Combinations May Be the Future for Ovarian Cancer

Immunotherapy and PARP inhibitor combinations may be the future of ovarian cancer treatment, says Samir N. Khleif, M.D.

Clinicians are seeking alternatives to chemotherapy because, despite an 80 percent response, 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.

Researchers have defined multiple tumor-associated antigens, and in turn, tested and developed an array of vaccines. Unfortunately, vaccines have demonstrated limited efficacy in this setting.

“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.

Ovarian cancer is an immune-driven tumor. But the tumor itself is immune-suppressive environment. As a result, T cells are activated and captured by various mechanisms, but unable 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.

In response, physicians and researchers have proposed using PD-1 inhibitors and other checkpoint inhibitors in ovarian cancer, 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.

In Hamanishi et al, researchers observed two complete responses and one partial response after treatment with Opdivo (nivolumab) at 1 mg/k or 3 mg/kg every two weeks in 20 patients with platinum-resistant ovarian cancer. 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.

In a phase 1b study of Bavencio (avelumab) conducted by Disis et al, 10 mg/kg, in 124 patients demonstrated an objective response rate of 9.7 percent and stable disease in 44 percent. 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.

He added that addressing the immune suppressive state of the tumor microenvironment in ovarian cancer will likely require a multiplication of effort. “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 discovered that PI3K isoforms differentially regulate T_regs and T conventional cells (T_convs). Tregs are primarily dependent on the PI3K-delta isoform, whereas in T_convs, PI3K-alpha and -beta provide a redundant pathway to PI3K-delta. This dichotomy can be exploited to target T_regs by inhibiting the PI3K-delta isoform while leaving T_convs intact.

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

PARP has emerged as 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.

In results published by Clinical Cancer Research earlier this year, 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 attenuated 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.

Khleif added that multiple trials combining PARP inhibitors and checkpoint inhibitors are ongoing.