I wrote a few weeks ago about a firm called RGCC or Research Genetic Cancer Center, which sells what I see as an unproven RNA therapy to clinics throughout the US. The approach is called supportive oligonucleotide therapy or SOT. After buying it from RGCC, the clinics then sell SOT injections for Lyme disease, other infections, and cancer.
I wrote about my many concerns about SOT and the lack of rigorous clinical trial research backing it up. My overall SOT or supportive oligonucleotide therapy review was skeptical and noted serious potential risks.
In researching SOT, I also found another concerning situation. Some clinics market unproven cell therapies reportedly made by RGCC too. Some of these raise potentially serious risks. They even may relate to iPS cells, which (themselves and their differentiated progeny) should only be studied in rigorous clinical trials at this point. Not sold and injected into people.
Someday I hope that iPSC-based therapies that are safe and effective will be available for patients. That time has no yet come though.
Let’s carefully go through this troubling situation with RGCC cell therapies marketed on clinic websites.
US clinics also market unproven cell therapy from RGCC: VAXO-Q-RE?
There are multiple kinds of unproven cell therapies at these clinics.
For example, some clinics that are marketing SOT also seem to sell an unproven cell therapy product called VAXO-Q-RE from RGCC. Here’s a Florida alternative medicine site selling VAXO-Q-RE. The marketing suggests to me the strong possibility that this might be an unapproved cellular drug within the scope of the US:
“VAXO-Q-RE is a product that is developed for autologous Adoptive Cellular Therapy. It consists of the basic players of innate and adaptive immunity. Briefly, macrophages and Natural Killer cells (innate immune cells) and activated Dendritic Cells, T cells and antibody producing plasma cells (adaptive immune cells).”
and
“RGCCs laboratories use patients’ isolated peripheral blood mononuclear cells as a source for the in vitro production of VAXO-Q-RE. Macrophages and Natural Killer cells are selected and expanded in large numbers. Monocytes are used as a source for the production of DCs. DCs are then pulsed with synthesized peptides designed specifically to mount an immune response against tumor proteins. These peptides are selected carefully so as to activate both T
lymphocytes (CTLs) as well as antibody producing cells aiming at long term memory cells and overall protection. VAXO-Q-RE is composed of 2 doses, with one dose containing innate immune cells (macrophages and Natural Killer cells) and a second dose containing adaptive immune cells (CTLs and antibody producing cells)”
I see no indication of FDA approval for this.
Possible VAXO-Q-RE risks
Such a combination immune cell therapy would have many potential risks. For example, I believe these activated immune cells could lead to healthy tissue damage.
This kind of product also would need rigorous clinical trial testing in my view prior to marketing. Have there been strong clinical trials done on the VAXO-Q-RE? A Clinicaltrials.gov search found no trial results for VAXO-Q-Re. Are there results of strong trials in other databases? As an update, on Facebook RGCC said they started a trial in India on VAXO-Q-RE, but searching every month of 2023 (the Indian database requires listing the month) for VAXO-Q-RE, I got no results for trial listings. Admittedly, I’m not an expert on using the India clinical trial search database so I could have missed something. It also doesn’t allow for searching by sponsor name or other things like Clinicaltrials.gov does.
I did find a PDF from RGCC on VAXO-Q-RE on a Colorado integrative medicine clinic website. It cited one paper: Adoptive transfer of activated immune cells against solid tumors: A preliminary study.
As with the two papers on RGCC’s SOT approaches, here again we see the word “preliminary,” yet the products are already apparently in use in patients in the US?
A simple Google search for VAXO-Q-RE found many American clinics marketing it, which raises risks in my view.
Also some product related to iPSCs?
“RGCC guarantees the cells have had no genetic (DNA) tampering whatsoever and will have a document of sterility accompany each sample. RGCC are hopeful we’ll also be given the actual number of iPSC’s received for each person. CD34 cells (AKA induced pluripotent stem cells- iPSCs) are hematopoietic stem cells. Their role is to give rise to other blood cell types. They are normally found in the bone marrow of (pelvis, femur, sternum), umbilical cord blood and peripheral blood…(CD34 cells) AKA iPSC’s have no anticancer effects. However, in many studies they have been used in combination with chemo (Mega Therapy) or as an adjuvant arm in immunotherapy. Their use is to replace damaged tissue.”
What are the “many studies”? What is the evidence that RGCC iPSC (CD34) can replace damaged tissue? So far I haven’t found clear evidence.
There could be serious safety concerns too if iPSCs are involved somehow and are not entirely absent from the final product that is injected. For instance, one might worry about teratoma development.
FDA issues?
There is also some confusing regulatory type language included on that clinic’s page on these “iPSC” cells.
On the one hand it says they are a biological drug (which would require FDA pre-market approval). However, then it says they would be regulated as a 361 product, a category which includes biologics that are generally not drugs, and the page argues pre-market approval is not needed.
These are conflicting statements and very unclear.
As I said earlier, it seems at least possible to me that VAXO-Q-RE may be a biological drug too.
SOT and unproven cell therapies
Overall, while not apparently as widespread as SOT use in the U.S., the marketing of these unproven cell therapies here raise serious questions too.
I see them as potentially highly risky.
Will the FDA at least look into this situation? So far, I have not seen any indication that the FDA has done anything about supportive oligonucleotide therapy or SOT.
There have been suggestions that European regulators such as in Poland may have already taken some steps related to SOT. Hopefully we can learn more concretely about that soon.
References
- Colorado clinic menu of RGCC cell therapy and other offerings
- PDF from RGCC on VAXO-Q-RE
- PubMed search finding no results on VAXO-Q-RE
- Clinicaltrials.gov search finding no results on on VAXO-Q-RE.
Dear prof. Dr. Knoepfler,
I do wonder why you ignore or you choose to ignore many ICH-GCP rules that also apply in the US. But again, these rules and requirements are familiar with clinicians and not scientists that are working in basic research like you. Can you please let us know how closely you are involved in clinical research or trials? That may give us a very good inside.
Coming back to your comments, it is obvious that you try to skip taking position on actual point and you try to raised others as you see them fit.
To be precise, again you are confusing and mixing even more of what is considered as drug and what is considered as biological product that is no or minimal manipulated. Either way it is obvious that your goal is not to find what is actually happened but you try to justify your already predefined false opinion.
The text that you are referring to is an old version that is referred to the actual study performed to demonstrate the efficacy of RNAi in patients, using specific molecules (siRNA) and not to the clinical originated that is used under autologous mode (microRNAs).
Also, I repeat that we cannot be responsible what the clinics and doctors promote as material. They should be updated and accurate but we know that is not always happened, it is not possible to control all the web.
Additionally, it clearly stated that the iPSCs are haemopoietic CD34+ve cells hence you as expert in the field you should not confuse them with pluripotent stems cells or embryonic stems cells. But according to your text it is obvious that you do.
Then it is obvious that you are not familiar with what MRA stand for and that is a part between ICH-GCP consortium between countries. You bring examples of drugs but not of biological products for autologous use which they have not altered their biological purpose (this is the definition of minimal manipulation). So, as you realize this is misleading information that you wrote in your text and I am assuming that this was written by mistake and not for any other reason.
But nevertheless, that verifies the original statement that it is disappointing when anyone from an academic environment makes subjective assessment and claims. We expect to raise the new scientist under the spirit of objective mentality and not develop a predefines opinion and we try to support it irrelevant to the evidence. Ideally Universities is the environment where the new ideas are freely expressed and objectively assessed for their validity. But as it seems this is not true for all universities.
The other issue is that even if you only isolate RNA from a patient’s blood and then give that RNA back to the patient, in that context in the US, the RNA is still likely to be considered a drug. For instance, it’s not clear that the FDA’s minimal manipulation standards even apply to RNA isolated from blood or blood cells.
Dear prof. Dr. Knoepfler,
Ι came across the article you posted on “The Nice” blog regarding our services in RGCC and I have to admit that your statements were quite a shock.
If you recall our email conversation, I wrote to you that what you read in the article is not what the individuals received since the preparations are considered as microRNA isolates from a blood sample which is minimally manipulated. (It is micro-RNA and not mRNA as you state in your X/former Twitter statement). Then I indicated / pointed out that these have fallen to the EMA regulation 1394 of 2007 which is regulated from the directive 2004/23/EC of the European Parliament.
Besides that, obviously you ignore that since 2017 there is an MRA between FDA, EMA, Swissmedic and the relevant authority in Canada.
Additionally, the US FDA has a similar regulation called 21 CFR 1271, and specifically part 361 which is under PHS act.
They clearly stated what is considered minimal manipulated product and which are classified as substantial manipulated products.
Once again, it appears that you are missing information, since these processes weren’t taken into consideration. From your statement it is obvious that you are mixing a research article with the clinical application of minimal manipulated cells and cell products.
Then we also have to accept that the planet has many countries with much better recruitment rates than the US for conducting clinical trials.
To that extend it is known that China, India and Russia are considered the best from the recruiting rate point of view, countries to conduct clinical trials. Hence why only you take for granted that clinicaltrial.gov has all clinical trials registered. As it seems you are not so familiar with clinical trials and further processes on drug development. I suggest that you contact the relevant CRO that is conducting our trials, Clinfinite.
We are part of an 8-billion people world, and it is important to have the overall picture and exclude none.
Furthermore, it seems you have not conducted any research about us, and you make statements that are by far not correct. For instance, you confused the minimal manipulated products with the research products, and you presented them as if they are the same.
Also, you realize that we cannot monitor every clinic and clinicians personal marketing strategy. To that extent we agree that there may be many inaccuracies on these websites. But these are entities that we cannot control or monitor beforehand.
Finally, allow me to say that the publication of online articles such as yours, needs also to follow (especially from someone from the academic era) rules of objectivity according to journalism regulations and also the consent of the other side is needed, for what one is presenting is actually reflecting the truth.
With this article, it appears that you have a predefined opinion and are selectively searching for evidence to support it.
It is really surprising how someone that comes from an academic environment, seems to have a subjective view / positioning and promotes a false personal opinion as true ignoring selectively facts and not proceeding on objective assessment of evidence.
It is truly unfortunate for the younger generations of scientists if they are trained under such a concept and mentality. I want to believe that none of the above-mentioned attempts were made on purpose and that you will take into consideration the observations, to avoid future misunderstandings and mistakes.
Finally, we would like to bring to your attention two links that caught our notice as we were investigating your publication. Unfortunately, it seems that we are not the only ones who have noticed serious deficiencies regarding what you claim to represent and express opinion on. We are bringing this to your attention, as well as to the attention of your readers.
1. When Lab Research Scientists Play Doctors -The Knoepfler Files – Regenexx
2. The Passion of Paul Knoepfler-A Review of the Niche Blog
At this point, please consider that we are genuinely committed to taking action, so that no false or incomplete information or statement involving or related to our company remains unanswered.
Dr. Papasotiriou,
Thanks for your detailed comment. I have a few questions to follow up.
It’s not clear to me that SOT miRNAS marketed in the US would fall under 361. In my view they seem more likely to be 351 drug products. Since this is something the FDA decides, do you have some indication from the FDA that the RGCC SOT is not a drug?
It’s also not clear to me that an MRA between the FDA and any European authorities bears on whether SOT is a drug in the US. Do you have any documentation to back up that the MRA bears on FDA regulation of SOT in the US?
For instance, we see cell therapy drugs approved in Europe all the time but they have to be separately approved by the FDA in the US. Why wouldn’t that be the case for SOT too? (as a side question: Is SOT officially approved for use by EMA? You claim it doesn’t need such approval?)
You state that I confused the research products with the minimally manipulated products. I have some more questions to try to clarify this. In your research article on SOT and cancer you state:
“SOT production – administration. Following the validation of siRNA, modified dsRNA molecules were designed and produced using the Oligomaker48 DNA/RNA Synthesizer. dsRNA molecules were then freeze-dried and tested for the presence of pathogens as well as for the tightness of each tube and send to the clinicians. Upon arrival, SOT was reconstituted in 1 ml of water for injection and dissolved. Then, the solution was placed in a syringe and added 9ml of water for injection. The final solution was applied intravenously.”
Note that your other paper on SOT use in Lyme disease has a similar methods section described SOT production in a lab.
So your text says the SOT product was modified and made in a lab and then used in patients in the clinical study. That’s part of why I got the impression it is likely a drug as used in the US.
Ae you saying that the RGCC SOT supplied products for use in patients at clinics in the US are different and are not synthesized in a lab like described in your clinical trial papers? Are you saying that instead the SOTs used in patients are strictly only made from the patient’s blood and not modified in any way? Is that why you think they meet the minimal manipulation criteria?
If the SOTs used in patients at clinics are not the same as the SOTs used in your published research article, what is the evidence that the different SOTs (the one’s you state are minimally manipulated) used in clinics throughout the US are helpful and safe? Do you have separate studies on those products showing efficacy and safety? I don’t see any such published studies.
I’m glad you recognize that some clinics using SOT in the US may have issues. I realize that there is a whole world beyond the US, clinical trials can happen elsewhere, etc. but my focus here is on use of products within the US by the clinics and so the FDA’s rules apply.
Finally, I’d also like to take this dialogue as an opportunity to ask about why RGCC cell therapy products appear to be used at clinics in the US as well. Do you argue that these cell products also do not need FDA approval prior to clinical use? They aren’t cellular drugs? Can you also comment on whether iPSCs are involved (and if so, how) in the production of one or more of the RGCC cell therapy products marketed by clinics in the US?
If through our dialogue and your answers to my questions there are any apparent needed changes in the post on SOT use by clinics in the US, I’m likely to be happy to make such changes.
Going back to it again, I think I was confused by your email as to whether there was a lab-synthesis step (using the RNA isolated from blood just as a template and not as the end product) for the SOT products used in patients in the US.
Also, this RGCC patient guide does not suggest the SOT product is limited to what can be isolated from patient blood without any further steps: https://www.ipscell.com/wp-content/uploads/2024/02/1.SOT-Therapy-Patient-Guide-5.01.23.pdf. It says (emphasis mine):
How does the SOT THERAPY work?
A patient’s blood is sent to the RGCC lab where the scientists identify the appropriate gene that needs to
be silenced. Once they detect the potential genes for targeting, they validate these targets both in silico
and in vitro. The validation of target ensures the highest specificity and does not interfere with any other
targets. Once the different target genes have been validated, then the most appropriate gene is selected
and the laboratory creates an oligonucleotide, complementary to the mRNA for a specific region of this
gene. This in turn creates an anti-sense therapy.
These molecules are delivered to the clinic where the patient receive the one dose IV treatment.