Celldex huh?
A. IMA950 Rindopepimut (EGFRvIII).
Coincidentally, Celldex came out with updated phase II interim updates November 13-16, 2014, and from reading through the message board and Smith on Stocks, there is already a great deal of understanding regarding any potential ramifications.
i. Potential Niche for Rindopepimut.
Rindopepimut is owned by Celldex Therapeutics. It uses a peptide vaccine to target one particular antigen found on some tumors -- EGFRvIII. EGFRvIII is expressed in tumors in about 20-25% of glioblastoma patients. J Neurooncol. 2006 Jan;76(1):23-30. EGFRvIII is a functional and constantly activated mutation of the epidermal growth factor receptor EGFR, a protein that contributes to cell growth and has been well validated as a target for cancer therapy. Cells expressing the EFGRvIII mutation are constantly signaled to divide, resulting in very aggressive tumors and a poor prognosis.
On their website, Celldex Therapeutics states, "Unlike EGFR variant, EGFRvIII has not been detected at a significant level in normal tissues, but it has been identified in glioblastoma; therefore, targeting this tumor-specific molecule is not likely to impact healthy tissues.” That is in theory, in practice, Celldex’s Rindopepimut therapy already logged a “potentially related” severe case of cerebral edema in a 42 patient compassionate use study -- according to an abstract in the Journal of Neuro-Oncology. (2014) 16 (suppl 5):v115-v116.
Conclusion:
Glioblastoma patients that have tumors expressing this particular antigen present the potential therapeutic niche for Rindopepimut. If this therapy were to become first line standard of care for patients with both newly diagnosed and recurrent GBM expressing the EGFRvIII antigen, it would encompass 20-25% of the total GBM patient population. However, as discussed below, this percentage is actually illusory when considering competition, because once tumors expressing EGFRvIII are eliminated, Rindopepimut is no longer efficacious against GBM progression.
ii. Potential Competition between DCVax and Rindopepimut.
As some people already know, the competition between Rindopepimut and DCVax is likely modest at best. Let's take a look at the main scientific reasoning behind this. In addition to tumor EGFRvIII expression being limited to about 20-25% of the GBM population, a major problem with EGFRvIII targeting is immunologic escape after progression-free survival with epidermal growth factor receptor variant III (EGFRvIII) peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28(31): 4722–4729.
In other words, tumor cells express hundreds of antigens, and even within the patients whose tumors express EGFRvIII, there are other tumor cells that do not. Once a tumor specific antigen therapy like Rindopepimut eliminates the EGFRvIII antigen it is targeting, tumor cells not expressing that mutation rapidly increase and subsequently the cancer returns. Moreover, as time passes, more mutations arise due to the accelerated mutation rate in malignant cells. Consequently, the problem with tumor specific antigen therapies is that cancer inevitably escapes.
DCVax, on the other hand, uses all the antigens from the tumors in the body. DCVax theoretically additionally targets tumors that express EGFRvIII biomarkers (in addition to hundreds of other tumor expressed antigens). Rather than scientists determining which antigens to target, the body’s own personalized dendritic cells uptake abnormal tumor antigens, migrate to nearby lymph nodes and instruct t and b cells to target those abnormal biomarkers expressed on those tumor cells. DCVax Dendritic cells are properly matured ex vivo and selected to ensure the patient's DCs have the best chance to do their job correctly and overcome tumor induced immune suppression. DCVax dendritic cells are also preactivated with attenuated bovine tuberculosis bacillus and interferon gamma; because dendritic cells uptake and express attenuated virus fragments prior to in vivo administration, the attenuated virus itself is not injected into patients. Still, the inclusion of dendritic cells expressing these particular viral fragments assists in initiating an extremely reliable immune response.
Rindopepimut was only tested on patients with EGFRvIII specific tumor expression, which again, only accounts for 20-25% of the global GBM patient population. In Celldex's ongoing phase II open label trial for recurrent GBM patients with EGFRvIII, updated interim result improvements, while better than standard of care, are modest. PFS and OS are demonstrating 2-4 month improvement over SOC. Although significant for patients, if these results continue to manifest themselves in this manner, it is at best an incremental advancement. Three phase II Rindopepimut trials on newly diagnosed GBM with EGFRvIII resulted in 5-7 months OS advantage over historical/contemporary controls. A larger ongoing 700 patient phase III Rindopepimut trial in newly diagnosed GBM patients expressing EGFRvIII tumors is expected to demonstrate efficacy; however, tumor escape (as noted previously) will likely shorten the durability of response significantly. The primary results for Celldex’s phase III trial in newly diagnosed GBM patients are not due until late 2016 or early 2017.
So what do we know about DCVax efficacy in the EGFR variant tumors, and more specifically, in the EGFRvIII expressing tumors? Remarkably, serendipitously and somewhat curiously, as of November 13-16, 2014, we now have a maurine (mouse) trial at our disposal that resulted in poorer response against EGFRvIII tumors than the remaining tumor types when treated with either 1. DCVax(L?) 2. Novolomib and 3. DCVax(L?) with Novolomib. No one else, from my humble review of the literature, has delved into whole tumor lysate pulsed dendritic cells' effect upon EGFRvIII tumors, but I suspect the phase III DCVax trial results will include pathology data regarding EGFRvIII. Upshot? I would not place too much stock in said ‘well timed’ maurine study without further confirmation.
In my opinion, a. due to the realization that the DCVax-L trial will likely provide EGFRvIII data and b. due to the fact that soley EGFRvIII targeted tumors ultimately escape Rindopepimut therapy once this mutation is eliminated and c. Celldex's sudden rush to move forward phase II open label results for FDA approval based upon otherwise premature incremental results from a small study, Celldex is concerned, and should be.
While this article focuses on the biological aspects for treatment, it should also be noted that Northwest Biotherapeutics already has FDA and German (PEI) manufacturing approvals. NWBO is already commercially producing DCVax-L for patients in Germany, it received unprecedented regulatory designations in Great Britain and Germany, it developed a patented manufacturing process to lower therapeutic costs for patients, and NWBO is years ahead of competitors regarding European regulatory product advancement. In Newly Diagnosed GBM, NWBO is at least one full year ahead of Celldex in their phase III trials, and Celldex is potentially two to three years behind NWBO in regulatory progress within Europe.
EGFRvIII is found in many other types of solid tumor cancers; but to date, I am not aware that Celldex is initiating additional trials.
Conclusion: Rindopepimut’s potential 0 to 25% of GBM market is uncertain until the phase III DCVax-L and Rindopepimut trial results in newly diagnosed GBM patients are published. Potential competition from Rindopepimut is modest at best.
There are many reasons to believe the overall response rate against all GBM patients eventually treated with DCVax-Direct will be higher than the 80% response rate reported for DCVax-L. Each percent over 80% for Direct likely leaves less therapeutic range and market share for Rindopepimut. Recently, DCVax-Direct results in other cancer types confirmed it can overcome the local and systemic immunosuppressive effects presented by cancerous tumors. It can switch back on the patient’s correct immune system response to intracellular diseases like cancer — called the THI response -- while restoring balanced CD4/CD8 ratios, and like DCVax-L, it utilizes all abnormal antigens from tumors that are selected, engulfed and thereafter potently expressed by dendritic cells to T and B cells within the lymph nodes.
iii. Potential Collaboration between DCVax and Rindopepimut.
Could Celldex and NWBO form a cocktail to treat patients with EGFRvIII tumors? While GBM ultimately escapes the attack on EGFRvIII by Rindopepimut via loss/termination of this particular mutation, DCVax — especially in the case of DCVax Direct — would most likely prevent further escape because it addresses the remaining/hundreds of tumor antigens that would remain unaddressed by Rindopepimut. Despite a serious event of cerebral edema in a 42 patient compassionate use study possibly related to Rindopepimut therapy, overall safety appears excellent in both therapies.
Conclusion: Potential Collaboration by combining the two treatments is theoretically plausible (in the EGFRvIII tumor expressing population) and may only be ruled out (or ruled in) through additional formal studies for combination therapy (aka: cocktails). If successful, this might provide earlier remission with longer durability in that patient population than was previously achievable.
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