Immunotherapy drugs for breast cancer

JohnSmith

The following is from the 'Cancer Research Institute' webpage for IO in Breast Cancer.
It's been updated as of March 2016, by Dr. Leisha Emens of Johns Hopkins.

The immunotherapies can be broken into these categories:
- Therapeutic Vaccines
- Checkpoint Inhibitors / Immune Modulators
- Adoptive Cell Therapy (ACT)
- Oncolytic Viruses
- Antibodies (mAbs)
- Adjuvant Immunotherapies
- Cytokines

Therapeutic Vaccines

Cancer vaccines are designed to elicit an immune response against tumor-specific or tumor-associated antigens, encouraging the immune system to attack cancer cells bearing these antigens. Several trials of vaccines, given alone or with other therapies, are currently enrolling breast cancer patients:

• NeuVax (nelipepimut-S or E75) is under investigation to prevent breast cancer recurrence among patients with low-to-intermediate levels of HER2 expression (HER2 1+ and 2+) following surgery. A phase III trial (PRESENT) is now fully enrolled (NCT01479244). The trial has been granted a Special Protocol Assessment (SPA) by the FDA, meaning that, if the trial meets its pre-specified endpoint, it will fulfill the necessary criteria to file for regulatory approval. There is also a phase IIb trial of NeuVax for node-positive or triple-negative following standard-of-care treatment (NCT01570036), and a phase I/II among neoadjuvantly treated node-positive and -negative HER2 3+ patients not achieving a pathological complete response, or adjuvantly treated node-positive HER2 3+ patients (NCT02297698).
  UPDATE - JUNE 2016:
  The Neu-Vax Phase 3 clinical trial (PRESENT) has been stopped (cancelled). NeuVax was unable to prevent recurrence in this clinical trial.
  The Independent Data Monitoring Committee (IDMC) recommended that the PRESENT clinical trial be stopped due to futility.
  Source: https://globenewswire.com/news-release/2016/06/29/852251/0/en/Galena-Biopharma-Discontinues-NeuVax-nelipepimut-S-Phase-3-PRESENT-Interim-Analysis-based-on-Independent-Data-Monitoring-Committee-Recommendation.html
• A phase I study of two vaccines - INO-1400, targeting TERT, which has been detected in more than 85% of all human cancers, and INO-9012, targeting interleukin 12 (IL-12), which enhances immune cell activity - for patients with select tumors, including breast cancer (NCT02327468).
• A phase I trial of OBI-833 vaccine, which targets the Globo H marker that is commonly found on a variety of tumors cells, for patients with select metastatic cancers, including breast cancer (NCT02310464).
• A phase I study of the MAG-Tn3 vaccine, which targets Tn carbohydrate antigen that is overexpressed in a number of tumor types, for patients with localized breast cancer at high-risk of relapse (NCT02364492).
• A phase I trial of a HER2 peptide vaccine in patients with breast cancer (NCT02276300).
• A phase I trial of a dendritic cell vaccine in patients with metastatic breast cancer (NCT02479230).
• A phase I trial of a personalized vaccine in patients with persistent triple-negative breast cancer following neoadjuvant chemotherapy (NCT02348320).
• A phase I trial of a personalized vaccine plus Poly-ICLC, a Toll-like receptor 3 agonist, in patients with persistent triple-negative breast cancer following neoadjuvant chemotherapy (NCT02427581).

Checkpoint Inhibitors / Immune Modulators

A promising avenue of clinical research in breast cancer is the use of immune checkpoint inhibitors. These treatments work by targeting molecules that serve as checks and balances in the regulation of immune responses. By blocking inhibitory molecules or, alternatively, activating stimulatory molecules, these treatments are designed to unleash or enhance pre-existing anti-cancer immune responses. Several checkpoint inhibitors, targeting multiple different checkpoints, are currently enrolling breast cancer patients:

Pembrolizumab (Keytruda®, MK-3475): A PD-1 Antibody

• A phase III trial for patients with metastatic triple-negative breast cancer, versus chemotherapy (NCT02555657).
• A phase II trial for patients with breast cancer, with an HDAC inhibitor and anti-estrogen therapy (NCT02395627).
• A phase II study for patients with triple-negative or hormone receptor-positive metastatic breast cancer, in combination with chemotherapy or anti-estrogen therapy (NCT02648477).
• A phase II trial for patients with metastatic inflammatory breast cancer who have received prior chemotherapy with clinical response (NCT02411656).
• A phase II trial for patients with metastatic triple-negative breast cancer (NCT02447003).
• A phase I/II trial for patients with advanced cancer, including triple-negative breast cancer, combined with PLX3397, a tyrosine kinase inhibitor of KIT, CSF1R, and FLT3 (NCT02452424).
• A phase I/II study for patients with advanced cancer, including breast cancer (NCT02318901).
• A phase I/II trial for patients with advanced cancer, including breast cancer, in combination with chemotherapy (NCT02331251).
• A phase I/II study in patients with triple-negative breast cancer, combined with niraparib, a PARP inhibitor (NCT02657889).
• A phase I/II trial for patients with metastatic triple-negative breast cancer, in combination with chemotherapy (NCT02513472).
• A phase I study in patients with refractory cancer, including triple-negative breast cancer, combined with MGA217, an antibody that targets B7-H3 (NCT02475213).
• A phase I study for patients with advanced tumors, including triple-negative breast cancer, in combination with a JAK inhibitor, INCB039110, or a PI3K-delta inhibitor, INCB050465 (NCT02646748).
• A phase I neoadjuvant trial for patients with triple-negative breast cancer, in combination with chemotherapy (NCT02622074).
• A phase I study for patients with breast cancer that has metastasized to the bones (NCT02303366).

Nivolumab (Opdivo®): A PD-1 Antibody +/- Ipilimumab (Yervoy®): A CTLA-4 Antibody

• A phase II study of nivolumab after induction treatment for patients with triple-negative breast cancer (NCT02499367).
• A phase I trial to test nivolumab and ipilimumab, plus entinostat, an HDAC inhibitor, for patients with locally advanced or metastatic HER2-negative breast cancer (NCT02453620).
• A phase I study to test ipilimumab (Yervoy) combined with MGA217, an antibody that targets B7-H3, in patients with refractory cancer, including triple-negative breast cancer (NCT02381314).
• A phase I study of nivolumab in combination with chemotherapy for patients with recurrent metastatic breast cancer (NCT02309177).

Durvalumab (MEDI4736): A PD-L1 Antibody +/- Tremelimumab: A CTLA-4 Antibody

• A phase II trial of durvalumab, tremelimumab, or the combination for patients with advanced tumors, including triple-negative breast cancer (NCT02527434).
• A phase II study of durvalumab and tremelimumab in patients with metastatic HER2-negative breast cancer (NCT02536794).
• A phase I/II trial of durvalumab, tremelimumab, and Poly-ICLC, a Toll-like receptor 3 agonist, in patients with advanced, measurable cancers, including locally recurrent breast cancer (NCT02643303). This is sponsored by the Cancer Research Institute.
• A phase I/II trial of neoadjuvant durvalumab with chemotherapy for stage 1-3 triple-negative breast cancer (NCT02489448).
• A phase I/II trial of durvalumab in combination with olaparib, a PARP inhibitor, or cediranib, a VEGF inhibitor, in patients with advanced solid tumors, including breast cancer (NCT02484404).
• A phase I/II trial of durvalumab plus epacadostat (INCB024360), an IDO inhibitor, in patients with select advanced tumors, including triple-negative breast cancer (NCT02318277). IDO is expressed by a number of tumor types and correlates with poor prognosis.
• A phase I/II study of durvalumab plus ibrutinib, a BTK inhibitor, in patients with relapsed or refractory tumors, including breast cancer (NCT02403271).
• A phase I trial of durvalumab for patients with breast cancer, in combination with selumetinib, an inhibitor of MEK 1 and 2 (NCT02586987).
• A phase I study of durvalumab plus tremelimumab for patients with breast cancer (NCT02639026).
• A phase I study of durvalumab and tremelimumab for patients with advanced solid tumors, including non-triple-negative breast cancer (NCT01975831). This is sponsored by the Cancer Research Institute.
• A pilot study of tremelimumab and brain irradiation for patients with breast cancer that has metastasized to the brain (NCT02563925).

Atezolizumab (MPDL3280A): A PD-L1 Antibody

• A phase III trial for patients with previously untreated metastatic triple-negative breast cancer, in combination with chemotherapy (NCT02425891).
• A phase II first-line neoadjuvant trial for patients with triple-negative breast cancer, along with chemotherapy (NCT02530489).
• A phase I/II study in patients with advanced cancer, including triple-negative breast cancer, in combination with varlilumab (CDX-1127), an anti-CD27 antibody (NCT02543645).
• A phase I trial for patients with HER2-positive breast cancer, given with HER2 inhibitors (NCT02605915).
• A phase I trial for patients with select advanced cancers, including breast cancer (NCT01375842).
• A phase I study of CPI-444, which targets the adenosine-A2A receptor that suppresses the anti-tumor activity of immune cells, +/- atezolizumab for patients with advanced cancer, including triple-negative breast cancer (NCT02655822).

Other Drugs

• A phase II study of IMP321, a LAG-3 fusion protein, in patients with hormone receptor-positive metastatic breast cancer, in combination with chemotherapy (NCT02614833).
• A phase I/II trial of MEDI6469, an anti-OX40 antibody, for patients with stage 4 breast cancer who have failed prior hormone or chemotherapy (NCT01642290). OX40 is a costimulatory molecule expressed after T cell activation that enhances T cell survival and anti-cancer effector function.
• A phase I/II trial of PDR001, a PD-1 antibody, in patients with advanced cancers, including triple-negative breast cancer (NCT02404441).
• A phase I study to test MGD009, a B7-H3 x CD3 DART protein, in patients with unresectable or metastatic B7-H3-expressing cancer, including breast cancer (NCT02628535).

Adoptive Cell Therapy (ACT)

Another avenue of immunotherapy for breast cancer is adoptive T cell transfer. In this approach, T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system's anti-cancer response. Several trials of adoptive T cell transfer techniques are currently under way for patients with breast cancer, including:

• A phase I trial of chimeric antigen receptor (CAR) T cells targeting cMet - which is abnormally activated in cancer and correlates with poor prognosis - is being tested in metastatic breast cancer refractory to at least one standard therapy or newly diagnosed patients with operable triple negative breast cancer (NCT01837602).
• A phase I study of immune cells engineered to target the mesothelin protein, which is overexpressed in certain cancers, in patients with advanced cancer, including breast cancer (NCT02414269).
• A phase I study of T cells engineered to recognize the NY-ESO-1, MAGE-A4, PRAME, survivin, and SSX markers in patients with solid tumors, including breast cancer (NCT02239861).

Oncolytic Virus Therapies

Oncolytic virus therapy uses a modified virus that can cause tumor cells to self-destruct and generate a greater immune response against the cancer.

• A phase I/II trial of PexaVec (JX-594), a virus engineered to secrete GM-CSF and delete a kinase gene that is typically seen on cancer cells with a mutated RAS or p53 pathway, for patients with advanced breast cancer (NCT02630368).

Antibodies (mAbs)

Monoclonal antibodies are molecules, generated in the lab, that target specific antigens on tumors. Many antibodies are currently used in cancer treatment, and some appear to generate an immune response.

• A phase III study of margetuximab (MGAH22), an anti-HER2 antibody, plus chemotherapy versus trastuzumab (Herceptin®) plus chemotherapy in patients with HER2-positive metastatic breast cancer (NCT02492711).
• A phase II study of margetuximab (MGAH22) in patients with relapsed or refractory advanced breast cancer whose tumors express HER2 at the 2+ level and lack HER2 gene amplification by FISH (NCT01828021).
• A phase II trial of glembatumumab vedotin (CDX-011), an antibody-drug conjugate, in patients with advanced triple-negative breast cancer whose cancer cells make a protein called glycoprotein NMB, to which CDX-011 binds (NCT01997333).
• A phase I/II trial of TRC105, an antibody targeting endoglin, which is a protein that is overexpressed on endothelial cells and is essential for angiogenesis, the process of new blood vessel formation, in patients with hormone receptor-positive and HER2-negative breast cancer (NCT02520063).
• A phase II trial of MCS110, an antibody that targets the macrophage colony-stimulating factor, in patients with advanced triple-negative breast cancer (NCT02435680).
• A pilot study of QBX258, which targets interleukin 4 (IL-4) and interleukin 13 (IL-13), in patients with stage 1-2 breast cancer related lymphedema (NCT02494206).

Adjuvant Immunotherapies

Adjuvants are substances that are either used alone or combined with other immunotherapies to boost the immune response. Some adjuvant immunotherapies use ligands - molecules that bind to proteins such as receptors - to help control the immune response. These ligands can be either stimulating (agonists) or blocking (antagonists).

• A phase I/II trial of durvalumab plus epacadostat (INCB024360), an IDO inhibitor, in patients with select advanced tumors, including triple-negative breast cancer (NCT02318277). IDO is expressed by a number of tumor types and correlates with poor prognosis.
• A phase I trial of motolimod (VTX-2337), a Toll-like receptor 8 (TLR8) agonist, in patients with metastatic, persistent, recurrent, or progressive solid tumors, including breast cancer (NCT02650635).
• A phase I study of entinostat (KHK2375), a small molecule drug that targets both cancer cells and immune regulatory cells, in patients with advanced or recurrent breast cancer (NCT02623751).

Cytokines

Cytokines are messenger molecules that help control the growth and activity of immune system cells.

• A phase I/II study of interleukin 12 (IL-12) in patients with metastatic breast cancer (NCT02423902).

- See more at: http://www.cancerresearch.org/cancer-immunotherapy/clinical-trial-finder

live_deliciously

So many thanks John for all your continued research and helping us laymen understand what all these new trials mean.

letmywifelive

The hard part is to decide which one is appropriate, timing and highest benefit. Thats why having a good oncologist is so very important.

specialk

johnsmith - don't know if you wanted to include the GP2/AE37 Phase II Her2+ breast cancer recurrence prevention peptide vaccine trial in your section. This trial is done recruiting but is ongoing. Here is the link, I am a participant, as are several other BCO members. The future is a bit unknown regarding whether there will be a Phase III as the news regarding AE37 has recently shown less than desired results, and GP2 (the arm I am enrolled in) has preformed very well, but has some funding and litigation issues involving the vaccine innovator and current pharma company.

https://clinicaltrials.gov/show/NCT00524277

JohnSmith

Breast Cancer Vaccines and Checkpoint-Inhibitor Immunotherapy

Q&A | March 15, 2016 | MBCC 2016, By Elizabeth A. Mittendorf, MD, PhD

As part of our coverage of the 33rd Annual Miami Breast Cancer Conference, held March 10-13 in Miami, Florida, we spoke with Elizabeth A. Mittendorf, MD, PhD, associate professor at the department of breast surgical oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas, who presented at the meeting on cancer vaccines and checkpoint inhibitors.

Cancer Network: How has being both a surgeon and immunologist, shaped your views of the potential clinical roles of cancer vaccines?

Dr. Mittendorf: As a surgeon, I see and treat patients with early-stage breast cancer that is potentially curable. Unfortunately, despite our best treatment—surgery, chemotherapy when indicated, radiation if required—we still see recurrences in up to 20% of these patients. I think it is not unreasonable to hypothesize that this recurrence is in part attributable to a failure of the immune response against the cancer—hence my enthusiasm for vaccines that could potentially augment that antitumor immunity, thereby decreasing the risk of recurrence.

Cancer Network: In what settings do breast cancer vaccines show the most promise?

Dr. Mittendorf: Secondary prevention. There is currently one vaccine that is being investigated in a phase III trial—NeuVax—which is made up of an immunogenic peptide combined with an immunoadjuvant. The trial is vaccinating patients in the adjuvant setting with the goal being to determine if vaccination can decrease the risk of recurrence.

Cancer Network: Is there reason for optimism that cancer vaccines might prove useful against advanced breast cancers?

Dr. Mittendorf: In my opinion, vaccines as monotherapy are not likely to be successful in advanced breast cancer. With that said, it is possible that vaccines could be administered as part of a combination strategy with other drugs that could augment the immune response such as certain chemotherapy regimens, trastuzumab, or other immunomodulatory drugs such as the checkpoint blockade agents.

Cancer Network: What insights do epidemiologic studies, such as those regarding childhood infections and cancer risk, offer for cancer immunotherapy?

Dr. Mittendorf: There is epidemiologic data to suggest that individuals who have had childhood infections (ie, chicken pox, pertussis, and other febrile illnesses) have a decreased risk of developing cancer. It is likely that these individuals develop adaptive immune responses against epithelial antigens. These responses could be augmented in the setting of a premalignant condition (ie, a colonic adenoma, or ductal carcinoma in situ), thereby tipping the scales back in favor of the immune response, leading to elimination of the threat of malignancy.

Cancer Network: Are the KEYNOTE trial reports to date reason for optimism about immune checkpoint blockade's potential against breast cancer?

Dr. Mittendorf: Absolutely. These trials have confirmed that pembrolizumab (anti-PD-1 antibody) is fairly well tolerated by breast cancer patients and suggest some clinical activity. Through the portfolio of KEYNOTE trials, which have enrolled the different subtypes of breast cancer, we're likely to learn more about which subtypes of breast cancer are most likely to respond to pembrolizumab as monotherapy, which in turn would suggest which subtypes might need additional immune stimulation (ie, a combination strategy) in order for the checkpoint blockade agent to be effective.

Cancer Network: What is the significance of PD-L1 expression in tumor cells vs the tumor microenvironment?

Dr. Mittendorf: Whether PD-L1 expression on the tumor cells is required for response to anti-PD-1 or anti-PD-L1 therapy remains a subject of much discussion. Data from the JAVELIN trial presented at the San Antonio Breast Cancer Symposium in December suggested that PD-L1 expression on the tumor was less important than PD-L1 expression on immune cells in the microenvironment—what they referred to as "immune hotspots."

Cancer Network: Do you anticipate clinical roles for checkpoint blockade in secondary prevention? Breast cancer treatment in combination with other agents, like trastuzumab? (Are there other promising combinations? Do you anticipate immunotherapy combinations that exploit different immune system pathways?)

Dr. Mittendorf: I see a potential role for checkpoint blockade in the adjuvant setting (effectively secondary prevention) in high-risk patients in whom the risk/benefit ratio favors using these agents, which do have some toxicity associated with them. As an example, the SWOG cooperative group is developing a trial that will evaluate pembrolizumab in patients with triple-negative breast cancer who have at least 1 cm of tumor or positive lymph nodes after neoadjuvant chemotherapy. With respect to using in combination with other agents—yes; in fact the PANACEA trial currently accruing in Europe is combining pembrolizumab with trastuzumab in patients with HER2-positive metastatic breast cancer.

See more at: www.cancernetwork.com/mbcc-2016/breast-cancer-vaccines-and-checkpoint-inhibitor-immunotherapy#sthash.Ab6h2geE.dpuf

funthing42

I'm glad someone is still trying to fight cancer others are stuck in standardized care. If I hear the standard of care one more time. Yuck! Thanks for all the research.

I need help. I'm extremely upset! No nodes Stage 1 runs a muck.

Now they are pushing Imbrance and latzrole.

They say I do not have Ca any where elese.

But I want a treatment that I can see the progress. I really do not know which forum to go to.

I want remission gee whiz. Just venting no one offering any solutions or even trying at this point.

JohnSmith

Disrupting cancer: Napster creator & former Facebook President Sean Parker pours $250M into Immunotherapy research

More validation that Immuntherapy is the future backbone of all cancer treatment.

His foundation is responsible for a $5 million grant in Dec 2012 to Stand Up to Cancer (SU2C) and Cancer Research Institute (CRI) which helped to establish a Immunotherapy 'Dream Team'.
We need a sense of urgency to accelerate the paradigm shift. Today's announcement is a massive cash injection into this game changing initiative and will quicken the pace of discoveries from bench to bedside.

cb123

Hi John,

Glad you're here in the forum. I too have been finding a lack of info/study about immunotherapies for breast cancer. Immunogenic indeed!

I'm looking forward to your links and just wanted to thank you for not only taking the time to share, but for taking the time to find and study them.

Your wife is a very smart girl to have picked you for a husband.

Thanks for sharing,

cb

cb123

Hello again John,

Wow, you have done my homework for me and now where to begin? I now have 14 pages of your posts to peruse and cannot thank you enough for the links.

I too feel that immunotherapy is the wave of the future for cancer. Here's the video that brought me here today. Other days, it's other videos. I'm a big fan of YouTube. For you, this will be the basic How Does Immunotherapy Work info and in the end, it's related to Melanomas, but it does give folks the basics of the 5 or 6 ways it works.

Off I go to use your links to try find something I can believe in. Something I might even want to try.

Thanks again, cb

JohnSmith

After losing a close friend (Laura Ziskin) to Lobular Breast Cancer, billionaire Sean Parker (Napster, Facebook) decided to do something.
In 2012, he donated $5 million to Stand Up to Cancer (SU2C) and the Cancer Research Institute (CRI) which helped to establish a Immunotherapy 'Dream Team'.
Recently, he donated $250 million to establish the Parker Institute for Cancer Immunotherapy, an initiative that encourages collaboration instead of competition among researchers.

Six hospitals will work together towards new discoveries. Those hospitals include:
- MSKCC (Memorial Sloan Kettering Cancer Center in New York City)
- UPenn (University of Pennsylvania in Philadelphia)
- MD Anderson (University of Texas in Houston)
- Stanford (Palo Alto, California)
- UCSF (San Francisco, California)
- UCLA (University of California, Los Angeles)

Tonight, 'Dateline NBC' will broadcast an episode about his $250 Million initiative to accelerate immunotherapy.
Here's a preview: http://www.nbcnews.com/dateline/video/hacking-cancer-his-name-is-sean-parker-688973891984
The full episode airs today, Sunday May 22 ~7:00pm.
Record it with your DVR if you can't watch it live this evening.

funthing42

Thank you John for giving hope.

funthing42

I did the caris biomarkers. I was hoping it would give doctors a ah hah moment. Tumor markers are the same and caring around cancer in my nodes and a skin on my chest. Since Feb.

fluffqueen01

I participated in the trial that special K reference but received AE37 vaccine. Last I heard they were thinking it might work better for triple negative but I haven't heard much in a while.

letmywifelive

Just read this. Although for primary Brain Tumors, still highly encouraging and designated breakthrough therapy by FDA.

http://wthitv.com/2016/05/21/brain-cancer-breakthr...

http://www.cancer.duke.edu/btc/modules/Research3/i...

Longtermsurvivor

Hi LMWL,

I've been interested in the story about use of polio virus in brain cancer for a while, having had friends who've died of glioblastoma multiforme. I wonder whether the research will pan out and be helpful to those who will be diagnosed later.

It may take a long time to find out though!

This is only Phase I clinical trial to determine possible, toxic dosing, not whether the treatment will work in this type of brain tumor, never mind other cancers.

Here's the trial description from clinical trials.gov

PVSRIPO for Recurrent Glioblastoma (GBM) (PVSRIPO)

Purpose of the Study: To determine the maximally tolerated dose (MTD) or optimal dose of PVSRIPO when delivered intracerebrally by convection-enhanced delivery (CED). To obtain correlative mechanistic evidence of PVSRIPO's effects on infected WHO Grade IV malignant glioma tumors and to estimate progression-free survival (PFS) and overall survival (OS) in recurrent WHO Grade IV malignant glioma patients. To obtain information about clinical response rates to intratumoral inoculation of PVSRIPO. To estimate the efficacy of PVSRIPO administered at the optimal dose.

First received: December 1, 2011

Last updated: May 10, 2016

https://clinicaltrials.gov/ct2/show/NCT01491893

The recent 60-Minutes special on the Duke trial may have been overly optimistic - or at least, not telling the whole story.

Promising brain cancer trial given breakthrough status by FDA

May 12, 2016

http://www.cbsnews.com/news/promising-duke-university-polio-brain-cancer-trial-given-breakthrough-status-60-minutes/

60-Minutes did a special on the topic in 2015 too and both television shows garnered criticisms:

What '60 Minutes' Still Isn't Saying About The 'Miracle' Glioblastoma Drug

MAY 16, 2016

http://www.forbes.com/sites/arleneweintraub/2016/05/16/what-60-minutes-still-isnt-saying-about-the-miracle-glioblastoma-drug/#7cd75d491da8

What '60 Minutes' Got Right And Wrong On Duke's Polio Virus Trial Against Glioblastoma

MAR 30, 2015

http://www.forbes.com/sites/davidkroll/2015/03/30/60-minutes-covers-dukes-polio-virus-clinical-trial-against-glioblastoma/#63c35e7c69b5

CBS proclaims 'cancer breakthrough' – doesn't explain what FDA means by that term

May 13, 2016

http://www.healthnewsreview.org/2016/05/cbs-proclaims-cancer-breakthrough-doesnt-explain-what-fda-means-by-that-term/

More than half of 60 Minutes devoted to "Killing Cancer" but still no independent perspective

March 30, 2015

http://www.healthnewsreview.org/2015/03/more-than-half-of-60-minutes-devoted-to-killing-cancer/

I've been reading health news for decades and have shared hundreds of stories with others with cancer and my rare genetic condition. News releases whether from hospitals, academia, research or pharmaceutical companies are often (usually) unpaid commercials that tell only part of the story.

The HealthNewsReview Toolkit has helped me to analyze overly optimistic news stories and press releases, so I don't offer hype...only grounded hope. http://www.healthnewsreview.org/toolkit/

After 25 years in the breast cancer world and over 4 decades researching my rare genetic condition, I've seen too many promising treatments come and go - often before they even reach needy patients. Other treatments for breast cancer like HER2 treatments and aromatase inhibitors have become standard treatments - hurray!

LMWL, you've told us that your wife is in an urgent situation. I hope she can find proven or even promising treatments available for her soon. While it's interesting to watch the research unfold, I fear results will come too late for most of us.

Keep looking at/for proven and promising treatments available to her now, while keeping an eye out for what might work in the future.

Warmest healing wishes, Stephanie

JohnSmith

This is a nice IO piece written by the Oncology Nursing Society a couple weeks ago.
http://connect.ons.org/issue/june-2016/up-front/immunotherapy-is-changing-the-future-of-cancer-care

Here's an excerpt:
"The Promise of Immunotherapy:
We're finally seeing responses in historically, very difficult diagnoses to treat like advanced melanoma and lung cancer. Squamous cell lung cancer had not seen an improvement in second-line treatment for 15 years prior to nivolumab's (Keytruda) approval. And that's not for a lack of trying.
Before the advent of immunotherapies, metastatic melanoma had an average survival timeline of six months. Low survival rates and a lack of treatment options didn't provide patients with much hope. Then the immunotherapy gate opened when ipilimumab was approved in 2011. Since then, we've had eight new treatments approved for melanoma. We've seen patients come out of hospice. We have patients with advanced melanoma who are years out from treatment with no evidence of disease. Think about what that means - all the birthdays, anniversaries, graduations, weddings, holidays, births, and all the wonderfully mundane moments in between. That is real. That is changing lives - not just the patient's but everyone's surrounding them.
The oncology field is excited about immunotherapy, and these treatments are just getting started. With the hope for increased research funding in the near future, immunotherapy will likely benefit as it is applied to a wider spectrum of cancers and more treatment options are developed.
It's not a silver bullet and doesn't work for everyone or in every diagnosis. But we are definitely seeing more people responding and that's equating to longer lasting responses. What's not to get excited about?"

Longtermsurvivor

Two articles from the NYT - breast cancer not mentioned in either

Harnessing the Immune
System to Fight Cancer

New drugs and methods of altering a patient's own immune cells are helping
some cancer patients — but not all — even when standard treatments fail.

By DENISE GRADY

JULY 30, 2016

http://www.nytimes.com/2016/07/31/health/harnessin...

What Is Immunotherapy? The Basics on These Cancer Treatments

By DENISE GRADY and ANDREW POLLACK

JULY 30, 2016

http://www.nytimes.com/2016/07/31/health/what-is-i...

JohnSmith

Antigens and Neoantigens. Learn these words.
A new CRI Blog post from Dr. Arthur N. Brodsky, Ph.D. regarding the latest cancer Immunotherapy news at #CICON16 (CRI-CIMT-EATI-AACR International Cancer Immunotherapy conference).
http://www.cancerresearch.org/news-publications/our-blog/september-2016/cicon16-cancer-antigens-and-the-development-of-pe

Also, here's a different perspective of the highlights from Day 1 of #CICON16 in NYC:
http://www.sugarconebiotech.com/?p=1022

Longtermsurvivor

FYI: Interesting article at STAT today:

Beware the hype: Top scientists cautious about fighting cancer with immunotherapy

JohnSmith

Stephanie - I saw you post this on the Sandpiper trial thread and knew it would end up here.

Yup! Good piece. According to the article, the scientists are "going to science the shit out of it." (in the words of Matt Damon's, stranded astronaut from the film The Martian). Love that!

Longtermsurvivor

Hi John Smith,

Good to know you get to forum 8 for MBC & Stage IV folks.

Hadn't seen you post there, then realized your wife is Stage II and you're a caregiver, so you can't really get through that door. You can peer in the window though and I'm glad you're tracking the SANDPIPER trial too. It's important that we be fully informed, even while information is scant.

I've not been so diligent with peering into this news forum, because I get so much of my news directly from the medical/scientific journals, news releases and other sources. Will try to be better at looking in though.

Most of my interest in new treatment directions is academic and to connect others with what they want & need - information and support.

Being on hospice greatly relieves my mind and heart as I'm no longer seeking my next treatment horizon, but focused on my own distant horizon called death to those remaining and home to those who've journeyed on.

Reminds me of the poem that follows.

Here I come!

Sending much gratitude and warmest regards, John, Stephanie

Gone From My Sight

I am standing upon the seashore. A ship, at my side,
spreads her white sails to the moving breeze and starts
for the blue ocean. She is an object of beauty and strength.
I stand and watch her until, at length, she hangs like a speck
of white cloud just where the sea and sky come to mingle with each other.

Then, someone at my side says, "There, she is gone."

Gone where?

Gone from my sight. That is all. She is just as large in mast,
hull and spar as she was when she left my side.
And, she is just as able to bear her load of living freight to her destined port.

Her diminished size is in me -- not in her.

And, just at the moment when someone says, "There, she is gone,"
there are other eyes watching her coming, and other voices
ready to take up the glad shout, "Here she comes!"

And that is dying...

~ Henry Van Dyke

Fallleaves

cp418 posted this study back in August, but I thought it belongs on this thread, too, because it involves immunotherapy in conjunction with chemotherapy. It's a small study.

Five-year disease-free survival among stage II-IV breast cancer patients receiving FAC and AC chemotherapy in phase II clinical trials of Panagen

"Disease-free survival rate (17 %) of patients with IIIB + C stage breast cancer receiving standard of care therapy is within the global range. Patients who additionally received Panagen demonstrate a significantly improved disease-free survival rate of 50 %. This confirms anticancer activity of Panagen."

"In all likelihood, tablet form of Panagen acts via interaction of fragmented dsDNA with immune cells resident in the intestinal lymphoid tissue. Active substance of Panagen is delivered to the upper GI tract in the form a tablet with a gastro-resistant coating where it falls apart and the substance is dissolved in the intestinal lumen. DNA fragments eventually reach mononuclear cells of Peyer's patches, lymphoid follicles of appendix and solitary follicles resulting in their activation [37]. Following activation, various immune cells of intestinal lymphoid tissue migrate into the lymph and blood circulation and reach immunocompetent organs. These immune cells stimulate proliferation and mobilization of hematopoietic progenitors or their immediate committed progeny via direct cell-cell contacts or cytokine secretion.

Similarly, dendritic cells resident in the intestinal lymphoid tissue become activated by dsDNA [33–36] and enter the lymph/bloodstream. Upon anchoring in lymphoid organs (mesenterium), these dendritic cells engulf cancer neo-antigens that become available as a tumor cell debris produced by the concurrent chemotherapy. These events culminate in the development of adaptive anticancer immune response."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC49908...

(Proskurina, 2016)

Longtermsurvivor

Recent news story for news writers from Health News Review:

http://www.healthnewsreview.org/2016/10/six-tips-w...

xxx

Six tips for writing accurately about cancer immunotherapy drugs

POSTED BY Joy Victory

Immunotherapy drugs that stimulate the immune system to fight cancer are a hot news topic, buoyed in part by high-profile apparent success stories like that of U.S. President Jimmy Carter who was diagnosed last year with metastatic melanoma.

As evidenced by some recent headlines, these stories tend to focus on the positive outcomes:

• TIME: A new cancer therapy leads to remissions
• The Guardian: Immunotherapy: the big new hope for cancer treatment
• Kansas City Star: For some KU cancer patients, altered immune cells give new hope
• ABCNEWS.com: The remarkable cancer treatment that helped Jimmy Carter combat brain tumor

The excitement around immunotherapy is understandable–for a small number of people, they work. These powerful patient stories often overshadow the reality that for most people, they aren't very effective and carry significant drawbacks.

Drawing upon several of our reviews on this topic, we've put together the following tips to help journalists balance out their coverage on these drugs:

1. Discuss the steep costs

We always advocate for costs to be included in news stories looking at health interventions. This is especially important for pricey checkpoint inhibitors like Keytruda, the drug Carter used. As we point out in our review of a Reuters story looking at trial results for Opdivo, another checkpoint inhibitor, a year's worth of treatment costs about $250,000. Even with insurance, the out-of-pocket costs for these drugs are sending some patients into bankruptcy.

The pricetag alone is a staggering detail that readers deserve to know. And so are the fascinating unintended consequences that impact all of us.

And what about when drugs are still experimental? The Washington Post handled this well in a recent story about a t-cell immunotherapy for kids, as we note in our review of their story, because they give a cost estimate based on similar drugs already available.

2. Know your endpoints

In cancer trials, many studies rely on what are known as "surrogate endpoints" to measure the success of a treatment, instead of primary endpoints like overall survival rates, which require a big, long trial to reach statistically significant findings.

It varies, but these surrogates usually include how long the treatment kept the cancer from spreading ("progression-free survival"), or how much it shrunk or reduced tumors ("objective response rate").

For journalists, what matters here is that you explain how positive results related to surrogate endpoints are no guarantee of a longer, healthier life compared to standard treatment (see this chart for a very easy-to-understand explanation).

"Surrogate markers such as PFS and ORR are valuable in drug development; however, their utility and need for longer follow up need to be acknowledged," said oncology researcher Mike Thompson, MD, PhD, of Aurora Healthcare in Milwaukee.

This means if you are writing about a surrogate endpoint like tumor shrinkage, be specific and use actual numbers. And, as we discuss in our review of a Boston Globe story about a modified herpes virus treatment for cancer: Remind readers that surrogates often don't tell the whole story.

The Globe story indicates that the treatment caused some tumors to shrink for at least six months, particularly in those whose cancer had not yet spread to internal organs. But the overall discussion of benefits is lacking some important details. What does "shrink" mean? And when it says that 16% "responded," what exactly does that mean? (Of course, 84% did not respond — a statistic that also was worthy of comment in our view.)

Finally, important outcomes, such as length of survival, are not presented nor compared with alternatives. One study reported that median survival was 23.3 months with the new drug vs. 18.9 months with the comparison treatment — a finding that would have been easy to include. The FDA also had cautioned in a news release that Imlygic, the drug under study, "has not been shown to improve overall survival."

3. Ask: Does this drug extend life? Improve quality of life?

Lack of evidence around survival benefits is far more widespread than just the drug written about in the Globe piece. As a Milwaukee Journal Sentinel/MedPage Today analysis found, of 54 new cancer drugs approved in the last decade, "the FDA allowed 74% of them on the market without proof that they extended life. Seldom was there proof of improved quality of life, either." When extended survival was shown, their analysis found it usually only amounted to a just a few extra weeks or even days.

In the above example from the Boston Globe, the FDA disclosed that the drug had not been shown to improve overall survival. But, often news releases from the FDA, drug industry and medical research centers don't clearly explain what the limitations were, as we saw in our news release review on the drug Tecentriq.

In this case, the FDA news release notes that a Tecentriq trial measured tumor shrinkage as the main outcome. Survival isn't addressed. Yet–and our hats off to them for doing so–the New York Times wrote about Tecentriq and wisely pointed out that it is unknown whether the treatment makes a difference in survival.

4. Don't assume these drugs are easier on the body

The oncologist goes deep with publisher Gary Schwitzer on many of these issues, from surrogate endpoints to the flailing promise of precision oncology. Take a listen here.

Immunotherapy drugs are often described as "lifesavers" and "game changers." A recent Pittsburgh Post-Gazette story described how the side effects may even "pale" in comparison to chemotherapy.

And for some people, that's true. But the reality is these drugs have severe side effects, and can produce disabling conditions, including severe colitis and widespread arthritis.

"These are treatments that have toxicities, and they may be different (and in some cases worse) than the toxicities from standard chemotherapy," said Deanna Attai, a breast surgeon and assistant clinical professor of surgery at the David Geffen School of Medicine.

Also important to know is that our understanding of immunotherapy's full impact is still unfolding, something hinted at in this Medpage Today story about the "novel" emergence of inflammatory arthritisamong immunotherapy patients at a cancer center affiliated with Johns Hopkins.

Some of this is because these drugs are relatively new and therefore carry unknown risks, and some of this is because, as this systematic review concluded, reporting of immune-related adverse events in research trials involving immunotherapy is suboptimal and "often incomplete."

5. Understand how these drugs fit (and don't fit) into "precision oncology"

Immunotherapy should not be confused with precision oncology, which is the notion that genetic sequencing can reveal mutations that help optimize treatment. Instead of focusing on the type of cancer (lung or breast or colon, for example), treatment is targeted based on the type of genetic mutation seen. In some cases, an immunotherapy drug might be used, but mostly it involves other types of cancer drugs.

What immunotherapy and precision oncology have in common is a lot of hype over relatively lackluster results, notes Dr. Vinay Prasad, a hematologist-oncologist and Assistant Professor of Medicine at the Oregon Health and Sciences University, who wrote about the "precision-oncology illusion" in Nature.

"Data from some 2,600 people enrolled in a sequencing programme at the MD Anderson Cancer Center in Houston, Texas, showed that just 6.4% were paired with a targeted drug for identified mutations. Similarly, the Molecular Analysis for Therapy Choice (NCI-MATCH) trial at the US National Cancer Institute has enrolled 795 people who have relapsed solid tumours and lymphoma, but as of May 2016 it had only been able to pair 2% of patients with a targeted therapy."

And, even in the rare cases where a drug is found to be a good match for the patient's biological markers, this doesn't guarantee blockbuster results. Prasad reports that only about 30% of these patients see any improvement.

"At best, we may expect short-lived responses in a tiny fraction of patients, with the inevitable toxicity of targeted therapies and inflated cost that this approach guarantees," he says in the Nature review.

6. Determine if your patient interview is with an 'exceptional responder'

And yet, even though they do not represent the typical scenario, it's this "tiny fraction" of patients who have exceptional results– from immunotherapy or precision oncology treatments–who often make their way into news stories, Prasad says.

"When you read the lay public coverage of cancer medicine today, you would walk away with the idea if only you could get your tumor sequenced, you could be almost assured of finding out something we already have that could give you a tremendous lease on life," he said in a podcast interview with us. "That's the narrative that's been put out over and over in anecdotal news stories about the one person who does really well."

Yet, more often than not, that one person is what oncologists like Prasad call a "super responder."

"In reality, many people profiled are unusual before they took the drug: They already lived far beyond expectations," Prasad said.

This is why it's important to interview a variety of patients, and not just the ones with incredible results. (That said, stories that only profile one patient can be done well, as we saw in our review of a Philadelphia Inquirer story about one man's ups and downs of using a type of immunotherapy for leukemia.)

To make sure that an exceptional patient isn't misleadingly portrayed as a typical patient, Prasad offered tips on how to sift them out. His advice included asking the following:

1. Before the super-responder patient got the "new" drug, had their course been average? Or were they already beyond average? Did they respond wonderfully to early therapy?
2. Did they already outlive life expectancy?
3. How many prior treatments had the super-responder gotten? How many treatments does the average person get? (Because people with naturally slow growing cancers live long enough to get many treatments.)
4. What was the best response to therapy (did the cancer shrink or just grow slower)?

Bottom line: There is understandable excitement surrounding these drugs that extend life for some patients who've run out of options. But as journalists, we have a responsibility to not let this enthusiasm run beyond what the evidence can support–what Prasad calls fostering false optimism.

"People who are suffering from cancer have one of the most challenging…experiences any of us can have," Prasad said in the podcast interview with us. "We do them a service if we can do better by covering cancer therapies for what they are, by being more accurate about the use of new drugs."

zarovka

Great article on the state of immunotherapy!

Thank you stephanie.

>Z<

heidihill

New approach tests the strength of immunity

https://www.sciencedaily.com/releases/2016/10/161027094824.htm

"The test, which we've named the CaFlux, is rapid, sensitive, and can test a broad array of antigenic targets," says senior author Yuri Sykulev, M.D., Ph.D., a Professor of Microbiology and Immunology and of Medical Oncology at the Sidney Kimmel Cancer Center at Jefferson "A future application of this test could help determine who might respond with a sneeze versus who might respond with anaphylactic shock before it happened."

zarovka

thank you heidi!

Artista928

Good read on real side effects of immune system fighting cancer..

http://www.nytimes.com/2016/12/03/health/immunotherapy-cancer.html

JohnSmith

Promising news from the 2016 SABCS conference regarding a trial combining Immunotherapy with Chemo for TNBC.

The Immunotherapy drug Pembrolizumab (Keytruda, an Anti-PD1 therapy) combined with Eribulin (Halaven) demonstrated a 33.3% objective response rate for patients with metastatic triple-negative breast cancer who received 0 to 2 prior lines of therapy.
http://www.onclive.com/conference-coverage/sabcs-2016/pembrolizumab-eribulin-combo-shows-promise-for-tnbc

Here's a 3 minute video that summarizes the news: http://ecancer.org/video/5564/pd-1-therapy-with-eribulin-for-triple-negative-mbc.php

This is an interim analysis of an ongoing trial, so the data is not mature. Patients need to be followed longer to determine benefit. Another update will be provided in Summer 2017. However the early results offer a glimmer of hope. As some have expected, TNBC are benefiting by Immunotherapies since TNBC typically present a higher tumor burden (which the immune system can see once the "parking brake" is released with checkpoint inhibitors like Keytruda). TNBC also tend to have higher immune cells called lymphocytes or TILs in or near the tumor, which is good since they can attack the cancer once the "brake" is released.

The phase II portion of the study continues to enroll participants with metastatic TNBC (https://clinicaltrials.gov/ct2/show/NCT02513472)
12 different states across the US are still enrolling patients.

This is just one clinical trial. As a reminder, throughout the US and Canada, there are ~250 different trials for breast cancer that involve some type of Immunotherapy.

JohnSmith

Pembrolizumab (Keytruda) promising in Metastatic Triple-Negative Breast Cancer.
Results from a Phase Ib trial that focused on 32 triple-negative breast cancer patients who were positive for PD-L1 suggest that the PD-1 inhibitor pembrolizumab has activity and an acceptable toxicity profile as single-agent therapy in heavily pretreated, advanced triple-negative breast cancer (TNBC).
Read more here: http://www.cancernetwork.com/news/pembrolizumab-promising-metastatic-triple-negative-breast-cancer

TectonicShift

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