Tag Archives: research

CAR-T and related immunotherapies


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One of your co-subscribers to this blog contacted me and asked if I would write a blog about CAR-T cells, and I have decided to include the closely related bi-specific antibody therapies. I am very intimidated by even attempting this, because the complexities of this field are daunting, so please do NOT show this post to your PhD immunologist cousin.

As most readers probably know, the immune system consists broadly of the “humoral” and “cellular” arms. When you get corona virus, (or any other virus) both arms are activated. Broadly speaking, your B-cells (lymphocytes that live in the lymph nodes and also circulate in your blood stream) make antibodies that attach to targets (“antigens” – in the case of corona virus, the spike protein you are tired of looking at on TV is the target antigen we hope a vaccine can be made from) and can inhibit the virus or can clear the antigen from your circulation. Antibodies consist of proteins (chains) that combine with each other and this is where things start getting VERY complex, but a single B-cell can make only one type of antibody (called a monoclonal antibody). Whether you know it or not, if you have an interest in prostate cancer, monoclonal antibody technology is “why you are here” – PSA detection was made possible by isolating a monoclonal antibody that would bind to Prostate Specific Antigen. But with modern recombinant DNA techniques, the chains that make up these antibodies can be combined in highly variable ways never found in nature. The history and complexity of the antibody story is illustrated here from this article. Screen Shot 2020-06-13 at 10.31.25 AM

The Y-shaped figure above is “an antibody” and the colored chains are the proteins in the antibody that can be extremely variable and give the antibody its ability to bind to any target. Note that the two arms of the antibody could be designed so that one arm would bind to one target and the other arm could bind to a different target. Voila! You could design one arm to bind to PSMA and another to a killer T-cell that would link a killer cell to your cancer cell.

Screen Shot 2020-06-13 at 10.42.33 AM

 This is the general idea behind an innovative cancer approach you may hear about called BiTE. In this figure, the working part of the tips of two “Y” antibodies have been linked and when injected into a patient, in theory the “killer” T-cell is forced to bind to the tumor cell via its “TAA” or tumor antigen. If you are a dedicated reader of this blog, you already are thinking about a great target antigen I previously introduced you to, PSMA

Now on to my VERY oversimplified description of CAR-T cells. The terminology refers to Chimeric Antigen Receptor – T cells. The science of these is related to the above description of antibodies in the following way: On the surface of the T-cells in your lymphocyte library is a completely different group of proteins that allow the T-cells to bind to and recognize antigens, much like the antibody system we discussed above. These proteins combine in chains on the surface of the cells to form “T-cell receptors”. Unlike the antibody system, their interactions with antigens are further modified by requiring recognition of “self”. Non “self” is why people who receive a kidney or heart transplant must receive drugs to suppress the immune system that will reject the transplant. Unfortunately cancer cells are mostly recognized as “self” so we don’t reject them. BUT… again using recombinant DNA technology, the T-cell receptors (TCR) can be re-designed so they DO recognize a tumor target, even though it is “self”. You can start with lazy, somewhat unresponsive T-cells that might be in the blood or even infiltrating a tumor, take them out, modify the receptor (dramatically as shown in the following figure), and force them to recognize a cancer, then re-infuse them into the patient like any blood transfusion.

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In the figure (taken from this article), the “antibody like” part of the receptor that controls “self” is CD3 and the “antibody like” part of the TCR receptor that binds to a tumor antigen or virus infected cell are the green proteins marked alpha and beta. The recombinant magic that is WAY beyond this blog is everything on the right. If you have the time and interest in really delving into CAR-T therapy for cancer, you really do have to read this article. But, for those who wonder “so why aren’t we doing this?”, the Cliff’s Notes answer is that (1) it is VERY expensive – each patient has to have his/her T-cells taken out and modified, expanded, then re-infused; (2) it has only worked well for blood cancers like leukemias so far; and (3) even though PSMA or some similar tumor target might be thought to be “tumor specific”, it turns out these targets are often expressed in low levels in places like your brain or lung. When the CAR-T cells begin attacking your normal tissues, you are in a world of hurt. If you have followed the COVID-19 story, you may have heard about the “cytokine storm” that is killing people by destroying their lungs. As you might imagine, combining these approaches with the other “hot” area of immunotherapy, the PD-1 inhibitors I have previously written about could make CAR-T treatment more effective but the toxicities even worse.

I hope this has been helpful and that your immunologist cousin or highly informed oncologist will forgive the effort to simplify a very promising but challenging field. I’m also grateful to the myriad of incredible researchers who have put this all together for us “cancer fighters” and their dedication is equally as worthy of honor as other warriors on front lines.

 

 

 

 

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Filed under General Prostate Cancer Issues, Prostate cancer therapy, Targeted treatment

COVID-19 and “the news”


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This won’t be a long blog, but since I anticipate lots of news this week regarding an article that was published a few days ago, I thought I would provide a “heads up” to my prostate cancer “groupies”. What makes the news and becomes “viral” is interesting and I haven’t had the opportunity to watch the sequence up close personally before. My wife is a pediatric infectious disease expert with specific interest in Kawasaki Disease. As you most likely have seen in the news over the past few days, SARS CoV2 now seems to trigger a KD type of illness in children. This became apparent a little over a week ago with calls flying back and forth from around the world among her friends, notably because Michael Levin, from London had seen some cases and sounded the alarm among the international colleagues. So, from “insider info” to public alarm seems to take about a week.

As you know from faithfully reading this blog, I predicted that men on androgen deprivation therapy might be protected from SARS CoV2 about 6 weeks ago and that physicians/scientists with access to large databases would be able to show this. And, true to the prediction, this past week an article appeared showing just that. I have summarized the data for you on this slide:

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It will be interesting to see this get picked up and “sensationalized” by the media over the coming days. And it is already underway. I am aware of a conference call with the CDC and another being hosted by the Prostate Cancer Foundation this coming week. So consider yourselves forewarned! CNN, FOX, ABC, etc. etc. will be all over it…

Now, as I also predicted, I would bet that there will be prospective studies looking at ADT as a form of therapy for COVID19 starting soon (if not already underway). My favorite design would be with the approved agent, remdesivir in a randomized prosepective trial. Male patients sick enough to be admitted to a hospital would all receive remdesivir, and 1/2 would receive ADT in the form of an anti-androgen (e.g. enzalutamide, apalutamide or darolutamide) or a single injection of a month of a GnRH analog like degarelix (Firmagon), or the androgen synthesis blocker abiraterone/prednisone (Zytiga). I would hope that this kind of approach could help men (and maybe even women) fight the virus by blocking TMPRSS2 as I previously showed you in the graphic on the original blog. Now YOU are the insiders!

PS, I think that another approach could be starting everyone in a nursing home “under attack” could be starting all the occupants on finasteride. Blocks DHT production from T and is very well tolerated in the  pcpt trial. Lower DHT -> lower TMPRSS2 -> lower viral replication.

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Filed under General Prostate Cancer Issues, Prostate cancer therapy, Uncategorized

Thanksgiving for an oncologist


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First, I want to thank those readers who generously helped me reach my goal of fundraising for the annual Movember effort to increase awareness and support research into prostate cancer and men’s health. If you are so inclined and want to make a last minute contribution, you may do so here: https://mobro.co/michaelglode?mc=1 My itchy, scraggly moustache is destined to come off tomorrow!

Second, it has been an incredible journey since my internship to watch the evolution of our understanding of cancer. In 1972, when my mother called to tell me (a young medical intern) she “had a little lump in her breast” – it turned out to be not-so-little, and she fought the disease for another 4 years before succumbing – we had little we could do other than surgery and in some cases radiation. Even adjuvant chemotherapy (the CMF treatment) had not been published yet. During the next decade, remarkable strides were made in finding new drugs, most notably cisplatin, that allowed cures of previously lethal diseases – especially testis cancer.

Then, while on sabbatical in Helsinki in 1986, I found an article to present at our journal club that I thought would revolutionize medicine. The PCR reaction opened the door to rapid DNA sequencing. When I returned to my lab in Denver, my PhD colleague, Ian Maxwell had already started to use the technique with his own jury-rigged thermal cycler, but it would be 3 or 4 more years until a medical student in his/her 3rd year clinical rotation would be able to tell me what PCR stood for. Recognizing there would be a generation of physicians who “missed out” on what would be the revolution, I was able to help start a catch-up course in Aspen, Molecular Biology in Clinical Oncology, that is still ongoing. As a “fly on the wall” I was able to listen to the world leaders in molecular oncology (including this year’s Nobel Prize winner, Bill Kaelin) describe their research that unlocked the mysteries of how cancer works. Fly-fishing with some of them on the Frying Pan was a bonus to be cherished!

As the cancer story unfolded, I was able to participate in many clinical trials, bringing new treatments that emerged to my patients. Thanks to the brilliant writing of Siddhartha Mukherjee, author of “The Emperor of all Maladies“, it became possible for my patients to begin to understand the nagging question, “how did this happen to me?” And now, this week, a brilliant article summarizing all we know about the genes and mutations that cause cancer has appeared in the New England Journal. I invite you to read that (it’s free online) if you want to join me in peering over the horizon to the future of cancer medicine. It is both overwhelming and humbling.

The privilege of living through the last half of the 20th century and into the 21st is one of the most amazing journeys one could ask of a human lifetime. As I ponder it, looking out on the snow I will get to ski on next week and enjoying my grandchildren and family, I am truly thankful to have been here. Happy Thanksgiving to all!

 

 

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Filed under General Prostate Cancer Issues, Movember

Black holes and genetic laws


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I just finished reading Stephen Hawking’s last book, Brief Answers to the Big Questions, which I found more accessible than A Brief History of Time, written more than 30 years ago. Hawking’s abilities to explain the very (for me) abstract concepts of how no information can flow out of black holes and that the amount in there is somehow directly related to the cross sectional area of the hole was satisfying. As a very math challenged individual, I’m also a fan of Heisenberg and the perplexing issue that in the quantum/wave world of particle physics, you just can’t be certain about position and momentum. Yet, there are certain laws, like the speed of light, that are never violated, at least in the universe we live in.

So what does this have to do with genetics and prostate (or other) cancers? Here is a law: A always pairs with T, and C always pairs with G. In our biologic universe, without this law, no life as we know it could exist (prions may be an exception, but that gets too far into the definition of “life”). Yet, just as with the uncertainty of Heisenberg, the base pairing in DNA/RNA is not completely inviolable. Mistakes are made…and this can result in cancer. Cancer is a genetic disease and for anyone who hasn’t read it, I still recommend you avail yourself of the incredibly well written book, The Emperor of All Maladies. In the short time since that book was written, the explosion in our understanding of how genetic errors and cancer are related has been difficult to keep up with. The Cancer Genome Atlas (clever name, eh?) is but one example, and its use by scientists skilled in math (ugh) continues to help classify cancers based on how their mutations drive them rather than just how they look under the microscope or which organ they started in. Here is the math and the results one such analysis has on predicting survival for stomach cancer:

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As you can see, the prognosis and potentially the treatment for one subtype of “stomach cancer” might be very different for one patient than for another. Bringing this technology to prostate cancer, we already know the mutational landscape is vast. For example, this article looked at 1,013 different prostate cancers and found 97 significantly mutated genes, including 70 not previously recognized, and many present in <3% of cases. There is hidden good news in this story, in that the same mutational uncertainties that can give rise to cancer (breaking the law of AT-CG) also allows our immune systems to react to the novel mutated proteins that cancers now display. For an interview from this week’s NEJM on gene editing, click here.

Keeping up with this world of laws, broken laws, and “black holes” will be a remarkable challenge for patients and oncologists alike. My final recommendation for reading about this is a terrific article you can find here by George Sledge, one of the outstanding leaders in our field. He notes that even the most skilled oncologist, paired with the smartest of patients, will be unable to keep up. But remember this, you can’t go faster than the speed of light. That’s the law!

 

 

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Tweet Storm from ASCO GU


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The American Society of Clinical Oncology (ASCO) along with other professional societies sponsors an annual symposium focused on GU cancers, with a day and a half devoted to prostate cancer. You can view all of the abstracts on screening, detection, and management of localized disease here. If you have an area of specific interest (for example, the use of MRI in detection) you can use the search function on your browser to find articles of interest. On the mac, it is “command+f” keys for both safari and chrome. You then type “MRI” into the box and use “command+g” to scroll through all of the abstracts. You come up with very interesting new information like an abstract on page 108, “MRI targeted biopsy dramatically increases detection of clinically significant prostate cancer while reducing the risk of indolent cancer detection.”

If your interest is more on the newest studies for advanced prostate cancer, you can go here, and do the same thing. What you will find, of course, is that the avalanche of information is pretty hard to digest. When we started ASCO OnLine in the early 90’s, the technology was limited, but now it overwhelms. We are left to hope that the experts who select the most important abstracts to be presented will have done a good job, but that presumes they know our individual interests, which of course they can’t. When tweeting became available, I decided I was too old. I did sign up for a handle, @ascotwit, that I used in a couple of meetings but in general, I haven’t found twitter to be very helpful, even though some of my younger colleagues tried to help me and we even wrote an an article about it. (…I certainly don’t think it is a good way to run a country…but I digress).

So to you, my loyal followers, and with no attempt to correct spelling (why should I if the leader of the free world doesn’t do it?), here are the tweets from the oral abstract presentations that I would have sent out if I was a twitter user:

Ipi + novolumab – “checkmate 650) therapy duration  only 2.1 or 1.4 months. Only 1/3 reached maintenance phase with ~1/2 of patients dropping out for toxicity. compared to patients in melanoma trial getting about 4 doses.“if you can’t get the drug in, you can’t see a response” 25% of patients had a response in cohort 1. They tend to respond early The subsets are those who had PD-1 positivity or high tumor mutation burden.

  • Scher assay. Getting to CTC 0 was useful in predicting better survival and was better than looking at a drop of 50% in PSA. The development of a show term outcome marker remains elusive. 46% of the patients who lived 13 weeks were not included because of not enough CTC’s
  • #140 ARAMIS study – efficacy and safety of darolutamide in nmcrpc.  Different structure than end and app and does not cross blood/brain barrier. men with no mets and psa dt <10 months. ADT + placebo vs dark. met free survival 18 months vs 40 months . overall survival 83% vs 73% placebo at 36 months. also improved time to pain, time to skeletal, time to cytotoxic chemo. Tolerance was excellent with no difference in AE rates. Fatigue 15.8% vs 11.4% (see nejm this week)
  • Final analysis of Phase III Latitude study. High risk met castrate naive pca newly diagnosed
    • High risk gleason >/= 8
    • Abi vs placebo + ADT. 
    • Final analysis showed hazard ratio of 0.66. OS 36.5 months vs 53.3 months. Time to pain progression was much longer (see slide). High volume patients clearly benefited most
  • #687 ARCHES trial ADT +/- Enz
    • included both low and high volume CHAARTED criteria, as well as could have had prior docetaxel or not. 2/3 had gleason 8-10; 18% had prior doce in the hormone sensitive setting
    • Primary endpoint was rPFS or death. secondary: time to spa progression, new rx, spa undetectable rate objective response rate
    • rPFS HR =0.39 across all subgroups including those who had previous doce Time to spa progression was 91% at 12 mo vs 63%. 68% got 0 psa vs 18%. 
    • Fatigue and hot flashes were worse but mostly grade 1/2. 93% of patients still alive. at 14.4 months
    • DISCUSSION
    • Is M0 crpc really important? New imaging techniques – does it even exist??. Inflection point of doubling time <6mo is important predictor (matt smith curve). Cost: for Enz 220k/year of life saved. PFS2 is the time to progression or death on the theft therapy. The Latitude trial suggests delay in time to next endpoint.  
    • Cost for abi/p is still 10k/mo but generic is now approved
    • discussion of which one to use. not strictly comparable patient populations. need cost effectiveness randomized trial?
  • # 2 Choline scan can replace conventional imaging, but has poor negative predictive value – identifies mets earlier but no way to say that the earlier management changes makes any difference.
  • #144 – small. initiation of apalutamide early may result in prolonged effect looking at psa2 See screen shot. Earlier treatment for non-metastatic disease is likely better than waiting for mets. There are 3 potential agents (enz, apa, dur). Delaying time to symptoms is also very important. Suggests that anything you add later still does not make up for starting early.
  • #365 – yu. Pembro + olaparib in doce pretreated patients with mCRPC. Needed disease progression after doce, randomized to cohort A Pembro + olap 68% had measurable disease. 41% with visceral disease. None of the patients had DDR mutations by biopsy or circ. dna. 12% response rate. 39% had some measurable disease response. they will expand from 42 to 100 patients. Continue randomizing to other cohorts.
  • #146 Chen Genetic drivers of poor prognosis and enz resistance in mcrpc. 86% patients had ar gain. Complete biallelic loss of RB1 median OS 14.1 months vs 42 months (not looked at in association with enz resistance -they didn’t look). WNT btea catenin pathway was highest abn asso with resistance. CTNNB1 mutation found only in enz resistant patients and was also associated with  poor prognosis similar to the RB1 
  • #147 – compared 3 arms. MDT upfront with SBRT. vs abi/ADT up front vs ADT up front. Assumed 10 years. Markov model. Looked at  cost effectiveness. ADT upfront low cost/low effective. Abi/ADT is not cost effective compared to MDT. Willingness to pay threshold of $100,000/qaly. Costs would need to decline by 90% to be the dominant strategy. MDT is a cost effective treatment. Did not look at MDT + upfront ADT with or without abi. Model assumed 1-3 extracranial metastases using data from STOMP and M1 Stampede.
  • #148 Doce +/- enz CHEIRON study. N=246. Combo arm more toxic with neutropenia. disease control 89% combo vs 73%. But no difference in overall survival but most patients did go on to receive 2nd gen adt.

Reading through them, with misspellings, poor wording, and probably containing some real errors (don’t rely on this “tweet” – go to the abstract to verify anything above) I realize how challenging it is to keep up these days. My best suggestion to ALL cancer patients is that they find a physician who is focused on their particular disease if at all possible. I fear the era of being a general medical oncologist is over (and certainly over for a 71-year-old like me). While any of us could use the NCCN guidelines (or other practice guidelines from organizations like ASCO or AUA) to care for patients, there is little that can replace the actual experience one gains by participating in the development of new agents that are rapidly coming into clinical use these days. If you can think of a solution, don’t tweet to me because I have no idea how to use it and don’t “follow” many people. However, I welcome your comments on this old fashioned blog, and can even throw in an emoji (of sorts):   😉  Have a great February and remember, the prostate is our only heart shaped organ.

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It’s MO time – please help!


To view this post on my blog site, sign up for future posts, and read more info relevant to prostate cancer, please click here. Donate to my moustache here. Even better, grow your own and get your friends to help out here. The more of us who join in, the wider the recognition of men’s health issues.

In my career fighting for the cure of prostate cancer, two organizations (besides the National Cancer Institute) have been outstanding partners. Movember was started by a couple of friends in a bar in Australia. This became the answer to a long standing jealousy of mine for something as popular and effective as the Susan G. Koman Foundation and Race for the Cure. I often refer to our prostate cancer journey when I lecture by noting how we “crawl for the cure” while our sisters are racing. In 2016, the NCI budget for breast cancer research was $519.9 million, more than twice as much as that for prostate cancer at $241 million. This, in spite of the fact that prostate cancer deaths this year are 3/4 as common (29,430) as breast cancer deaths (40,920). It’s not a contest really, since all cancer research is moving the field forward rapidly, but Movember has been incredibly helpful in sponsoring research and advocating for us.

The other organization, Prostate Cancer Foundation, shows how much a single individual with great connections and personal motivation can do. Michael Milken deserves enormous credit for his vision and leadership. I personally benefited from grants given out by the foundation, and even more from their amazing annual meeting that draws together prostate cancer researchers from around the world to share data and ideas. Dr. Howard Soule is a key factor in PCF’s incredible success and his name should be as well known as Susan G. Koman in my view.

I hope you will join with all of us in fighting for the cure in prostate cancer. Grow one, or support someone who is growing, and tell your friends. The progress and future has never been brighter, and our hairy upper lips should show it!

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