Immunotherapeutic Niches, Competition and Collaboration. Part I: Vaccines.
This is Part 1 of 5 on DCVax and other immunotherapeutic approaches against cancer. Because there are more treatments in various company pipelines than one can shake a stick at, this discussion is limited to most major treatments recognized recently in the Journal of Nero-Oncolgy, plus I am including another group called immunostimulants. I know Pyrr and L. Smith covered much of this territory previously, and my only thought is to simply log this exercise/self-imposed assignment to enhance my own due diligence and perhaps provide yet another reference set of old posts to keep in your personal files.
In all there are 17 therapies that can be broken down into four approaches that treat cancer. The four Immunotherapeutic Approaches herein are:
I. Vaccination,
II. Cellular,
III. Immunomodulation,
IV. Immunostimulants.
This message/post (Part I) will discuss Vaccination Therapeutic Approaches. Each therapy is broken down into three components: Niche, Competition and Collaboration. Below are 4 vaccines presented in this discussion.
A.IMA950 Rindopepimut (EGFRvIII) is a vaccination immunotherapeutic approach using Tumor-specific antigen vaccine (aka: TSA).
B. ICT-107 is a vaccination immunotherapeutic approach using Tumor-associated antigen vaccine (TAA).
C. HSPPC-96 (Aka: Prophage) is a vaccine therapeutic approach using HSP96 vaccine.
D. DCVax-L is a vaccine approach using dendritic cells partially matured and activated outside the body (ex vivo) with whole tumor lysate, interferon gamma plus an attenuated virus.
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A. IMA950 Rindopepimut (EGFRvIII).
(Note: Coincidentally, Celldex came out with updated phase II interim updates this past weekend, 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. "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. EGFRvIII can turn normal cells into malignant cells by way of its oncogenic properties, providing a constant growth signal to tumor cells which express it. Consequently, cells producing EGFRvIII have an enhanced capacity for unregulated growth and are associated with more aggressive disease and worse prognosis."
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 the tumors expressing EGFRvIII are eliminated, Rindopepimut is no longer efficacious against GBM progression.
ii. Potential Competition between DCVax and Rindopepimut.
As some of you already know, the competition between Rindopepimut and DCVax is likely modest at best. Let's take a look at the main scientific reasoning for 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 prolonged 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.
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 antigens). Rather than scientists determining which antigens to target, dendritic cells select abnormal tumor antigens and instruct t and b cells to target those abnormal biomarkers expressed on tumor cells. Moreover, DCVax Dendritic cells are properly matured ex vivo and selected to ensure these DCs have the best chance to do their job correctly and overcome tumor microenvironmnet 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 Celldexs' ongoing phase II open label trial for recurrent GBM patients with EGFRvIII, updated interim improvements are modest. PFS and OS are demonstrating 2-4 month improvement over SOC. Although significant for patients, if these results continue to manifest themselves, 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 discussed previously) will likely shorten the durability of response significantly.
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, we suddenly have a maurine (mouse) trial at our disposal after this past weekend 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 (as cited above) and c. Celldexs' 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.
Conclusion: Rindopepimut’s potential 0 to 25% of GBM market is uncertain until the phase III DCVax-L and Rindopepimut trial results are published. However, because EGFRvIII targeted cancer ultimately escapes with EGFRvIII negative tumor mutation, if Rindopepimut ever made a 1st line therapy for its indication, DCVax would likely be called upon to address the remaining escaped antigens. Potential competition from Rindopepimut is modest at best.
Additionally, while it is too soon to tell, and the UCLA neurology department is not releasing any further news on its recently published abstract of a phase II DCVax-Direct trial confirming effective innate and adaptive tumor targeting, there are many reasons to believe the overall response rate against all GBM patients treated with DCVax-Direct will be higher than the 80% response rate claimed for DCVax-L. Each percent over 80% for Direct likely leaves less therapeutic range and market share for Ridopepimut. Direct results on other cancers recently confirmed it can overcome the immunosuppressive intratumoral and systemic effects presented by the tumor microenvironmnet. It can switch back on the patient’s correct immune system response to diseases like cancer — called the THI response -- while restoring balanced CD4/CD8 ratios, and like DCVax-L, it utilizes all abnormal antigens from the tumor selected and expressed by the dendritic cell.
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 — could prevent further escape because it addresses the remaining/hundreds of tumor antigens. Safety is excellent in both therapies, so that would not likely become a roadblock.
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), and/or clinical practice for successive treatment regimens (aka: 1st and 2nd line therapy). If successful, this might give earlier remission with longer durability in that patient population than was previously achievable.
B. ICT-107
(Coincidentally, like Celldex/Rindopepimut, Immunocellular/ICT-107 came out with a phase II trial update this past weekend. In the case of ICT-107 however, the trial was blinded, and the phase II primary endpoint was already reached.)
i. Potential Niche for ICT-107
Immunocellular owns the right to ICT-107. ICT-107 is an autologous (patient-derived) dendritic cell (DC) vaccine that targets six different antigens (peptides that are tumor markers) associated with glioblastoma multiforme (GBM) or brain cancer: AIM-2, MAGE-1, TRP-2, gp100, HER-2, IL-13Ra2. At least four of these tumor-associated antigens are highly expressed on cancer stem cells (CSCs). ICT-107 is designed for use following surgical tumor resection and in combination with standard treatment with radiation and chemotherapy. In clinical trials, ICT-107 is potentially effective against 30% of the overall GBM tumor population. HLA-A2 positive unmethylated MGMT patients comprise approximately 15-20% of the broad GBM population and HLA-A2 positive methylated MGMT patients comprise approximately 10-15% of the broad GBM population.
Conclusion:
One might be tempted to conclude that HLA-A2 targeting by ICT-107 plus EGFRvIII targeting via Rindpepimut covers up to 55% of tumors within the global GBM population. This is incorrect for at least 3 reasons. 1. HLA-A2 and EGFR-vIII can overlap in tumor patient populations. 2. Tumors expressing both attributes are vulnerable to EGFRvIII peptide treatment. 3. Only a subset of the HLA-A2 population demonstrates clinically remarkable efficacy, and this subset only constitutes 10-15% of the GBM population. Also, as with Rindopepimut, ICT-107's niche is predominantly transient due to tumor escape — although complete remission/cure has been achieved in a very small patient population. (Notice tumor escape appears more difficult when more antigens are targeted by the therapeutic vaccine. ICT-107 targets 6 antigens, but Rindopepimut only targets one antigen.)
ii. Potential competition between DCVax and ICT-107.
With the latest results from the phase 2 ICT-107, it is quite clear that patients with HLA-A2 positive methylated tumor expression can achieve impressive PFS survival — 15+ months beyond standard of care. OS survival has not matured yet, but they are likely to demonstrate equally striking results. However, this patient population only amounts to 10-15% of the GBM population. An encouraging finding is that the more a tumor expresses this antigen, the longer people stay in remission. This confirms not only a qualitative confirmation for immunotherapy, but an additional quantitative relationship as well.
There does not appear to be any current literature discussing any possible efficacy data relating to DCVax therapeutic response upon HLA-A2 tumors positive methylated MGMT, but theoretically, DCVax also targets the abnormal biomarkers associated with this mutation. Once again, one hopes that the DCvax-L phase III trial will test and report any and all HLA-A2 tumors both positive and negative MGMT. Regardless, ICT-107 can only encroach upon (at most) 10-15% of DCVax bandwidth restricted to Glioblastoma. If one takes into account Rindopepimut, their combined market share is not likely to exceed 30% of the GBM market and DCVax is likely to be utilized at some point in the treatment regimen for this subclass.
Importantly, neither Rindopepimut nor ICT-107 are targeted toward other glioma types/grades. NWBO technology can be used against all glioma types, and all solid tumors.
iii. Potential Collaboration between DCVax and ICT-107.
Unlike Rindopepimut, there may be more concern in directly combining DCVax and ICT-107 during the same vaccination. Tolerance from excessive dosage can occur when too many dendritic cells are administered to a patient. It may be difficult, especially in the very carefully dosed and timed DCVax-Direct, to incorporate ICT-107. 1st and second line therapy successive treatment may prove more valuable.
C. Prophage Series G-100
i. Potential Niche for Prophage series G-100
Agenus own the rights to Prophage series G-100. Prophage is a protein peptide complex consisting of a 96 kDa heat shock protein (Hsp), gp96, and an array of gp96-associated cellular peptides. The response to Prophage seems to be more pronounced in those patients with less expression of the checkpoint ligand PDL-1 on the white blood cells, suggesting that combinations of Prophage with checkpoint modulators like PD-antagonists might make Prophage even more effective in a greater percentage of patients with GBM.
PDL-1 is expressed in approximately 25% of the GBM patient population.
Conclusion:
Theoretically, Prophage vaccines can target all cancers, however, no approved products are on the near horizon. Prophage is also currently being studied against melanoma in a phase I trial. Consequently Prophage's only niche appears to target GBM perhaps with some focus on tumors not expressing PD-L1.
ii. Potential Competition.
Unlike the previous two therapies discussed, prophage is not designed to target any preset tumor antigen(s). Instead, the proprietary process selects specific antigens in a patient’s specific tumor(s) increase expression when cells are exposed to elevated temperatures or other stresses.
This process ultimately uses more antigens Rindpopepimut and ICT-107, and is personalized personalized to the particular patient’s tumor(s); however, unlike DCVAX, Prophage does not use all the antigens from the tumor, and the personalized selection/activation process is not accomplished by the dendritic cell, instead the antigens are selected by through a man made proprietary process.
The results in the July phase II open label trial demonstrated 9 month overall survival advantage over historical controls, and PFS surpassed historical comparisons by 10 months. (Notice, again, as we move up the chain from 1, 6 and now many tumor antigens the overall results and durability improve). Pragmatically, it is hard to imagine that Prophage will perform at this level in a phase III controlled trial. Moreover, DCVax-L (which utilizes all the tumor antigens) Phase 2 trials results demonstrated 21 months OS against the same historical control in their phase II trial, and PFS surpassed the above historical comparison by 17 months. (Notice DC-Vax uses all the antigens and returns selection control and expression to the dendritic cell
A phase III GBM trial has not been initiated Prophage.
While this therapy actually offers a more straight forward head to head comparison, it appears DCVax-L is superior.
iii. Potential Collaboration
IMHO, the two antigen targeting selection processes are incompatible.
