Question:
Hello Rene and Edward,
Thanks to your inspirational story, we have been on our own journey curing cancer with immunotherapy. My boyfriend was diagnosed with synovial sarcoma on his right hand 1.5 years ago and had the tumor removed with clear margins. Everything was great until March 2017 when we found out he had nodules in his lungs. We found Rene and Eddy's book a few days after the diagnosis, and after consulting our doctors, who told us that the chances of curing him with chemotherapy were close to zero, we decided to put all our efforts into immunotherapy.
We recently travelled to Tijuana and were able to get Coley's toxins. We are doing more research before starting the injections, and we would like to know more about your experience.
I read in your blog (http://cancerwife.com/content/were-back-alive-and-kicking) that after 2 months of tumor shrinkage with Coley's toxins monotherapy there was reversal regrowth. I couldn't find your theories as to why this happened and was wondering if you could elaborate. Also, do you think too frequent injections of Coley's toxins caused too much immunostimulation and thus cachexia? Or do you have other theories as to why Rene experienced cachexia? It would help us greatly in planning our treatment course.
Thank you so much for your time and kindness.
Your story gives us hope and strength every day,
DY and YS
Answer:
We're so sorry your boyfriend is going through metastatic synovial sarcoma.
I need to clarify that back in 2009/2010 when we were first pursuing immunotherapy, I could not get the modern immunotherapies that are available now via clinical trial or off-label (checkpoint blockade, T cell therapies, etc). If I were to have lung mets now, we wrote about our immunotherapy strategy in Chapter 16 - section "What I would do if my cancer returns".
If I had lung mets now, I would probably not chose to do intravenous infusions of Coley's Toxins, as many of the modern immunotherapies available now are more powerful and effective than Coley's, when used together in a synergistic combination. The mechanism of Coley's and its effect on the immune system is not fully understood, so it is very hard to say why it caused regression in my jaw tumor, then was not able to control the growth after some time. The balance of the immune system is very delicate.
That said, since you ask about Coley's Toxins:
1) Source of Coley's
We were very careful with the formulation of Coley's Toxins that I received. It was made by MBVax, a Canadian company, that has stopped production for several years due to lack of funding (beginning of Chapter 8). Back in 2010, Issels used MBVax's Coley's Toxins. I do not know what formulation of Coley's Toxins they use now.
The dosage of Coley's for IV infusions needs to be diluted accurately, and titrated up from the lowest possible dosage. Please double check these are accurately done, and consult with the manufacturer of the Coley's Toxins for advice.
2) Cachexia
I was constantly doing immunotherapy for a very long time, cycling between dendritic vaccine, NK cell vaccine, Coley's Toxins IV infusions, cryoablation. We feel the prolonged highly inflammatory treatments contributed to tipping the balance towards chronic inflammation/ cachexia (Chapter 15 - section "Cachexia: a wasting syndrome").
3) Omega 3
Related to cachexia and lung mets, do pay close attention to the single case report by Dr. Pardini (Chapter 15, section "Quenching the fire with fish oil"). Patient DH's metastatic sarcoma tumors in the lungs disappeared after 10 years of maintaining a high omega 3 supplementation and low omega 6 diet (he is still in remission). My lung tumors stopped popping up after I started the same. This dietary intervention may be easier and safer to do than Coley's Toxins for sarcoma lung mets - but be aware that if you are undergoing immunotherapy treatments that require acute inflammation, high omega 3 may counteract that. I started this intense dietary intervention when I stopped all immunotherapy treatments.
4) Cryoablation/ laser lung surgery
How many lung mets are present? In all lobes?
The reason I ask is it may be possible to cryoablate or laser resect lung tumors without compromising on lung function. Often lung tumors are considered "unresectable", but that may be because traditional wedge-resection lung surgery removes too much healthy lung along with the tumor.
The story of sarcoma patient John (Chapter 14 - section "Turning attention to my lungs") shows how he was able to stay alive even after having 100+ lung tumors with cryoablation and laser lung surgery. Note, he did not have systemic immunotherapy all this time, but perhaps the combo of laser lung surgery (physical removal/destruction of tumor) coupled with cryoablation (the destruction of tumor and attraction of the immune system) was sufficient in his case to keep his tumors under control.
My sarcoma oncologist believes that the physical removal/destruction of my lung tumors right when they appeared (with cryoablation) was very critical to keeping my cancer under control. I agree with that, but I believe for long-term control of cancer, there also needs to be systemic immune control. Cryoablation by itself may or may not achieve this, thus we layered my cryoablation with other immunotherapies. There are many powerful combinations that are possible nowadays, I hope you'll be able to look into those and also achieve a state where your immune system is keeping the cancer in check (Chapter 16 Table 3).
Hello Rene and Edward,
My boyfriend is soon starting a clinical trial involving NY-ESO-1-specific TCR-engineered T cells. We are looking into the possibility of combining other immunotherapies as well as various supplements and diet modifications to increase his chances of successful treatment since it seems that only about half of the patients respond to the TCR treatment.
We are thinking about the ketogenic diet and fish oils. I am aware that you recommend against omega-3 supplements during active immunotherapy due to their powerful anti-inflammatory potential, but I was wondering what you think about supplementing fish oils for the purpose of modifying his omega 3:6 to 1. Although T cell and NK cells do seem to need some inflammatory cytokines to get activated and mobilized, it appears that PGE2 (derived from omega 6) is inflammatory and highly immunosuppressive. It seems to have pro-tumor effects by activating Tregs and MDSC as well as recruiting tumor-associated macrophages and inactivating T cells and NK cells. Although some omega 3 derivatives also seem to increase Treg populations and to some extent inactivate T cells, DHA and EPA seem to have more anti-tumor than pro-tumor effects. I feel that quelling the inflammation (or at least balancing it) by modifying his ratio would actually help T cells be more effective. I was wondering if you have any opinions regarding this.
Always thank you for your kind input,
DY
We are so glad YS is able to get into a NY-ESO-1 TCR trial.
We do understand your sense of urgency to maximize the immune response against the tumors. However, we caution against doing too many things at the same time (which we have done many times). As we experienced, the problem comes when the result is not desirable. Which treatment inhibited a good response and should be omitted, or were all the treatments ineffective? It becomes very hard to evaluate. We would only combine treatments/supplements at the same time when we are fairly certain there will be no conflict or problems between them.
Our thoughts:
A) During TCR trial - We would be very cautious to do things during immunotherapy treatment, especially with TCR therapies, one of the strongest immunotherapies and with severe side effects (the story of Jane - off-target and cytokine storm, Chapter 6 section “Dramatic results and dangerous side effects of adoptive therapy”, pg 89-91). Researchers and doctors are still trying to understand the factors that make TCR therapy effective, so it’s hard to know what will improve or counteract its effectiveness while on the therapy. We personally would not take supplements that enhance the immune system when on TCR therapy, as there will be a massive amount of immune activity when the T cells are infused in.
Personally, we would not take omega 3 or do the ketogenic diet during active immunotherapy treatment. However, lowering omega 6 in the diet is something that is low risk for interfering with the treatment. The omega 3 and/or ketogenic diet could be done before or after the trial (see B) below)
(resources to calculate omega 6: http://curingcancerbook.com/nutrition-facts-low-omega-6-diet-and-ketogen...)
B) Before TCR trial - Short course (2 weeks) of ketogenic diet and/or intense omega 3/6 *before* the trial would be something we could see ourselves doing, preferably followed by some time (~2 weeks) before the trial starts. But, you will need to carefully examine if the ketogenic diet and/or high omega 3 would cause changes in blood tests (or other criteria) that would disqualify YS from the trial. These dietary interventions would not be worth it if that happens.
C) Monitoring - The determination of whether the TCR therapy is effective or not is very crucial, as effective immunotherapy treatment can be initially misinterpreted as “failed treatment” (story of Jake, Chapter 16 “Work with a doctor experienced in immunotherapy”, pg 276-277).
Have oncologists familiar with immunotherapy advise about YS’s response to the NY-ESO-1 TCR therapy. The oncologist running the trial would be one such doctor (as CAR-T is not a “simple” immunotherapy that any oncologist can administer, as it requires laboratory processing and careful monitoring of side effects). For another opinion, possibilities are a melanoma oncologist who has experience with immunotherapy or another oncologist with CAR-T experience.
D) Preparing for treatments after TCR trial - Establish relationships with doctors for future treatments if NY-ESO-1 TCR therapy doesn’t work. One possibility TCR therapies "don't work" is that it only targets NY-ESO-1 positive tumors. Due to the heterogenous nature of tumors, NY-ESO-1 negative tumors will not be targeted by the adoptive T cell therapy. Thus, a suggestion for non-responding tumors is cryoablation followed by PD1.
Would you mind to share:
1) Where the NY-ESO-1 TCR trial is being run? And the oncologist running the trial?
2) The number + size of tumor(s) in the lung? (and anymore elsewhere?)
Hello Rene and Eddy,
Thank you for your thought out response, and sorry for the delayed post. Just wanted to update you regarding our situation. YS finished the treatment part of the trial a few months ago and is currently being monitored for side effects and treatment efficacy. This is the link from clinicaltrials.gov, if you are interested: https://clinicaltrials.gov/ct2/show/NCT02457650?term=ny-eso-1&rank=17
We also added Keytruda to his treatment. His last scans were a few days ago and they showed about 10 nodules in his lungs bilaterally, with the biggest one being 9 mm. It was almost the same as the scans back in July and March of this year. The doctor said that the number of nodules seems to have decreased, but he's not sure since they are so small. I guess it's good news that the lesions are stable. We are thinking about cryoablation if the number decreases and are currently trying to figure out how to get neoantigen vaccines made.
I know there is no right answer to this, but do you think we should be more aggressive (add CTLA 4 inhibitor, targeted therapy, local ablation, etc) when his lesions seem to be stable with the current treatment? How did you decide on when to add or hold off on additional treatments?
Always thank you for your response,
DY
Dear DY,
Re the mentioned clinical trial, did YS receive treatment in China via Geng Tian, M.D., Ph.D?.
I am interested in enrolling in the trial.
As always, thank you for your response,
Raymond
We're so glad to hear YS received NY-ESO-1 adoptive T cells and Keytruda. It's great news that the tumors are stable, and may have even shrunk.
It may take some time after Keytruda to see tumor regression (and tumor flare beforehand) - note the story of Jake (Chapter 10, pg 166-167).
CTLA4 - We would add CTLA4 when it's clear that PD1 along with attempts to generate/infuse T cells (eg - cryoablation, radiation, adoptive T cell therapy) isn't working. The side effects of CTLA4 can be severe, leading to pausing of treatment.
Some questions we have:
1) When was the NY-ESO-1 adoptive T cell administered? And the Keytruda?
2) Have you found a cryoablation doctor? We know Dr. Littrup has gone to China to train doctors there, but don't have any info. We've gotten info about cryoablation from this ASPS sarcoma forum, ask Olga for leads on cryoablation doctors: http://www.cureasps.org/forum/viewforum.php?f=55
Hello and thank you for your reply.
The T cells were administered on July 29th, and the Keytruda was started a week before that.
Back in April, when we were in the US, we made contact with Dr. Littrup's office and were hoping to get an appointment, but they told us that we needed to get a referral from a US doctor to do that. We had consultations with sarcoma specialists in big cancer hospitals in New York and Texas, but they told us they couldn't give us referrals because there wasn't enough evidence cryoablation would help.
Could we ask how Rene was able to get consultations with Dr. Littrup? We are at loss on how to get a referral.
If we can't get to Dr. Littrup we are thinking about cryoablation in Japan or China.
4 years ago when I did cryoablation with Dr. Littrup last, he was still at Karmanos Cancer Center (Detroit, Michigan) and I did not need a doctor's referral (all patient-driven).
Dr. Aoun is still at Karmanos and is also highly experienced, having been trained by Dr. Littrup. He did some of my lung cryoablations too. The info on contacting Dr. Aoun should be on the ASPS forum link in my previous reply. Let me know if you have any problems finding it.
If Dr. Aoun cannot do it, you can ask him for cryoablation doctor referrals in Asia (for future palliative needs in case YS cannot travel to the US).
Question:
Was Keytruda only given before the T cells? Any Keytruda given after the T cells? If so, when?
(Thinking about case study of melanoma patient described in Chapter 11, section "Radiation: an immunotherapy accessible to all", pg 183-184, Figures 36-37)
Ah, I see. Thank you for the info. We'll let you know how things go as we move towards complete remission.
The Keytruda was given a week before the T cells and then every 21 days (ongoing).
That is amazing that YS got Keytruda before and after the T cell trial! The logistics for that must have been tremendous.
Is the Keytruda from your Japan doctor, or the Chinese hospital running the trial?
Just to clarify, I mentioned "future palliative needs (for cryoablation)" as an alternate way to ask for cryoablation doctor referrals in Asia, if the doctor says cryo can't be done. We hope cryoablation for palliation will never be needed!
Wishing YS continued positive response!
One thought -- the ss patient Heather (Chapter 6) who received NY-ESO-1 adoptive T cell therapy had dramatic shrinkage of lung tumors, but after a while, there were stubborn tumors that didn't shrink even with repeated NY-ESO-1 T cell therapy. Then they did radiation + PD1, and eventually there was loss of control with the lung tumors.
Our thought was that perhaps the stubborn tumors didn't have NY-ESO-1 anymore, and perhaps radiation wasn't successful in generating T cells against the tumor. We haven't heard many positive experiences about radiation with lung tumors.
When there is an opportunity for surgical removal or physical destruction of a small number tumors, it should be taken to prevent the tumors time to metastasize more. We would consider laser lung surgery for lung mets that can't be cryo'd, above radiation.
Have you looked into laser lung surgery in Germany? (Chapter 14, section "Turning attention to my lungs", pg 231-234)
If cryoablation is not a possibility, and if it's clear that the tumors are stable (not actively shrinking), it may be a real possibility to remove and/or burn away the 10 tumors YS has with laser lung surgery. Laser lung surgery requires open chest surgery, so it's not trivial. When we consulted with Dr. Rolle, his advice was to see if the tumor can be cryoablated first, if it can't be cryoablated, then he would be willing to do laser lung surgery. Dr. Rolle has operated on patients with 100's of lung tumors.
I read here that Dr. Rolle has retired, but there is a doctor who was trained by Dr. Rolle to do laser lung surgery: http://www.cureasps.org/forum/viewtopic.php?f=51&t=1227
Rene and Eddy,
Always thank you for your input; it helps us tremendously in planning our next steps.
The Keytruda is from a hospital in Hong Kong. We switched over because it was closer to hospital running the trial.
It's very unfortunate that the T cell therapy wasn't curative for Heather... It seems dangerous to rely only on the NY-ESO-1 antigen.
We haven't looked into laser sung surgery yet, but it seems worth contacting Dr. Drewes.
A question regarding laser lung surgery vs. radiation (or other local ablative methods):
We understand that cryoablation is the best option, but if cryoablation can't be done for all nodules, what would be the advantage of laser lung surgery over other ablative methods for getting rid of the remaining nodules? If other ablative methods can be used, would it be better than laser lung surgery since there is a chance (however small) that they stimulate an immune reaction?
DY
There is a balance between using cryoablation/ radiation for *potential* immune effect vs. *definitively* removing tumor with laser lung surgery.
Personally, if only some my lung tumors can be cryoablated, I would cryoablate those few tumors, then remove the others with laser surgery. If none of my tumors could be cryoablated, I would remove them all with laser surgery, even without the potential immune effect with other types of ablation/radiation, as there are side effects to the lung.
Advantage of laser lung surgery over cryo -
1) laser lung surgery can find very small ones not detectable on scan (by palpation)
2) if too many nodules cannot realistically cryo (at least not in one session)
Radiation cons:
1) radiation side effects to the lungs
2) risk of tumor cells becoming radiation-resistant (tumors cannot become resistant to cryo or laser lung surgery)
3) I personally haven’t heard of successful stories from patients who did radiation of lung tumors + PD1.
Advantage of laser lung surgery for non-cryo-able tumors:
1) *definitively* get rid of remaining tumors: from our experience, once tumors appear, it’s best to kill them off asap. I’ve been using cryo to kill off my lung tumors once they grow to about 1cm (and it’s been 4 yrs since my last cryo, with no sign of the cryo’d tumors regrowing). But if cryo is not possible, laser lung surgery is my choice.
2) retain max amount of healthy lung tissue
One pitfall of managing sarcoma lung mets is that tumors can become so numerous that patient is deemed "non-operable". It’s “non-operable” because traditional surgery would remove too much healthy lung tissue. So, in chosing treatments for sarcoma lung mets, it’s important to preserve as much healthy lung tissue as possible. Laser lung surgery is able to preserve healthy lung tissue. Illustrated by patient John's story and info on laser lung surgery (Chp 14, section “Turning attention to my lungs”, pg 231-232)
I'm thinking of patients who may be looking for off-label Keytruda - if the doctor is willing to prescribe Keytruda off-label to other patients, could you share the name of the doctor and hospital? Thanks!
Thank you very much for your detailed response. My boyfriend says he will ask the Hong Kong doctor if he's willing to prescribe off-label to other patients. We will keep you updated as move forward!
Hello Rene and Edward, hope you're doing well.
My boyfriend is doing the high dose omega 3 supplementation, but he's having some gastrointestinal problems after taking them. He also tried Med Omega, but the taste makes it really difficult to keep down. Do you have any recommendations as to how he could ease into the omega supplementations? Did Rene have any issues, and if so, how did she deal with them? Were there some days Rene was not able to take the supplements?
We're sorry to hear the fish oil has been difficult to take. Rene's stomach is quite tolerant of the fish oil/ DHA. But Eddy has a more difficult time with the fish oil (diarrhea afterwards) so we've had to find creative ways for him to take it.
Ramping up the fish oil/ DHA also helps ease the digestive system into it.
Our tips for taking the fish oil (just updated): http://www.curingcancerbook.com/diet/high-omega-3-supplementation
Hello Rene and Eddy,
YS is planning to cryoablate some lymph nodes that seem tumorous. We read in your book that you did cyclophosphamide before your cryoablation and that Yervoy would have similar effects. We are thinking about using Yervoy. Is there a particular regimen you think would be most effective? In the paper you cited (by Dr. Allison) the mice were given CTLA-4 inhibitors on day 1,4,7,10 after cryoablation (day 0), but we read you did cyclophosphamide before the cryoablation. Is there a timing you think is optimal, and do you think a one-time injection would have sufficient effects? We are wary of doing Yervoy since YS is also on Keytruda.
Also, is there anything else you would recommending doing with cryoablation? We are also planning to do dendritic cell infusions right after cryo.
Thank you,
DY and YS
DY and YS, we just read about the striking effect of microbiome/antibiotics on PD-1 efficacy. "simply avoiding antibiotics while taking PD-1 blockers could boost patient responses from the current 25% to 40%" This news article has links to the journal articles (http://www.sciencemag.org/news/2017/11/your-gut-bacteria-could-determine...).
We will post on our facebook page if we find other pertinent info (https://www.facebook.com/immunecure/).
My email has changed because the MBVax website is no longer functional.
Great book!
I have some news, send me an email.
Best, Don
Hello Don,
Would it be possible to know what news you have? We are very interested in the possibility of reviving the manufacture Coley's Toxins.
Thank you,
DY
Hi DY,
I am writing a book "The Reinvention of Coley's Toxins" including the following paragraph in the Forward:
This book contains a complete disclosure of certain intellectual property developed by MBVax Bioscience with which a reasonably competent chemist with some good equipment can make an optimal version of Coley Fluid, an inexpensive cancer therapy that can eradicate metastatic disease. This information is hereby conveyed into the public domain and is free to use by any organization or private individual in any country.
The book is currently almost finished and should be available by the end of June.
If you like, I can send you a notification when the book is available on Amazon.
Best,
Don Macadam
donmacadam@kwic.com
Dear Mr Macadam,
I have send you an email to the provided address.
I would be extremely privileged to get an answer from you at your convinience concerning getting my hands on some reliable Coleys toxin today in 2018.
Sincerely,
Marc Ouellette
marc_ouellette@videotron.ca
Wow, that's incredible news, Don! Your work will give hope to so many people affected by cancer.
Will your book be available on kindle? That would be great as Amazon doesn’t ship to many countries.
Please do send me a notification when your book is out! I look forward to reading it.
Thank you for sharing this great news,
DY
The book will not be available on kindle but it will be also be available from other book retailers including direct from the publisher (volumesdirect.com) who does ship to all countries.
Don
Hi Rene and Eddy,
Hope all is well. Random question: did Rene avoid carbs and sugars, including fruits and milk, during the time she did not do the ketogenic diet?
YS is doing well. Just recovered from pneumothorax surgery and is curious about dietary changes.
Thanks,
DY
When I'm not on the ketogenic diet, I maintain a low omega 6 diet. I do eat carbs, fruit, full-fat dairy (as it's low omega 6). I avoid sugar. Other dietary restrictions are to maintain low omega 6: http://www.curingcancerbook.com/diet/low-omega-6-diet
Dear DY,
I saw your post about the clinical trial that YS did via https://clinicaltrials.gov/ct2/show/NCT02457650?term=ny-eso-1&rank=17
Did YS go to China to be treated by Geng Tian, M.D., Ph.D?.
I am interested in enrolling in the trial.
Thank you
Raymond
Hi Raymond,
YS actually lives in China, but he did have to travel all the way to Shenzen, where the hospital is located. He had to stay there for about a month and a half for the actual treatment, but he had to go back and forth before and after the treatment for various exams (blood work, pathology, etc). It’s a good idea to contact them and also look into the logistics. A heads up would be that they didn’t seem to speak much English.
Take care,
DY
I have received several emails from readers of this forum about difficulties obtaining a copy of my new book The Reinvention of Coley’s Toxins.
The book is listed on the US Amazon.com website but they demand has been high and they remain out of stock. An additional complication is Amazon do not ship to all countries.
My book is also available direct from the publisher in Canada and they usually have stock, sell in US or Canadian funds and ship by UPS anywhere in the world. Orders can be placed by email to sales@volumesdirect.com
The Reinvention of Coley’s Toxins
Donald H. MacAdam
ISBN 978-0-9959218-2-5
278 pages, illustrated, color
$19.95 (US) $25.95 (CDN)
Book summary:
This is the story of a small company with limited financial resources that brought back “Coley’s Toxins” and proved a modern version of this historical product was able to induce complete and lasting regression of cancers that no longer responded to conventional therapies.
Coley’s Toxins were invented in 1893 by Dr. William Coley when he was 29 years old. In the following 43 years Dr. Coley treated about one thousand inoperable (incurable) cancer patients with better results than would be expected for a comparable group of patients today.
Until the last pharmaceutical manufacturer ceased production in 1951, Coley’s Toxins was a mainstream cancer therapy with thousands of physicians treating many tens of thousands of patients. Outcomes were respectable but not as good as achieved by Dr. Coley.
Dr. Coley’s patients fared better than those treated by other physicians because Coley’s Toxins prepared for Dr. Coley’s personal use were more effective than the commercially available formulations.
Beginning in 2006, MBVax Bioscience produced a modern version of the formulation used by Dr. Coley and provided it free of charge to physicians anywhere in the world who could legally import the product and administer treatment.
Clinical results included complete regressions (cures) of inoperable and/or metastatic breast cancer, lymphoma, melanoma, lung cancer, esophageal cancer and stomach cancer.
In spite of these results and the support of leading cancer researchers, medical regulators in Canada, Europe and the U.S. denied permission to commence clinical trials.
Don MacAdam
I do not know of any current manufacturers of high quality Coley's Toxins since MBVax made its last shipment of Coley Fluid in 2015. However, having published the detailed manufacturing protocol in my book "The Reinvention of Coley's Toxins", I expect several labs will begin manufacturing the product. If the MBVax manufacturing protocol is followed without any deviation the resulting vaccine should be equivalent to MBVax Coley Fluid.