Tag Archives: immunotherapy

PCa Immunotherapy (for people in a hurry)


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I just finished reading Niel deGrasse Tyson’s book on astrophysics that was pretty understandable. Although I am no immunology expert, and certainly not at the academic achievement level of Dr. Tyson, I have made monoclonal antibodies in my lab and participated in several prostate cancer immunotherapy trials, so I’ll give this a try. My inspiration comes from a truly excellent and comprehensive review on the topic by Laccetti and Subudhi that appeared in Current Opinion in Urology. I will follow their outline with my own “layman’s view” and comments.

Provenge (Sipuleucel-T) was the first immunotherapy ever approved for treating Pca, and has been available since 2010. To be eligible, you have to have failed standard androgen deprivation therapy (though not necessarily the newer agents) and have metastases that can be detected on bone or CT scans. While the treatment works, has been shown to slow the rate of PSA increase and prolong survival, it is complex to administer. You need to donate your own immune cells for “activation” in a treatment facility, following which you receive them back as a transfusion. The process is repeated 3 times and costs in the range of $100K. Many of us wish it was even more effective given the costs and inconvenience, and of course all patients want to see their PSA go down with ANY treatment, which doesn’t happen often with this treatment. Efforts to improve the efficacy have included earlier use when patients are still hormone sensitive and combining SipT with ipilimumab, an antibody that enhances immune responses.

A number of [somewhat] more traditional vaccines are in trials. In a phase II trial, Prostvac, utilized a pox virus approach to deliver PSA (as the antigen) along with co-stimulatory molecules to help the immune system recognize and kill PSA producing cells. Although the phase II data looked very promising, the phase III trial was closed in September when the data did not support continuing to treat patients. Given this disappointment, it is not surprising that the immunologists/clinicians pursuing the goal of a successful prostate cancer vaccine would turn to the “checkpoint therapies” as a possible way to induce the body to fight prostate cancer.

Perhaps the best known of these approaches (due in part to intense advertising on the evening news channels) are nivolumab (Opdivo™) and pembrolizumab (Keytruda). The general idea here is that the immune system would potentially constantly be fighting our own body parts if there wasn’t a way to turn it off. Examples include diabetes (immune system attacks the insulin secreting cells of the pancreas) or rheumatoid arthritis (immune system attacks your joints). The checkpoint system, known as PD-1 (programmed cell death protein 1) is a shutdown system whereby the attacking T-cells are turned off by the PD-l1 ligand, a protein that can also be secreted (unfortunately) by the cancer cells. Thus the cancer cells can turn off our own immune system which is trying to attack and kill the cancer. The checkpoint antibodies effectively throw a monkey wrench into this system, allowing the immune cells to do their thing (and of course, as you would predict, the side effects can include attack of other “self” organs like the lung or colon or pituitary gland). This approach has shown real promise in melanoma, lung cancer, head and neck cancer, bladder cancer, and in some patients with colorectal cancer. Another checkpoint player is ipilimumab, which was first approved for melanoma and also releases “blunted” T-cells to go on the attack. Unfortunately, none of these checkpoint inhibitors have been promising by themselves in early tests in advanced prostate cancer, but there is optimism that by combining them with some of the vaccines in trial, or, perhaps by timing their use with androgen deprivation or radiation therapy when lots of pca cells are dying we will see improved responses. There are 19 actively recruiting studies at clinicaltrials.gov with the terms “vaccine, prostate cancer, recruiting”.  As with many of the challenges in prostate cancer, the best time to use an immune approach is likely early on, when the disease burden is low (for example, a Gleason 9 patient with NO evident metastases). These trials are challenging because such patients are fortunately uncommon, and because these men also can live for many years with current treatments, making the evaluation of a new treatment modality difficult.

2017 was a year when we lost one of the most inspiring teacher/researchers in prostate cancer, Dr. Donald Coffey. The good news is that his legacy lives on in the large number of researchers who continue to push the frontiers of prostate cancer diagnosis and treatment. We owe him a great debt of gratitude for his tireless efforts to advance this field of medicine. I predict it won’t be long until we have the kinds of exciting pca immunotherapies that have made such a remarkable difference in melanoma and other cancers.

 

 

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Prostate Drug Costs


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Most readers will have seen something in the popular press over the last 6 months regarding the increasing awareness of oncology drug costs. For example, there have been very nice commentaries in the New England Journal of Medicine like this one, that deals with the cost of nivolumab, a PD-1 pathway inhibitor that is approved for treating melanoma and may show promise in a number of other cancers like kidney cancer. The final paragraph is telling:

Hand clapping for science is now inextricably linked to hand wringing over affordability. Drug prices are increasing more rapidly than their benefits, and the growth in spending on drugs has started to outstrip growth in other areas of health care. Addressing this problem requires realizing that cost-effectiveness assessment — a step that we are not even ready for in the United States — has limitations when one considers the price of the comparator and the impact on overall budgets.

I have opined elsewhere in this blog site on the excitement over the new immune-stimulating drugs that show promise. Indeed, some may be able to improve the response to prostate vaccine approaches. The question is whether we can afford all of these drugs, who decides, how they decide, and what methods they use. In the past, a QALY (quality adjusted life year) has been used to benchmark some of the things we do in medicine. In a nice NEJM perspective article, the classic “$50,000/QALY” benchmark was reviewed, but the authors suggested that given medical progress and inflation, a more realistic number might be as high as $100,000 or $150,000. The costs of the newer prostate cancer drugs such as abiraterone, enzalutamide, sipuleucel-T, cabazitaxel etc. have not escaped attention. Medscape had an article on this over 2 years ago. I am no expert on Markov models, differing ways to evaluate cost-effectiveness, and the economics of medicine. But as a simple way of explaining the challenge, how much is cisplatin, a cornerstone of curative treatment for testis cancer, the number one cancer of young men in their 20’s worth? If you can answer that, then how much would it be worth if you were using the same drug as a third line to treat prostate cancer, where responses are rare except in the case of the small cell variant, but no one is cured? In the case of the young testis cancer patient, many years (or QALY’s) are achieved while in the case of even the “sensitive” form of prostate cancer, the benefit would be in months at best. Should testis cancer patients have to pay huge sums because it works so well for them and prostate cancer patients less? And how do we figure in the drug development costs in a fair way that retains a financial incentive for the pharmaceutical companies and researchers to keep working for new discoveries?

Added to this is my own experience when I have described using a highly expensive (sometimes toxic) drug to a patient with well-known, very limited (but measurable, approved, and “covered” by Medicare or insurance) benefit. Often when I am honest and say, “this may help for a while, but is not a cure,” to a patient who may have very few symptoms at all but is progressing based on a rising PSA, the reply will be “what choice do I have”? That is a great question. If someone else is paying for some very expensive drug, why not try it? Although I know that the ethicists feel “my wishful answer” is unethical, I would like to be able to say something like this: “Well Mr. Smitherton, Medicare has decided that if you would rather take the money and apply it to your grandchild’s college fund, they will be willing to divert the costs (or some proportion of them) to that cause because ‘we’ [society] feel that should be your choice, rather than having us pay for a relatively ineffective, expensive drug if you don’t think it is worth it, or if you value his/her education over a few months of additional life span.” If wishes were horses, beggars would ride. And if I was qualified in ethics, I would probably not be writing this. That’s my 2¢ – or maybe it should be my $20,000??

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Sensational results, 4-MU, Viruses, and “the drive-by media”


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An intriguing part of writing this blog is how much I learn from my patients. It also turns out that I learn ABOUT my patients. I suppose nothing should surprise me about this in the digital age, where presumably all of you can find my address, social security number and probably what brand of oatmeal I like ! (I’ll save you some time there, try McCanns Steel Cut Irish Oatmeal, it’s terrific…). For the past month or so, one after another has come in with the question, “So, what do you think about 4-MU?” or “Did you hear about poliovirus killing cancer?” Actually, I have heard next to nothing about either, but of course I was intrigued as to where my patients get their information.

Starting with the 4-MU story, it seems it was featured on that bastion of “fair and balanced news,” FOX. I sincerely hope that is not the primary source for your news, and that you don’t subscribe exclusively to a certain talk show host who calls everybody but himself the “drive-by media”. If you want serious journalism, I’d suggest the NYT, WSJ, and NPR for a pretty good balance of real news. None of them carried the two stories I’m going to go over here. Further, if you ever hear of a story with interest in medicine, I suggest you go immediately to Google Scholar, which is absolutely wonderful at finding abstracts, patents, and journal articles on almost anything in medicine. And if you want to know if a novel treatment in development is available in your area or anywhere else, for that matter, do your search at ClinicalTrials.gov.

Well, using combinations of all of the above to learn about 4-MU, (which stands for 4-methylumbelliferone) I found that FOX decided to sensationalize a mouse study published by some University of Miami investigators. 4-MU turns out to inhibit synthesis of hyaluronic acid, a major component of synovial fluid and the “goo” or intracellular matrix. It has been studied in the past to inhibit some bacterial and viral replication, and indeed there is even a clinical trial with 4-MU listed as going on in chronic hepatitis. The Miami researchers found that in mouse models 4-MU inhibited prostate cancer metastases, which gained excitement because it is supposedly a non-toxic supplement. While I try to keep an open mind, there is a long history of various natural products working in mouse models that then have little or no activity in the real world of human cancer. We, ourselves, discovered that acai juice and the milk thistle derived molecule, silibinin, had minimal/no activity in prostate cancer, in spite of promising results in animals. My judgment regarding 4-MU is that it would indeed be of interest to study in human prostate cancer, and hopefully it would work, but until such a trial is done, I would not recommend taking it if you find a supplier somewhere on the Internet or similar.

The poliovirus story is a bit more complicated. It gained patient attention via a 60 minutes presentation.  Many tumors, including the highly lethal glioblastoma brain tumors, have receptors on their cell surface for the virus. Through very elegant and complex recombinant DNA technology, investigators at Duke University engineered a novel virus that could induce death in the brain tumors after direct injection. In an ongoing Phase I clinical trial, they are seeing dramatic responses after direct injection of the tumors in the brain, in part because of a “violent” immune response. The key here, however, is direct injection. It may be possible to build on this, but direct injection of oncolytic viruses into head and neck cancers, lung cancers, and even prostate cancers in the past have not had the desired results. Moreover, what we really want, is some sort of virus that a) can seek out every metastatic cell in the body [brain tumors seldom metastasize, but kill people by local growth], and b) produce that immune response after infection. I have written elsewhere about the promise of the immune checkpoint inhibitors, and I encourage you to go to my blog site and read about those ongoing efforts. Meanwhile, I hope that the search strategies I have outlined in this blog will help you do your own research to answer the question, “Doc, have you ever heard????….”

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