Immunotherapy Combinations Have Mechanistic Rationale in Ovarian Cancer

Samir N. Khleif, MD

Samir N. Khleif, MD

Immunotherapy combinations with PARP inhibitors or checkpoint inhibitors may represent the future of treatment for patients with ovarian cancer, said Samir N. Khleif, MD, during the 2017 ASCO Annual Meeting.¹

Alternatives to chemotherapy are needed for the treatment of ovarian cancer because despite an 80% 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 (T_regs) that block an immune response, production of the enzyme IDO (leading to activation of suppressive populations of T_regs) 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 nivolumab (Opdivo) at 2 dosages (1 or 3 mg/kg every 2 weeks) in 20 patients with platinum-resistant ovarian cancer, producing 2 complete responses and 1 partial response.²Levels 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 Ib study of avelumab (Bavencio), 10 mg/kg, in 124 patients demonstrated an objective response rate of 9.7% and stable disease in 44%.³Another study of nivolumab in 17 patients with recurrent/refractory epithelial ovarian cancer, showed 1 partial response and 2 patients with stable disease after treatment.⁴“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 T_regsand T conventional cells (T_convs) are differentially regulated by PI3K isoforms. T_regsare primarily dependent on the PI3K-delta isoform, whereas in T_convs, PI3K-alpha and -beta provide a redundant pathway to PI3K-delta.⁵This dichotomy can be exploited to target T_regsby inhibiting the PI3K-delta isoform while leaving T_convsintact.

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 T_regsand 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 T_regsand 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 aBRCA1-deficient murine ovarian cancer model compared with treatment with CTLA-4 or PD-1/PD-L1 monoclonal antibodies alone.⁶

A PARP inhibitor enhanced apoptosis and tumor volume shrinkage within the tumor microenvironment when given in addition to a PD-1/PD-L1 blocker.⁷PARP 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.

References:

1. Khleif S. Immuno checkpoint therapy combinations with PARP or with other checkpoint inhibitors in ovarian cancer. Presented at: 2017 ASCO Annual Meeting; June 3-6, 2017; Chicago, IL.
2. Hamanishi J, Mandai M, Ikeda T, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer.J Clin Oncol.2015;33(34):4015-4022. doi: 10.1200/JCO.2015.62.3397.
3. Disis ML, Patel M, Pant S, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with recurrent/refractory ovarian cancer from the JAVELIN Solid Tumor phase Ib trial: Safety and clinical activity.J Clin Oncol.2016;34 (suppl; abstr 5533).
4. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.N Engl J Med.2012;366(26):2455-2465. doi: 10.1056/NEJMoa1200694.
5. Ahmad S, Abu-Eid R, Shrimal R, et al. Differential PI3Kδ signaling in CD4+ T cell subsets enables selective targeting of T regulatory cells to enhance cancer immunotherapy.Canc Res.2017;77(8):1892-1904. doi: 10.1158/0008-5472.CAN-16-1839.
6. Higuchi T, Flies DB, Marion NA, et al. CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in BRCA1-Deficient Ovarian Cancer.Cancer Immunol Res.2015;3:1257-68.
7. Jiao S, Xia W, Yamaguchi H, et al. PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression.Clin Cancer Res.2017; doi: 10.1158/1078-0432.CCR-16-3215.