Encouraging Immunotherapy Cancer Collaborations Between Government (NIH) and Eleven Pharmaceutical Companies.bjgabrielsen : October 20, 2017 4:20 am : 2017
As described in recent website blogs, utilizing one’s immune system to combat cancer (immunotherapy) is at the cutting edge of prostate cancer research and cancer research in general. I am personally familiar with an on-going National Cancer Institute (NCI) clinical trial combining the prostate cancer vaccine Prostvac and the checkpoint inhibitor antibody Opdivo® (nivolumab), currently approved by the FDA for the treatment of non-small cell lung cancer. On October 12th, it was reported that the National Institutes of Health (NIH), the nation’s medical research agency announced a partnership with eleven leading biopharmaceutical companies to accelerate the development of new cancer immunotherapy strategies. This Partnership for Accelerating Cancer Therapies (PACT), a five-year public-private research collaboration totaling $215 million is part of the Cancer Moonshot. PACT will initially focus on efforts to identify, develop and validate robust biomarkers — standardized biological markers of disease and treatment response — to advance new immunotherapy treatments that harness the immune system to attack cancer.
NIH, the nation’s medical research agency, includes 27 Institutes and Centers of which the National Cancer Institute (NCI) is the largest. NIH is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases.
New immunotherapies have resulted in dramatic responses in certain cancer cases. They have also been the focus of intense investment by biopharmaceutical companies seeking to provide new options for patients who do not respond to other cancer therapies, but they don’t work for all patients. Development and standardization of biomarkers to understand how immunotherapies work in some patients, and predict their response to treatment, are urgently needed for these therapies to provide benefit to the maximum number of people.
The biopharmaceutical companies are expected to contribute $55 million over the five years while NIH will contribute $160 million. For more information and for the companies involved, see the following link. For more information about NIH and its programs, visit www.nih.gov
For the many years I have been treated for prostate cancer, I have been blessed by God with a wonderful, caring, praying and compassionate wife. I am sure this has helped my current asymptomatic status and hopefully my prognosis. This theme was amplified today when I read the following article published October 9th in MedlinePlus, a health-based news service from the U.S. National Library of Medicine of the National Institutes of Health. The article describes the clinical benefits of a happy marriage as they relate to cardiovascular disease; however I see no reason why it couldn’t be extrapolated to prostate and other cancers. I suggest you read the linked article.
Men ages 55-69 who don’t get PSA (prostate-specific antigen) screening tests for prostate cancer may want to reconsider that choice based on an April 2017 recommendation from the United States Preventive Services Task Force (USPSTF), a government advisory medical panel who evaluate the benefits and harms of health services. A few years ago, this same panel discouraged many men from having the PSA test.
As most of you know, the PSA test measures a protein level that rises both in men with prostate cancer and other prostate disorders. The test has several shortcomings including the risk of a false-positive result. Only about one in four men with an elevated PSA level who undergoes a prostate biopsy actually has prostate cancer according to the National Cancer Institute. However, a biopsy can have serious side effects such as bleeding, infection and pain. Up to half of prostate tumors identified by the PSA test and confirmed by a subsequent biopsy are harmless and will never cause symptoms or death. Yet many men proceed to treatment with surgery or radiation for low-risk cancers even though treatments can cause long-term side effects such as incontinence and erectile dysfunction.
In 2008, the USPSTF advised men 75 and older to pass on PSA screenings concluding that the potential harms outweighed the benefits of cancer detetction. In 2012, the panel extended the recommendation to include all men saying in essence “do not screen” resulting in a serious decline in PSA screening. Meanwhile the number of men over 75 diagnosed with prostate cancer that has metastasized rose from 7.8% to 12% according to the Journal of the American Medical Association Oncology. Authors of the study suggested that the decline in PSA screening led to the rising number of men being diagnosed with advanced prostate cancer.
The USPSTF has now reversed its course to some extent encouraging men ages 55 to 69 with average risk to discuss PSA testing with their doctors and share the responsibility for deciding whether or not to be screened for prostate cancer. The group still discourages testing for men younger than 55 or older than 69. Other groups such as the American Urological Association advise men with a family history of prostate cancer or African-American ancestry to begin screening (including a digital rectal exam) before age 55. It is also reasonable for select healthy men in their early 70’s to request screening too since they may live an additional 15-plus years.
It is suggested you ask your doctor if you should be screened and why. For more information on prostate symptoms, see the Sept. 25th post. If you decide to be screened, discuss how often you should be tested; every other year makes sense for many men while annual testing may be preferable for those with risk factors.
Risk factors include age, race and family history. As you get older, the risk of developing prostate cancer increases dramatically. The average age at diagnosis is between 65 and 70 years. Black men are at highest risk whereas rates for white men and hispanics are 40-50% lower. Asian, Pacific Islander and American Indian men have the lowest rates. You have double the risk if you have a first-degree relative (father or brother) with prostate cancer. Second-degree relatives (uncle or grandfather) with prostate cancer confer only a small risk increase.
(Much of this material was taken from the Sept. 2017 issue of the University of California Berkeley School of Public Health Newsletter.)
As many of you readers know, I have early stage, asymptomatic but advanced prostate cancer. After treatment with Provenge, I was informed (perhaps divinely through a former colleague) of a National Cancer Institute (NCI) clinical trial currently recruiting patients like myself. The protocol involves treatment with the vaccine Prostvac and the antibody therapy, Opdivo. I had written about this in earlier posts. Since that time, Yervoy (ipilimumab) has been removed from the trial and most recently a large Phase 3 trial of Prostvac has been discontinued. Independently, I had been informed about the potential toxicity of Yervoy which reinforced my anticipation of the trial; but then the news of Prostvac’s lack of success seriously dampened my enthusiasm. It was just at that time when a devotional (August 13th) from Our Daily Bread Ministries placated my fears and inflated my faith that I was indeed pursuing the right track in my treatment.
The message was from an Old Testament prophet named Habakkuk who served as an inspiring example of someone who argued with God yet came to the point of trusting Him regardless of the impending circumstances. Habakkuk states (Hab. 3:16-19), “I heard and my heart pounded, my lips quivered at the sound; decay crept into my bones and my legs trembled.” However in contrast, “though the fig tree does not bud and there are no grapes on the vines, though the olive crop fails and the fields produce no food, though there are no sheep in the pen and no cattle in the stalls, yet I will rejoice in the Lord, I will be joyful in God my Savior.”
What do we do when circumstances are beyond our control or when the outlook seems hopeless? The prophet Habakkuk’s situation was out of his control and the fear that he felt terrified him. The coming judgment could be catastrophic. Yet, in the midst of the impending chaos, Habakkuk made a choice to live by his faith and rejoice in God. He did not place his confidence and his faith in his circumstances, ability or resources but in the goodness and greatness of God. His trust in God compelled him to proclaim: “The Sovereign Lord is my strength; he makes my feet like the feet of a deer, he enables me to treat on the heights.”
When we are faced with difficult or unknown circumstances, we too have only to place our faith and trust in God to be our strength. He is with us in everything we face.
Are you unsure of whether or not you have a personal relationship with God? See the following.
An independent Data Monitoring Committee (DMC) recommended that the Phase 3 PROSPECT study of Prostvac in men with metastatic hormone-resistant prostate cancer (mCRPC) should be discontinued due to inadequate results. Prostvac did not improve overall survival. The PROSPECT trial (NCT01322490) was a randomized, double-blind, and placebo-controlled Phase 3 trial that included 1,298 mCRPC patients from 200 sites in 15 countries. These men had minimal or no symptoms associated with their mCRPC. The trial evaluated whether Prostvac, alone or in combination with granulocyte macrophage colony-stimulating factor (GM-CSF), could improve overall survival compared to a placebo. GM-CSF is a cytokine or signaling molecule that can also stimulate the immune system. It stimulates the production of granulocytes and monocytes, two types of cells in the immune system that are important for fighting infections.
Previous studies evaluating more than 2,000 participants suggested that Prostvac immunotherapy was well-tolerated. In a Phase 2 trial, this immunotherapy showed potential in prolonging survival in men with advanced prostate cancer. However, the interim analysis for the Phase 3 PROSPECT trial suggested that Prostvac may not be as effective as hoped. It is hoped that combination therapies including Prostvac may be more effective. Copenhagen, Denmark-based Bavarian Nordic’s hopes of salvaging Prostvac now rest on whether it can boost the effect of other immuno-oncology agents, notably Bristol-Myers’ PD-1 and CTLA-4 checkpoint inhibitors Opdivo and Yervoy. Publicly, Bavarian Nordic has not given up hope that the cancer vaccine can complement these drugs. For further details, see the Sept. 15th FierceBiotech article and Sept. 21st Prostate Cancer News Today.
Prostvac had been in late stage Phase III development (PROSPECT trial) for metastatic, hormone-resistant prostate cancer patients who are either asymptomatic or minimally symptomatic. It is a therapeutic pox virus cancer vaccine directed at PSA-producing cells. It is administered with or without GM-CSF (granulocyte macrophage colony-stimulating factor, a protein secreted by immune system cells that functions as a white blood cell growth factor. Prostvac immunotherapy (administered by s.c. injections) is intended to trigger a specific and targeted immune response against prostate cancer cells and tissue by using virus-based immunotherapies that carry the tumor-associated antigen PSA (prostate-specific antigen) along with 3 natural human immune-enhancing costimulatory molecules collectively designated as TRICOM (LFA-3, ICAM-1, and B7.1 When PSA-TRICOM is presented to the immune system in Prostvac, cytotoxic T lymphocytes (CTLs) are generated that may recognize and kill PSA-expressing cancer cells.
This website has been covering Prostvac development for several years. See blogs posted August 5th, 2014 and May 15th, 2017 among others.
An article from Fox Chase Cancer Center in Philadelphia published Sept. 21st in the U.S. National Library of Medicine MedlinePlus described a list prostate cancer symptoms. Prostate cancer symptoms may be confused with signs of other common but noncancerous disorders, such as benign prostatic hyperplasia. Symptoms of prostate cancer may include: trouble starting to urinate; weak or interrupted flow of urine; urinating more often, particularly during the night; trouble emptying the bladder; pain or burning during urination; bloody urine or semen; painful ejaculation; and/or chronic pain in the back, hips or pelvis. Although about 1 in 7 men will be eventually be diagnosed with prostate cancer in his lifetime, the warning signs of the disease are often vague and may be confused with other conditions.
Prostate cancer is rare in men younger than 40 years old but once they reach 50, the risk increases. Nearly 6 out of 10 men with prostate cancer are older than 65 years old, the Fox Chase specialists said. Black men are more likely than men of other races and ethnicities to be diagnosed with prostate cancer and die from the disease. Black men are also more likely to develop advanced disease and have the condition at a younger age.
Genetics may also play a role in why some men develop prostate cancer. Men whose father or brother have the disease are more than twice as likely to also be diagnosed. The risk increases if several family members are affected and if these men were diagnosed at a younger age. Men who are 55 and older should discuss their risk factors for prostate cancer with their doctor and determine if screening is right for them.
Additional Studies of Opdivo (nivolumab) in Combination with Rubraca in Prostate Cancer and Other Applications of Opdivo.bjgabrielsen : September 13, 2017 2:25 am : 2017
Editorial note: I am writing some of this post while awaiting Hurricane Irma to pass my home directly in about 1-2 hours.
Opdivo® (nivolumab) and the prostate cancer vaccine Prostvac are being combined in a National Cancer Institute clinical trial described in posts on this website dated May 15th and August 7th, 2017. Bristol Myers Squibb and Clovis Technology will collaborate to assess the combination of Opdivo® (nivolumab) and the PARP inhibitor, Rubraca (rucaparib) in Phase 2 and 3 clinical studies in patients with different cancer types, including prostate cancer.
The companies plan to launch a Phase 2 study to investigate the safety and effectiveness of the combination treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). All studies are expected to begin before the end of 2017.
“We are very enthusiastic about studying Rubraca and Opdivo® in combination, and the potential to create new treatment options for patients with multiple tumor types, as well as for patients beyond those with BRCA mutations,” according to Patrick J. Mahaffy, Clovis Oncology’s president and CEO. “This substantial clinical collaboration in ovarian, triple-negative breast and prostate cancers represents a significant effort by Clovis and Bristol-Myers Squibb to realize that potential,” he said.
Cancer cells are constantly multiplying, but the division process is sometimes associated with errors that may cause their death, such as DNA breaks. If cancer cells repair these breaks, they survive and keep multiplying.
Rubraca is an oral inhibitor of PARP proteins (PARP-1, PARP-2, and PARP-3), which are involved in DNA repair. By inhibiting these proteins, Rubraca prevents cancer cells to repair their DNA. Indeed, previous studies have shown that PARP inhibition promotes inflammation, cell death, and increases the action of T-cells within tumors.
Opdivo® acts upon a protein called programmed cell death-1 (PD-1), which inhibits the immune system’s ability to detect cancer cells. By inhibiting PD-1, Opdivo® restores the body’s capacity to activate the anti-tumor response and fight cancer cells. Because of its potential role as an enhancer of the immune system’s response, Opdivo® is under evaluation in a broad range of clinical trials across all phases in a variety of tumor types. For more information, see the following.
Additional results involving Opdivo® include an article published September 11th in MedlinePlus describing research suggesting that Opdivo® — a drug that works with the immune system to fight melanoma — is more effective than the current standard of care for patients who’ve had surgery to remove advanced tumors. In addition, an August 17th post from the National Cancer Institute Current Contents stated that the Food and Drug Administration has approved Opdivo® for patients with metastatic colorectal cancer that has one of two specific genetic features and whose disease has progressed after chemotherapy.
The National Cancer Institute (NCI, the largest of the institutes of the National Institutes of Health, NIH) recently published an excellent fact sheet describing many aspects related to prostate-specific antigen (PSA) testing. Specific subjects addressed include: a) what is the PSA test? b) Is the PSA test recommended for prostate cancer screening? c) What is a normal PSA result? d) What if screening shows an elevated level? e) Limitations and potential harms of using the PSA test for prostate cancer screening; f) Recent research on prostate cancer screening; g) How is the PSA test used in men who have been treated for prostate cancer? h) What does a PSA increase mean for men who have been treated? i) How are researchers trying to improve the PSA test?
Decreasing bone mineral density (BMD) is also an undesirable side effect of androgen deprivation (hormonal) therapy (ADT). The therapy is associated with many potential adverse effects, including significant bone loss and increased risk for low trauma or fragility fractures similar to that in persons with primary osteoporosis. A recent review of clinical trial results revealed that patients with non-metastatic prostate cancer receiving ADT can benefit from osteoporosis therapies, known as bisphosphonates e.g. (Fosamax, Boniva), and from Prolia (denosumab), which significantly increase bone mineral density (BMD). The review, entitled “Bone Health and Bone-Targeted Therapies for Nonmetastatic Prostate Cancer” was recently published in the journal Annals of Internal Medicine.
The new study by researchers at the University of Toronto found that non-metastatic prostate cancer patients starting or continuing ADT had significantly less BMD loss when they were given bisphosphonates (a class of medicines that slow down or prevent bone loss) and Prolia (the only FDA-approved therapy for cancer treatment-induced bone loss), compared with those receiving a placebo, normal care, or other active treatments.
The review set out to evaluate the effectiveness of drug, supplement, and lifestyle interventions currently employed as measures to prevent fractures, improve BMD, and delay osteoporosis in non-metastatic prostate cancer patients. Bisphosphonates were found to increase BMD over a placebo, but had no effect at preventing fractures among patients with non-metastatic prostate cancer. Prolia, administered subcutaneously every six months in a 60 mg concentration, improved BMD and reduced the incidence of new vertebral fractures, according to the results of one clinical trial.
According to Dr. David Samadi, MD, chairman of urology at New York’s Lenox Hill Hospital, “this study should remind all urologists of the gap in regards to bone health care for men with prostate cancer. More testing of bone mineral density both before and during ADT treatment is an important step in identifying those men who may be at risk. One beginning step is to do a risk assessment tool evaluating men with prostate cancer receiving ADT and educating them on the adverse effects of ADT. We also need to be mindful of talking to our patients about their diet and lifestyle making sure they are getting adequate sources of calcium and exercising regularly,” Samadi said.
I have been on a vacation but am now resuming publishing pertinent posts.
As has been written before, several potential side effects accompany hormonal therapy for prostate cancer. A MedlinePlus e mail received today from the National Institutes of Health (NIH) National Library of Medicine discussed the potential heart risk posed by early hormone suppression treatment of prostate cancer. The take-home message from a new study is that “patients with localized prostate cancer should be followed to minimize the health effects of androgen-deprivation therapy on the cardiovascular system,” said study author Reina Haque, a researcher with the Kaiser Permanente Southern California Department of Research & Evaluation. The advice given is that “patients should consider heart-healthy lifestyle changes, and physicians should actively monitor the patient’s health for early signs of heart disease.”
In recent years, there’s been an expansion in use of hormone-suppressing treatment for prostate cancer. The treatment was previously restricted to advanced prostate tumors, but now it’s being given to a growing number of men with early stage prostate cancer that has not spread to other parts of the body. However, the safety and effectiveness of androgen-deprivation therapy for these men hasn’t been investigated, the study authors said.
In the new study, researchers assessed outcomes for more than 7,600 men with early stage prostate cancer. The investigators tracked the men for up to 12 years, starting when they were diagnosed between 1998 and 2008. The researchers factored in certain heart risk factors — things such as overweight/obesity, history of smoking, diabetes, high blood pressure or if they required heart medications. The study found the men with early stage prostate cancer who did not already have heart disease, but who received hormone-depleting treatments had an 81 percent higher risk for heart failure. Meanwhile, those who already had heart disease when they received the anti-hormone treatment also had a greater risk for heart rhythm problems, including a 44 percent increased risk of an irregular heartbeat. These men were also three times more likely to develop “conduction disorder,” which occurs when electrical impulses to the heart are interrupted.
The findings allow men with localized prostate cancer to consider the positive and negative effects of androgen-deprivation therapy and discuss it with their physicians. “If they move forward with the therapy, patients should work with their physicians to adjust their lifestyle to reduce the risk of cardiovascular disease.”