So, when I was messaging with Soumen79, the question of APCEDEN and efficacy, and my thoughts on it came into discussion, and I wanted to do a post on some of the immune system directed treatments, and why we are not taking a victory lap yet... Let's begin with CAR-T...
CAR-T stands for Chimeric Antigen Receptor T cells--cells engineered to target specific cancer cells and destroy them-see below:
This has proven far more effective with blood cancers than solid tumors. I have listed an article below on CAR-T in MCRPC--the abstract is a good summary, and see Figure 3 for some of the barriers to success:
At the bottom of this article, it gives some information on Provenge. I did find articles on APCEDEN. but to my knowledge, there are no phase 3 trials for it. There is the story of Fuzzman77 on another forum, and I listed an article below:
According to my messages from APAC Biotech that makes APCEDEN, the cost is about $25,000 for a years worth of vaccines. They are now using CTC's in producing the vaccine if no tumor lysate is available. There is also a company in Mexico doing this and you can contact TEBozo about them. Like the CAR-T, there are barriers to success and i found the article below informative:
The issues that I have with Provenge is the cost, and the fact that patients using this "late in the game" may not have as good an outcome. APCEDEN is more reasonably priced, but has not generated the clinical data from trials that I desire in a treatment. Then, there are the barriers to success. This, also has promise, but like most vaccines, I would prefer to use it earlier than later.
Lastly, the BiTE therapy involves using a bispecific T-cell engaging antibody that binds on PSMA (tumor)and CD3 on the T cells to activate the T cells. I like to think of this as teenagers in a gym dance..(Does anyone remember these??). The guys (cancer) are on one side of the gym, and the girls (T cells) are on the other. Not necessarily engaging, but then the music (BiTE) comes on and the two begin to engage each other. There has been some information given on a promising BiTE-AMG-509. I have put a great video on BiTE with Oliver Sartor and Alicia Morgans below:
I think this has really good potential because of the ability to put the T cells and Pca together which overcomes some of the ability of cancer cells to evade detection. As scientists work on overcoming barriers to successful treatment, I believe, like Sartor, that we will see some real progress in treating PCa with BiTE, and possibly, this could be part of a cure...
The Science is Coming !!! and it gives us....HOPE !!!
Don Pescado
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Fish, I am just finishing up the great trilogy of works by Siddhartha Mukherjee with his newly released Audiobook (easier to listen) “Song of the Cell”. The second half of this book is a masterclass on the components, mechanisms and regulation of the immune system. Including how it relates to cancers, and why that is so challenging. This follows on his “Emporer of All Maladies” on the history of the fight against cancer; And “Gene”, a very deep dive into the genome and genomics.
Provides a deep and current perspective, much expanded science since attending med school in the late 70s. Pablito
The old days of "cut, burn, and poison" are coming to an end with precision medicine. The ability to ID genetic defects and target them, as well as the new drugs coming like bromodomain inhibitors make the possibility of a 3 drug combo holding PCa in check much more likely. As I say, the future of cancer treatment is immunotherapy and not taxane based tx.
I will have to give these books a read when all my "fun" projects are over...For now, they consume my time...
WIth the 50 year focus on genetics (with little efficacy for cancer treatments) and the more recent focus of immunotherapies, it seems we need a summary post of the renewed research on cancer metabolism, now sometimes referred to as "metabolomics". I have been chasing that rabbit for a number of years (down many different rabbit holes), but with his command of the Nick Lane evolution of life cellular metabolics, I nominate our friend and fellow PCa brother, Pablo Cabo, to do the honors.
Along with Don Pescado's recent updates (and the always updated SOC provided everywhere), that would give a good foundation for seeing through some of the fog for evolving treatments in the road ahead. For me personally, the appeal in understanding the specifics of PCa metabolism is that many of these functions can be acted on with interventions that involve lifestyle mods, changes to diet, well-researched supplements, and long-used and readily-available pharma products - and the results can often be monitored with standard blood/metabolic/hormone labs from our regular docs or reasonably-priced walk-in labs. One way we can take an active role in controlling our common disease - while we impatiently wait for that magic PCa silver bullet.
What say ye, Sir Pablo?
BTW - Happy T'Day to you and the rest. Ciao - K9
PS Just to seed the effort, here are several of the many research papers that look at PCa cancer metabolism:
Metabolic reprogramming in prostate cancer - British Journal of Cancer, Published online 2021 Jul 1.
Enhanced Succinate Oxidation with Mitochondrial Complex II Reactive Oxygen Species Generation in Human Prostate Cancer - International Journal of Molecular Science, Published online 2022 Oct 12.
Yes I did actually have too much T Day dinner (after cooking all day). But it was fun to share with Johane, Mateo and some new friends here in Cabo. I’m thinking carefully about your invitation to unpack these topics, including metabolic flexibility and re-programming and the cellular signaling pathways that impact that. Genetic modifications (mutations) that enable or disable those pathways along with immune evasion, and tumor micro-envirnonment that protect and enable cancer invasion and spread.to,
Such a quagmire, actually. Yet incredibly interesting in its orchestration. The Beast is extremely sophisticated in its expression. I keep seeing epigenetic as central to much of this, and perhaps hold the keys to the kingdom. We indeed can influence epigenetic expression with certain natural supplements, nutrients and medications (including Sirolimus as one notable example). But the vast majority of epigenetic regulation is a finely tuned and interconnected system with positive and negative feedback loops, check points (as with immune mechanisms) and escape valves ( such as with management or ROS and NOS). We know so little of the whole picture that we easily could do more harm than benefit by leaning on the tuned systems too hard. (Example: Cytokine storm and auto-immune diseases from BiTE and CAR-T impacts on T cell regulation.)
Wise to tread carefully when deploying unproven interventions. Stick mostly with the best proven epigenetic modifiers such as exercise (!), hormesis factors in lifestyle. Natural and safe phytochemicals (Quercetin, Fisetin, Sulforaphane, Curcumin, ECGC would be my big 5); certain medications such as a statin, ASA and celecoxib anti-inflammatories), Skeletal protective drugs, Sirolimus, Dasatinib and perhaps Metformin. Optimize gut microbiome. Consider certain hormones such as D3, K2 and Melatonin. And carefully balance possible benefits vs risks of anti androgen therapies, ADT, AART, IADT and BAT.
So much, before we even get to diet, fasting, IMF or keto, etc. Only thing we know for sure there is that plants are good (yet not much sugary fruits). And I am not a good example in that I eat meat frequently and drink wine. So we may need another poster-boy there. 🤷🏼♂️ Knowledge is satisfying even when it is (not yet) power.
like many polyphenol supplements, absorption for bioavailability is a concer. So I choose a Liposomal Fisetin, Vitablossom brand. 2 softgels have 1000 mg Fisetin plus 200 mg Quercetin.
I have been using Now brand Quercetin with Bromelain. It’s Inexpensive. However there are liposomal versions for that which I may switch to. Orgabay liposomal Quercetin looks good for example. 2 softgels have 1600mg Quercetin , Bromelain and some Zinc. Just one of those added to the 2 Fisetin would be 1,000 mg. Enough for everyday supplementation of both.
I'm mostly in agreement with your educated assessment - and, in fact, am a current user of the largest majority of your listed supplements (sans the ones requiring scripts - I do currently use natural similars for metformin and statin), regularly practice some form of dietary/fasting (I now prefer to think of it a "time-restricted eating") with a 3-day water-only fast every 3 mos or so, and exercise routines shown to provide metabolic benefits. I might add the beneficial effects to metabolism and emotional stability of a regular meditation & mindfulness practice, of which I know you are well-acquainted. Unexplored territories might even include the emerging benefits of psychoactive substances on metabolic states that, even if not medically beneficial in controlling cancer, might be beneficial in countering various treatment SEs.
The recognition that the genome is more like the hardware and the epigenome the software (*) that regulates the metabolic functions has now restored the interest in research focused on metabolism. Lots of good science now being done in this area.
As always, thanks for your well-regarded comments and sharing of your own exploratory n=1 treatment journey. We all learn for the experiences we share and yours is a unique one that many here and elsewhere are following with interest.
Keep working on that winter tan (free Vit D while the rest of us are having to supplement) and enjoy the rest of your holiday season. Ciao - K9
(*) One of the first revelatory reminders to me was that every cell in the body has the full gene component to be any other type of cell; i.e., a skin cell carries the genetic information to be a kidney cell. With that knowledge, the analogy I like is that "the genes are like hardwired switches and the epigenome is the software that flips those switches to an on or off position." Knowing all the various environmental conditions caused by what we are exposed to or create can affect how those switches get flipped on or off, it seems that understanding how those actions/interventions affect the epigenome is as important as anything else we can hope to know.
exactly so, cujoe. And epigenetic is in its infancy. Unintended consequences of intervention quite likely. Beware, as every K9 know when approaching an unfamiliar pack. Be humble and bring treats. Sniff, bow, then play. But ever ready to retreat.
As a poster, I have always felt challenged on how do you break down huge and complicated information for mass consumption by our forum members. (This post as an example). The Science is not like reading Jack London.
One must realize that not everyone is an MD, NP, or highly educated 🐶 ( cujoe emoji). A significant amount of this, I end up on the deep dive.
Agree, great fish. The waters are deep and mysterious. Unseen currents and other hazards lurk.
I feel more comfortable doing the deep dives here on FPC with challenging compadres than oh HU,, where I try to keep it to simple support for personal decision making. Or propose alternative views for consideration and discussion with treating physicians.
The science first makes the landscape visible to greater degrees. That is why I so much like the books by such as Nick Lane and Siddhartha Mukhergee are so great, synthesizing the best scientific views in historical context. Unpacking how all of our biology has evolved and works, in health, in disease including cancer specifically and aging. Then the clinical trials test the boundaries and show us the deficiencies. The “norms” and the “exceptions” as Mukherjee’s personal “Rules of medicine” as a practicing oncologist indicate.
And the broadened view of the Kreisler cycle and related metabolic mechanisms explored in Lane’s “Transformers” shows. The metabolic activities and adaptations in cancer are entirely normal evolutionary adaptations to meet cellular requirements of cells. Warburg and reverse-Warberg are just small pieces of a larger integrated mosaic of reaction pathways to meet demands and deal with excesses and deficiencies of resources. A dance where the “materials move” and “energy flows”.
Thanks for walking this halting journey with me I thoroughly enjoy and am stimulated by it. Mateo del Sur
You have given me some Christmas ideas as gifts for me...That reading should help me occupy my cold WV winters. I am glad you find discussions here to be stimulating with us.. Proposing certain topics and ideas in other locations may put one on the wrong side of some BloPo-MFers......... (Bloggers/Posters/ Meta Friends)... and what did you think MFers was about??? No, don't tell me. !!!
The findings of new targets-genetic and epigenetic, nanoparticle drug delivery systems, etc is why I am so optimistic about the possibilities of a cure. Each day, more knowledge is attained. We are in the Golden Age of Oncological Research.
The Science really is Coming !!!..Chronic disease state in 5 years if the drug companies stop screwing around and get some of the new class of drugs into Phase III.
I am working through the new book 'song of the cell' . Should've gotten audiobook, reading this a bit of slog but really looking forward to the second half when i get to it over the holidays. cheers!
Yes, I go with the Audiobooks for all of Mukherjee and Nick Lane’s deep offerings. So I can take my long walks while absorbing it. The first chapters are just a review of history and well known basics on cellular life, familiar to almost everyone from basic biology. But it sets the stage for deeper dives. The immunology chapters are enlightening in how we deal with the constant assaults of infections, inflammation and healing, and cancers. And towards the end now, the mechanisms of aging from cellular perspective.
“The Gene” is also amazingly rich and astonishing perspectives of the complexity and coordination. Again, the Audiobook is a good way to go with it! Glad you are undertaking it. Please share what is most valuable to you. Paul
I just ran across this post elsewhere and am sure you will be interested in seeing it. The source and post are reproduced below along with the slide graphic:
* * *
Basem Goueli MD/PhD/MBA
CEO and Founder of CancerLight, CEO and Founder of CancerClarity, Medical Director for Xbiotech, Pharmaceutical Consultant, Full-time Hematologist/Medical Oncologist, True Precision Medicine Expert
1w Edited
This is one of my favorite PowerPoint slides of ALL TIME.
All credit goes to Wells Fargo Investment Group who made this slide, and to a person whose name I can't disclose.
What you are looking at is the BATTERY of cellular therapies that have been developed to combat cancer.
Not only that, but you're looking at these therapies arranged in an unbelievably elegant fashion.
Many people talk about using genetically engineered cytotoxic T-cell lymphocytes, known as chimeric antigen receptor T-cells (CAR-T), to kill cancer.
However, very few people ACTUALLY KNOW the extent of what's happening in the field as we speak.
Until now!
Not only are people engineering cytotoxic T-cells, but they are trying to engineer macrophages (CAR-M), NK-T cells (CAR-NKT), B-cells (CAR-B, not shown here), neutrophils (CAR-N), gamma-delta T cells, etc.
Tumor infiltrating lymphyocytes (TILs), which basically involves isolating lymphocytes from tumors, growing them ex vivo, and giving them back to the patient with high-dose IL2 or the like, are all the rave in melanoma right now.
But did you know about all the other types of lymphocytes being isolated from tumor cells using the same principle?
On top of all that, it's important to know that CAR-Ts are not created equal as they can be autologous (patient derived) or allogenic (derived from a donor, so called "off the shelf" CAR-T).
With all of that in mind just LOOK at the slide. You can see several therapies have crossed the finish line and are currently available (center of the circle). This includes kymriah, abecma, carvykti, yescarta, tecartus, and breyanzi.
But there are a TON MORE in trial.
There are 8 different cellular therapies targeting HER2 alone.
And that's part of what I want people to take from this slide.
THE OTHER PART IS IT'S VERY EASY TO GENERATE A CAR-T AND TRY TO SELL IT TO A COMPANY.
The "wow" factor of hearing someone say they made a new cellular therapy should be LOST on you by now.
It's like AI. Everyone talks of AI as though it's novel. IT'S NOT.
Don't be fooled by people trying to wow you with the term AI, and don't be fooled by people trying to wow you with the term cellular therapy.
Make them prove to you why they are truly different from all the rest!
Show them this slide if you need to and tell them, "That don't impress me much!"
And one last thing...
If you have been paying attention you know that I don't believe in smoke and mirrors.
I don't believe in rhetoric or bullshit.
And I don't talk about the present, so much as I look to the future.
I don't talk about things in a way you can get ANYWHERE ELSE.
Consider this slide exhibit A.
I am happily giving out the answers to the test FOR FREE.
So stay tuned because I'm just getting warmed up.
***Downloadable version of slide available in comments.
Truly interesting slide, K-9. Just intersecting with what I learned from the immunology/immunotherapy chapters from “Song of the Cell”. (Mukherjee had personal connections with some of the earliest patients and clinicians for these.)
Problem is actually, not only with targeting the cancers with some specificity, but avoiding off-target damage and especially unleashing auto-immune damage and cytokine storm, etc. No simple answers to that. It is certainly a cautionary tale.
Also telling that those products that have “crossed the finish line” appear to be all in the quadrant for autologous (patient’s own cell derived ) CAR-T domain.
To my knowledge, it also seems that nearly all of the effective immuno treatments so far have been for systemic diseases, like hematologic cancers - with acting on solid tumors being much more challenging.
There is a select group of CLL patients who have seemingly been "cured" of a near universally "incurable, but now mostly chronic disease". Those are patients who have failed the other conventional treatments and been lucky to respond to CAR-T therapy. Here is a link to the blog of one of the founders of the patient support organization, CLL Society, who was successfully treated with CAR-T after failing treatment with BTK inhibitors. Like you, MB, he is an MD, so his insights are especially revealing. (The first link is to his initial blog post when he decided to begin CAR-T treatment and the second is to his entire blog-post history.)
The big problem with CAR-T therapies involves overcoming the tumor microenvironment, and the fact that these T cells eventually get "exhausted" and stop functioning as needed to sustain the immune response. The tumor microenvironment involving Tregs or regulatory T cells that blunt the immune response and macrophages getting "hijacked" by the tumor to block penetration of immunotherapies. After a while, these T cells get "exhausted" from fighting the tumor defenses and the tumor wins.
There are now Armored CAR-T cells that seem to offer better tumor penetration and allow the T cells to fight longer. One of my long overdue updates involves some macrophage modifiers that are in clinical trials that enhance immune response.
Cancer is a tricky beast that evolves and finds ways to survive no matter what. Add the "cold" tumor environment of PCa to the mix and it makes PCa an even tougher "nut" to crack.
It is why a multiple front attack is what is needed with an emphasis on developing memory T cells that will recognize the threat, and stimulate a new attack for recurrence.
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