OPERA: a phase II trial of oregovomab plus non-platinum chemotherapy in PARP inhibitor/platinum-resistant ovarian cancer.

A consensus regarding subsequent therapeutic strategies for patients with platinum- and poly (ADP-ribose) polymerase inhibitor (PARPi)-resistant ovarian cancer is lacking. These patients typically receive non-platinum-based chemotherapy; however, survival outcomes remain poor. Compared with chemotherapy alone, combination therapy with novel target agents can provide additional benefits to these patients. Oregovomab, an investigational murine monoclonal antibody against CA-125, has shown promising efficacy in a phase II study in patients with recurrent ovarian cancer. Herein, we described the rationale and design of OPERA/KGOG 3065/APGOT-OV6, a multicenter, investigator-initiated, two-cohort, single-arm phase II trial, aimed at examining the efficacy of oregovomab plus non-platinum-based chemotherapy in patients with PARPi/platinum-resistant ovarian cancer. The primary end point was the objective response rate, according to RECIST 1.1.Clinical Trial Registration: NCT05407584 (ClinicalTrials.gov).

OPERA/KGOG 3065/APGOT-OV6 is a promising phase II studies that test new drug (oregovomab) on the patients with poly (ADP-ribose) polymerase inhibitor (PARPi)/platinum-resistant epithelial ovarian cancer. PARPis have changed the treatment landscape of ovarian cancer in a relatively short time. PARPi/platinum-resistant epithelial ovarian cancer refer to a subtype of recurrent epithelial cancer of ovarian, tubal or peritoneal origin who experienced disease progression despite treatment with a PARPi or platinum-based chemotherapy drugs. Although various new drugs have been tested to improve the treatment response in resistant patients, a consensus regarding the international standard of treatment is yet to be established, despite the poor survival outcomes of these patients. OPERA/KGOG 3065/APGOT-OV6 has been designed to add oregovomab, a murine monoclonal antibody to cancer antigen-125 (CA-125), to non-platinum chemotherapy (pegylated liposomal doxorubicin or paclitaxel) for patients with ovarian cancer determined as PARPi/platinum-resistant and ineligible for bevacizumab treatment. The results of this study will aid in developing effective treatment strategies for patients with PARPi/platinum-resistant ovarian cancer.

Translational immune correlates of indirect antibody immunization in a randomized phase II study using scheduled combination therapy with carboplatin/paclitaxel plus oregovomab in ovarian cancer patients.

The standard-of-care (SOC) first-line therapy for ovarian cancer (OC) patients is plagued with high relapse rates. Several studies indicated the immune system's prominent role changing the disease course in OC patients. Chemo-immunotherapy regimens, currently being explored, include oregovomab, which is a monoclonal antibody specific for the OC associated antigen carbohydrate/cancer antigen 125 (CA125) that yielded promising results when administered together with SOC in a previous study. The QPT-ORE-002 multi-site phase II randomized study demonstrated that in patients with advanced OC, oregovomab combined with first-line SOC improved overall and progression-free survival, compared to SOC alone. The study included an Italian cohort in which we demonstrated that adding oregovomab to SOC resulted in increased patient numbers with amplified CA125-specific CD8+T lymphocytes/ml peripheral blood counts, which might explain the improved therapeutic effect of SOC + oregovomab over SOC alone. Predictive for oregovomab efficacy was a less suppressive immune environment at baseline as indicated by low numbers of circulating myeloid-derived suppressor cells, subset type 4, and a low neutrophil-and-monocyte to lymphocyte ratio.

Front-line chemoimmunotherapy for treating epithelial ovarian cancer: Part II promising results of phase 2 study of paclitaxel-carboplatin-oregovomab regimen.

In the Part I, we have discussed the background of CA125 and the development of anti-CA125 monoclonal antibody (MAb) to highlight the potential role of CA125 and anti-CA125 MAb in the management of women with advanced stage epithelial ovarian cancer (EOC). Glycosylation change either by N-link or by O-link of CA125 is supposed to play a role in the modification of immunity. Anti-CA125 MAb, which can be classified as OC 125-like Abs, M11-like Abs, and OV197-like Abs, is often used for diagnosing, screening, monitoring and detecting the mesothelin-related diseases of the abdominal cavity, particular for those women with EOC. Additionally, anti-CA125 MAb also plays a therapeutic role, named as OvaRex MAb-B43.13 (oregovomab), which has also been extensively reviewed in the Part I review article. The main mechanisms include (a) forming CA125 immune complexes to activate the antigen-presenting cells; (b) triggering induction of CA125-specific immune responses, including anti-CA125 Abs against various epitopes and CA125-specific B and T cell responses; and (c) triggering CD4 and CD8 T-cell responses specific for B43.13 to produce specific and non-specific immune response. With success in vitro, in vivo and in primitive studies, phase II study was conducted to test the effectiveness of chemoimmunotherapy (CIT) for the management of EOC patients. In the 97 EOC patients after optimal debulking surgery (residual tumor <1 cm or no gross residual tumor), patients treated with CIT had a dramatical and statistically significant improvement of both progression-free survival (PFS) and overall survival (OS) compared to those treated with chemotherapy alone with a median PFS of 41.8 months versus 12.2 months (hazard ratio [HR] 0.46, 95 % confidence interval [CI] 0.28-0.7) and OS not yet been reached (NE) versus 42.3 months (HR 0.35, 95 % CI 0.16-0.74), respectively. The current review as Part II will explore the possibility of using CIT as front-line therapy in the management of advanced-stage EOC patients after maximal cytoreductive surgery based on the evidence by many phase 2 studies.

Front-line chemo-immunotherapy for treating epithelial ovarian cancer: Part I CA125 and anti-CA125.

The current standard therapy of epithelial ovarian cancer (EOC) is the combination of surgery (primary cytoreductive surgery or interval cytoreductive surgery) and platinum-based chemotherapy (mainly using paclitaxel and carboplatin either by neoadjuvant chemotherapy and/or by postoperative adjuvant chemotherapy) with/without adding targeted therapy (mainly using anti-angiogenesis agent- bevacizumab). After front-line chemotherapy, the advanced-stage EOC can be successfully controlled and three-quarters of patients can achieve a complete clinical remission. Unfortunately, nearly all patients will recur and progression-free survival (PFS) of these patients is seldom more than 3 years with a dismal median PFS of 12-18 months. With each recurrence, patients finally develop resistance to standard chemotherapy regimen, contributing to fewer than half of women who survive for more than 5 years after diagnosis with a median overall survival (OS) of 40.7 months. Due to the lower PFS and OS, particularly for those advanced-stage patients, novel therapeutic options during the front-line therapy are desperately needed to decrease the occurrence of recurrence, and the majority of them are still under investigation. It is well-known that overexpression of CA125 has been associated with attenuated cellular apoptosis, platinum chemotherapy resistance, tumor proliferation and disease progression, suggesting that anti-CA125 may play a role in the management of patients with EOC. The current review is a Part I which will focus on development of anti-CA125 monoclonal antibody, hoping that alternation of the front-line therapy by chemo-immunotherapy will be beneficial for prolonged survival of patients with EOC.

Oregovomab: an investigational agent for the treatment of advanced ovarian cancer.

Introduction: Ovarian cancer (OC) represents the leading cause of death among gynecological cancers. Despite novel compound classes like vascular endothelial growth factor (VEGF) inhibitors or poly-ADP ribose polymerase (PARP) inhibitors are available, which improve significantly efficacy of platinum-based chemotherapy, OC prognosis remains poor and innovative strategies are needed. The induction of tumor specific immune response with a therapeutic intent is a very challenging approach. Oregovomab is a murine monoclonal antibody direct to the tumor-associated antigen CA125 that stimulate a host cytotoxic immune response against tumor cells expressing CA125. Areas covered: This paper reviews the preclinical and clinical published data underlying the use of oregovomab in advanced OC. A literature search was performed in PubMed for oregovomab, ovarian cancer, anti-CA125, and on ClinicalTrials.gov for currently ongoing trials. Expert opinion: Oregovomab demonstrated a significant improvement in progression-free and overall survival in advanced OC treatment when administered simultaneously with first-line chemotherapy. This promising schedule is currently investigated in a phase III trial. Since oral treatments as PARP-inhibitors have recently been approved in the OC first-line setting, the possible role of oregovomab needs still to be defined, also considering the intravenous route of administration. The easy to manage toxicity profile makes oregovomab an ideal candidate for association strategies.

Antibody-based immunotherapy of solid cancers: progress and possibilities.

Monoclonal antibodies remain a primary product option for novel cancer treatment. The properties of an antibody are a function of the antigen specificity and constant region incorporated. The rapid advance in molecular understanding of cancer biology and the host-tumor interaction has defined a new range of targets for antibody development. The clinical success of the checkpoint inhibitors has validated immune modulation and mobilization as a therapeutic approach. Solid cancers are distinguished from hematologic malignancies because the solid tumor stroma contains significant tumor promoting and immune dampening elements less prominent in hematologic cancer. This review highlights how engineered monoclonal antibody products are emerging as potential cornerstones of new more personalized cancer treatment paradigms that target both tumor and the stromal environment.