vaccines have demonstrated limited efficacy in this setting.

Ovarian cancer is an immune-driven tumor, but because of the immune-suppressive environment within it, T cells are activated and captured by various mechanisms, leading to an inability of the T cells to generate a proper immune response. These mechanisms include accumulation of intratumoral T regulatory cells (Tregs) that block an immune response, production of the enzyme IDO (leading to activation of suppressive populations of Tregs) by tumor cells, and suppression of effector T cells by engagement of PD-1 with PD-L1.

“When we think of our approach to vaccines, it’s pretty naïve to think that a vaccine is going to generate T cells, and the T cells are going to be taking care of a tumor that is that immune suppressive,” said Khleif.

Accordingly, the use of PD-1 inhibitors and other checkpoint inhibitors in ovarian cancer has been proposed, but so far, the data are scant. The expression of PD-1 in ovarian tumors is dependent on the grade of the tumor, with high-grade tumors having higher expression.

Hamanishi et al studied the activity of Opdivo (nivolumab) at two dosages (1 or 3 mg/kg every two weeks) in 20 patients with platinum-resistant ovarian cancer, producing two complete responses and one partial response. Levels of PD-L1 expression did not seem to influence response, “which might be a little bit different than other diseases like lung cancer,” he said.

A phase 1b study of Bavencio (avelumab), 10 mg/kg, in 124 patients demonstrated an objective response rate of 9.7 percent and stable disease in 44 percent.3 Another study of Opdivo in 17 patients with recurrent/refractory epithelial ovarian cancer, showed one partial response and two patients with stable disease after treatment.

“As a single agent, so far, we have some responses but we did not break that tolerance yet,” Khleif said, and noted that the responses rarely lasted very long.

Multiplication of effort is probably needed to address the immune suppressive state of the tumor microenvironment in ovarian cancer, he said. “That is why combination immune therapy is going to be, and is, the name of the game.” Chemotherapy is known to induce PD-L1 expression and lead to enhanced infiltration of CD8-positive cells in the tumor, possibly enhancing the efficacy of checkpoint inhibitors.

Khleif’s team has found that Tregs and T conventional cells (Tconvs) are differentially regulated by PI3K isoforms. Tregs are primarily dependent on the PI3K-delta isoform, whereas in Tconvs, PI3K-alpha and -beta provide a redundant pathway to PI3K-delta.5 This dichotomy can be exploited to target Tregs by inhibiting the PI3K-delta isoform while leaving Tconvs intact.

In a mouse model of lung cancer, co-administration of an inhibitor of PI3K-delta with a tumor-specific vaccine decreased the number of suppressive Tregs and increased the number of vaccine-induced CD8 T cells within the tumor microenvironment, resulting in a large reduction in tumor volume. The results “offer a mechanistic rationale to employ PI3K-delta inhibitors to selectively target Tregs and improve cancer immunotherapy,” the authors concluded.

PARP is an important target in ovarian cancer. PARP inhibitors have been shown to have clear beneficial effects on clinical outcomes in the treatment of ovarian cancer in several clinical trials. The combination of a PARP inhibitor with CTLA-4 blockade improved overall survival in a BRCA1-deficient murine ovarian cancer model compared with treatment with CTLA-4 or PD-1/PD-L1 monoclonal antibodies alone.

A PARP inhibitor enhanced apoptosis and tumor volume shrinkage within the tumor microenvironment when given in addition to a PD-1/PD-L1 blocker. PARP inhibition was able to attenuate anticancer immunity via upregulation of PD-L1, and blockade of PD-L1 re-sensitized the PARP inhibitor-treated cancer cells to T-cell killing, the authors found. Multiple trials combining PARP inhibitors and checkpoint inhibitors are ongoing, said Khleif.