Tag Archives: medical research

A VERY NEW IMMUNOTHERAPY FOR CANCER WINS THE 2015 LASKER-DEBAKEY CLINICAL MEDICAL RESEARCH AWARD! 

Cancer is "The Big C" for patients, doctors, and research scientists! (http://dr-monsrs.net)
Cancer definitely is “The Big C” for many patients, doctors, and researchers!   (http://dr-monsrs.net)

Many critics of spending billions of dollars on cancer research typically point to the fact that a general cure for neoplastic diseases had not been discovered (see:  “After Spending Billions, Why have Scientists Not Yet Found a Cure for Cancer?” ).  That now is no longer a convincing question, thanks to the basic and applied research of James P. Allison, PhD (University of Texas M. D. Anderson Cancer Center, in Houston).  His breakthrough experiments and new ideas for anticancer therapy led to remissions and probable cures for some cancer patients who previously had no hope.  This article briefly describes Dr. Allison’s research on the functioning of specialized cells in the immune system, which led to discovery of a very new effective approach for therapeutic treatment of cancer.

The Lasker Awards. 

Each year, the Albert and Mary Lasker Foundation [1] bestows 3 Lasker Awards: Albert Lasker Basic Medical Research Award, Lasker-DeBakey Clinical Medical Research Award, and, Lasker-Bloomberg Public Service Award.  The 2015 Lasker Awards and Laureates all are nicely described on the Foundation website: http://www.laskerfoundation.org/media/index.htm .  Lasker Awards are considered to be most prestigious for medical science,  and the awardees often are considered to be likely to soon receive a Nobel Prize.

Dr. Allison has just won the very prestigious Lasker-DeBakey Clinical Medical Research Award for 2015 for his innovative new immunotherapy against cancer [2-4].  He previously has received numerous other honorary awards, including the 2014 Breakthrough Prize in Life Sciences [5] and the 2014 Szent-Györgyi Prize from the National Foundation for Cancer Research [6].

A new kind of anti-cancer immunotherapy is developed by Dr. Allison [2-6]! 

Many different immunology-based therapies against cancer have been investigated, but most have produced only limited clinical benefits.  The experimental treatment of cancer with antibodies that specifically bind to molecular components produced by cancer cells has not been successful.  Dr. Allison’s early research investigated the molecular mechanisms for how some cells of the immune system, T-cells, work in the cellular immune response to recognize and kill bacteria, viruses, and abnormal cells in the body. T-cell activities are nominally independent from antibody responses of the immune system.

Detailed research about T-cell surface receptors, binders, and cofactors led to Dr. Allison’s recognition that there are both positive on-signals and negative off-signals regulating T-cells.  One of the down-regulators is a receptor protein named, CTLA-4; upon binding of CTLA-4 to it’s targets, the activation and proliferation of T-cells are turned off.  This negative regulation is normal and is believed to prevent active T-cells from attacking the body’s own constituents (i.e., autoimmune diseases).

Most immunologists have long thought that the immune system should recognize, attack, and kill cancer cells.  Thus, it was a mystery why such does not happen.  This puzzle led Dr. Allison to ask whether CTLA-4 might be turning off a T-cell response against cancer cells.  He tested this hypothesis by developing antibodies that specifically bind CTLA-4 molecules, thereby inactivating their functional activities, including the down-regulation of T-cells.  When these antibodies were injected into laboratory mice bearing a transplantable tumor, there was a large proliferation of T-cells and strong killing of cancer cells inside the tumors!  Injecting control antibodies which bound other proteins had no effects on T-cells, so the tumor-bearing mice died.  Thus, these and other experimental results showed that stopping the normal down-regulation of T-cells released them to give a strong response against neoplastic cells.  The brakes on T-cells had been released by Dr. Allison, so their endogenous anti-cancer activities now went full speed ahead!  The go/no-go interaction between CTLA-4 and T-cells now is known as an immune checkpoint.

The next step in this ongoing research project involved translating the findings from basic research into applied clinical research with experimental treatment of human cancer patients.  After finally finding a pharmaceutical company willing to collaborate with production and testing of anti-CTLA-4 human antibodies, Dr. Allison began initial clinical trials of this experimental treatment of cancer patients who had not responded to any usual surgical, chemical, or radiation therapy.  In some cases the new immunotherapy worked quite well!  A standardized commercial version of human anti-CTLA-4 antibodies was approved for clinical use in 2011; over 30,000 cancer patients now have received the new immunotherapy.  This new cancer treatment is not just another promise of some hoped for future development; it is here today, and actually saves the life of some cancer patients.

Ongoing research in anti-cancer immunotherapy by Dr. Allison and other scientists [2-6]. 

The door now was opened to try this very new kind of anti-cancer therapy with different patients, different cancers, and different therapeutic protocols.  The effects of anti-CTLA-4 antibodies had dramatic results for some patients with malignant myeloma, a blood cell cancer that usually is fatal within one year.  The anti-CTLA-4 therapy put some, but not all, myeloma patients into long-term remission (i.e., over 14 years)!  New research, both by Dr. Allison and by other clinical research scientists, seeks to find: (1) why some malignant myeloma patients do not respond to this new therapy, (2) which additional cancers can be treated by this immunotherapy, (3) whether manipulating other proteins regulating T-cell activities will provide additional curative effects, (4) will combination treatments of cancers (e.g., immunotherapy with concurrent chemotherapy) give even better curative effects, and, (5) can manipulating other immune checkpoints have therapeutic effects against any non-cancer  diseases?

Special features of this very new kind of immunotherapy. 

Some distinctive very special features of this new kind of immunotherapy must be recognized by all readers!

(1)  The new curative therapy is targeted against the immune system, and not against cancer cells.

(2)  T-cells can effectively kill cancer cells; thus, an endogenous response is what kills the cancer cells.

(3)  Endogenous activities of T-cells against neoplastic cells normally are halted by activities of CTLA-4.

(4)  Right now, this new immunotherapy probably cures several types of cancer in some patients.

Concluding remarks. 

Dr. James Allison deserves immense credit for coming up with new ideas and new research findings about the immune system, and for asking new clinical questions.  He is an superb example of how PhD scientists investigating pure basic science in a laboratory can contribute much to applied clinical research.  Individual scientists having creativity, curiosity, enthusiasm, and the guts to think new thoughts, just like Dr. Allison, are the best hope for more important discoveries in all branches of scientific research.

Dr. Allison very clearly has made a wonderful contribution to modern clinical medicine.   All of us can hope that additional cancers finally will be conquered with the results from further research studies and innovative medical developments.  In addition, new approaches to immunotherapy might also benefit patients with some non-cancer diseases.

Recommended videos by and about Dr. James Allison! 

“James Allison’s Cancer Research Breakthrough”, 2014, is available at: http://www.youtube.com/watch?v=ySG2AwpSZmw&spfreload=10 .

“Dr. Jim Allison – 2014 Szent-Györgyi Prize”, 2014, is available on the internet at: http://www.youtube.com/watch?v=YGu2uzV9QOM .

“James P. Allison, Ph.D. on Targeting Immune Checkpoints in Cancer Therapy”, 2015, is available at:  http://www.youtube.com/watch?v=CoBkuTOPJqg .

 

[1]  Lasker Foundation, 2015a.  Foundation overview.  Available on the internet at:  http://www.laskerfoundation.org/about/index.htm.

[2]  Lasker Foundation, 2015b.  Lasker-DeBakey Clinical Medical Research Award.  Award description.  Available on the internet at:  http://www.laskerfoundation.org/award/2015_c_description.htm .

[3]  Lasker Foundation, 2015c.  Lasker-DeBakey Clinical Medical Research Award.  Award presentation by Michael Bishop.  Available on the internet at:  http://www.laskerfoundation.org/awards/2015_c_presentation.htm .

[4]  University of Texas M. D. Anderson Cancer Center, Newsroom, 2015.  MD Anderson immunologist Jim Allison wins Lasker-DeBakey Award.  Available on the internet at:  http://www.mdanderson.org/newsroom/news-releases/2015/allison-wins-lasker-award.html .

[5]  University of Texas M. D. Anderson Cancer Center, Newsroom, 2013.  M.D. Anderson researcher Jim Allison wins Breakthrough Prize for his innovative cancer immunology research.  Available on the internet at:  http://www.mdanderson.org/newsroom/news-releases/2013/immunology-research.html .

[6]  National Foundation for Cancer Research, 2015.  The Szent-Györgyi Prize for progress in cancer research.  Available on the internet at: http://www.nfcr.org/prize .

 

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WHISTLEBLOWERS IN SCIENCE ARE NECESSARY TO KEEP RESEARCH AND SCIENCE-BASED INDUSTRIES HONEST! 

 

Direct quotations from Dr. Peter Wilmshurst, given in published statements. (http://dr-monsrs.net)

Quotations by Dr. Peter Wilmshurst, taken from various published statements.     (http://dr-monsrs.net)

 

Anyone, even professional scientists with a PhD or MD, can make an honest mistake.  However, falsification or other dishonesty by a research scientist is an inexcusable breach of trust.  Since the goal of research is to find the truth, mistakes or alleged falsehoods must be investigated and corrected, in order to let science progress.  Whistleblowers in science have been rather few, largely because it is so much easier to keep quiet and overlook falsehoods or even criminal misrepresentations; speaking out or initiating inquiries about corruption in research typically leads to counter-allegations, challenges to professional reputation, prolonged court cases, and, only small penalties for proven wrongdoers.  Hence, most doctoral scientists keep quiet, particularly if an allegation involves someone with a higher professional rank; this is known as the “code of silence”.

This article describes the amazing adventures of a clinical and research cardiologist in Britain, Peter Wilmshurst, MD, who became a successful whistleblower.  During his medical research work, he found clear unethical and criminal misconduct by individuals and companies, so he courageously initiated several inquiries.  Unlike many others, Dr. Wilmshurst refused to be silenced by bribes or threats, and ultimately forced honesty to prevail.  Dr. Wilmshurst undoubtedly is nothing less than a heroic medical scientist!

Whistleblowing by Dr. Wilmshurst protected heart patients from a dangerous new drug [1-5]! 

In the 1980’s, Dr. Wilmshurst was invited by a very large pharmaceutical company in the UK to participate in their clinical research trial evaluating the efficacy of a new oral drug intended to strengthen cardiac contractions in patients with heart failure.  His research data showed no effects upon contractility in patients, and revealed very dangerous side effects.  According to the company, research data from their own researchers were strongly and uniformly positive.

When he reported his research results to the manufacturer, he was asked to suppress his negative findings.  Wilmshurst refused to do that, and would not keep quiet about his research results despite threats. Later, it was revealed that several other independent researchers had found adverse results similar to those of Dr. Wilmshurst, but fear had prevented them from announcing their findings.  The company published the results of this clinical trial without including Wilmshurst’s research findings.  The government health agencies, professional medical organizations, and several science journals heard Wilmshurst’s pleas for an official investigation, but all were afraid to do anything!  More and more reports from clinical physicians showed numerous medical problems arising in treated patients; finally, marketing this new drug in the UK and the US was stopped by the manufacturer, but sales and usage continued in some developing countries.  Only after a large write-up about Dr. Wilmshurst and his dispute in the Guardian newspaper (UK) was this dangerous pharmaceutical completely withdrawn from the entire world.

More whistleblowing by Dr. Wilmshurst protected migraine patients from a dangerous new medical device [1-5]!

Dr. Wilmshurst had published a research report in 2000 linking migraine to a fairly common developmental defect in the heart, patent foramen ovale.  His expertise as a cardiologist and medical researcher led to an invitation to be a research consultant in a large clinical trial of a new implantable device manufactured by a small company in the US; with implantation into the heart, this was supposed to close the cardiac defect.  The clinical trial examined whether its use would also stop recurring migraine attacks.  His echocardiogram results for treated patients differed greatly from those gathered by the cardiologists implanting the new devices on behalf of the manufacturer.  The company disputed Dr. Wilmshurst’s research findings and claimed that echocardiograms from the implanting cardiologists were correct, but his results were wrong and invalid.

That company then refused to include his research results within their published report on the clinical trial.  The company’s presentation of their clinical trial at a cardiology meeting in Washington did not mention his divergent interpretations of post-implantation echocardiograms, but Dr. Wilmshurst was in the audience (i.e., he had presented some of his own research at this meeting that did not concern this experimental device).  A reporter interviewed Dr. Wilmshurst at this meeting and published some of his comments about the divergent data for this experimental device.  Two weeks later, the company’s lawyers notified him of a lawsuit in the UK for defamatory libel; several more lawsuits for libel followed.

Media and medical journals began describing Dr. Wilmshurst’s ongoing fight against these lawsuits, which cost him much personal money over several years of worrisome court proceedings.  Perhaps in response to their estimates that all these trials would have a total cost of over 14 million dollars, the small manufacturer abandoned production of the new device and went out of business; the bankruptcy ended the lawsuits.  Dr. Wilmshurst again had successfully fought research misconduct and commercial fraud, thereby saving clinical patients from any grief with this ineffective new device.

Important lessons to be learned from Dr. Wilmshurst’s activities [1-5]. 

Several disconcerting lessons about both dishonesty and honesty in research can be learned from this determined British medical researcher and whistleblower.

(1)  Since scientific research is conducted by humans, it is easily subject to unethical conduct due to government inaction, overriding ambition, personal greed, selfish commercial interest, silence about professional wrongdoing, wrongful self-interest, etc.

(2)  Money and commercial interests make total honesty particularly difficult for scientists in cases where their research results contradict or call into question what is desired; research must seek the truth, and is distorted when it looks for only a predetermined result.

(3)  Industrial companies often can pressure and overwhelm individuals by using their large financial resources for bribes, teams of specialized lawyers in expensive lawsuits, direct threats to impugn professional reputation and personal integrity, etc.

(4)  The most common reaction upon finding dishonesty in science is simply silence and a refusal to become involved; this is very easy to do, but such tolerance of dishonesty can hurt innocent people (i.e., patients) and probably is itself a form of dishonesty.

(5)  The penalties and punishments for dishonesty in research are usually small or absent, which then encourages more dishonesty; some scientists even have a very successful career with repeated dishonesty that is widely known [2].

(6)  Corruption within all aspects of medical research is much more extensive than is commonly thought.

The ultimate goal of science is to find the truth, no matter what it might be.  Independent research is the best human means to decide what is true and what is false.  Whistleblowing serves to promote honesty in business, government, and science.  Court cases usually are initiated to pressure and intimidate whistleblowers to keep quiet or repudiate their earlier research findings and conclusions.  Judges and lawyers do not know enough about science to decide about controversies in research (see:  “What Happens when Scientists Disagree? Part V: Lessons to be Learned When Scientists Disagree” ).  As Dr. Wilmshurst has stated, “The law courts are not the best way to determine scientific truth.” [4].

Peter Wilmshurst is a unique individual, and certainly is a hero! 

Dr. Wilmshurst stands up for honesty even when other research scientists say nothing and ignore obvious wrongdoing, compromise their professional ethics by research misconduct, or show no personal integrity.  His personal characteristics and professional standards as a medical research scientist make him a great role model for young scientists, physicians, and research workers in all the disciplines of science.  He does not fear getting involved and announcing the truth even when that means making shocking disclosures about highly placed figures, esteemed professional organizations, very famous science and medical journals, successful large industrial operations, and, malfunctioning agencies in the national government.

It should be obvious that Dr. Wilmshurst is a very distinctive individual who successfully fought against large manufacturing companies, government agencies, professional medical associations, professional science journals, lawyers and courts, and blatant threats to his reputation as a professional clinical researcher.  He could do all of that because he is an ethical scientist with exemplary honesty, personal courage, and professional integrity.  Whereas he speaks out about dishonesty in research, many others choose to keep silent and refuse to challenge dishonesty and corruption; thus, dishonesty in science is widely tolerated [1].

Peter Wilmshurst should be honored for his career-long dedication to honesty and high professional standards in research!  In 2003, he received the HealthWatch Annual Award in the UK for his work against corruption and fraud in medical science [1].

Further information is directly available from Dr. Wilmshurst on the internet! 

A wonderful video presentation by Peter Wilmshurst, “The Role of Whistleblowers in Improving the Integrity of the Evidence Base”, is highly recommended to all reading this article (see:   https://www.youtube.com/watch?v=Xze-yPubFIY ).

Also highly recommended to all by Dr.M are both the written version of the speech given by Dr. Wilmshurst on the occasion of his receiving the HealthWatch Annual Award for 2003 (see:  http://www.healthwatch-uk.org/20-awards/award-lectures/65-2003-dr-peter-wilmshurst.html ), and, a very recent 2015 interview of Dr. Wilmshurst by R. von Bredow & V. Hackenbroch for Spiegel Online International, “Whistleblower on Medical Research Fraud: ‘Positive Results Are Better for Your Career'” (see:  http://www.spiegel.de/international/zeitgeist/spiegel-interview-with-whistleblower-doctor-peter-wilmshurst-a-1052159.html ).

Concluding remarks.   

Whistleblowers are essential to help keep everyone honest!  Even large companies and very famous scientists can become dishonest, unethical, or unprofessional.  Lack of honesty in scientific research can lead to grave practical problems for unsuspecting innocent people.   For medical research, Dr. Wilmshurst states appropriately, “Truth should not be decided by those with greatest wealth using bullying and threats to make a scientist retract what he or she knows is true.” [4].

[1]  P. Wilmshurst, 2004.  Obstacles to honesty in medical research.  HealthWatch – UK, Newsletter #52, 2003 HealthWatch – UK Award Lecture.  (see:  http://healthwatch-uk.org/20-awards/award-lectures/65-2003-dr-peter-wilmshurst.html ).

[2]  P. Wilmshurst, 2007.  Dishonesty in medical research.  Medico-Legal Journal 75:3-12. (see:  http://www.medico-legalsociety.org.uk/articles/dishonesty_in_medical_research.pdf ).

[3]  R. Smith, 2012.  A successful and cheerful whistleblower.  The BMJ (British Medical Journal) Blogs, October 10, 2012.  (see:  http://blogs.bmj.com/bmj/2012/10/10/richard-smith-a-successful-an.d-cheerful-whistleblower/ ).

[4]  R. A. Robbins, 2012.  Profiles in medical courage: Peter Wilmshurst, the physician fugitive.  Southwest Journal of Pulmonary and Critical Care, April 27, 2012/4:134-141.  (see:  http://www.swjpcc.com/general-medicine/2012/4/27/profiles-in-medical-courage-peter-wilmshurst-the-physician-f.html ).

[5]  P. Wilmshurst, 2012.  Justice Committee – written evidence submitted by Dr. Peter Wilmshurst.  UK Parliament, House of Commons, Select Committee on Science and Technology.  (see:  http://www.publications.parliament.uk/pa/cm201213/cmselect/cmsctech/163/163vw17.htm ).

 

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