Generex Biotechnology Corp. (fka GNBTQ)

[docj]

Borrowed from an extremely knowledgeable poster from elsewhere:

"This new scientific article about trial design is interesting. It’s authored by researchers that worked with Antigen Express on the prostrate Phase I and in some form with the Phase II for her2 1+, 2+, 3+. In their discussion of the BC Phase II they reiterate what Joe has explained. That’s the fact that Herceptin wasn’t approved for treating 3+ high her2 expressing patients when the study started in 2007. Herceptin is basically a cure so after it was approved it’s not possible to get a greater statistically significant result vs cure. Yet they note the success of AE37 and how better trial design would illustrate this:

Exploring Essential Issues for Improving Therapeutic Cancer Vaccine Trial Design
Constantin N. Baxevanis 1,*, Sotirios P. Fortis 1, Alexandros Ardavanis 2 and Sonia A. Perez 1
1 Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital,
Received: 11 September 2020; Accepted: 9 October 2020; Published: 10 October 2020

“It has to be mentioned that this study (NCT00524277) was started in January 2007, before Trastuzumab had become the standard-of-care adjuvant therapy for HER2-overexpressing patients. Toxicities were in their vast majority of grade 1, with none greater than grade 3. Patients in the vaccine group (AE37/GM-CSF) developed significant AE37-specific IFN? and proliferative responses as well as DTH reactions as compared to the placebo arm (GM-CSF). Aside from the immunological responses, there were no clinical benefits, as there were no significant differences for the entire study population in terms of disease-free survival (DFS) between the vaccine and control arms, and therefore the trial was characterized as negative. However, when patients were subgrouped by clinicopathological parameters, AE37 was associated with improved clinical benefits. This was the case for patient subgroups stratified by stage (advanced; i.e., stage IIb/III), HER2 expression (low expression) or molecular group triple-negative breast cancer (TNBC). The best clinical benefits were obtained in vaccinated advanced-stage/low-HER2 expressors (log rank p = 0.039, HR 0.375) and advanced-TNBC patients (p = 0.078, HR 0.184). We should mention that these results were obtained despite the small number of per treatment patients enrolled (i.e., patients who received all six primary vaccinations), subgrouped into either advanced-stage/low- HER2 expression (n = 78), or advanced-stage/TNBC (n = 18) expression (27.6% and 6.4% of the total per treatment patients, respectively) [24]. Therefore, our study clearly shows that AE37 + GM-CSF may significantly reduce recurrence rates in selected patients, suggesting an appropriate patient population for further clinical development of this vaccine. This AE37 phase II randomized study provides a paradigm by which to clarify that a complete appreciation of therapeutic cancer vaccines can only be achieved when tested in clinical settings that best support their aim—that is, to reinforce the endogenous T cell response against tumor antigens—and should not be expected to achieve clinical results in control groups responding better to a certain standard-of-care. Consequently, the data from the AE37 study suggest that BCa patients with HER2-overexpressing tumors exhibit no clinical responses upon vaccinations, which is very likely given that DFS rates in these patients are very low, reflecting the benefit of adjuvant Trastuzumab therapy. For this reason, these patients are less likely to benefit from the vaccine (although they may respond to it), at least in the time frame of a follow-up predicted for this trial (i.e., five years post enrollment), because the majority of them respond successfully to Trastuzumab, thus obscuring vaccine effects on recurrences and making the standard-of-care one potential reason why the HER2-overexpressing AE37-vaccinated BCa patients failed to demonstrate meaningful clinical benefits in this instancs.”

“Thus, it is conceivable that AE37 vaccinations could prove to be better in the advanced stage, in cases of low-HER2 expression and, in particular, in individuals with the triple-negative subtype of BCa. There are two reasons for this: first, these patients are not eligible for Trastuzumab as a standard-of-care, and thus lack any beneficial effects from this type of passive immunotherapy; second, because they have a higher risk of recurrence within the five years of the trial.”

“ As discussed above, the data from the AE37 phase II trial demonstrated that vaccinating BCa patients in the adjuvant setting can be successful in certain subgroups and can also significantly prevent extended recurrences. In the same study, it was also clear that the Kaplan–Meier survival curves for the vaccine vs. the control groups separated at later time points, which is in line with other immunotherapy trials. This delayed effect is justified by the mechanism of action of cancer vaccines that first need a period to activate the immune system before exerting antitumor effects, followed by clinical responses. Consequently, patients who recur at earlier time points will have high tumor burdens by the time the immune system develops antitumor reactivity, and thus will have less chances to benefit from vaccination. Because of the vaccines’ delayed therapeutic effects when designing vaccine clinical trials, statistical planning should consider that the vaccination protocol may not be capable of preventing early recurrences. Hence, modified statistical models will be required for sample and power calculation to properly and efficiently incorporate the delayed effect in an effort to improve the design of randomized phase II and III clinical trials [42].”

I culled out a few paragraphs. For greater context read the actual article here:

https://res.mdpi.com/d_attachment/cancers/can...-02908.pdf";