44 replies to this topic

[solbanger]

Only problem is that the Blushwood Tree only grows in a small area in Australia. The compound in the berry EBC-46 apparently was tested on a variety of animals including dogs, horses and Tasmanian Devils and was seen to shrink melanoma tumors with incredible success with many of the animals appearing free of the disease. Human trials are soon. Although the article is from 2014 I am wondering if there is any progress? Dr. Boyle of the QIMR Berghofer Medical Research Institute in Queensland quoted for the press

 

"In more than 70 per cent of pre-clinical cases, the response and cure was long-term and enduring, with very little relapse over a period of 12 months."

 

 

http://www.dailymail...s-approved.html

 

Anyone aware of follow ups to this research?

Edited by solbanger, 15 February 2017 - 05:54 AM.

[Ark]

Interesting, i wonder if one can get seeds to plant?

[joelcairo]

The benefits seem to come from intratumoral injection. That's not a dealbreaker, but it makes the treatment untenable in many cases. There are quite a lot of different substances that can cause enormous death and disruption within a tumor, or cause the immune system to attack it vigorously, but in practice there seems to be little interest in them.

[mag1]

Wonder whether this one could be reformulated perhaps in chitosan or liposomes to reach past the intratumoral problems. Sounds quite powerful.

Any word on the two clinical trials taking place in Australia? They have been ongoing for three years now and apparently some patients have had responses.

What is the limiting factor stoping this going systemic? Toxicity?

Edited by mag1, 15 February 2017 - 10:59 PM.

[jondoeuk]

The benefits seem to come from intratumoral injection. That's not a dealbreaker, but it makes the treatment untenable in many cases. There are quite a lot of different substances that can cause enormous death and disruption within a tumor, or cause the immune system to attack it vigorously, but in practice there seems to be little interest in them.

 

With image guideline (MRI, CT and/or ultrasound) you can reach almost any tissue within the body. The reason why most drugs aren't injected into tumours is due to a number of factors such as trial costs, they aren't the right kind and you need to come up with a regime that is both feasible and simple to apply to patients.

 

As for claim there is little interest then this isn't the case. According to the Chairman, President and Chief Executive Officer of Aduro Biotech the reason why Novartis made a $750 million deal with them was mostly due to this preclinical study https://www.ncbi.nlm...les/PMC4440852/  The majority (~ 50-90%) of patients with solid tumours don't respond to checkpoint inhibitors (CI's). Using this STING agonist via IT injections could address this unmet medical need by increasing the proportion of patients who will respond to anti-PD-1 and other CI therapies. Novartis have a number of these (CI's) in trials right now. I know there are a wide range of other immunotherapies being tested in trials using IT injections. There are other preclinical studies like these http://clincancerres.../21/5/1127.long https://www.ncbi.nlm...les/PMC2649692/ which in my view should be transitioned to a Phase I. You can even combine other treatments like cryoablation with these http://cancerres.aac...t/72/2/430.long https://www.ncbi.nlm...les/PMC4645509/

Edited by jondoeuk, 19 February 2017 - 03:32 AM.

[mag1]

Wow, good one!

 

Other treatments such as Rose Bengal have also been shown to induce a bystander effect after intratumoral injection. Not completely sure, though, twhether this would apply to the Blushwood tree treatment.

[mag1]

jondoeuk, might you have some insight into the chemical structure of ADU-S100?

 

On first glance the best I can think of is a two joined copies from the top right of

https://en.wikipedia...clic_nucleotide

[joelcairo]

Rose Bengal was one of the substances I was thinking of that have demonstrated interesting anticancer activity when injected intralesionally, but are making little if any progress towards general clinical use. Others include Imiquimod, some oncolytic viruses or bacteria, bee venom, maybe mistletoe, etc. There's interest, I mean I'M very interested in them and the research is alive, but it's not clear any of these will be included as part of a standard of care for cancer soon or ever. Obviously I'm generalizing, but I've seen this pattern again and again when researching various potential treatments.

 

The reason the treatment may be untenable is that in many cases tumors present in a manner that is too small and diffuse to make injection practical or even possible. I can't estimate what the percentage of cases would be, but it is not uncommon. And in the cases where there IS a small number of well-defined tumors to treat, there are already reasonable options such as focused radiation or surgical removal. Intralesional therapies must not just work but must be proven to be superior to the alternatives, or they will not be used. These are the roadblocks. I would personally like to see a lot of these therapies proven and adopted so that we could add them to the toolbox and start refining exactly how to use them most effectively, but as I said progress is disappointingly slow.

[mag1]

joelcairo, you are so correct. It is very difficult to understand why such a large proportion of medical research especially cancer is so stagnant.

Much of the clinical research appears to be stuck in limbo often for decades. It is not that these potential fail, it is more that

they enter an eternal development cycle.  It is not difficult at all to find numerous such examples.

 

It really is completely ridiculous.

 

The regulatory rule perhaps should be that after a product has been development for say 15 or 20 years a meta analysis would

be done and if there were reasonable though perhaps not conclusive signs of efficacy present then the product could be

marketed on an as is basis.

 

It must be extraordinarily frustrating for patients to watch as these products never appear to move forward.

 

I was fairly surprised with Rose Bengal.

This one has been inching forward for years and years.

 

Even still the share price has now essentially reached zero.

The market has completely lost confidence in the company, at the same time they have an ongoing phase 3 trial in melanoma

and their product could actually help people with metastatic melanoma achieve a complete response.

 

Your comment about how other similar products can block up the development path for later products which often

can be better was very insightful. Some of the currently marketed chemotherapy products must make the FDA

cringe. The FDA approved some of these and decades later they are still being marketed and some of them

are known to have no therapuetic benefit. About the only biological effect some create is toxicity.    

 

 

[Danail Bulgaria]

 

The benefits seem to come from intratumoral injection. That's not a dealbreaker, but it makes the treatment untenable in many cases. There are quite a lot of different substances that can cause enormous death and disruption within a tumor, or cause the immune system to attack it vigorously, but in practice there seems to be little interest in them.

 

With image guideline (MRI, CT and/or ultrasound) you can reach almost any tissue within the body. The reason why most drugs aren't injected into tumours is due to a number of factors such as trial costs, they aren't the right kind and you need to come up with a regime that is both feasible and simple to apply to patients.

 

As for claim there is little interest then this isn't the case. According to the Chairman, President and Chief Executive Officer of Aduro Biotech the reason why Novartis made a $750 million deal with them was mostly due to this preclinical study https://www.ncbi.nlm...les/PMC4440852/  The majority (~ 50-90%) of patients with solid tumours don't respond to checkpoint inhibitors (CI's). Using this STING agonist via IT injections could address this unmet medical need by increasing the proportion of patients who will respond to anti-PD-1 and other CI therapies. Novartis have a number of these (CI's) in trials right now. I know there are a wide range of other immunotherapies being tested in trials using IT injections. There are other preclinical studies like these http://clincancerres.../21/5/1127.long https://www.ncbi.nlm...les/PMC2649692/ which in my view should be transitioned to a Phase I. You can even combine other treatments like cryoablation with these http://cancerres.aac...t/72/2/430.long https://www.ncbi.nlm...les/PMC4645509/

 

 

Injecting the drug inside the tumor is not an obsticle (except some locations in the brain).

 

Intratumoral injections also can be done laparoscopically.

 

Further, for many locations a methode can be designed to place the needle directly in the timor (with manual control only) on a way that it goes without damaging important structures.

[mag1]

seivtcho, this is an important point. These cyclic dinucleotides appear to offer large potential in the treatment of cancer, though it appears necessary to inject a tumor for the anti-cancer effect. Many people even with severe cancer might not have a tumor directly on the skin that could be injected. If the immune response were to be the same when injected into more deeply seated cancers, then the CDN treatment could be a broadly applicable treatment for cancer.

 

A reference to confirm this assumption would be very comforting.

 

Anyone know of other biotechs that are actively pursuing CDN therapies?

Patents for CDNs indicate that even more potent formulations have been demonstrated.

Edited by mag1, 20 February 2017 - 05:41 PM.

[jondoeuk]

seivtcho, this is an important point. These cyclic dinucleotides appear to offer large potential in the treatment of cancer, though it appears necessary to inject a tumor for the anti-cancer effect. Many people even with severe cancer might not have a tumor directly on the skin that could be injected. If the immune response were to be the same when injected into more deeply seated cancers, then the CDN treatment could be a broadly applicable treatment for cancer.

 

A reference to confirm this assumption would be very comforting.

 

Anyone know of other biotechs that are actively pursuing CDN therapies?

Patents for CDNs indicate that even more potent formulations have been demonstrated.

 

Immunicum http://immunicum.se/pipeline/ are using allogeneic dendritic cells via IT injection for patients with HCC, metastatic RCC or GIST and you can seem some data here http://immunicum.se/...ctober-2016.pdf

 

Then there is NW Bio https://www.nwbio.com/dcvax-direct/ who are using autologous and activating the DCs using a proprietary method. In this Phase I multiple different types of solid tumours were injected https://www.nwbio.co...ides9-21-16.pdf They worked with Dr. Ravi Murthy at MD Anderson.

 

Going back to CDNs then it shouldn't be too hard to inject deep seated tumours. In this preclinical study they used it alongside radiotherapy http://cancerres.aac...content/76/1/50 You can even combine it with a TLR9 agonist (a number are in Phase I trials right now) for a synergistic effect http://onlinelibrary....201445132/full

 

Other companies pursuing these are Venn Therapeutics http://venntherapeut...m/pipeline.html http://www.abstracts...esentation/5963 and Spring Bank Pharmaceuticals https://pipelinerevi...unotherapy.html to name a few.

 

Another drug to watch is 3M-052/MEDI9197 (a Phase I is ongoing) http://cancerres.aac...Supplement/1475 http://www.abstracts...esentation/6080 Combining this with a TLR9 https://jitc.biomedc.../2051-1426-2-12 works better than either alone for large established tumours.

 

Edited by jondoeuk, 21 February 2017 - 12:09 AM.

[mag1]

Wow, very impressive.

 

Somewhat scary that some of these treatments appear available already on the grey market.

Probably would want human trials before trying these as you want to make sure that the human immune system works in the same way as that of a mouse.

 

There is a whole field that has been opened up with research. Love to see how the adopted T cell and other engineered T cell approaches will fit into this.

 

Jon, you have a high level of insight into these treatments. I am very interested in your timeline for when we might see the Cure emerge.

Things have been moving in this direction for quite a while. With cancer beginning to achieve durable complete remissions might mean that we are closer than many realize.

 

Will it be the immune drugs or perhaps the metabolic ones that push us over the line?

 

[Danail Bulgaria]

...

 

A reference to confirm this assumption would be very comforting.

 

...

 

A reference to confirm this assumption is too wide as a task.

 

A better is you to say which organ you think cant be injected.

 

Currently intratumoral injections are being made in the lungs and in the gynecology. Needle biopsies are being done in the liver, endoscopically biopsias have been taken from the pancreas. and the guts, laparoscopic interventions are for the abdomenal and the chest cavity. There exists methods for directly injecting the heart with a needle for another reason (heroic attempts to revive a stopped heart). I dont know a place in the body, that a needle hasnt penentrated in. The risks for some locations is another topic.

You give the ready drug Injecting will be designed in weeks.

[joelcairo]

You're making it sound too easy. I am optimistic about the potential of intralesional injections, but despite modern imaging techniques this process is complex and prone to error when the tumor is deep. I know someone with lung cancer, which doctors tried to biopsy approximately 5 times with a needle. None of the attempts were successful (no cancerous cells obtained). It was subsequently demonstrated they did have cancer, and the tumor was not small.

[Danail Bulgaria]

You provide the drug (low cost, please)   

The medics will manage the rest. 

[Danail Bulgaria]

lol 

wait a minute  

from the main cited link 

http://www.dailymail...l#ixzz4ZMRsrS8O 

 

the drug treats 

"melanoma models, as well as cancers of the head, neck and colon"

All of these are easily injectable. 

 

[solbanger]

Followup. Apparently the Australian press did do an investigation into Blushwood.

 

This link has pics of one dog that was treated with the extract. It also has the broadcast interview with a woman who had a tumor under her armpit destroyed in days using the EBC-46 compound.

 

This link goes to a herbal medicine site but there are other links on Google if you simply search the term Blushwood. Apparently a lot of people are seeking a way to find seeds of the plant and grow it themselves.

 

https://www.dherbs.c...lls-in-minutes/

 

I also thought it was interesting that as far back as 2012 people were talking about Blushwood on the AboveTopSecret website. http://www.abovetops...hread875116/pg1

 

 

I was thinking to myself that this might be useful against Pancreatic Cancer types as well as Prostate cancers if a way is found to inject directly into the organ. This compound could be a type of preventative medicine of sorts since those two cancer types typically grow slowly over the years. Once they become big is when they become a real problem.

[jondoeuk]

Followup. Apparently the Australian press did do an investigation into Blushwood.

 

This link has pics of one dog that was treated with the extract. It also has the broadcast interview with a woman who had a tumor under her armpit destroyed in days using the EBC-46 compound.

 

This link goes to a herbal medicine site but there are other links on Google if you simply search the term Blushwood. Apparently a lot of people are seeking a way to find seeds of the plant and grow it themselves.

 

https://www.dherbs.c...lls-in-minutes/

 

I also thought it was interesting that as far back as 2012 people were talking about Blushwood on the AboveTopSecret website. http://www.abovetops...hread875116/pg1

 

 

I was thinking to myself that this might be useful against Pancreatic Cancer types as well as Prostate cancers if a way is found to inject directly into the organ. This compound could be a type of preventative medicine of sorts since those two cancer types typically grow slowly over the years. Once they become big is when they become a real problem.

 

For localised prostate cancer (stage 1 and/or 2) then it could be useful. With the radical prostatectomy or radiotherapy then there is a one-in-three chance the cancer will return. There is a higher risk of complications from surgery in men who have previously had radiotherapy so this is rarely undertaken.

 

As for pancreatic cancer then the biggest problem are the liver and lymph node mets as most patients are diagnosed at a late stage. For both then we need to a multimodality approach. It will be interesting to see what inhibiting FAK does. This should not only reduce cancer stem cells but also decrease a number of different components of the stroma and certain immunosuppressive immune cells in the tumour microenvironment http://www.cell.com/...8674(15)01121-6 http://www.nature.co...ll/nm.4123.html http://mct.aacrjourn...10/11/2135.long Assuming data is positive then I'd like to see what combing this with a local TLR9 agonist http://www.abstracts...esentation/6175 a STING agonist http://cancerres.aac...content/76/1/50 and/or anti-ctla4 https://www.ncbi.nlm...les/PMC3962508/ in the primary does. We need to prime an effective systemic CD8+ T cell immune response (and more) to inhibit the growth of distal untreated lesions and EBC-46 doesn't do this.

Edited by jondoeuk, 06 March 2017 - 04:45 AM.

[mag1]

Could always prevent prostate cancer:

 

Dying For Love: Perimenopausal degeneration of vaginal microbiome drives the chronic inflammation-malignant transformation of benign prostatic hyperplasia to prostatic adenocarcinoma

P 44-47
April  2017

Medical Hypotheses

[jondoeuk]

 

 

Initial ADU-S100 (STING agonist) monotherapy data will come later this year (clinical trial identifier: NCT02675439). The anti-pd1 combo study (using PDR001) will start 2H.

Edited by jondoeuk, 30 March 2017 - 01:54 PM.

[joelcairo]

Look at the last 2 charts, of ADU-S100 in combination with anti-PD1 immune therapy. Zero growth of the injected or distal tumors! I've seen thousands of these charts, but I don't recall anything ever stopping tumor growth in its tracks like this.

 

The only thing I'm wondering is, if the tumor volume started out as essentially zero, then how did they do an injection?

 

[mag1]

Yes, when I saw that figure I was also very impressed.

 

It was a little confusing the way the chart depicted the growth curve.

It appears that they did not put the treatment and control on the same sub-figure, though the treatment clearly had an overwhelming effect.

 

clinicaltrials.gov talks of this trials continuing until 2020.

I am guessing that the results are too overwhelmingly positive to wait 3 more years.

[jondoeuk]

Look at the last 2 charts, of ADU-S100 in combination with anti-PD1 immune therapy. Zero growth of the injected or distal tumors! I've seen thousands of these charts, but I don't recall anything ever stopping tumor growth in its tracks like this.

 

The only thing I'm wondering is, if the tumor volume started out as essentially zero, then how did they do an injection?

 

Dr. Dubensky didn't go into any detail. I'm assuming (rightly or wrongly) once the tumour grew to 100 mm3 they started treatment.

[jondoeuk]

Intratumoral G100 to induce systemic immune responses and abscopal tumor regression in patients with follicular lymphoma http://abstracts.asc...199_188822.html

 

More than 40% of the FL patients experienced objective responses based on WHO criteria (at least a 50% tumour reduction), including substantial tumour shrinkage in untreated, unirradiated distal (abscopal) lesions. The safety profile remains favourable at higher doses than those previously reported in merkel cell carcinoma patients. G100 resulted in favourable tumour microenvironment changes. An increased intratumoral expression of inflammatory cytokines/chemokines, T cell infiltration, and an increased frequency of clonal tumour infiltrating lymphocytes, were observed.

 

This is currently recruiting participants https://clinicaltria...how/NCT02501473

[mag1]

jon, love to hear your take on the latest news in mitochondrial replacement: A published clinical trial!

Is this as big as I think it is?

Restarting OXPHOS in cancer, or genetically modifying mitochondria to have anti-cancer properties could have huge implications for caner treatment.

This could be a gateway to unlocking the metabolic dimension of cancer.

 

 

http://sci-hub.cc/10...ito.2017.03.004

http://www.longecity...nt-has-arrived/

[mag1]

A TLR 7 TLR9 and monobenzone triple off the shelf immunotherapy.

Wonder about side effects from other melanocytes in the body such as the substania nigra in the brain

 

 

https://www.ncbi.nlm.../?term=20498710

Edited by mag1, 19 May 2017 - 01:53 AM.

[jondoeuk]

jon, love to hear your take on the latest news in mitochondrial replacement: A published clinical trial!

Is this as big as I think it is?

Restarting OXPHOS in cancer, or genetically modifying mitochondria to have anti-cancer properties could have huge implications for caner treatment.

This could be a gateway to unlocking the metabolic dimension of cancer.

 

 

http://sci-hub.cc/10...ito.2017.03.004

http://www.longecity...nt-has-arrived/

 

The first link doesn't work.

[jondoeuk]

A TLR 7 TLR9 and monobenzone triple off the shelf immunotherapy.

Wonder about side effects from other melanocytes in the body such as the substania nigra in the brain

 

 

https://www.ncbi.nlm.../?term=20498710

 

A few dual TLR 7/8 agonists are in the pipeline/clinic. MedImmune have updated their trial (NCT02556463) to include patients with CTCL and combine it with radiotherapy and/or durvalumab. Dynavax are working on one and have a TLR9 in a number of trials as we speak. Then there is nektar who plan to file for an IND for their own (NKTR-262) sometime this year. Once the Phase Ia has been done they will add NKTR-214 (CD122 agonist) in the Phase Ib http://files.shareho...-_Mayl_2017.pdf (start at page 14)

Edited by jondoeuk, 01 June 2017 - 07:15 PM.

[jondoeuk]

Intratumoral G100 to induce systemic immune responses and abscopal tumor regression in patients with follicular lymphoma http://abstracts.asc...199_188822.html

 

More than 40% of the FL patients experienced objective responses based on WHO criteria (at least a 50% tumour reduction), including substantial tumour shrinkage in untreated, unirradiated distal (abscopal) lesions. The safety profile remains favourable at higher doses than those previously reported in merkel cell carcinoma patients. G100 resulted in favourable tumour microenvironment changes. An increased intratumoral expression of inflammatory cytokines/chemokines, T cell infiltration, and an increased frequency of clonal tumour infiltrating lymphocytes, were observed.

 

This is currently recruiting participants https://clinicaltria...how/NCT02501473

 

Intratumoral Injections May Change Soft Tissue Sarcoma Microenvironment http://www.oncothera...icroenvironment

 

''The team conducted a study with 15 metastatic STS patients. All of the patients had undergone a median of 3 prior lines of therapy and the mean tumor size was 5.6 cm. Each patient received the intratumoral injections weekly for 8 to 12 weeks. Among these 15 patients, 12 received concurrent radiation for 2 weeks and three patients received G100 alone for 6 weeks prior to radiation.

The researchers found there were no grade 3 or higher treatment-related toxicity and local tumor control was achieved in 14 of the patients (93%). In six patients (40%), stable disease occurred after treatment and one patient had complete regression of their injected tumor. Pollack, who is an assistant professor at the Fred Hutchinson Cancer Research Center in Seattle, said the study showed that the injections resulted in what appeared to be systemic expansion of tumor-specific T cells. The researchers found in seven patients evaluable for tumor-associated macrophages, 71% had a shift from an M2 to M1 phenotype. In all patients who received G100 alone, there was an increase in T-cell infiltration into their tumors.''

 

The company plan to combine this with CMB305 http://abstracts.asc...99_191129.html http://www.immunedesign.com/pipeline/ in those with STS

Edited by jondoeuk, 01 June 2017 - 07:28 PM.