Chemo Enhanced Immuno-Therapy

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.

Quest 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. The antibody has undergone the following advanced clinical development:

Conclusions derived from Oregovomab Clinical Trials:

• Benign Safety Profile; Well Tolerated
• Good Quality of Life for patients undergoing therapy
• Relatively unobtrusive administration.
• Novel Mechanism of Action (reprogramming immune response) that targets CA125 tumor marker to elicit T-Cells that attack the cancer
• Importance of Serum CA125 levels were established as the injected antibody complexes with CA125; and the resulting complex improves antigen presentation by dentritic cell
• CA125 and/or Tumor Specific T-Cell induction was associated with survival advantage
• 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
• Oregovomab in combination with front-line chemotherapy can elicit a better immune response as chemotherapy seems to act like an immune stimulatory agent

The observation that front-line carboplatin-paclitaxel administered in combination with Oregovomab immunotherapy results in a more vigorous immune response to the immunization than observed with Oregovomab in the post front-line mono-immunotherapy maintenance setting was counter-intuitive. The common perception that cytotoxic chemotherapy is incompatible with immunotherapy doesn’t seem to apply in this clinical setting. It is to be noted that the observations regarding the relationship of chemotherapy to induce immunity as reported from these studies have been confirmed in other tumor vaccine programs; and there is a growing appreciation in the cancer immunotherapy community that cytotoxic therapy can provide the immune system better access to injured cells and also dampen the immune suppressive pathways that serve to turn off immune reactions. Further analysis of the front-line chemo-oregovomab immunotherapy study (n=40) yielded the following observations:

• Immune responses were stronger relative to those achievable in a mono-immunotherapy protocol
• Carboplatin-Paclitaxel has immune Adjuvant properties when administered concurrently with Oregovomab
• Generation of a specific T-Cell response was associated with a directionally favorable clinical response  
• Preliminary progression free survival (PFS) outcomes favor the simultaneous infusion of Oregovomab and immunotherapy
• Chemo-Immunotherapy with Oregovomab is well tolerated.

 Quest recently acquired Oregovomab and other related antibodies for further clinical development. Based on the clinical experience to date, the Company believes further clinical trials are warranted with Oregovomab in combination with front-line chemotherapy for the treatment of ovarian cancer. Quest is currently seeking strategic partners/investors to demonstrate this counter-intuitive approach of using cytotoxic chemotherapeutic agents to overcome the cancer tumor resistance to immunotherapy. If successful, such an approach could potentially be extended to other cancers such as breast, lung, pancreas, stomach or prostate, etc as Quest already hasin its possession antibodies against MUC1, PSA, CA19.9 and TAG72.

Draft Trial Design of Oregovomab Combination Chemo-Immunotherapy

The company is currently in discussion with collaborating advisors to finalize a definitive Phase IIb trial design that will lead to a Phase III regimen.  A study of approximately 120 stage III/IV ovarian cancer patients is anticipated. The Phase IIb study will evaluate the efficacy of adjuvant OvaRex® MAb administered in combination with current front-line chemotherapy (e.g., carboplatin / paclitaxel) to patients with advanced ovarian cancer (chemo-immunotherapy). The primary objective of this study will be to assess humoral and cellular immune responses of Oregovomab when used as an adjuvant immunotherapy in conjunction with standard chemotherapy in patients with advanced ovarian cancer. Safety and tolerability of the treatment regimens will also be evaluated in all study patients. It is anticipated that the study will enroll 120  patients split into four groups with escalating doses of OvaRex® MAb with the purpose of identifying an optimal regimen for a confirmatory front line Phase III protocol to follow.

Selected Publications:

“The Immune Adjuvant Properties of Front-line Carboplatin-Paclitaxel: A Randomized Phase 2 Study of Alternative Schedules of Intravenous Oregovomab Chemoimmunotherapy in Advanced Ovarian Cancer”  Braly et al, J Immunothr 2009; 32:54-65.

“Oregovomab Maintenance Monoimmunotherapy Does Not Improve Outcomes in Advanced Ovarian Cancer” Berek, et al, J. Clin. Oncol. 2009; 27:418-425

“CA125 velocity at relapse is a highly significant predictor of survival post relapse: results of a 5-year follow-up survey to a randomized placebo-controlled study of maintenance oregovomab immunotherapy in advanced ovarian cancer” Berek, et al, J Immunothr 2008; 31:207-214.

“Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer” Berek, et al, J. Clin. Oncol. 2004; 22:3507-3516