Immunotherapy drugs for breast cancer
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What a wonderfully informative post, JohnSmith. I am reading what you have said carefully. I am not clear, however, as to who might be eligible for this type of treatment. I still do not know what my stage is but it is a Grade 3, Invasive Ductal Carcinoma, Triple Negative Breast Cancer. I am in Canada, and not sure if this is even available to to Canadians. Is it only for Stage IV Advanced Cancer patients, or is it something that is coming into wider use? Our Province is said to be lagging behind the rest of the country in Health Care.
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nancy - TNBC is considered the breast cancer most likely to respond to immunotherapy. talk a look a the post from marijen, just before yours. She lists resources from the Cancer Research Institute that will help you find trials. there are trials in canada and they can help you find them.
>Z<
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zarovka, thank you for your suggestion about tthe post to read. I will do that now. Have a great day.
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Hi,
Thank you for posting this info.
Looks like most of the trials have already ended or about to end. Where can we read about the results? Thank you!
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scarlex. the truth is that very very few trials post their results. it's a huge issue. in general, significant positive results get reported. the rest is really hit or miss.
>Z<
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I believe there are basically two ways to put cancer into remission, immunotherapy and oncolytics. Oncolytics is arguably a form of immunotherapy so maybe just one. I have been disappointed with the lack of progress, which I feel is due to a lack of effort, in oncolytics. Very little research in the US but I stumbled upon this trial for ovarian cancer at MDAnderson
http://www.mayo.edu/research/clinical-trials/cls-2...
As well as this presentation by the lead researcher from May 2016 suggesting that we are getting somewhere In case the link doesn't work, search YouTube for "Ovarian Cancer Research and You" - Harnessing Viruses For Ovarian Cancer Immunovirotherapy.
https://youtu.be/2A8kT-PhSKYKeep an eye out.
>Z<
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I had seen a list of triple negative phased studies back in 2015 or early 2016 and it showed a good portion were to end in 2017. Haven't seen that happen yet. I think only Katruda was given fast track so far. I don't remember where I saw this list as my wife was estrogen positive and she was on tamoxifen so it didn't apply to her. Her estrogen pos turned triple negative and she's on Xeloda with her numerous spinal mets gone or in remission.
Charge on Xeloda!
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I see I have some catching up to do after a few days away. My understanding of Immunotherapy is that it is sed for Stage IV cancer. I still don't know what stage I am because the sentinel node biopsy was still not in last Wed after three weeks. It is Thanksgiving here, so will call tomorrow and see what I can find out. Fingers crossed! Take care everyone
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I want to see this happen. If I have a recurrence I will not do chemo or radiation so it might be my only hope.
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The key to making PDL-1 inhibition work for more than a limited subset is to combine PDL-1 inhibitions with other therapies that overcome immune suppression. This article summarizes the most promising combinations as of Dec 2017. One of them stands out because they have expanded the trial to include TNBC. Most work on checkpoint inhibition is not being done on breast cancer so this is great news.
Anti-PD-1 in combination with IDO inhibitor (epacadostat)
Indoleamine 2,3-dioxygenase 1 (IDO) is an immunosuppressive enzyme that modulates T-cell function (10). It catalyses the cleavage of L-tryptophan, with the metabolites promoting regulatory T-cell generation and blocking of effector T-cell activation, which can contribute to immune surveillance avoidance by tumour cells. Epacadostat is a potent and selective inhibitor of IDO which, combined with ipilimumab and pembrolizumab (11) in proof-of-concept studies, has shown strong efficacy with improved response rates compared with prior data for immune checkpoint inhibitors alone, with minimal additional toxicity. Recently, a large programme of trials of epacadostat plus pembrolizumab was initiated in patients across five tumour types: metastatic melanoma, non-small cell lung cancer, bladder cancer, renal cell carcinoma, and squamous cell carcinoma of the head and neck. Combinations of epacadostat plus nivolumab are also in clinical trials.
This is the trial.
https://clinicaltrials.gov/ct2/show/NCT02178722
The results reported in 2016 on an initial group of 19 pts who were treatment-naive for advanced melanoma, are 4 CRs, 7 PRs, and 3 SDs. Basically 14 of 19 people responded with stable disease or better. Normally we are seeing 20% response rates to PDL-1 inhibition. If I had TNBC, I would be looking at this trial.
>Z<
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Apologies if this is not a good place to post this, but I learned of two immunotherapy trials for tnbc:
The other is by Novartis: A Multi-Centered Randomized Phase II Comparison of Single-Agent Carboplatin versus the Combination of Carboplatin and Everolimus for Treatment of Advanced Triple-Negative Breast Cancer
I'm sure they are listed on Clinical Trials so one can learn more about them.
I'm currently in the Tapimmune trial so I won't be looking into either of these. It is discouraging that there are trials that don't post results or we (patients) don't learn much from them. Some of you are so much more knowledgeable than I am. I'm just happy that there is research activity.
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Thanks aterry. This is the place. How is the Tapimmune trial treating you?
>Z<
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My experience with the Tapimmune trial has been good. I'm in the cytoxan arm so the first month I had an infusion with the usual reactions to that. The 2nd, 3rd month I had virtually no reaction to the injection--just slight swelling & pinkishness at the injection site that went away after 2 hours. I had the 4th shot on Wednesday and this time in addition to the initial swelling (which went away after 2 hours) an area of swelling & pinkishness & itching, about 1 1/2" in diameter, developed 12 hours later and is just now fading. Still that seems like a very mild side effect compared to chemo. The next phase for this trial is enrolling but I haven't seen which of the 4 variations for delivery will be used.
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My experience with the Tapimmune trial has been good. I'm in the cytoxan arm so the first month I had an infusion with the usual reactions to that. The 2nd, 3rd month I had virtually no reaction to the injection--just slight swelling & pinkishness at the injection site that went away after 2 hours. I had the 4th shot on Wednesday and this time in addition to the initial swelling (which went away after 2 hours) an area of swelling & pinkishness & itching, about 1 1/2" in diameter, developed 12 hours later and is just now fading. Still that seems like a very mild side effect compared to chemo. The next phase for this trial is enrolling but I haven't seen which of the 4 variations for delivery will be used.
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Thanks aterry. Keep us posted, please.
>Z<
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Doctors Said Immunotherapy Would Not Cure Her Cancer. They Were Wrong.
By GINA KOLATAFEB. 19, 2018
Oriana Sousa, 28, who lives in Marinha Grande, Portugal, had a rare, aggressive form of ovarian cancer. Traditional treatments failed, but with immunotherapy her tumors shrank so much that there is no evidence of disease. CreditDaniel Rodrigues for The New York Times
No one expected the four young women to live much longer. They had an extremely rare, aggressive and fatal form of ovarian cancer. There was no standard treatment.
The women, strangers to one another living in different countries, asked their doctors to try new immunotherapy drugs that had revolutionized treatment of cancer. At first, they were told the drugs were out of the question — they would not work against ovarian cancer.
Now it looks as if the doctors were wrong. The women managed to get immunotherapy, and their cancers went into remission. They returned to work; their lives returned to normalcy.
The tale has befuddled scientists, who are struggling to understand why the drugs worked when they should not have. If researchers can figure out what happened here, they may open the door to new treatments for a wide variety of other cancers thought not to respond to immunotherapy.
"What we are seeing here is that we have not yet learned the whole story of what it takes for tumors to be recognized by the immune system," said Dr. Jedd Wolchok, chief of the melanoma and immunotherapeutics service at Memorial Sloan Kettering Cancer Center in New York.
"We need to study the people who have a biology that goes against the conventional generalizations."
Four women hardly constitutes a clinical trial. Still, "it is the exceptions that give you the best insights," said Dr. Drew Pardoll, who directs the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Medicine in Baltimore.
The cancer that struck the young women was hypercalcemic small cell ovarian cancer, which typically occurs in a woman's teens or 20s. It is so rare that most oncologists never see a single patient with it.
But Dr. Douglas Levine, director of gynecologic oncology at New York University Langone Medical Center, specialized in this disease. A few years ago, he discovered that the cancer was driven by a single gene mutation. The finding was of little use to patients — there was no drug on the horizon that could help.
Women with this form of ovarian cancer were sharing news and tips online in a closed Yahoo group. Dr. Levine asked to become part of the group and began joining the discussions. There he discovered patients who had persuaded doctors to give them an immunotherapy drug, even though there was no reason to think it would work.
The women reported that their tumors shrank immediately.
The idea behind immunotherapy is to dismantle a molecular shield that some tumors use to avoid an attack by the body's white blood cells.
The immune system sees these tumors as foreign — they are fueled by hundreds of genetic mutations, which drive their growth and are recognized by the body. But when white blood cells swarm in to attack the cancer cells, they bounce back, rebuffed.
Immunotherapy drugs pierce that protective shield, allowing the immune system to recognize and demolish tumor cells. But the new drugs do not work against many common cancers.
Those cancers are supported by fewer genetic mutations, and experts believe that the tumor cells just do not look threatening enough to the body to spur a response. So the immune system leaves them alone.
Lung cancer, a genetic type of colorectal cancer and melanoma have huge numbers of mutations, and immunotherapy drugs often are successful in treating them. Cancers of the prostate, pancreas, breast, ovaries — and most other tumors — carry few mutations.
"These are the cancers that rarely respond," Dr. Pardoll said.
The idea that the drugs might work against something like hypercalcemic ovarian cancer, which is fueled by just one genetic mutation, just made no sense.
"For the vast majority of cancers, there is an amazingly clean correlation between response to therapy and mean mutational load," Dr. Pardoll said.
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Ms. Sousa returned to work as an organizational psychologist and works out vigorously every day.CreditDaniel Rodrigues for The New York TimesBut there were a few oddball exceptions. An unusual skin cancer called Merkel cell carcinoma responded to immunotherapy, scientists found. It is caused by a virus, and researchers suggested the infection itself draws the attention of the immune system.
Mesothelioma also responded, perhaps because the asbestos that caused it also inflames the immune system. And some kidney cancers responded to immunotherapy treatment; no one knows why.
And then came a handful of women with a rare ovarian cancer. Oriana Sousa, 28, a psychologist in Marinha Grande, Portugal, was one of them.
She found out she had cancer in December 2011. She knew something was wrong — for several months she had been feeling tired, constipated and endlessly thirsty. She began vomiting and had abdominal cramps. But her doctors told her she was fine and not to worry.
Finally, her aunt, a nurse, suggested she see a different doctor, who performed a CT scan of her abdomen. It revealed a huge mass. The doctor operated to find out what it was. Two days later, he gave her the bad news: Cancer, and a really terrible form of it.
For the next four years, Ms. Sousa's doctors tried to control the cancer, giving her rounds of chemotherapy, radiotherapy and surgery. But every time, new tumors emerged.
"I suffered a lot, and I felt I had no life," she said.
Things are different now. In 2015, she finally persuaded a doctor to give her an immunotherapy drug, nivolumab. Immediately, her tumors shrank and continued shrinking as she continued with the drug — so much that her doctors now say she has no evidence of disease. Life has returned to normal.
"Generally after work, I go to the gym and do classes and work out," she said. "People who don't know what I have been through, they can't imagine I am an oncology patient."
What saved her? Dr. Eliezer M. Van Allen, a cancer researcher at Dana-Farber Cancer Institute, has come across one clue.
He found that a gene mutated in kidney cancer was sort of a master regulator of other genes, controlling which were turned on and when. But the regulated genes were normal and did not produce proteins that the immune system might recognize as abnormal.
Nonetheless, patients responding to immunotherapy were the ones with the master gene mutation. "We saw this result and weren't sure what to make of it," he said.
Dr. Levine and his colleagues found the same phenomenon in patients with hypercalcemic ovarian cancers. One explanation, he and Dr. Van Allen said, is that the immune system may recognize that cells in which genes are erratically turning on and off are dangerous and should be destroyed.
"That is strictly hypothesis," Dr. Levine cautioned.
One thing is clear, though: When pathologists examine these tumors, they find white blood cells in them — as if the immune system were trying to attack. And that finding has led both Dr. Pardoll and Dr. Padmanee Sharma of M.D. Anderson Cancer Center in Houston to plan new clinical trials.
They know that immunotherapy fails most patients, even those with cancers that are most likely to respond. So they have set out to create a test to determine who might respond to immunotherapy and then treat those patients — regardless of their cancer type.
Dr. Sharma's study, funded by the Parker Institute, is getting ready to enroll patients. The researchers will look at pathology slides of patients' tumors to see if white blood cells are worming their way into the cancers. If so, the patients will get an immunotherapy drug to help activate their white blood cells to attack the tumor.
If there are few white blood cells in the tumor tissue, patients will get a combination of two immunotherapy drugs to help move more white blood cells into the tumor and help them attack.
"The trial is written for all comers," Dr. Sharma said. "If we have learned anything, it is that it is not the tumor type we are treating — it is the immune system."
At Johns Hopkins, Dr. Pardoll and his colleagues are planning a similar trial. They will be looking for tumors — it does not matter what type — that have a protein, PD-L1, on the surface that repels the immune system. Any patient whose tumor fits that description will get an immunotherapy drug.
It's a shot in the dark. But sometimes such a shot finds the mark, as Ms. Sousa will tell you.
"Incredible things happen, and against all the odds," she said.
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I like that the trial is open to all takers.
This is another study from Barcelona published in Nature as well as one from Genentech (both mouse studies only) on how TGF beta Inhibitors could make tumors more responsive to immunotherapy.
http://www.nature.com/articles/nature25501
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Thanks Heidi. I talked with my immotherapy specialist on Monday. He stressed that a biopsy of a tiny piece of a single tissue can tell you very little about the cancer because of the heterogeneity of tumors as they develop. I like that the trial is open to all takes as well.
>Z<
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since these are mice, they probably examined the whole tumor and microenvironment, or as mentioned the peritumor stroma.
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Thanks Husband. The Hallwang clinic in Germany combines PDL-1 inhibition with a personalized dendritic cell vaccine and sometimes a preparatory dose of chemo. I've seen 3 credible complete remissions out of Hallwang with this technique recently but only with TNBC. TNBC evolves differently and evades the immune system through immune suppression rather than withdrawing MHC1 receptors. This makes TNBC a much easier target for immunotherapy and my gut is that Hallwang has cracked that nut. As Cure-ious notes, the private clinics outside the US have gone further, faster with developing immunotherapy. They have more flexibility to experiment and tailor treatments to the individual.
This option is not helpful for me and my ERPR+ cancer but if anyone with TNBC and $100K to spare could potentially benefit.
>Z<
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Alternative clinics like Hallwang in Germany or elsewhere in Europe offering experimental drugs are probably nowhere near equipped to handle some very serious side effects of these drugs. I wouldn't go near them except maybe for Vitamin C infusions or other relatively harmless treatments.
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Heid - That's a good point. They are experimenting. The risks need to be considered. However, the risks of checkpoint inhibition, and many drugs, are understated and often poorly managed in the regular US healthcare system. Many of us are at the point where the risks of going beyond the standard of care are less dangerous than the known, measured, reported consequences of following the standard of care.
>Z<
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Z, Hallwang has a history of questionable practices. Farrah Fawcett went there and I believe she regretted it. I only remembered that when I saw a picture of the clinic. Things may have changed, certainly their treatments have changed (and prices have gone up). The pictures on the Internet of Hallwang Clinic are still the same as this picture of a thalasso therapy center at http://www.waldeck-klinik.de/
The Hallwang website also raises red flags for me with the testimonials (unethical in Germany) and the lack of names (who is in the medical team?) and research publications. I agree some people are at the point of wanting to try anything and maybe Hallwang treatments are worth it now, if they weren't before. But more of us and science as a whole would benefit if they published data on their protocols. Going outside of approved clinical trials may be good business practice but not good scientific practice.
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Heidi - Hallwang has had credible successes recently with TNBC combining proven therapies in a way that makes complete sense but is not practiced in the standard setting. Immunotherapy treatment needs to be tailored to the individual and combined in varying ways to get results. We don't have a process that can validate and translate to the clinic individualized treatments that involve multiple therapies, we can only deal with populations. I talked again with my immunology specialist here in Japan. One of the leading researchers in the world. He stressed that every cancer is individual. In fact you get only limited clues from the broad categories we use to inform treatment decisions. He also observed that you have to take certain risks when you don't have other good options.
The question, then, is whether the standard of care is a good option relative to the risks of these private clinics. I have managed scientific research for years. I believe the standard of care has veered way off course as has the direction of cancer research generally. This is due to a risk averse "science" fetish when what we are fighting is a guerilla war, a clinical environment that cannot function without recipes as well as the economic drivers that everyone points to. But really it is our ideas our ideas about medical science and how science should translate to cancer treatment have failed us in the cancer setting.
I am not looking at Hallwang. I don't have TNBC and I do have questions about their ERPR+ protocol. Buyer beware, they have some silly stuff going on. Still, my best options incorporate standard treatments in novel regimes with other non-approved treatment and are not available in a regular cancer clinic. The only question is what I can afford. Although these options are far cheaper than even the cost of my diagnostic scans, insurance does not pay for it. It never will. Given the course of research and government approvals of treatment, the treatment I need will never get to the clinic.
So, you have to take certain risks when you don't have other good options.
>Z<
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Do you know how many people die for every success that they have or how long they live after a success? They probably don't publish those statistics. That is why these advertisements/testimonials are considered unethical. With clinical trials the risks are usually known to the medical world and results can be reviewed. 10 years ago I was advised not to join a stem cell transplant trial because of the risks relative to other options for my individual case. I appreciated that the triallists did not keep secrets from the medical world.
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I agree in many respects but who wins on ethics I am not sure. The more I get into this, the more I am disgusted by the trajectory of cancer research.
We know that chemotherapy is approved based on time to progression, not overall survival. When we do measure overall survival, it is often not improved by these regimes. The trials work like this ... yay we've improved time to progression two months, lets get this money maker in the clinic. Sometimes we get overall survival numbers, usually they are weak. The ethics of the standard of care regime have their issues. Ethics are tricky.
But my main issue is the approach of the Cancer Research Machine which plods through each treatment individually looking for a single magic pill ... that is just never going to get us to a manageable disease. Cancer has too much jazz going on. Is it ethical to spend all that effort fighting the wrong battle when so many women are dying? I believe that this diseases will be managed first in private clinics by good doctors, not by the Research Machine, which is failing.
The vast majority of women with MBC who follow the standard of care will die a premature death from the disease. There is risk anywhere you turn when you are in this situation. I have a hard time distinguishing the standard of care from the private clinics as far as risk and benefits and credibility.
I have enough of a scientific background to weed out people who are blowing smoke and that is critical when going off the beaten path. But the fact is that my regular MO is following a recipe most of the time and otherwise blowing smoke. She doesn't understand the drugs she prescribes or their side effects, hasn't actually read the trial results. She is typical of the breed. The standard clinic as a safe place is not something I have experienced. My MO scares the pants off me frequently.
>Z<
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Thanks for the interesting discussion, Heidihill and Zarovka.
I have nothing to add but have for some time been wanting to ask you, Zarovka, if you have blogged or anywhere reported on your immunotherapy experience in Japan.
I don't want to pry, however, so if that's not public information, I fully understand!
Thanks,
M
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MRock - I had a conversation with fighterm on inspire about the therapy. It's a good read because fight is a molecular biologist with a healthy skepticism. I am in total agreement with Heidi that these approaches need to be considered critically. There is a lot of nonsense going on.
https://www.inspire.com/fighterm/journal/natural-k...
Feel free to PM me for more info.
>Z<
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Thanks, Zarovka! I know of fighterm and look forward to reading your conversation!
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Z, I am treated in a private cancer center that does trials with the Research Machine. They also have cancer immunologists on board, including specialists in checkpoint inhibition. But the difference is that they are accredited by various European and international bodies. Medicine should not be a free for all and some oversight is necessary to protect patients. False or misleading advertising can mean financial ruin for many patient families. This is heartbreaking, too.
I have taken plenty of risks in my treatment and have had many discussions with my MO about risks. Fortunately we have a good rapport. For example, I asked for bisphosphonates along with 3 chemo agents (TAC) from the very start and with the same frequency (every three weeks), not standard then but probably a good move as later studies confirmed concurrent bisphosphonate treatment to be beneficial. So I really understand the need for doctors to part from the script. We are all different. I survived 5 years of bisphosphonates without any necrotic bones in my thighs or jaw. Some patients are not as lucky and are not able to withstand the chemical onslaught. But a good doctor will be able to help patients assess risks. I hope you find one who does this and who can guide you through this bewildering MBC maze.
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