I have been struggling how to address this one, ever since Regeneus announced its “approval” to run its RGSH4K trial. To be clear to readers unfamiliar with the circumstances, this is not an approval from the Therapeutic Goods Administration (TGA), this is merely the institutional ethics approval for the clinical site running the study (Regeneus has not sought approval, or notified the TGA). Ethics approval is part-and-parcel of any clinical trial and grown-up companies don’t treat it as anything another than an important step in a process.
To further clarify why the TGA doesn’t appear to have a say in the matter, Regeneus’ formally stated position is that the RGSH4K cancer vaccine is exempted under the TGA’s biologics regulatory framework. This means that Regeneus feels that it doesn’t require any authorisation from a regulatory body to administer its therapeutic to patients. I have previously commented on the TGA’s growing awareness of this issue, and I have also previously commented on my opinion that Regeneus lacks credibility as a company, and especially lacks scientific accountability and rigour. This latest foray in cancer immunology only reinforces my negative stance on this company and in the interest of setting patient expectations appropriately, I am going to tell you why.Firstly, in the case of Regeneus’ assertion that it can conduct this study under a TGA exemption, they are very likely wrong. My assumption is that Regeneus’ position is that their cancer vaccine (stylishly designated as “RGSH4K”) falls under s.4q of the Therapeutic Goods (Excluded Goods) Order No. 1 on the basis that it is an autologous, single-course treatment under the supervision of a medical practitioner (paraphrased). This might be true for other Regeneus programs, but it is not the case here because it is a formulated product that, according to their ANZCTR disclosure, contains the patient’s “tissue”, an immunostimulant and an adjuvant (I will discuss each of these in turn below). Moreover, their clinical trial protocol includes a dose escalation of the immunostimulant to ascertain therapeutic efficacy. Since the use of the adjuvant and the immunostimulant (by the way, I hate that term but it is their term not mine) involves co-administering clinical-grade materials to the patient (but not manufactured by the physician), and are part of the expected mechanism of action, I would strongly argue that this “cocktail” is out of scope under the excluded goods order. That’s not to say that Regeneus can’t do a notified study to the TGA (i.e. under the CTN scheme) but to make the marketing implication (which it does) that it is an exempt product is misleading.
Where is the TGA? I mean, seriously?
Secondly, and before I present my views on the individual components of this “therapy”, I want to make a comment on the ethics review process for this study. I am in no way implying that the medical research institutions involved in the RGSH4K study are unethical, and it is also my view that almost any institutional conflict of interest can be managed via independent review and public disclosure. However, at face value, it is hard to see how the institution that has granted intellectual property rights to a company for a vaccine, and then receives sponsored clinical research (as is at least implied by the Regeneus’ announcements) to conduct clinical studies using that same vaccine, isn’t conflicted. Frankly speaking, until Regeneus clarifies how it has established an independent ethics review process that is not institutionally conflicted, I view the ethics approval for this study as unsound. It may very well be that Regeneus has done everything correctly, but the typical showmanship of their public disclosure process has not demonstrated it, and this concerns me.
Now… onto the therapy itself. Before I do a detailed breakdown, I want to clearly state that – as always with Regeneus – it’s very hard to tell precisely what they are doing. There is only really one credible publication by Chris Weir et. al. in Cancer Immunology Research (full PDF here) and a provisional patent application that seems to roughly align with Regeneus’ ANZCTR description. If my analysis of the components of RGSH4K don’t actually correspond to what Regeneus actually plans to administer to patients, then I am happy to correct this explanation, but obviously if that turns out to be the case they could do a lot better job of describing their technology as well.
Component #1 : The Tumour Lysate
The first thing I want to say, is that we know that murine (rat/mouse) glioblastoma (GBM) models are highly receptive to treatment because they lack the heterogeneity of real-world GBM. Therefore you should always take efficacy claims in “models” with a large pinch of salt. Also, the core idea of RGSH4K, which is to vaccinate the patient with their own tumour cells is far from a new idea. Whole tumour lysates, partial tumour lysates (because we know that apoptotic tissue has (unsurprisingly) better vaccination properties) and pulsed tumour lysates with dendritic cells have been shown to induce an immune response that may be beneficial to patients. However, to date, none of these strategies have yielded a controllable, robust product and there have been enormous number of notable failures using the basic premise of Regeneus’ vaccine strategy.
Let me be clear, this is not a new idea. I’m also not going to address the impact of using excised tissue, the immediate changes in the tumour system biology when it is removed from its environment, or the effect of storing the tissue, etc. I’m not going to insult your intelligence, hopefully you are smart enough to know that beef mince that has been sitting in the freezer for 6 months is not quite the same material as muscle on a cow standing in a sunny field munching clover.
Component #2 : The “Immunostimulant”
Firstly, I want to state up-front, that Regeneus has been blatantly misleading about this component of the vaccine. In its press release it described a proprietary immunostimulant, however in its ANZCTR disclosure it discloses the immunostimulant as being streptavidin. Streptavidin is not a proprietary immunomodulatory molecule, we have known about the immunogenic properties of streptavidin for a couple of decades and streptavidin-biotin interaction has been extensively studied for a wide variety of cancer targeting strategies, including cancers of interest to Regeneus. Also, both the animal publications and the patent strongly imply that the tumour lysate (component #1) is flushed with biotin prior to the addition of streptavidin. This makes a lot of sense, as otherwise the streptavidin has nothing to substantially bind (“glue”) to and it would mostly just clear to the kidneys (though component #3 helps slow this down). It is possible that Regeneus is using a proprietary variant of streptavidin (many researchers have studied ways of changing the immunogenicity of streptavidin) but then this needs to be disclosed in its ANZCTR filing and, if this is the case, then it’s even harder to make the case for an exempt product.
Anyhow, the bottom line is that the immune system doesn’t like streptavidin. When streptavidin binds to tumour proteins and cell lysates (either because of its innate “stickiness” or because the tumour lysate has been flushed with biotin), it definitely causes a directed immune response. Therefore it’s possible that this strategy will induce an immune response. I say “possible” to grant Regeneus some scientific latitude but I don’t really mean it because they don’t have the evidence to really support it. The sort of bizarre thing about this vaccine is that we have so many “immunostimulatory” adjuvants like interleukins, GMCSF, etc. that have been extensively studied in patients – why streptavidin?
Component #3 : The “Adjuvant”
The whole mix is then bundled up with Freund’s Incomplete Adjuvant (FIA). FIA is just an oil emulsion that has two effects. Firstly, it’s a little bit immunostimulatory in its own right (because the body doesn’t really like non-metabolisable oils – a.k.a “mineral oil” – injected into it) and secondly it has formulation benefits that stabilise the whole “cocktail”, which makes it hang-about when it is delivered intra-dermally (though the skin) and prolongs the formation of antibodies against the overall “mix” (which then go and pootle off and program the immune system to its amazing stuff and hopefully cure cancer).
Putting it all together
Basically, in a nutshell, this vaccine involves taking the patients “banked” tumour tissue, blitzing it, probably spinning it down with a centrifuge and taking the “useful” bits, adding a little streptavidin (and possibly some biotin), adding a little Freund’s and voila! None of the individual pieces are proprietary, maybe putting them all together is. I don’t really know but I think that it’s highly unlikely.
But will it work?
Firstly, it is my opinion that Regeneus vastly over-states the efficacy of the dog study. The dog study was poorly controlled, involved a wide range of animals (breeds) and nine different cancers. Also, the dogs included in the study had a very wide range of treatment history and stage of disease. Therefore although it may be possible to characterise an immune response and the formation of antibodies (this is done in the paper) it is not statistically possible to state with any certainty from the animal studies conducted to date, that the vaccine is efficacious. Indeed we know from all the great work being done in checkpoint inhibitors like PD-1 and CTLA-4, that the status of the immune system (i.e. whether it is depleted or not) and the presence of T-cells in the tumour, basically determines the susceptibility of the cancer to an immunomodulatory strategy.
Moreover, the clinical study planned (now “approved”) by Regeneus exhibits a similar lack of robustness. It is basically an open-label, all-comers type of study for patients that have had an incredibly diverse journey in the progression of their disease. I’m not saying that Regeneus’ magic bullet wont yield anything, I am saying that if there is any kind of patient improvement/stability or prolongation of life, it is not going to be possible to state with scientific certainty that it was due to RGSH4K.
My biggest concern is that if there is any kind of immune response whatsoever, a shamelessly self-promoting company (that sails very close to the wind in terms of scientific claims) will call it a preliminary “success”, especially based on the wishy-washy specificity of their ANZCTR disclosure. In my most pessimistic scenario, the result of this study is effectively a dose-escalation of streptavidin, at which a certain dose there are the known clinical symptoms of an immune response. Or that the RGSH4K cocktail causes some chills or skin-lesions or something that is then claimed to be an “immune response”. I can just imagine the press release now : “100% of patients demonstrate an immune response to RGSH4K”. Yuk.
The other issue with this somewhat underwhelming product (and underwhelming clinical study) from a Phase I vantage, is that we know going into the whole exercise that it is very probably going to be 100% safe. The patient isn’t likely to keel over from autologous tumour lysates – that’s a given. We know FIA is harmless because it is a bog-standard part of many vaccines, so nothing new there. We also have a reasonable amount of clinical experience with streptavidin (and its ilk) to know it isn’t going to impart a worrisome safety signal, particularly at the teeny doses that are planned. Of course, Regeneus knows this, and so one can already imagine the stock rocket that will fly when they announce that the primary end-point of the Phase I study, which is safety, was nailed. Double yuk.
So, I stated at the outset, my goal was to shed some light on this program, my concerns, it’s potential limitations and some of the issues around Regeneus’ public communication. My main goal, however, is to inform patients that are thinking about going on this study.
The only really ethical thing about what Regeneus is doing, is that the patients that will participate are end-of-life patients with no other treatment options. They are not being deprived of any other treatment (hopefully they have exhausted all other clinical trial participation options and are not seduced into this study as a viable alternative to a grown-up cancer immunology trial). They will unlikely suffer from receiving the treatment – a very important consideration in terms of quality of life in these patients. And … maybe, just maybe, someone will benefit. The immune system is weird like that.
Would I encourage a loved one to participate in the study? Yes – because when you have metastatic melanoma, or glioblastoma, you should try everything within reason. Even the hope of something happening is a positive thing for a cancer patient.
Do I expect it to work?