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Mechanism of Action

Available data suggests, indirect immunisation with low dose oregovomab administration offers a targeted low-dose strategy for immune system-mediated tumor cell death. Selected immune cell functions are induced to enhance cellular phagocytosis and complement activation (CDC). Immune system T-cells are targeted to tumor cells by antibody fragments and system inhibitory signals are interrupted using receptor binding antibodies to augment the T-cell response.

Furthermore, available data suggests that the immune system element activation is thus induced by oregovomab administration, where the primary mechanism is its ability to form immune complexes with serum CA-125 that enhances the efficiency of CA-125 uptake by antigen-presenting cells that allows unique presentation of immunogenic peptides via MHC I and MHC II leading to an effective cellular immune response. Suppression of inhibitor T-reg cells by scheduled chemotherapy provides a magnitude of specific anti-CA-125 cytotoxic T-cells that may mount an anti-tumor response, potentially resulting resulting in improvement of clinical outcomes.

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CA-125 (MUC16) is a high molecular weight mucin that is a well-established marker of ovarian cancer. It is shed into the circulation and its measurement has been utilized in disease diagnosis, monitoring and prognosis. ). The induction of tolerance to CA-125 expressing tumor cells by suppression of natural immunity is a hallmark of ovarian cancer and thus any direct or immunomodulatory engagement of CA-125 may disrupt these consequences. There is evidence of a positive correlation between CA-125 serum levels and CA-125 T-cell specific proliferation after oregovomab administration.
The Immune Complexes generation by MAb-B43.13 is unique among immunotherapy agents and may provide a tangible and functional mechanism forCA-125 tumor-specific immune stimulation.
Specific chemotherapy agents have been shown to deplete T-reg cells at the circulating and or tumor infiltrate level and thus inhibit their immunosuppressive influence . A T-cell subset known as T-reg cells can inhibit the response to antigenic stimulation and these appear to be present in ovarian cancer patients.Thus an appropriate chemoimmunotherapeutic combination can create a mechanism to boost the magnitude of immune responses to produce effective clinical tumor cell killing and positive clinical outcomes.

Discussion of Phase-II Proof Of Concept Study

Study QPT-ORE-002 (NCT01616303) was a phase 2, randomized, multi-center study, assessing first-line chemotherapy (carboplatin-paclitaxel) versus combination chemoimmunotherapy (oregovomab + carboplatin-paclitaxel) in 97 patients with advanced epithelial ovarian, adnexal or peritoneal carcinoma following optimal debulking surgery.

Study Design

Study Results

In the above study, Subjects treated with oregovomab + paclitaxel/carboplatin had a clinically significant improved PFS (median 41.8 months) compared to paclitaxel/carboplatin alone (median 12.2 months) by the K-M method (p=0.0027) and a HR=0.44 by multivariate Cox PH method (p=0.0029).

The subjects treated with oregovomab + paclitaxel/carboplatin also had a clinically significant improved OS (median NE) compared to paclitaxel/carboplatin alone (median 43.2 months) by the K-M method (p=0.0042) and a HR=0.34 by the multivariate Cox PH method (p=0.0077), as well as a clinically significant improved time to clinical progression (TTCP) (median 43.1 months) compared to paclitaxel/carboplatin (median 13.6 months) by the K-M method (p=0.0014) and a HR=0.40 by the multivariate Cox PH method (p=0.0019).

Subjects treated with oregovomab + paclitaxel/carboplatin had minimal and low grade additonal adverse event issues as compared to paclitaxel/carboplatin chemotherapy.

Sensitivity analyses using worst-case scenarios and follow-up quality supported the clinical outcome results and demonstrated a lack of systemic bias.

Conclusion

A potential for clinical benefit from the addition of oregovomab treatment to standard-of-care paclitaxel/carboplatin chemotherapy in front-line treatment of patients with Stage III/IV cancer of epithelial ovarian, tubal, or peritoneal origin after optimal debulking surgery, is supported by the magnitude of improvement evidenced by the clinical outcome endpoints in this multicenter study. Oregovomab has a novel immunotherapeutic mechanism of action that in combination with the immunomodulating effects of the standard-of-care chemotherapy has generated evidence that it has the potential to trigger immune response which may substantially improve standard-of-care chemotherapy, with an improved safety profile. It represents a potential advancement in the front-line management of ovarian cancer.

Publications of Results:

Brewer M, Angioli R, Scambia G, Lorusso D, Terranova C, Panici PB, Raspagliesi F, Scollo P, Plotti F, Ferrandina G, Salutari V, Ricci C, Braly P, Holloway R, Method M, Madiyalakan M, Bayever E, Nicodemus C. Front-line chemo-immunotherapy with carboplatin-paclitaxel using oregovomab indirect immunization in advanced ovarian cancer: A randomized phase II study. Gynecol Oncol. 2020 Mar;156(3):523-529. doi: 10.1016/j.ygyno.2019.12.024. Epub 2020 Jan 6.

Battaglia A, Buzzonetti A, Fossati M, Scambia G, Fattorossi A, Madiyalakan MR, Mahnke YD, Nicodemus C. 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. Cancer Immunol Immunother. 2020 Mar;69(3):383-397. doi: 10.1007/s00262-019-02456-z. Epub 2020 Jan 3. Erratum in: Cancer Immunol Immunother. 2020 Jul;69(7):1389.

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