OncoVAX immunotherapy is a patient-specific (personalized) vaccine composed of irradiated, but metabolically-active, autologous tumor cells compounded with TICE® BCG, a live, attenuated mycobacteria which serves as a potent adjuvant. Using a proprietary method for dissociating and purifying cancer cells from a resected tumor, this autologous vaccine induces a robust and functional immune response. By using the entire tumor and relying on the immune system to determine which epitopes are unique, the vaccine provides a treatment in which no preconception of "known" or shared tumor antigens is needed. However, a series of steps were required to bring this treatment from proof of concept to therapeutic reality.
The first randomized, multicenter, Phase III clinical trial [46
] for OncoVAX was attempted in stage I/II/III colon cancer patients under the auspices of the Eastern Cooperative Oncology Group (ECOG). While the final results showed no significant clinical benefit, this study was instructive for a number of reasons.
First, vaccine preparation was accomplished in a decentralized fashion, with each clinical site manufacturing the autologous vaccine in their respective pathology departments. Due to the logistical realities of OncoVAX preparation, this study clearly demonstrated the requirement for a central manufacturing facility to assure adequate quality control (QC) and quality assurance (QA), providing a more standardized approach to vaccine production. Additionally, this oversight needed to extend from the primary facility to the clinical sites where the final vaccine was compounded with TICE® BCG. Secondly, based on the results in the guinea pig model, the treatment protocol for this study only involved three intradermal vaccine injections, delivered each week beginning 28 to 35 days after tumor resection. The first two injections were compounded with TICE® BCG while the third vaccination was comprised autologous tumor cells alone. The final injection without adjuvant is critical for monitoring whether the immune system has been trained to react to cells previously defined as “self.” Active and potent immune responses toward these cells manifest as a DTH reaction visible at the site of injection (Figure 6). This visible response is still the best in vivo
indication of T-cell specificity and activity. Indurations greater than 5 mm are considered a significant indication of a specific T-cell response. Additionally, this reaction serves as proof of concept that with prior adjuvant stimulation the immune system has been trained to recognize these cells, and hopefully any MRD remaining after surgery. Not surprisingly, induration size correlates well with patient outcome (Figure 6).
Lessons learned from the previous study were incorporated into the next Phase III clinical trial (8701). This study [47
] utilized a centralized manufacturing facility to address the QC and QA issues encountered in the previous trial. This required processing to occur within a reasonable geographical area, consequently, production was centralized at the Free University in The Netherlands, a reasonable distance from the 12 Dutch hospitals participating in the trial. Additionally, pathologists participating in the study needed to modify their standard sampling procedures to provide maximum tumor material for vaccine production while allowing for adequate diagnosing and staging. Following resection and staging, tumor samples were sent to the production facility for dissociation, cryopreservation, irradiation, and administration. The treatment protocol was also augmented to include a four vaccine regimen: three initial weekly treatments (two with TICE® BCG, one without) and a six-month follow-up booster inoculation.
The follow-up booster was added based on the results of a side Phase II trial [48
] that suggested initial immune responses begin to wane 6 months after the induction vaccinations (Figure 7). However, due to the addition of a fourth inoculation, larger tumors were required for sufficient vaccine production. With a minimum requirement of 3-3.5 grams of tumor, this trial was logistically limited to stage II/III patients. An additional study change involved stratifying patient randomization by tumor stage to power for a prospective analysis.
Subjects randomized to the control group (n=126) received no further treatment after surgical resection and were followed according to scheduled assessments. For subjects randomized to OncoVAX (n=128), patients received the four vaccine program outlined above. OncoVAX was well-tolerated, with 102 of 128 patients receiving all four vaccinations. To determine the extent of DTH reactivity, injection sites were measured for indurations 48 hours after the third and fourth immunizations. Subjects were defined has having achieved cellular immunity if the average of both measurements were greater than 5 mm. By this criterion, 97% of patients achieved effective cellular immunity after the fourth inoculation.
When patient response in the OncoVAX cohort was determined during follow-up, in an Intent-to-treat analysis, no statistically significant differences in recurrence free survival (RFS), overall survival, or recurrence-free intervals (RFI) were observed. However, when a prospective analysis of patients was analyzed by stage, subjects with stage II disease had clinically meaningful and statistically significant outcomes in both RFI and RFS. Both five-year event-free rates and log rank rates were improved with OncoVAX treatment in stage II patients (Figures 8 and 9). The favorable 16.4% difference between control and OncoVAX patients represents a 41.4% relative risk reduction of disease progression (5-year survival p=0.008; log-rank analysis p=0.018). Overall survival (Figure 10) showed a statistically significant improvement in stage II OncoVAX treated patients (17.5%) over those patients in the control group (27.3%). The favourable 9.8% difference represents a 33.3% relative risk reduction (5-year survival p=0.014; log rank analysis p=0.074).
In the intent-to-treat (ITT) population of all randomized stage II patients, there were 43 recurrences. The five-year recurrence free interval p-value (0.01) and the log rank analysis p-value (0.004) was highly significant, it was discovered in referee pathology diagnosis that this included a proportion of B1 patients (9 control and 4 treated patients). These were excluded in the separate Stage II (B2, B3) analysis, the control and OncoVAX treatment groups, respectively. When compared to the control group, the favorable 16% difference represents a 57.1% relative risk reduction in the recurrence of colon cancer in the OncoVAX group (five year survival p=0.026; log-rank analysis p=0.008).
Trends towards efficacy in overall survival was not statistically significant in the full intent-to-treat population. A pre-specified stratification of the trial to analyze by tumor stage demonstrated that Stage II patients separately reached statistical significance with a p value of 0.014 on a five year analysis.
Since this study was completed, surgical techniques associated with colon cancer treatment have greatly improved. Minimally invasive laparoscopic surgery has become more feasible than open colectomy, especially for patients without locally advanced disease. However, a recent multi-institutional study of 872 patients compared these surgical techniques and determined that while patients preferred the minimally invasive option, time to tumor recurrence was still equivalent after a median follow-up of 4.4 years [49
]. These results have also been confirmed in T3 and T4A & B colon adenocarcinoma patients [50
]. Thus, the recurrence-free interval curve in the surgical resection only control group is still valid today.
A more recent study by de Weger, et al. [51
] updated 8701 patient results with 15-year follow-up data. The event-free survival data are presented as a Kaplan-Meier plot in (Figure 11) for the original study (all 254 patients). OncoVAX patients still demonstrated improved survival compared to surgical patients alone at 15 year follow-up [HR=0.62 (95% CI: 0.40-0.96), p=0.033]. Using formalin-fixed paraffin embedded blocks from 196 of these patients, the authors also determined OncoVAX treatment was particularly effective for patients with microsatellite instability and microsatellite stable Dukes B tumors. The long-term, stable results observed with OncoVAX treatment can only be achieved with a robust immune response employing long-term immunological memory and surveillance. All of these aspects are essential prerequisites for successful and impactful cancer treatment.
Safety was comparable in the OncoVAX treatment cohort compared to surgery alone. One patient treated with OncoVAX was hospitalized for treatment of a flu-like syndrome and the event resolved nine days later. Another patient required discontinuation of OncoVAX treatment due to a 21 x 32 mm ulceration which developed after the second inoculation (BCG had been omitted due to adverse events after the first inoculation). However, as a group, control patients more commonly experienced non-fatal serious adverse events. Thirty-three patients in the OncoVAX group (25.8%) and 46 patients in the control group (36.5%) experienced at least one non-fatal serious adverse event. Taken together, stage II colon cancer patients had fewer non-fatal serious events and improved recurrence-free and overall survival.
In the adjuvant setting, effective treatments are lacking for stage II colon cancer patients. To address this need, the FDA has requested a second, confirmatory, randomized controlled Phase III trial of OncoVAX in stage II colon cancer patients. Based on a protocol approved by the FDA, this study will be carried out under a Special Protocol Assessment (SPA). An SPA granted by the FDA provides a mechanism for the sponsors and the FDA to reach agreement on size, execution, and analysis of a clinical trial that is intended to form the primary basis for regulatory approval.
The primary endpoint of this pivotal Phase III trial is RFS with an interim and final primary analysis with one and three years follow-up, respectively. The study is powered to detect a 50% improvement in RFS with 90% certainty. If a robust statistical significance is achieved during the interim analysis (median follow up of 1.5 years or 70% of the expected events), the Biologic License Application (BLA) can be filed. Past clinical trials using the optimum four immunization regimen (8701) will be accepted as supportive studies during the FDA review of the BLA. This critical and careful approach to the clinical development of OncoVAX should allow for approval in stage II colon cancer patients, which remains a population of true “unmet medical need.”