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Products Under Development * Oregovomab

OREGOVOMAB: An Immunotherapeutic Approach for the Treatment of Advanced Ovarian Cancer

Ovarian cancer is the most common cause of gynecologic cancer deaths in the United States. Cytotoxic therapy produces high initial response rates; however, a recent intergroup study involving more than 4,000 patients was unable to improve progression–free or overall survival in any of the 4 experimental combinations that added a third drug with documented single agent activity to standard front-line treatment. Improvement in primary treatment outcomes may require a novel therapeutic strategy such as the integration of a biologic agent.

OncoQuest is developing the high affinity monoclonal antibody Oregovomab (MAb B43.13) for the treatment of ovarian cancer. Oregovomab targets the circulating tumour-associated antigen CA125, which is shed from the surface of human epithelial ovarian cancer cells; the antibodies induce broad cellular and humoral immune responses against CA125 via complex formation. Unlike free CA125, CA125-MAb B43.13 complexes can prime dendritic cells, leading to downstream activation of T-Cells. More than 950 ovarian cancer patients has been treated with oregovomab in a number of clinical trials at various stages of the disease.

Conclusions derived from Oregovomab Clinical Trials:

  1. Benign Safety Profile; Well Tolerated
  2. Good Quality of Life for patients undergoing therapy
  3. Relatively unobtrusive administration.
  4. Novel Mechanism of Action (reprogramming immune response) that targets CA125 tumor marker to elicit T-Cells that attack the cancer
  5. Importance of Serum CA125 levels were established as the injected antibody complexes with CA125; and the resulting complex improves antigen presentation by dendritic cell
  6. CA125 and/or Tumor Specific T-Cell induction was associated with survival advantage
  7. Oregovomab treatment alone is not enough to drive an anti-cancer response in late stage ovarian cancer patients who are in the remission stage of the disease following exhaustive chemotherapy and with low levels of serum CA125
  8. Oregovomab in combination with front-line chemotherapy can elicit a better immune response as chemotherapy seems to act like an immune stimulatory agent

Earlier attempts to engage the immune system with oregovomab in ovarian cancer patients was successful in generating B-cell and specific T-cell responses in combination settings but insufficient specific immune response was produced in the mono-immunotherapy clinical trials conducted in the maintenance period following front line chemotherapy. Clinical trials looking at the time to relapse (progression free interval) failed to demonstrate a treatment effect for this application, although long term survival outcomes were not obtained. In contrast, two clinical trials conducted in the front line and recurrent settings in which tumor antigen was at higher levels and cytotoxic compounds were also administered demonstrated stronger cellular and humoral immune responses. Furthermore evidence regarding dose schedule and choice of cytotoxic agent has been generated, and preclinical combination chemo-enhanced immunotherapy studies confirmed the human findings in transgenic murine and human in vitro model systems. These studies have demonstrated that generation of a tumor-antigen specific CD8 IFN-gamma T-cell response (as performed in the laboratory of Whiteside/Butterfield, University of Pittsburgh) is associated with significantly improved clinical outcomes in terms of progression free and overall survival. Two reports have been published by OncoQuest investigators detailing these findings in the front line (Braly et al., J Immunother 2009) and also in second-line recurrent disease settings (Gordon et al., Gyn Oncol 2004). Preclinical studies done in a MUC1 transfectoma mouse model indicate a combination of anti-MUC1 antibody, AR20.5, in combination with gemcitabine can indeed enhance immune response and survival (Hollingsworth, personal communication). Thus in both MUC1 and CA125 associated malignancy, the OncoQuest antibody technology when used in combinatorial settings and with available tumor antigen has the capacity to significantly enhance specific tumor immunity. Furthermore, recent insights into the use of additional non-specific immune modulatory approaches (such as TLR agonists) may further enhance this biological effect (Nicodemus et al., Am J Obstet Gynecol 2010). This biological outcome has been correlated with clinical benefit in recently approved immunotherapy products.

Current Clinical Strategy

OncoQuest’s combinatorial immunotherapeutic approach for the treatment of cancer includes three carefully planned proof-of-concept clinical trials to establish the superiority of the combinatorial immunotherapy either with front-line chemotherapy consisting of carboplatin/paclitaxel in ovarian cancer or gemcitabine in pancreatic cancer. The program will also clinically evaluate addition of a TLR3 agonist, Hiltonol, to the immunization. The successful results from these studies will lead to the design of a definitive product registration study. If access to a clinical grade PD-1 antagonist can be identified a clinical pilot assessing that combination would also be a strategic activity. Preclinical studies evaluating the interaction of OncoQuest’s immune stimulating antibodies and PD-1 are ongoing.

The studies are

  1. An 80 patient multicenter Italian cooperative trial to establish evidence for the clinical benefit associated with enhanced specific T cell immunity achievable by combining Oregovomab with carboplatin and paclitaxel in the initial treatment of advanced ovarian cancer (front-line).
  2. A Phase II clinical trial to evaluate the ability of a TLR-3 agonist (Hiltonol, Nicodemus et al 2010) to enhance the strength of the Oregovomab immune response generated in advanced ovarian cancer patients in combination with chemotherapy in both the front-line setting (to be conducted in Italy) and in the recurrent disease setting (to be conducted in US).
  3. A Phase II U.S. trial will use gemcitabine, another cytotoxic agent, in a cohort of patients with CA125 associated resectable pancreatic cancer.
  4. One of the endpoints in all three clinical trials will be the induction of CA125 specific T cells as measured by a well validated ELISPOT assay. CA125 specific T cell induction has been correlated with progression free survival and overall survival in our previous 40 patient Oregovomab combination therapy clinical trial. In addition, these three trials will verify safety, tolerability, disease free survival and overall survival.

Oregovomab Prior Clinical Development Experience

Oregovomab Prior Clinical Development Experience