Immunotherapy drugs for breast cancer
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Thanks, John. Following this thread carefully.
>Z<
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Having started Immune Dificency Therapy, 5 years ago, at the same time I started Stage IV therapy for my Advanced breast Cancer, I have believed that the Immune Therapy has played a big part in my still being alive, helping each cancer treatment along the way. Is anyone collecting such histories? Is there any way for those of us who happen to be treated for CVID or other Immune issue to connect? janetanne
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good to hear janetanne.
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Janetanne - I work with a couple of oncs who think outside the box and are trying to complement my standard therapy (Ibrance plus letrozol) with immune enhancing strategies. I am wondering how that compares with Immune Deficiency Therapy? What kind of protocol have you been on? What are the diagnostics that measure efficacy?
>Z<
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Here's a nice piece about a metastatic TNBC survivor and her successful journey in a Phase II immunotherapy clinical trial using Keytruda, the checkpoint inhibitor.
https://njmonthly.com/articles/health/the-long-and-winding-road-immunotherapyIt's finally happening! Stories of some Stage 4 breast cancer patients achieving success with immunotherapies are starting to trickle into the news.
A few of these women are part of the Facebook immunotherapy group [facebook.com/groups/TheCancerCure]. Feel free to read their stories.0 -
John -
Thank you so much for the article.
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Many breast cancer Oncologists still believe that Estrogen-fueled (ER+) disease is not very immunogenic. That dogma might exist because basic science researchers have a poor understanding of the mechanisms between the immune system and breast cancer. Last month, Mayo Clinic researchers took a step forward when they discovered in pre-clinical research that antibody-producing immune cells, known as B cells, are important in preventing Breast Cancer progression. Here's the news:
Lay summary: http://newsnetwork.mayoclinic.org/discussion/mayo-clinic-researchers-quantify-immune-cells-associated-with-future-breast-cancer-risk/Science Abstract: http://clincancerres.aacrjournals.org/content/early/2017/01/26/1078-0432.CCR-16-2026
If validated, how can the knowledge of these B-Cells be harnessed in Immunotherapy?
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Thank you for posting the Mayo article--especially for posting both the lay summary and the science abstract. It seems that there is so much going on that is pre-clinical. It is all very interesting but moves so slowly.
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Here is a summary of immunotherapy trials for ERPR+ cancer ...
This immunotherapy clinical trial at MSKCC does accept ERPR+ HER2- patients. The cancer can be ERPR+ but it has to be mesothelin expressing. There are actually several CAR-T trials for breast cancer that is mesothelin expressing, including one specifically for people with pleural infusions. The current trials, as of 18 months ago, have been summarized by Cancer Commons.
This interesting immunotherapy trial combines abemaciclib with keytruda. So that is a CDK 4/6 inhibitor and an immunotherapy treatment (PD-1 Inhibitor). For the folks in California, this trial is at UCSF. Principle Investigator ... Hope Rugo!! It's phase I, but both abemaciclib and keytrude are past phase III clinical trials ... it's the combination that is phase I.
I found this table of Immunotherapy trials for ERPR+ cancer from 10 months ago on Cancer Commons. The response rates are low for immunotherapy, particularly with ERPR+ cancer, but they increase when immunotherapy is combined with other drugs.
NCT02453620 Opdivo combined with Ipilimumab (immune), entinostat (targeted) for ER+/HER2-
NCT02309177 Opdivo combined with Nab-paclitaxel (chemo) for ER+/HER2-
NCT02648477 Keytruda combined with endocrine therapy for ER+/HER2-
NCT02411656 Keytruda alone for inflammatory BC
NCT02643303 Durvalumab combined with Tremelimumab vaccine for all types of BC
NCT01772004 Avelumab alone for all types of BC
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Thanks zarovka.
As of today, I found 257 different immunotherapy trials that are enrolling breast cancer patients throughout North America. I didn't break it down by biomarkers (ER, PR, HER2) but have to assume dozens are enrolling ER+ folks. The Cancer Research Institute (CRI) website [www.cancerresearch.org/cancer-immunotherapy] offers the most up to date list of trials. They have a trial search engine (which is run by a third party company, EmergingMed - https://platform.emergingmed.com/find-clinical-trials/cri).
Most of the Phase III and many of the Phase II trials are using first-generation monoclonal antibodies like Herceptin. The newer generation of immunotherapies like checkpoint inhibitors, adoptive cell therapy (including CAR-T), etc are more experimental and in Phase I or Phase II trials. These new therapies have not yielded much clinical benefit for the vast majority of ER+ disease, however so many of the trials are very new and the data is not mature.
As you mentioned, the best approach is combinations of these different therapies. Here's a short video from June 2016 that underscores the importance of "combination immunotherapy" (combining two different immunotherapy strategies). Yes, some may get lucky with single-agent immunotherapy but your chances of success increase when you combine immunotherapy approaches.
www.onclive.com/conference-coverage/asco-2016/bernard-fox-on-significance-of-immunoscore-validation-project
Here are some generic examples of a combination immunotherapy strategy:
Checkpoint Inhibitor + Vaccine
Checkpoint Inhibitor + Oncolytic Virus
Checkpoint Inhibitor + CAR-T
CAR-T + Vaccine
etc...
Combinations of immunotherapies will likely increase side effects but they will undoubtedly increase the chance of survival.0 -
New trial for those considering immunotherapy options! First in human, so not for the faint of heart, but promising.
Dose Escalation and Expansion of JTX-2011 Alone or in Combination With Anti-PD-1 in Subjects With Advanced Solid Tumors (ICONIC)
Here is an analysis from fightterm, a very knowledgeable scientist with cancer on Inspire.
The new drug is ICOS Agonist Monoclonal Antibody (mAb) JTX-2011. ICOS is a very important receptor that stimulates the production of effector T cells (cancer fighting cells) and at the same time reduces the number of Tregs, which are immunosuppressors. So it has a dual function. BTW, it was found that ipili treatment stimulates ICOS receptor (which is very good) and this way influences the Tregs. When ICOS receptor is disabled the response to ipili was not as good. But ICOS receptor expression can be stimulated not only by ipili, but by this new agonistic antibody, JTX-2011. So, it looks like a very good new drug, but of course, there can always be side effects, as the immune system might respond stronger than we need. Anyway it looks very promising to me, especially the arm with Opdivo . I always believe that 2 drugs are stronger than one, but some trials have been known to switch patients to the other arm if they are progressing in one arm. It's something that you can find out.
In my opinion, the opdivo/ JTX-2011 combination is very similar to the opdivo/ipili combo, except that the latter combo has been some time in the trials and gets positive results.>Z<
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Immunotherapy news from the #AACR17 conference in Washington DC:
Metastatic TNBC who were treated with the anti-PD-L1 cancer immunotherapy atezolizumab (Tecentriq) lived significantly longer (overall survival) compared with those who did not respond, according to data from a phase I clinical trial (https://clinicaltrials.gov/ct2/show/NCT01375842) presented at the AACR Annual Meeting 2017, April 1-5.
This study involves the largest cohort of patients with metastatic breast cancer treated with immunotherapy to be presented to date, and it is the first study to report data on survival for this subgroup.
"The most significant finding is the difference in the overall survival between patients who responded to atezolizumab and patients who did not respond. While all responders were alive after one year, the one-year survival rate for nonresponders was only 38 percent.
Another noteworthy finding is that metastatic TNBC patients treated with atezolizumab had a prolonged median duration of response of 21 months, which is substantially longer than what has been seen with any other treatment to date for this patient population."
http://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1034#.WOM0 -
Wow, good news. Better news would be when it's "Fast Tracked" by the FDA.
Wife now triple negative with mets to spine. She's on Xeloda with not too many severe SE's.
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Awesome news. There is a lady on this trial on Inspire. Doing great. And the trial is nowhere near over. Yay. We have a TNBC treatment!
>Z<
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Biomedical study demonstrates its blood test can predict response to cancer immunotherapy. The test helps to find out much sooner the pseudoprogression or progression. http://chronixbiomedical.com/chronix-biomedical-study-demonstrates-its-bloo d-test-can-predict-response-to-cancer-immunotherapy/.
After people take a couple of immunotherapy infusions the test shows if there is a response or not.
http://www.investegate.co.uk/chronix-biomedical/rns/chronix-test-predicts-r esponse-to-immuno-oncology/201703201400019311Z/copied from a post by fighterm on Inspire.
>Z<
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I've followed this thread for a while due to my interest in the topic. Now I'm really interested as I have signed up to participate in this Phase 2 Study of Atezolizumab With or Without Entinostat in Patients With Advanced Triple Negative Breast Cancer (https://clinicaltrials.gov/ct2/show/NCT02708680).
My MO has been eyeing this for me from the day she confirmed to me that my bc was back. I've been through Xeloda and then Gemzar, but neither slowed it down. Hopefully this will prove to be helpful. At least treatments are only an hour from home.
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rgc77 - Very interested in how you so.
>z<
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To add - I found a lot of mention about it in Twitter and the key attraction for this treatmentseems to be very low toxicity. I plan to call them on Monday and find out more.
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LMWL - I am looking at going to japan for something roughly related to that treatment but with "activated" natural kill cells ( a different piece of the immune system). Also gentler than the tumor infiltrating lymphcyte strategy. The answer is definitely in getting the immune system to recognize the cancer. I am very interested in where your research leads you.
I posting what I am doing and what I learn on this inspire thread because there is a biochemist who really understands immunotherapy (fighterm) on that forum. Feel free to use that NKC thread to get fightterms attention ... the treatments are related, fighterm is the one I would ask and I would love to follow the discussion.
>Z<
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C3d Protein of the complement sys reduces Tumor-Mediated Immune Suppression
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414554/
Tumors escape immune surveillance by engaging T cell checkpoint regulators and expanding Tregs (regulatory T cells with immunosuppressive properties), among other mechanisms. The complement system (a part of the immune system) has a role in the regulation of immune surveillance. Free C3d protein was able to disrupt immune checkpoint suppression that led to impressive 80% to 90% reductions in tumor burden among mice with murine lymphoma and melanoma.
C3d, a fragment of the third component of complement, inside tumor cells recruits, accelerates, and amplifies antitumor T cell responses, allowing immunity to reverse or even to prevent tumor growth. C3d enhances antitumor immunity independently of B cells, NK cells, or antibodies, but it does so by increasing tumor infiltrating CD8+ lymphocytes, by depleting Tregs, and by suppressing expression of programmed cell death protein 1 (PD-1) by T cells.0 -
Z, thank you for the information! Wonder when they will start clinical trials for BC patients.
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This is a great list of immunotherapy trials for all cancers. You can down select to trials for breast cancer and trials near you. There are 300+ immunotherapy trials for breast cancer, if this list is to be believed.
Cancer Research Institute Immunotherapy Trials.
The number of trials is overwhelming but they do have a system for matching people to trials.
#useful
>Z<
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This an interesting strategy - combining IL-2 and PD-1 inhibitor. Kind of risky to unleash both... you could get quite an immune response. But they seem to have it under control. For breast cancer, only looking at TNBC for the moment ...
A phase 1/2 study of a novel IL-2 cytokine, NKTR-214, and nivolumab in patients with select locally advanced or metastatic solid tumors.
That's one to keep an eye on.
>Z<
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Multi-peptide Vaccine With Basilixumab for Breast Cancer
hTERT is widely found in breast cancer cells and has a role in tumor growth and development, making it attractive for immunotherapy. Also, recent data suggest that breast cancer is potentially responsive to immunological therapies. In one trial, patients with advanced cancer received a series of hTERT vaccinations and 4 of 7 patients with advanced breast or prostate carcinoma developed hTERT-specific T lymphocytes. Partial tumor regression was observed in 1 patient. In a second trial, 19 HLA A2+ patients with metastatic breast cancer were vaccinated with hTERT 1540 peptide in adjuvant with GM-CSF. 68% of patients exhibited immunological responses with development of CD8+ hTERT-specific T-cells. Overall survival of vaccine responders was signifiantly better than the overall survival on non-responders. In order to expand the number of possible immune responses and to potentially bypass immune tolerance, multiple peptides have been added to the vaccine. In addition, the monoclonal antibody basiliximab is included to decrease the regulatory T cells which prevent the immune system to work against the tumor, and GM-CSF and Prevnar are used to boost the immune system. Subjects will receive a maximum of 28 vaccinations over a 24 months period.
The study started in June 2012 and should have reported data in 2015. Also the number of participants was projected to be 12. The trial is still recruiting.... in 2017, but they should have results. The trial information was recently updated, maybe they are gearing up for a new phase. Very interested in what people learn about this trial I think this could be a very important option because it seems to target MBC and overcome certain hurdles we've seen in immunotherapy.
Here are comments from the awesome fightterm on Inspire about this trial ...
The immune system ignores cancer cells very often due to weak immunogenicity of cancer cells and strong immunotolerance in the tumors. So the researchers take a piece of cancer ( often a peptide) that is present mostly in cancer cells and not in normal tissue and attach it to a piece of virus that immune system can easily recognize. Now immune system would recognize not only the viral part, but also the cancer part and try to kill those cells that contain that particular peptide sequence. That particular peptide sequence is the target of the vaccine. It can come from any protein that is present mostly in cancer cells (and as many cancer cells as possible). This particular vaccine in the trial has a peptide from enzyme survivin and a peptide from another enzyme hTERT that also happens mostly in cancer cells. As these two peptides are attached to a viral protein an immune response is generated to all parts of the vaccine. It creates T cells that recognize the targets and kill cancer cells containing these peptides (which are parts of survivin and hTERT in this case).
As tumors have high immunosuppressive environments due to accumulation of Tregs among other things, so another drug (Basilixumab) is given to diminish the number of Tregs......
This trial addresses several key points. It has 2 targets: hTERT and survivin peptides fused with CMV (virus). hTERT, a catalytic component of human telomerase, is undetectable in normal somatic cells but up-regulated in cancer and stem cells where telomere length is maintained by telomerase. Survivin is a member of the Inhibitor of Apoptosis Protein (IAP) family, which is overexpressed in most malignancies and totally absent in most of the normal tissues. This feature makes survivin an ideal target for cancer therapy. It orchestrates several important mechanisms to support cancer cell survival including inhibition of apoptosis and regulation of cell division. CMV-cytomegalovirus, is used the strengthen the vaccine (to alert the immune system to targets hTERT and survivin).
The clinical trial is also using a drug, Basilixumab, an antibody to the α chain (CD25) of the IL-2 receptor of T cells. This antibody was shown to diminish the number of Tregs (type of immunosuppressive cells) in tumors.
The drugs are administered with GM-CSF (Granulocyte macrophage colony-stimulating factor) and Prevnar (pneumococcal 7-valent conjugate vaccine).>Z<
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This article details some interesting points from a completely different angle: https://www.nytimes.com/2017/08/12/health/cancer-drug-trials-encounter-a-problem-too-few-patients.html
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Interesting article. The diversity of cancer, among many things, breaks the clinicat trial/FDA approva process.
>Z<
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I've been off threads for a while, but following this one. Appreciate your posts and Thanks Z!
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Repeating a post from FightTerm on Inspire. Clearest explanation of CAR-T therapy ever. Thank you fighterm.
Now it's a third generation of CARTs. They are improving with each generation. For those who does not know about CARTs I will give you some ideas.
It's a T cell from your blood that is modified in the lab. They put a small piece of antibody into the T cell receptor (TCR). Now the T cell will not look for neoantigens (because good neoantigens are rare), but go directly to the target of that piece of antibody and kill that cell. The target could be any overexpressed protein on the surface of cancer cells and not on normal cells. Example. If your cancer overexpresses mesothelin on the surface of cancer cells then the CAR T cell should have an antibody to mesothelin. A big army of anti-mesothelin CARTs will go out checking every cell and killing every cell that has mesothelin on Its surface.
1. Target mesothelin https://clinicaltrials.gov/ct2/show/NCT02792114 at Sloan Kettering
2. Target mesothelin https://clinicaltrials.gov/ct2/show/NCT02414269 (BC with pleural mets) Sloan Kettering
Other targets.
3. anti-CEA CARTs for liver mets https://clinicaltrials.gov/ct2/show/NCT02850536 University of Colorado
4. Target CD70 (if your cancer expresses CD70) https://clinicaltrials.gov/ct2/show/NCT02830724NIH
5. Target ROR1 https://clinicaltrials.gov/ct2/show/NCT02706392 Fred Hutch
6. Target cMet https://clinicaltrials.gov/ct2/show/NCT03060356 at UPenn
7. No need for a target. A engineered piece of DNA will produce NKR-2 receptor that is instrumental in finding the distressed (cancer) cells. NKR-2 was copied from Natural Killer cells that use this receptor to find distressed cells. Now T cells will use it to find cancer cells and kill them.
https://clinicaltrials.gov/ct2/show/NCT03018405The problem with checkpoint inhibitors was that the cancer cells need to have a high mutation load and strong antigens to activate the immune system and cause killing of cancer cells, but as we know most cancers don't have that. But they have overexpressed markers on the surface of cancer cells that are not expressed on normal cells (or have very little expression). So T cells are engineered to target those markers on the surface, thus redirecting T cells from looking for strong antigens to going directly to the cancer marker and killing those cells.
It's a more difficult approach as it involves getting out your own T cells and modifying them in the lab and infusing them back.
What is needed for successful CART cells therapy?
CARTs need to persist and to expand in the body (not quickly die off). If your cancer express a useful target for CAR T cell therapy it can be completely eradicated. The massive immune reaction happens if the CARTs attack cancer so strongly that there are too many cytokines in the blood produces by CARTs (called cytokine storm). This process is under control now, no one died of this anymore after initial deaths when this phenomenon was not known.There are many road blocks for any cytotoxic T cells (including CARTs) to enter solid tumors. New generations of CARTs take this hostile environment into account.
1. Tumors surround themselves with strong cancer associated fibroblasts that provide a shield agains T cells.
2. The microenvironment inside a tumor has low oxygen, low nutrients and low pH, all this is bad for T cells.
3. There is a lot of immunosuppression by regulatory T cells (Tregs), Myeloid derived suppressor cells (MDSCs) and tumor associated fibroblasts. A T cell comes and has big troubls getting in there.0 -
As a follow up to our New York Immunotherapy Patient Summit and Live Stream Broadcast, we would like to provide you with copies of the slides that were presented as well as share links to other resources you may find useful:
- Download the complete slide deck (PDF, 3.1 MB)
- Download our guide to the immune system and immunotherapy, "Cancer and the Immune System: The Vital Connection" (PDF, 12.7 MB)
- Browse the Cancer Research Institute website for information on immunotherapy for specific types of cancer
- Contact an Immunotherapy Clinical Trial Navigator to begin your search for treatment options
- Join the ImmunoCommunity and stay up-to-date on the latest in immunotherapy research and treatment
If you were unable to attend the New York summit and cannot attend one of the other summits in person, be sure to view the recorded sessions on our Facebook page.
Finally, several people asked me about opportunities to support CRI's mission. For those interested, you may donate by clicking on the link below.
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