Are you currently (or have you been) in a Clinical Trial?
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thank you for replying . Yes Im tripple negative .
Unfortunatly I can not acssess to clinical traial because I live in IRAN .
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Not sure if this was covered yet, but a phase 3 trial for BRCA-mutant (presumably would also apply to those cancers with other mutations in the DNA repair pathway) that combines PARP inhibitor with carboplatin and paclitaxel chemos in the BROCADE3 trial was recently reported in The Lancet. Patients were allowed two prior chemos in the metastatic setting. Median PFS for the combination was 14.5 months (remember it means half went longer)compared to 12.6 months for the chemo-alone group.
Interpretation
The addition of veliparib to a highly active platinum doublet, with continuation as monotherapy if the doublet were discontinued, resulted in significant and durable improvement in progression-free survival in patients with germline BRCA mutation-associated advanced breast cancer. These data indicate the utility of combining platinum and PARP inhibitors in this patient population.
https://www.thelancet.com/journals/lanonc/article/...(20)30447-2/fulltext
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Dear Andish, I am sorry you are in this situation but... first, no one can tell you how long you will live (oh, they have been wrong so many times before), and then no one knows if you can get to NED or not too. Iran is a big country and runs a lot of clinical trials (I just checked https://www.irct.ir/), so please ask your oncologist to look for them. If he/she is not willing to do that, try to maybe change the oncologist (I know it is not possible everywhere in the world) for the one who wants to fight for you. Also, please think of neighboring countries (Turkey, Saudi Arabia, etc.), they run lot's of clinical trials too. I know all of this can be overwhelming but there's no other way - just to fight for yourself. All the best, Saulius
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Andish, looks like Saulius gave you a good lead there for clinical trials in Iran. I was thinking maybe contacting Tehran University Medical School too? I don't know if that could help but I wish you luck. Don't give up.
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How to harness the full power of immunotherapy?
We know that cancer cells attract immune cells that shield them from T-cells that will kill them.Various strategies are being pursued to open up the cancer to the immune system, and combine those drugs with immunotherapy.
Another method also used in breast cancer is high levels of BIRC2 protein expression; BIRC2 prevents the cell from undergoing suicide, and protects it from cell death by the immune system or chemo. Losing BIRC2 makes the cells be killed more readily and attracts more cancer-killing immune cells.
Inhibitors of BIRC2, called SMAC mimetics, have already been in clinical trials, but didn't do a lot on their own. The idea is now to combine them with immunotherapy. Sounds like a 3-way combo of immunotherapy, anti-BIRC2, and a third drug to better expose the cancer to the immune system is what we need? Time to start talking SMAC..
https://www.sciencedaily.com/releases/2020/09/2009...
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Time to start talking SMAC..
Love this curious
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Cure-ious,
Thanks for posting the article. It’s really fascinating how cancer cells manipulate its microenvironment. They are really devious. Hopefully, all these recent research findings help find a more effective tool against cancer
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Cure-ious- interesting. it seems like a triplet of some kind will be the ticket.. some day this may all be garden variety treatment. hope springs eternal.
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City of Hope is reporting a strategy to broaden the use CAR-T cells directed against cancer cells that express CD19. Such cells are in use for cancers that over-express CD19 on their surface, but a lot of cancers don't do that, and/or don't seem to have any cancer-specific target to attract engineered T cells.
Their approach is to use it in combination with an oncolytic virus that will infect the cancer and cause the expression of CD19. This works in mice. They hope a clinical trial can start in 2022 for advanced solid tumors. Of course you'd have to say the infection would not necessarily hit every single metastatic cell in the body, and those cells not expressing CDK18 can still escape to grow another day... Seems a limitation to the design, but for patients right now something that can drop down a lot of the cancer with fewer side effects would still be a major benefit:
https://www.sciencedaily.com/releases/2020/09/2009...
However, there may be other better options. Just last December a Nature paper reported the discovery of a small molecule target that seems to be over-=expressed in all cancer cells and not in non-cancer normal cells. This so-called Universal Tumor Antigen was attacked in a UK patient by a specific T cell receptor, and now that they have this information, they can make a CAR-T that should go after all cancers without this work-around mentioned here, ie of making the cancer cells express CD19 so that they will be killed by the CAR-T. Ifr they can get a universal CAR-T up and running, then combine it with immunotherapy and something that gets rid of the brick wall shielding the tumor from the immune system- would that be enough?! Lordy, something has to hit big here, they are trying so many approaches
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Dear Cureious - do you talk about this one: https://www.cardiff.ac.uk/news/view/1749599-discov... ? I think they call this "dark antigen", and I think EnaraBio has some "rights" to the technology. Did not hear much from them lately...
Also MIT has something special (https://news.mit.edu/2019/car-t-cell-therapy-cance...) but again... mice...
Saulius
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Hi Saulius,
Yes, that's the one! CAR-T is in infancy, no trials have gone beyond phase 2 and there is a lot to work out before it shows any benefit for solid tumors. So much work that I assumed a couple of years ago it would never be a "thing" in my time. But the field has moved fast. One problem is that it requires cancer to have a unique protein "marker" to target the T cells to it, and make they won't interfere with normal cells. Those cancer markers are present in a few cancers but not breast (except for Her2), and in cases like Judy Perkins they undertake this laborious search patient by patient, combing through their specific cancer cells by proteomic analysis to find some proten marker uniquely expressed on the surface of the cancer (in her case I think they found 4 different cancer antigens to target, so she won the lotto). But this new discovery means that most or all cancers now have at least one marker that can be used to target the T cells to, using this universal antigen. They created a start up (ENARA) to move this to CAR-T clinical trials, and in the link below there is one paragraph that mentions them and says they hope to start one by the end of this year. Of course that will just be phase 1 for safety and tested as monotherapy, so its of limited use right now
https://www.labiotech.eu/cancer/t-knife-t-cell-the...
But then as your other links shows, besides the targeting they also have to work out how to get around the immunosuppressive environment that cloaks solid tumors. Their vaccine looks really good, no? Mice did not respond at all to CAR-T alone, but then many of them fully cleared the tumors when a immune boosting vaccine was added, and targeted to the lymph nodes. There are other immunotherapy combinations being tested to try to unmask cancer to the immune cell killing, so lots of options exist for combining those with CAR-T.. Just how long will it all take, though? On the other hand, we just need one promising clinical trial available to give a realistic good shot at benefitting from immunotherapy, then we can be in good shape for the later breakthroughs.
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I was really hoping CAR-T would be further along. Seems like solid tumors are really being tricky. Ever since my original diagnosis I kept thinking we just need to kick this can down the road & hopefully by then new treatments will be avail. I'm glad to be getting the immunotherapy but what next?
Cure-ious - do you know offhand if people have gone from one immunotherapy into another one, or is there any point? Like if I start progressing on atezolizumab does it make sense to try to get on pembrolizumab for example?0 -
Metarrestin
Anyone heard of this drug. NIH has a trial for it. NCT04222413interesting read https://www.cancer.gov/news-events/cancer-currents-blog/2018/metaresstin-metastatic-tumors0 -
Dee that sounds good and Bev its close to us... I know my MO isn't trilled with me going to a Phase 1...but if I progress on this...I may consider it.
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Dee,
That looks really interesting -- how the heck did you find that trial? The problem is that it's a Phase I trial. But it is a very intriguing idea.
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Hi.
Is anyone involved in the following clinical trial for TNBC vaccine?
https://clinicaltrials.gov/ct2/show/NCT03012100
I am very interested in the vaccine trials and I was hoping for input on the side effects of the various vaccines that are currently in the trial stage. Thanks
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Moth, Absolutely you can go from one immunotherapy combo to a different one, and its helpful to think what might synergize with the drugs you are getting in the current trial, and try to get them in the next treatment. Your immune system has been revved up by immunotherapy, so pick the next treatment to include some drug that you hope might synergize with that. People who take immunotherapy tend to have a longer overall survival, because even if the trial they got it on didn't do a lot, one or more of the subsequent treatments worked better. For example KattySmith, at the top of this thread, said that her MO directed her to an immunotherapy trial because he doubted she would respond to more chemo, and sure enough she responded to the immunotherapy but also to the Halaven that she took right after that. So worth thinking about what sequence of treatments might work best
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bevGen
I do a lot of my researching but missed this one.MBC Connect will send you trials that they think match your cancer. Some do some dont. The Metarrestin was one they sent me.
Dee
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AlabamaDee,
Very interesting find!!
Metarrestin "appears to work by killing cells that have developed a structure called the perinucleolar compartment (PNC) within their nuclei. These structures develop almost exclusively in cancer cells—especially the cancer cells in metastatic tumors—and not in healthy cells,"
The nucleolus is where ribosomes make proteins, and many cancer cells are very "addicted" to ribosomes because they have to express (or sometimes over-express) a ton of proteins that normal cells don't make. So in broader terms, Metarrestin seems to work like a ribosome inhibitor.
This reminds me of a study last year which showed that PARP inhibitors work not only on BRCA-mutant cells, but in fact 70% of all breast cancers, including many that do not have BRCA mutations, will probably respond to this important class of drug. Right now it is only for BRCA patients, but they found another effect they have on cancer cells that is not related to DNA repair or BRCA activity. Cancer cells treated with PARP inhibitors caused a protein DDX21 to leak out of the nuclelous, which poisons ribosome activity in the nucleolus. They are now trying to create a biomarker test based on this finding, so you could take a genomics test that would show that you have DDX21 in the nucleolus, which would indicate that the cancer has revved up the ribosomes and protein synthesis components and is likely addicted to it, and therefore you are a good candidate to respond to PARP inhibitors, regardless of your BRCA status.
I had forgotten about that work, but keep a PARP inhibitor on your list for the future, they just need to open up the eligibility requirements so we have access to this drug. PARP inhibitors are also tested with immunotherapy
https://www.eurekalert.org/pub_releases/2019-07/us...
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Cure-ious,
Thanks for confirming what I thought I had read about the PARP inhibitors -- and that is why this stuff sounded so familiar.
In somewhat related news, in a small bottom of the page article in today's Washington Post, it said that AbbVie has struck a deal on a cancer drug with a Chinese drug developer, I-Mab. Abbvie is getting the exclusive global license to develop and sell the Chinese company's cancer-fighting drug known as lemzoparlimab, also known as TJC4, which is an antibody used to treat multiple forms of cancer. According to the article, the drug therapy targets a "do not eat me" signal that allows cancer cells to avoid being targeted by a patient's immune system, blocking the signal to allow the immune system to "engulf and eradicate the malignant cells." Apparently, the Chinese company also has two other antibodies based upon the same drug, and AbbVie will develop those as well.
Could this mean that there are more immunotherapy treatments coming our way? And how do we get the FDA to move at lightning speed on these drugs/trials, now that we know that things might be able to be done just a little bit more quickly on drug approvals?
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Thanks cure-ious
I actually have PARP inhibitor on my list for future treatment because of the MRE11a mutation. you just gave me more reason to look at it closer
targeting the MRE11-RAD50-NBS1 (MRN) complex
PARP inhibitor findings suggest that defects in MRN complex may synergize with PARPi and elevate its efficacy.
https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-019-1100-5
Dee
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Hi Bev- Ha! Yes I saw the same story yesterday when I was looking up the status of CD47 antibodies- this is a different target for immunotherapy, and when I was first diagnosed I bought a few shares in the company Trillium Therapeutics because they do have a great antibody that hits it and I thought this would be a "good luck" investment. The company stock promptly sank like a stone, truly to pennies, but has rebounded a bit this year, it turns out you have to have a good business plan in addition to having a great drug to succeed in this business. In the meantime Stanford started out FortySevenInc, with a less effective monoclonal antibody, and they got bought out by Gilead and made a lot more money with a less effective drug, go figure).
Anyway, the trials all continue with CD47 (it is like PD1/PDL1, but is used by different cancers to hide from immune system). So far the big results have come in mostly from the blood cancers, but they are trying to get solid tumors to respond. The trillium drug still looks good but it is still dialing up the dose they are testing in what feels like the slowest series of sequential phase one trials in the history of the world..
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Dee- Exactly, they are starting to understand a whole network of homologous DNA repair defective proteins affect the same network as BRCA. And then this new work by Lee Krauss (who I knew when he was a grad student) shows that PARP inhibitors also have this unrelated effect of blocking extra protein synthesis so even those without mutant DNA repair proteins may well respond. So in your cancer PARP inhbition might work especially well, by inhibiting both the DNA repair as well as ribosome/protein synthesis pathways. And then get it in combo with some kind of immunotherapy and throw in whatever else is needed to make it all access the tumor, really how hard can this be?!
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Chemists have designed a compound that activates the STING protein, which is a strong stimulator of the immune system- the drug acts similarly to a natural compound that activates STING but has a very short half-life- the drug persists for a long time- works great in mice, nice story (as expected for a paper in Science). They hope to move this to clinical trials, test alone but especially in combination
https://www.sciencedaily.com/releases/2020/08/2008...
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Cure...does this DDX21 show in F1 or Tempus testing?
"so you could take a genomics test that would show that you have DDX21 in the nucleolus, which would indicate that the cancer has revved up the ribosomes and protein synthesis components and is likely addicted to it, and therefore you are a good candidate to respond to PARP inhibitors, regardless of your BRCA status."
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Hey Nicole,
No, your existing tests wouldn't have this information because all cells have DDX21, the question raised by this study is whether the DDX21 has accumulated in the nucleolus (a substructure of the nucleus) which would indicates that it is there to help the ribosomes to make a large amount of extra proteins, and that the cancer is likely addicted to this process. So it is the location of the DDX21 in the cell, rather than the level of expression or whether there is some mutation, that the test has to look at. To learn the location of DDX21, they need to look at the cancer cells under the microscope and stain for DDX21. The DDX21 protein has to be modified (ie, attached to a PARP moiety) in order for it to go to the nucleolus, and therefore in these cases the PARP inhibitor prevents that from happening and so protein synthesis stops and the cell dies or at least stops growing.And apparently about 70% of MBC cancers have this process going on.
Right now the researchers are looking at people in existing clinical trial to see if this test accurately predicts who will respond to PARP inhibitors in the clinic. So although PARP inhibitors may not be on your current list of recommended drugs, there is presumably great interest within the companies that sell PARP inhibitors to develop such a test and get it out there ASAP..
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Cure-ious,
Thanks for your helpful explanation of this. I had the same question as Nicole.
I did have to laugh at your last sentence, though -- I'm SURE that the drug companies want this out there.
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Thanks Cure...I GET IT NOW LOL
. You really are such an asset to this site 0 -
Bev,
Yep, the unrestrained greed of Big Pharma is the only thing that will actually come save us at the end of the day. Once they finally figure out which immunotherapy combo works for melanomas and lung cancer, and everybody and their dog has a piece of that action, they will swing their heads around and notice the great big juicy MBC patient pile and start crawling over to us. Our power is in our collective Market Share.
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I have a question about what happens when a trial is over. On the NIH clinical trials web page for my trial: “Estimated primary completion date...The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure...” and “Estimated study completion date...The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit)...“
So in simple language, what does this mean for me if I am still NEAD when these dates come up in 2021 and 2022? Does the sponsor, the pharmaceutical company, stop providing the study medications to me, and I have to try to get insurance to cover?
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