The last post discussed the concept of vaccines for prostate cancer. The second part of the PCF trilogy is an overall simplified view of the immune system, including the various cell types and how they work under both normal and cancerous conditions. This section also describes checkpoint inhibitors and how they are being developed to fight prostate cancer among other types. I again will not summarize the article here but refer the reader to the well-written review in the following link.
The third section describes checkpoint inhibitors in detail focusing on successful applications as well as those scenarios wherein their effects were less than desired. While prostate cancer is the main focus, application to other cancers is also discussed.
I just received an e mail from the Prostate Cancer Foundation (PCF) which consisted of a three-part review of immunotherapy as applied to prostate cancer. The review consists of three parts: a) Immunotherapy, a Vaccine for Prostate Cancer; b) Who’s Who in the Immune System; and c) Immunotherapy and Prostate Cancer. The review is so enlightening that I will focus only on part (a) here. The first part discusses how vaccines and checkpoint inhibitors work; when and how they are best administered; specific immune stimulators such as Provenge, PROSTVAC and GVAX; and, combining vaccines and checkpoint inhibitors. I urge the reader to take time and read these sections. There is so much useful information here. Carefully review and digest each section as it applies to your specific cancer issue. You can follow the link above or right here.
This linked article is an excellent personalized example of treating a man with metastatic prostate cancer and a mutated genetic defect in his BRCA2 gene. He was treated with the PARP inhibitor olaparib which is approved for ovarian cancer. The story itself needs little comment so I urge you to read the following link from the Prostate Cancer Foundation.
Men with low-risk prostate cancer have similar recurrence-free survival rates when treated with surgical robotic prostatectomy or brachytherapy, but those who received surgery had fewer urinary or sexual problems two years after treatment, a randomized trial in Italy has concluded. The study was recently published in the April 2017 issue of the Canadian Journal of Urology [Claudio et al, 24 (2), 8728-8733].
Treatment of early-stage or low-risk prostate cancer relies on active surveillance, surgery or radiation therapy. In particular, both robot-assisted radical prostatectomy (RARP) and brachytherapy (BP) — a type of internal radiation therapy in which radioactive seeds are placed inside or near a tumor — have been shown to effectively treat prostate cancer. However, until now little was known about their long-term effects. “Treatment decisions that men with low-risk prostate cancer have to make can be difficult, as a lot of it depends on what the patient is looking for and what type of experience their physician has to offer,” said Dr. David Samadi, chairman of urology and chief of robotic surgery at New York’s Lenox Hill Hospital
Italian researchers at Milan’s San Paolo Hospital conducted the single-center, prospective study from January 2012 to January 2016 to compare the outcomes of 165 patients randomly assigned to receive either RARP or BT. They followed all patients for up to two years after treatment, including clinical evaluation and determination of prostate-specific antigen (PSA) levels.
Researchers also evaluated urinary and erectile functions, and found that overall biochemical recurrence-free survival rates were similar among the two groups. Patients undergoing RARP had a 97.4 percent recurrence-free survival rate, compared to 96.1 percent reported in the BT-treated group. Biochemical recurrence is the term used when a patient’s PSA levels start rising again. “This was actually expected,” said Dr. Samadi. “A two-year follow-up is a short period of time to ascertain much difference between the two procedures.”
While the recurrence-free survival was similar in both groups, researchers saw different outcomes when analyzing sexual or urinary symptoms. Men undergoing BT regained continence faster than those who received RARP during the first six months of follow-up. But this difference was no longer significant after 12 months and 24 months. Interestingly, men in the BT group had more urinary symptoms during the two-year follow-up.
Regarding sexual function, both groups showed a decreased ability to maintain an erection right after treatment. However, RARP-treated men recovered potency much more quickly than their BP-treated counterparts. By the final follow-up, 90 percent of RARP-treated men were back to normal, compared to only 60 percent of men in the BT group. “These are factors any doctor and the men they see with low-risk prostate cancer need to take into consideration when making any treatment decision,” Dr. Samadi said. “When they make the comparison between RARP and BT, RARP clearly shows the upper hand in treating prostate cancer effectively and managing symptoms better at this stage.”
It must be noted that these results may vary somewhat with the experience of the medical personnel involved and should be discussed with one’s physician if applicable.
Collaborative-therapy: White American pelicans wintering in Florida Everglades; photo: BJ Gabrielsen;
Having advanced prostate cancer albeit at an early stage, I, in discussions with my Florida oncologist, had decided to pursue a course of immunotherapy first before using drugs that kill the cancer cells directly. I remembered writing previous website blogs in which several prominent oncologists and urologists recommended treating the cancer with immunotherapies first. I recently completed the three treatments comprising PROVENGE (sipuleucel-T) and recently posted a blog about the entire experience.
Meanwhile, I still keep in touch with former friends and colleagues at the National Cancer Institute (NCI) – National Institutes of Health (NIH) in Frederick and Bethesda, MD. Within a day or two of completing PROVENGE®, I received an email from an NCI friend describing a new NCI clinical trial in Bethesda, MD to determine the safety and efficacy of PROSTVAC (an NCI-discovered vaccine), coupled with two antibody therapies, nivolumab (OPDIVO®) and ipilimumab (Yervoy®), already approved for treating other cancers. The trial is recruiting two kinds of patients; men with localized prostate cancer who have elected radical prostatectomy and men like myself with advanced disease progressing on hormonal therapy. PROSTVAC is a cancer vaccine in that helps the immune system recognize and attack cancer cells, while ipilimumab (Yervoy) and nivolumab (OPDIVO) block certain mechanisms and signals within the body that prevent the immune system from attacking cancer cells. For specific trial information, see this link.
PROSTVAC is 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.
Nivolumab (OPDIVO®), is used as a first line treatment for inoperable or metastatic melanoma in combination with ipilumumab and as a second-line treatment for squamous non-small cell lung tumors and as a second-line treatment for renal cell carcinoma. It is a human IgG4 anti-PD-1 monoclonal antibody. Nivolumab works as a checkpoint inhibitor, blocking a signal that would have prevented activated T-cells from attacking the cancer, thus allowing the immune system to clear the cancer. PD-1 is a protein on the surface of activated T cells. If another molecule, called programmed cell death 1 ligand 1 or programmed cell death 1 ligand 2 (PD-L1 or PD-L2), binds to PD-1, the T cell becomes inactive. This is one way that the body regulates the immune system, to avoid an overreaction. Many cancer cells make PD-L1, which inhibits T cells from attacking the tumor. Thus, nivolumab blocks PD-L1 from binding to PD-1, allowing the T cell to work.
Ipilimumab (also known as MDX-101 and MDX-010 and marketed as Yervoy) is a human monoclonal antibody developed by Bristol-Myers-Squibb and approved for the treatment of melanoma. As a single agent, it failed in clinical trials in metastatic, hormone-refractory prostate cancer. However it may work better in combination therapy. It works by activating a patient’s own immune system by causing cytotoxic T-lymphocytes to potentially combat tumor cells. Specifically, it targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), preventing the antigen from interacting with its ligands and thereby activating the patient’s own immune system by causing these T-cells to potentially combat tumor cells. More simply, Yervoy blocks a switch that turns off an anti-tumor cellular response. Therefore, Yervoy is an agent that “blocks a blocker” thereby aiding the immune system to fight the tumor. The bad news however is that prostate cancer responds to Yervoy by increasing the expression of two other immune checkpoint molecules, PD-L1 and VISTA. And both send a “don’t-eat-me signal” to immune cells. That reaction is why Yervoy, by itself, offers little patient benefit.
Enzalutamide (Xtandi®) and abiraterone acetate (Zytiga®) are two approved hormone therapies commonly prescribed for men with hormone-resistant advanced prostate cancer. They block the androgen receptor signaling that is essential to the cancer’s growth. Although they represent breakthroughs in metastatic treatment, 20 to 40 percent of patients fail to respond to them. These men with advanced prostate cancer have an abnormal version of a prostate cancer protein that binds with testosterone. The protein is missing a key connector that binds to abiraterone and enzalutamide. The abnormal protein is caused by a genetic variant called AR-V7. Johns Hopkins researchers discovered that the variation, which lacks a portion of the full androgen receptor, was associated with resistance to abiraterone and enzalutamide. The drugs failed to block androgen receptor signaling, thus allowing prostate cancer cells to keep growing. Most patients who test positive for AR-V7 get limited or no benefit from abiraterone or enzalutamide. Conversely, Johns Hopkins researchers discovered that prostate cancer patients who lacked the AR-V7 androgen receptor variation survive longer than those with the variation. The initial study, “AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer” was published in the New England Journal of Medicine in 2014. A test for the genetic variant, AR-V7 was described further in this website’s October 13th, 2015 post.
An article in the April 24th, Prostate Cancer News Today, stated that Qiagen will begin marketing the test that Johns Hopkins University developed. If doctors know that a prostate cancer patient is resistant to the drugs, they can develop a more tailored treatment. The test, called AdnaTest Prostate Cancer Panel AR-V7, will detect that resistance. The test is called a liquid biopsy because it examines circulating tumor cells (CTC’s) in blood instead of tissue. It shows whether cancer cells in a blood sample have the AR-V7 variation.
In addition to the test being used in treatment, researchers can use it to help select patients for clinical trials. In a recent study, thirty-one men received Zytiga and 31 Xtandi. The results were clear. The PSA response rate was zero in patients with the AR-V7 variant. In other words, none of the patients with the variant responded to the drugs. In contrast, 54% of patients who lacked the variant responded to Zytiga, and 68% to Xtandi. Overall survival rates of patients with the variant were 5.5 months with Zytiga and 10.6 months with Xtandi. Patients without the variation survived beyond the duration of the study.
QIAGEN is working with several pharmaceutical companies on trying the test in prostate cancer clinical trials. They plan to make the AdnaTest kit commercially available this year.
Christmas for me has always been a joyous occasion but this past December, 2016 it included an element I had always dreaded. My prostate cancer had been kept under control with a combination of intermittent and continuous Lupron® injections for ten (10) years. Every time I had received positive results from my PSA tests, I felt as if God had given me a 4-month reprieve of life. I could forget my cancer for a while and live my life happily and productively until the next test. I knew I wouldn’t be cured but I had hoped above all hopes that the hormone therapy would work long enough for me to die of another, less-painful scenario. In December 2016, I found that the hormone treatments had stopped working and I was now classified with refractory, advanced prostate cancer though thankfully asymptomatic. My Florida urologist had always hoped that this “bad day” would never come but now he told me I could expect 2-3 “good years” of alternative treatments until metastatic disease would overtake me. He shook my hand and referred me to the care of my Florida oncologist. Upon seeing my oncologist, his first words to me were “what do you want to do now?” Though I am a Ph.D. scientist, I am neither an M.D. nor a trained oncologist so I looked at him with a sense of bewilderment and confusion. I later learned that this approach was something called “patient-centered care” wherein I was to be totally involved in my therapy. Information shared below indicates that my first choice of therapy, PROVENGE® (sipuleucel-T), way be the right one.
Well, in writing this website I knew something about the few therapeutic agents available to me at this stage, so my oncologist and I listed them including enzalutamide (Xtandi®), taxotere (docetaxel®), abiraterone (Zytiga®) and PROVENGE® (sipuleucel-T). In looking over my website listing of drugs currently under development for advanced prostate cancer, I was dismayed to note the significiant number of late clinical stage failures [e.g. custirsen (OGX-011), galeterone (TOK-011), orteronel (TAK-700), ipilimumab (Yervoy)] which reinforced the fact that my options were getting fewer and the prospect of dying of prostate cancer was becoming more of a reality. Since I am asymptomatic at this point, another possibility was to do nothing until symptoms or metastases appeared on various scans. I remembered that I had written a blog dated October 28th, 2014 wherein four prostate cancer experts had recommended the early use of PROVENGE® in treating refractory, asymptomatic disease. Fortunately, PROVENGE® was available for me at my specific treatment site and in April, 2017 I started my treatment which I will describe below.
PROVENGE was studied in Phase 3 clinical trials involving 512 men with metastatic, hormone-resistant prostate cancer in the IMPACT trial. It was found that PROVENGE had a more pronounced treatment effect in men with lower, decreasing baseline PSA. Thus, men with lower cancer burden may benefit most from PROVENGE therapy administered at an early stage of advanced cancer. These men may tend to experience less immunosuppression systemically and in the tumor microenvironment. Immuno-treatment such as PROVENGE also has a delayed onset of action and is capable of generating a sustained response. Therefore treatment earlier in the disease would allow more time for the patient to benefit from the therapy. This data seemed to fit my current status. My oncologist refers to me as “the best of the worst”.
As published in the June 2013 issue of Urology [Schellhamer et al; 81(6),1297-1302] the median overall survival in men whose baseline PSA was lower than 22 ng/mL was 41.3 months as opposed to 28.3 months in the control, untreated group for an overall median survival benefit of 13 months. Estimated 3-year survival for the lowest PSA group receiving PROVENGE was 62.6% for PROVENGE patients versus 41.6% for the control group.
Was God leading me in this choice? Clinical trial data for PROVENGE seems to indicate it is an excellent choice for me at this point. I have a sense of peace especially as God has paved the way for me in the administration of this therapy even to the point of giving me good, useful veins as would be needed (see below). Is it possible that God could extend one’s life even though His Word states that He has our days “numbered?” One day, my daily devotionals included a section from the Old Testament book of Deuteronomy, often not known for its inspirational themes but a more historical book. In this reading, Deuteronomy 6:2 seemed to leap out at me. It states that I should “fear (respect) the Lord your (my) God, to keep all His statutes and commandments…….all the days of your (my) life, and that your (my) days may be prolonged.” Did God intend to speak to me through this verse? Could He prolong my days? I cannot say for certain. But even though I don’t know how many years I have left, I daily “present my body a living and holy sacrifice acceptable to God which is my spiritual service of worship” according to Romans 12:1. I will trust in God’s wisdom and that of my physicians. I’ll keep writing this website. As I believe Jesus once told me (see video link), I’ll keep doing what He told me to do and He’ll care for my body.
How Provenge works: PROVENGE is a cellular immunotherapy designed to induce an immune response targeted against prostatic acid phosphatase (PAP), an enzyme (antigen) produced (expressed) by prostate cells and found in higher amounts in most prostate cancers. PROVENGE consists of a patient’s own white blood cells [T-cells, B-cells, natural killer (NK) and other cells] including antigen-presenting cells (APC), specialized white blood cells that help fight off foreign substances that enter the body. These APC cells send out signals to T-cells (other immune system cells) when an antigen enters the body. In PROVENGE, a person’s APC’s have been activated with a synthetic combination (recombinant) of two human proteins, PAP and granulocyte-macrophage colony stimulating factor (GM-CSF) an immune cell activator. These activated immune cells may be able to recognize and attack certain prostate cancer cells. During the process of generating PROVENGE from a person’s white cells, the resulting mixture remains active outside the body for only a matter of days. Therefore it is imperative that the patient and physicians adhere to a personalized leukapheresis and infusion schedule usually three days apart.
Approximately three days before receiving Provenge®, white blood cells (T-cells, B-cells, etc) are collected by passing whole blood extracted through a small tube (catheter, a large bore needle) placed in a vein in the right arm through a machine which extracts the white cells and the unextracted blood is returned through a smaller needle placed in a vein in the left arm. This process called leukapheresis usually takes about three hours. If the arm veins are insufficient for the blood collection, then a venous catheter will be placed into a vein in the next or upper chest. I was told at the blood bank that a catheter is necessitated in the majority of cases but even though some medical personnel have difficulty drawing my blood, my arm veins were of sufficient quality to be used (a real praise). The collected cells are then sent to a laboratory where PROVENGE is generated. The prepared sipuleucel-T (PROVENGE) solution (which has an expiration time) is then shipped to a local infusion center, where it is injected back within three (3) days after collection. The infusion takes about an hour. The entire collection, cell transformation and re-injection process is very time-dependent and requires strict coordination between blood-drawing centers, laboratory and infusion sites. While there are some side effects possible, I only experienced mild fatigue after the collection and infusion processes. The process is somewhat cumbersome yet very do-able and worthwhile if prescribed for your early stage advanced cancer.
A recent article from Prostate Cancer News Today (April 4th) stated that Yervoy (ipilimumab) showed little benefit when administered to 16 patients awaiting surgery with locally advanced prostate cancer at the University of Texas M.D. Anderson Cancer Center. The study was published in Nature Medicine.
Ipilimumab (also known as MDX-101 and MDX-010 and marketed as Yervoy) is a human monoclonal antibody developed by Bristol-Myers-Squibb and approved for the treatment of melanoma. It is currently undergoing clinical trials in metastatic, hormone-refractory prostate cancer among other cancers. It works by activating a patient’s own immune system by causing cytotoxic T-lymphocytes to potentially combat tumor cells. Specifically, it targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), preventing the antigen from interacting with its ligands and thereby activating the patient’s own immune system by causing these T-cells to potentially combat tumor cells. More simply, Yervoy blocks a switch that turns off an anti-tumor cellular response. Therefore, Yervoy is an agent that “blocks a blocker” thereby aiding the immune system to fight the tumor. The bad news however is that prostate cancer responds to Yervoy by increasing the expression of two other immune checkpoint molecules, PD-L1 and VISTA. And both send a “don’t-eat-me signal” to immune cells. That reaction is why Yervoy, by itself, offers little patient benefit.
Yervoy increased the numbers of T-cells in tumors, as well as another kind of immune cell, macrophages. But researchers also discovered that the tumor cell tissue had two proteins on their surfaces, PD-L1 and VISTA, that were not there before treatment. These proteins are called immune checkpoints because they can stop the chain of events that lead to an immune reaction. Basically they signal the shutdown of T-cells in the tumor environment. These results are prime examples of the dynamic state of the immune system; when a change is made in one specific area, it may manifest itself in other areas simultaneously. It is like trying to alter one card while not changing other cards comprising a house of cards.
“Observing immune response at one point in time doesn’t reflect what’s going on because the immune system is so dynamic,” said Dr. Padmanee Sharma, a professor of genitourinary medical oncology and immunology at the University of Texas MD Anderson Cancer Center. You can change the immune response with Yervoy, but what else changes becomes incredibly important.
I received the following article by e mail from a recent issue of Prostate Cancer News Today. I am posting it however I urge the reader to discuss the findings cited herein with a radiation oncologist if it may apply to your treatment.
According to an article published in the April 1st, 2017 edition of the Journal of Clinical Oncology, four weeks of radiation therapy at larger doses has the same effect as conventional radiation therapy administered to prostate cancer patients over eight weeks, according to results from a Phase 3 randomized clinical trial of 1,206 men in Australia, Canada and France. The findings provide a new standard of care for men at intermediate risk of prostate cancer. The PROFIT Phase 3 trial (NCT00304759) followed participants for a median of six years.
“External beam radiation, a treatment option for localized prostate cancer, is commonly used alone for men with intermediate-risk disease. The treatment is typically delivered in 37 to 42 sessions, given five days a week over the course of 7.5 to 8.5 weeks. Studies have suggested that hypofractioned radiation therapy, given over a shorter time with larger doses per fraction, is also an option, but some experts raised concerns about increased toxicity and reduced tumor control. Even so, modern radiation therapy techniques are highly specific and can deliver hypofractioned radiation therapy without increased toxicity by avoiding radiosensitive normal tissues. Researchers hypothesized that hypofractioned radiation therapy given in 20 fractions over four weeks would be similar in efficacy — and without increased toxicity — to standard radiation therapy, delivered in 39 fractions over eight weeks.”
Co-principal investigator Charles Catton, a radiation oncologist at Toronto’s Princess Margaret Cancer Centre, stated that “using modern radiation therapy techniques that are very precise, we determined there was no noticeable difference between eight- and four-week treatment regimens in terms of cancer control or side effects of treatment. In fact, for some men, the shorter regimen meant slightly fewer side effects (particularly regarding bowel function) and therefore improved quality of life. The compressed course of treatment is of great benefit to patients and also to the system in terms of being able to treat more patients in less time.”
Clinical trials are on-going at many institutions across the United States. Many men think about enrolling in a clinical trial only when there are no further treatment options for them. But trials are not just for advanced stages of disease. They can also include men recently diagnosed and treated. The trials cover areas such as screening, diagnosis, imaging and scans, quality of life, as well as surgery, radiation and other specific treatments and combinations. At some time, you might want to go to the clinicaltrials.gov site, and enter your pertinent areas of interest under “Search for Studies”. Hundreds may appear but they can be filtered under categories such as “recruiting”, “active not recruiting”, “completed”, “terminated” etc. You can also search them by location as well. You might want to ask your physician to demonstrate the site by incorporating your specific health status and generating a shorter list of pertinent recruiting trials. An excellent review of clinical trials (see the link) was recently published online by the Prostate Cancer News Today. It is concise and informative but will not be summarized here. The article also leads the reader to a Bayer Oncology Clinical Trial Finder wherein you can enter specific data and a listing of available trials can be sent to you. There is a wealth of information here and the reader is urged to spend some time perusing these sites. They also provide a picture of the current cutting-edge areas of research.
