Abstract AS24: Immunomodulatory antibodies for immunotherapy of ovarian cancer
Authors: Dai Min , Hellstrom Ingegerd , Yip Yuen Yee , Wei Huafeng , Hellstrom Karl Erik 
Published: August 2015

Abstract
Although surgical debulking plus platinum-based chemotherapy induces clinical remission in 70+ % of patients with advanced ovarian carcinoma, most of these patients relapse and novel treatments are urgently needed. Although clinical trials of various immunotherapies have not yielded significant benefit for ovarian cancer, the failures can now be better understood as an outcome of the highly immunosuppressive tumor microenvironment so that one needs to both overcome this immunosuppression and concomitantly activate tumor-destructive immunological mechanisms. One way to achieve this is to use monoclonal antibodies (mAbs) to molecules which regulate the immune response. Antibodies blocking the co-inhibitory molecules CTLA-4 or PD-1 have already demonstrated encouraging clinical activity, particularly in melanoma, and the combination of the two mAbs has improved efficacy with long-lasting remission in some patients.
We have evaluated the antitumor efficacy of mAbs against multiple co-signaling molecules, both individually and in combinations, in the ID8 syngeneic mouse model of ovarian cancer. In this model, small intraperitoneal tumor nests appear about 10 days after implantation and solid tumors as well as malignant ascites develop leading to death approximately 30 days after transplantation. Intraperitoneal injections of single mAb antagonists against co-inhibitory receptors (PD-1, CTLA-4, TIM-3, and LAG-3) or agonistic mAb targeting co-stimulatory molecules (CD137, OX40, GITR, and CD40) in mice that had been transplanted 10 days earlier with ID8 cells were ineffective. However, injection of a combination of anti-CD137 and anti-PD-1 mAbs significantly prolonged survival, and addition of a mAb to CTLA-4 further enhanced the antitumor efficacy with some mice surviving tumor-free &gt;150 days. The mAb combination greatly increased the number of tumor-associated CD8+ effector T cells in the peritoneal cavity and decreased the number of immunosuppressive Treg and MDSC cells with a prominent increase in the T effector to T suppressive cell ratios, and it rescued the function of exhausted T cells with a PD-1+TIM3+ or PD-1+TIM3– phenotype.
Importantly, pretreatment of the ID8-bearing mice with cisplatin, a drug routinely used to treat ovarian carcinoma, synergized with the anti-CD137/anti-CTLA4 mAb combination for a long-lasting and complete tumor regression in 80% of the mice.
Our findings, as well as results from preclinical studies and clinical trials at many centers, strengthen the concept of targeting co-stimulatory and co-inhibitory molecules by immunomodulatory mAbs for cancer therapy. A variety of such receptors is known, and their significance as therapeutic targets, individually or in combinations, merits preclinical characterization and clinical testing of the best candidates. For example, we have recently shown that a combination of mAbs to CD137+PD1+CTLA4+CD19 is superior to the anti-CD137+PD1+CTLA4 combination when tested in mouse melanoma and lung carcinoma models and causes permanent regression of melanomas with a surface area of 80-100 mm2 at the onset of treatment, and we are now evaluating this and other combinations in the ID8 model. Although we have not observed significant toxicity, caution must be exercised since CD137 agonistic antibodies have been observed to cause liver toxicity in clinical trials. Restricting the biodistribution of mAbs for treating ovarian carcinoma to the peritoneal cavity and entrapping them in nanoparticles, may favor efficacy and minimize systemic toxicity. “Translation” of the preclinical findings to clinical trials in ovarian cancer patients should be seriously considered.
Citation Format: Min Dai, Ingegerd Hellstrom, Yuen Yee Yip, Huafeng Wei, Karl Erik Hellstrom. Immunomodulatory antibodies for immunotherapy of ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS24.