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[ed. note: Michael Jorrin, who I dubbed “Doc Gumshoe” years ago, is a longtime medical writer (not a doctor) who writes for us a couple times a month about health issues and trends.  He does not typically write about specific investment opportunities, but has agreed to our trading restrictions… as with all of our authors, he chooses his own topics and his words and opinions are his alone]

There’s nothing like a report about a prominent person coming down with a serious illness to prompt the media to zero in on news about potential treatments for that particular condition.   The current focus of attention is Senator John McCain’s diagnosis of glioblastoma.   As we all know, he went back to Arizona for surgical treatment for a blood clot above his left eye.   On July 19th, it was reported that the surgery showed that he had glioblastoma, a usually deadly form of cancer of the brain.   According to the American Cancer Society, the five-year survival rate for persons over the age of 55 with glioblastoma is about 4%, making it one of the most lethal forms of cancer.

On that same date, July 19th, the University of Pennsylvania released the news that researchers at the university had been investigating the potential of CAR-T therapy for glioblastoma in a trial sponsored by Novartis.   This does not necessarily mean good news for Senator McCain, but it may mean good news for patients with glioblastoma in the future.   How far in the future is at this point a matter of pure speculation.

The University of Pennsylvania study followed 10 patients with glioblastoma.   All 10 patients had advanced cancers and had received some form of treatment.   Of the 10 patients, seven had undergone surgery to remove the tumor and three had not had surgery.   One of those 10 patients has survived for 18 months with stable disease, and in two other patients, the disease has progressed.   The other seven patients have died.   This could hardly be called a successful outcome for this small trial.   


But within that seemingly dire result there were signs that were clearly positive, or at least hopeful.   Up to this point, CAR-T has demonstrated results only in blood cancers, where it has been transformative, according to Dr Stefan Grupp of the University of Pennsylvania.   In the glioblastoma trial, these genetically modified “hunter” T cells successfully sought out and penetrated the glioblastoma tumor.   However, the T cells triggered an immunosuppressive response that will need to be overcome if the cancer is to be successfully defeated.   The researchers are hopeful that other current forms of treatment can be used along with CAR-T to deliver a treatment modality that will work.     

A bit of background about CAR-T therapy

If you already know about CAR-T and how it’s supposed to work, you can skip ahead, but if you haven’t been paying minute attention, here’s a primer.   Just to get it over with, the “CAR” part stands for ‘chimeric antigen receptor,’ and the “T” for T cells.   By now everybody knows about T cells, those cells in our immune system that are supposed to protect us from harmful invaders.    Those are the cells that are attacked by the human immunodeficiency virus (HIV) in people with AIDS, and the progress of the disease has usually been measured in terms of the patient’s T-cell level, because the virus attacked and disabled T cells.   Well, cancer cells also attack and disable T cells, and the CAR-T strategy is an effort to reverse that process such that T cells can be modified to attack and destroy cancer cells.

The part that enables the T cells to do battle against the cancer cells is the CAR, the chimeric antigen receptor.   Cancer cells have a protein on their surfaces which is classified as an antigen, meaning any molecule that can be recognized by the immune system as an invader.   In the case of many cancers, the term “antigen” is a bit deceptive, because in fact the immune system often does not recognize the so-called antigen as an invader, permitting the cancer cells to survive and spread.   

That’s where CAR comes in.   In the CAR-T strategy, the T cells are modified so that they do recognize the antigen.   They have been engineered with a receptor, the chimeric antigen receptor or CAR, which specifically recognizes the antigen on the cancer cell’s surface.   Designing a receptor that will recognize the antigen is a highly complex feat, requiring precise knowledge of the shape and molecular structure of the antigen, so that antigen and receptor essentially lock together.   

Once the T cells with the CARs on the surface encounter and bind with the cancer cells, the T cells move on to the task for which they are designed – attacking and destroying invaders.   

So far, the most effective strategy for employing T cells to treat cancer has involved removing a large population of T cells from the patient, genetically modifying them outside the patient’s body so that they will recognize and combat cancer cells, and then reinfusing them.   Once reinfused, the modified T cells will reproduce, retaining their genetic modifications, and join the battle against cancer cells.   This strategy has the enormous benefit of avoiding the side effects that occur when the process of T-cell engineering using CTLA-4 antibodies takes place inside the body.   These bio-engineered T cells, primed to recognize and attack cancer cells, are themselves a new generation of cancer-combating agents.            

Cancers where CAR-T therapy has been used successfully to date

This approach has been amazingly successful in cancers such as acute lymphoblastic leukemia (ALL) and also chronic lymphocytic leukemia (CLL).   Promising results have also been reported in some lymphomas.   Several small trials have been conducted, as is common with experimental cancer treatments, in patients who had basically run out of options.   In advanced ALL patients in whom no other treatment had worked, CAR-T therapy has resulted in many patients becoming entirely cancer-free, and many of these have continued to be cancer-free for several years.   These small trials have been so successful as to attract hordes of pharmaceutical companies to explore this strategy.   

One of the pharmaceutical companies that is out in front is Novartis (NVS), which was awarded breakthrough status by the FDA on July 7 2014 for its CAR-T agent CTL 019, which it is developing in collaboration with the University of Pennsylvania.   In a study in children and young adults with recurrent or refractory ALL, 36 of 39 patients attained complete remission.   Novartis is a cancer powerhouse, with nine patented cancer drugs besides Gleevec, and many more in various stages of development.

Another frontrunner is Juno Therapeutics (JUNO), which suffered a setback in their CAR-T candidate JCAR015 after very promising early results.   That agent was granted orphan drug status (which provides tax reductions and a period of exclusivity) by the FDA in November 2014 after a trial in ALL in which 14 of 16 patients attained complete remission.   But toxicity-related setbacks essentially forced Juno to put the development of JCAR015 on hold, at least for the time being.   However, they are moving forward with another CAR-T agent, JCAR017, which brought about a complete response rate in about 60% of patients with relapsed or refractory non-Hodgkin’s lymphoma, a tough group to treat.

Kite Pharma (KITE) is another strong contender in this arena.   Their lead drug, KTE-C19, demonstrated strong results in a small trial in 15 patients with diffuse large B-cell lymphoma, which is a subset of non-Hodgkin’s lymphoma.   Of those 15 patients, 8 were in complete remission and 4 in partial remission.   As a result of this trial, KTE-C19 was given orphan drug status by the European Medicines Agency.    And in December of 2015, Kite got FDA breakthrough therapy designation for KTE-C19 for the treatment of refractory, aggressive non-Hodgkin’s lymphoma.

Interestingly, Kite employs a retroviral vector to engineer T cells for this agent.   The effect of viruses on T cells also appears to be a part of the mechanism of action of Pfizer’s T-Vec.    Kite has planned several more trials with KTE-C19, as well as several trials with other candidate anti-cancer drugs that employ related mechanisms.   And Amgen (AMGN) is partnering with Kite in the development of CAR-T agents.

As I write this, the news emerges that Kite has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for axicabtagene ciloleucel as a treatment for patients with several forms of cancer, including relapsed/refractory diffuse large B-cell lymphoma, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma, who are ineligible for autologous stem cell transplant.  That agent is the first CAR-T drug submitted to the EMA.   It is currently under review by the FDA, which has set a Prescription Drug User Fee Act (PDUFA) action date of November 29, 2017.   PDUFA, in case you’ve forgotten, permits the FDA to collect money from the drug’s manufacturer to pay the costs of the approval process.   Pharmaceutical outfits may not like to cough up the money, but they very much like having an approval date on the calendar, so setting a PDUFA date for a drug is definitely Good News.

But what are the prospects for CAR-T therapies in solid tumors?

There’s no question that some CAR-T agents have been highly successful in treating leukemias and lymphomas.   Up to now, that success has not been of much help for persons with solid tumors – cancers of the breast, prostate, lung, colon, or brain.   That doesn’t mean that the basic CAR-T mechanism is any the less promising for solid tumors.   That mechanism has a large advantage over chemotherapy, which essentially relies on the essential greediness of cancer cells, such that if a toxic agent is in their environment, the cancer cells are likely to absorb it sooner than the normal cells.   The cancer cells may thus be poisoned and perish, while the normal cells take a nasty hit, but survive.

That technique for treating cancer has helped huge numbers of patients gain years – sometimes many years – of progression-free survival, but it is undeniably rough on the patient.   CAR-T therapy, in contrast, offers the promise of very specifically targeting the cancer cells, and the cancer cells only.  But there have been significant obstacles.

In the glioblastoma study at Penn, the CAR-T cells had an acceptable safety profile, crossed the blood-brain barrier, infiltrated the tumor, and prompted an immune response, resulting in reduction of the tumor antigen in cancer cells.   The specific tumor antigen targeted is the epidermal growth factor receptor variant three (EGFRvIII).   Factors that blocked success for the treatment were wide variations in EGFRvIII expression in patients as well as resistance in the tumor itself, which researchers showed became even more immunosuppressive following CAR-T cell infusion.    It is likely that both obstacles may be overcome, the first by targeting additional antigens other than EGFRvIII, and the second by adding existing drugs that target immunosuppressive molecules, such as checkpoint inhibitors which are successfully used to treat other cancers.

A note about those checkpoint strategies: PD-L1 & PD-1

The way this works is that T cells carry a protein that promotes programmed cell death, dubbed PD-1 (Programmed Death One); this is one way that they attack tumor cells.   In opposition, tumor cells carry a protein that links to and disables the PD-1 protein on T cells, dubbed PD-L1.   Antibodies to this link can restore the T cell’s immune function, and a number of agents that employ this mechanism have recently won FDA approval.   These include Merck’s (MRK) Keytruda (prembrolizumab), and Bristol-Myers Squibb’s (BSM) Opdivo (nivolumab).   Other Big Pharma outfits are on the case, including Pfizer (PFE), which is working with Merck KgaA on a PD-1 inhibitor that will target some major cancers – kidney, bladder, and lung cancer.

What this might mean for persons who are currently diagnosed with glioblastoma or another solid tumor cancer is a huge open question.   The only answer to this that I can think of is, “There’s hope!   Stay alive as long as you can, and maybe genuinely effective treatments will become available while you can still benefit!”   

“Staying alive,” for the non-baseball fans out there, is a strategy in baseball in which a batter keeps fouling off pitches until one pitch comes along that he (or she, there being female ball players) can wallop.   I remember a Yankee ball game in which Lou Piniella was at bat in a tie game in the bottom of the ninth with a man on second.   He must have fouled off fifteen pitches, to the immense frustration of the Detroit relief pitcher (a foul does not count as strike three) until he smacked a line drive over the first baseman’s head to score the winning run.   That’s the value of staying alive.

A few more recent bits of news on the health-care front

The first one I want to pass along to the Gumshoe crew is a fairly robust finding of an association between a person’s place of birth and the risk of becoming demented later in life.   This was based on an observational cohort study in 7,423 members of Kaiser Permanente Northern California.   In this group, birth in a state with high stroke mortality was associated with a 28% higher risk of dementia, after adjustment for age, sex, and race.   What makes this finding remarkable is that all of the individuals in this cohort were residents of Northern California, definitely not a high stroke risk area – so it’s not that living in a state with high stroke mortality was linked with that difference in the rates of dementia, but that simply having been born in that state accounted for the difference.   

When that cohort was divided according to ethnicity, it was found in that black individuals born in those states with high stroke mortality, the risk of dementia was 67% higher compared with non-blacks born outside the so-called “stroke belt.”   Black persons not born in a high stroke mortality state had a 48% increased risk of dementia, followed by non-black persons born in a high stroke mortality state, whose increased risk of dementia was 46%.   The nine states with high stroke mortality were Alabama, Alaska, Arkansas, Louisiana, Mississippi, Oklahoma, Tennessee, South Carolina, and West Virginia.   Overall, regardless of ethnicity, the 20-year risks at age 65 of becoming demented were about 30% for individuals born in a high stroke risk state, versus about 22% for those not born in a high stroke risk state.  

It’s a bit hard to swallow the notion that a person’s place of birth can have such a large effect on a condition that arises sixty or seventy years later.   But there has to be something to it.  The authors suggest a number of possibilities, including life-style habits acquired in childhood and youth that persist throughout life into the later years.   They also point out that in those high stroke mortality states, there were large educational disparities between the schools attended mostly by blacks and those attended by non-blacks.   Lower levels of education have been strongly associated with the risk of developing dementia.

The study authors concluded that “Poverty early in life can reflect a host of factors that could affect brain health and cognitive reserve, such as nutrition, lead exposure, chronic stress, and cognitive stimulation.   Poverty is highly associated with low birth weight and it is very likely that low birth weight disproportionately affected southern black persons in the 1920s, placing them at greater risk for elevated blood pressure, stroke, and cardiovascular disease mortality.”   (Gilsanz P et al.   JAMA Neurol. July 31, 2017. doi:10.1001/jamaneurol.2017.1553)

More about prostate cancer

You already know that the U. S. Preventive Services Task Force (USPSTF) specifically does not recommend prostate specific antigen (PSA) screening for prostate cancer, and you already know that your vigilant Doc Gumshoe has characterized this non-recommendation as a measure that will create More Work for the Undertaker.   And you may remember that since the USPSTF promulgated that recommendation, the incidence of late-stage and metastatic prostate cancer has increased – and not coincidentally, in my view, since omitting the PSA test means that cancers will not be detected at an early stage.

Here’s a bit of news coming from a sector of the health-care community that presumably knows a thing or two about prostate cancer: at the annual meeting of the American Urological Association (AUA) in Boston a couple of months ago, the results of a survey among 900 or so urologists and oncologists emphatically confirmed that those practitioners not only recommend PSA screening, but follow those recommendations themselves.   

The survey generated 869 usable responses, and the results showed that 92% of urologists, 89% of medical oncologists, and 85% of radiation oncologists recommended screening for their patients.   And as far as heeding their own recommendations, 94% of the screening-eligible men had either had PSA tests or were planning to do so in the future.   Among the female respondents, 69% recommended screening PSA tests to their first-degree male relatives.

There are some who would say, “Of course, urologists are going to recommend PSA screening, because if the results are positive, that means that those guys that had positive PSA tests will want to go on to the next step, and that means more business for those greedy urologists.   It’s all about the money!”

But you could say exactly the same thing about every single screening procedure that your doctor puts you through.   The results of the screening can always mean that you have to undergo some form of treatment, or, at the very least, more tests.   If you truly believe that the main reason physicians employ screening tests is to generate more income, you may have to put your faith in some other way of safeguarding your health.

However, the evidence from this survey is that when it comes to safeguarding their own health, the practitioners who know the most about prostate cancer overwhelmingly demonstrate their confidence in the validity of the PSA test, contradicting the USPSTF.

The reasoning of the USPSTF was not only that the PSA test was unreliable, but that a positive PSA test triggered a cascade of follow-up procedures, up to and including radical prostatectomy, which that august body considered to be in many cases unnecessary and also not cost effective.   Treatment for most prostate cancers, according to the USPSTF, was not necessary in most cases because the cancer progressed fairly slowly and in most men the age at which these cancers were diagnosed was sufficiently elevated that those chaps would perish from some other cause before the prostate cancer got them, thus taking the USPSTF off the hook.   It’s as though the mere act of taking the PSA test doomed a man to the whole dire sequence.

But the practice among the practitioners who actually deal with prostate cancer is to proceed very carefully, step by step – no headlong rush to treatment.   For men under the age of 60 with a positive PSA, a generally-agreed-upon strategy is active surveillance, meaning further PSA testing and repeat biopsies.   And that strategy has recently been confirmed by another report at the AUA meeting.

This report was based on a retrospective review of about 2,200 patients who had entered active surveillance between 1995 and 2016 at Mass General Hospital and the Sunnybrook Health Sciences Center in Toronto.   Of those patients, 432 were under 60 at the start of active surveillance.   Their median PSA level was 4.6 ng/dL, which is at the low end of the range indicating the likely presence of a cancerous tumor in the prostate gland.   Almost all the men – nearly 98% – had a Gleason score of less than 6, pointing to a fairly early stage cancer.

The big news is that after follow-up which in some cases went on as long as 22 years, not one single man in that group died of prostate cancer.   After five years of follow-up, 131 of those 432 men opted for some form of definitive treatment.   The most common reason was evidence of pathologic progression based on repeat biopsies, which led to definitive treatment in 88 men.   An additional 24 men decided to have definitive treatment based on rising PSA levels, and 15 men made that decision for other reasons.   The most frequent form of definitive treatment was radical prostatectomy, chosen by 82 men in this cohort.   But, to repeat the main take-away, in that group of 432 men who had gotten a diagnosis of prostate cancer, not one died of the disease.    

From my perspective, this report gives the most effective rebuttal to the USPSTF’s notion that PSA testing opens the floodgates to expensive and unnecessary treatment.   What it does is support the argument that PSA testing should start younger, with the goal of spotting cancers at an earlier stage, and treating only those cancers that show signs of progression.   The objective should be to save lives.   And if we can reduce the frequency of those advanced and truly deadly cancers, we’ll save money as well.

Some promising items

By promising I mean neither that a revolutionary treatment is likely in the short term, nor that investing a few bucks in the stock of a tiny pharmaceutical company is going to make us Rich Beyond the Dreams of Avarice (RBDA).   I mean only that there may be promising avenues of research, particularly in treatment areas that have resulted in repeated disappointment.   

For example, Alzheimer’s disease (AD): a Case Western Reserve team is carrying out experiments to explore the possibility that an existing drug may help to prevent AD by aiding the process whereby cholesterol is cleared from the brain.   The enzyme CYP46A1 breaks down about 80% of the cholesterol in the brain.   In mouse studies, scientists at the National Institute of Standards of Technology found that efavirenz, a drug used to treat HIV, binds to that enzyme and speeds up its activity, enabling it to bind more tightly to cholesterol.   (Efavirenz, by the way, is the widely used antiretroviral marketed as Sustiva by Bristol-Myers Squibb.)   

The Case Western team did further research to figure out why small doses of that drug speeded up the cholesterol-clearing process, while larger doses inhibited the process.   At low doses, efavirenz binds to a site on the enzyme that boosts cholesterol breakdown at another location on the enzyme.   This increase is enabled by changes in shape of the enzyme, which are initiated by the drug.   However, they found that in larger doses, efavirenz occupies the sites on the enzyme to which cholesterol would normally bind, thus preventing cholesterol binding and removal.    

In the mouse studies, efavirenz increased the cholesterol clearing process by about 40%.   The Case Western researchers estimate that efavirenz would be even more effective in the human brain, because the CYP46A1 enzyme plays a larger role in cholesterol clearance in humans than it does in mice.   And, they note, efavirenz could aid cholesterol clearance at doses of about one percent of the dose used to treat AIDS.   

Mouse studies by other scientists that used genetic manipulations in mouse models of Alzheimer’s disease showed that cranking up CYP46A1’s activity reduced development of plaque.   These studies also reported improvements in memory and learning.   And, even in plaque-free, normal mice, increased cholesterol removal resulted in memory improvement.   Conversely, mouse studies also found that suppressing CYP46A1 led to learning deficiencies.

Does that mean that all of us, as we move into that phase of life where the possibility of succumbing to AD begins to look like a genuine threat and not just a remote possibility, should start taking tiny daily doses of efavirenz?   Or does it mean that we should periodically submit our brains to servicing to clear out the crud, the way gourmands in France would spend a couple of weeks a year at some spa “taking the waters,” so that they could return to feasting on foie gras?   And, of course, which type of brain crud is the real cause of AD?   In any case, the continued diligence of our scientific community is definitely a Good Thing.

And one more…

These days, hormone replacement therapy (HRT) is nowhere near as popular among women as it was up to about 20 years ago, when around 60% of women in their perimenopausal years used HRT.   That proportion is about 23% of women today.   Fears of cancer in particular largely accounted for that enormous drop, but it also began to be seen as a practice that type-casts women as sex objects.   HRT was seen as a way to keep women desirable.   

But evidence is growing that HRT may have bona fide long-term health benefits beyond dealing with the effects of menopause.   A 14-year follow-up of 4,200 women who received a coronary calcium scan at Cedars Sinai Medical Center in Los Angeles showed that the women who had received HRT to relieve menopausal symptoms had less coronary atherosclerosis and lower mortality than those who had not used HRT.   Analysis of those health records showed that women using HRT were about 30% less likely to die than those not using HRT, and also more favorable coronary calcium scores.   

We need to emphasize here that those women were likely at an elevated risk for sustaining cardiac incidents.   Coronary calcium scans are not ordinarily performed on women unless there are specific risk-related reasons.   Also, it’s important to understand that the HRT benefits were seen in women who took HRT during menopause, and not as a long-term health-maintenance drug.   The North American Menopause Society emphasizes that in women who start HRT after menopause, or after the age of 60, there is an increased absolute risk of cardiovascular harms including coronary heart disease and stroke.   

That is entirely consistent with the findings of the Nurses’ Study, which reported outcomes in women who had taken HRT during their menopausal years, and also with the findings of the Women’s Health Initiative (WHI), which largely enrolled women well past menopause.   The Nurses’ Study reported clear benefits with HRT, including cardiovascular benefits, while the WHI initially reported risks.   We should note, however, that further analysis of the WHI data also reported benefits, particularly in women who took HRT only to relieve menopausal symptoms.

* * * * * * *

The HRT news is illustrative of the changes over time in views on quite a lot of health-care matters.   We remember when eggs, butter, and red meat were widely seen as arch-villains in our diet.   Then the focus switched to transfats, sugary drinks, and carbs in general.   When statins appeared, now a bit more than 20 years ago, the hosannas soared to the skies.   Now there are competing choirs – one sings hymns of praise, the other mutters imprecations.   Salt has been condemned as a major threat, and the American Heart Association recommends limiting consumption to about 1.5 grams per day – not much!   But international experts disagree, and published a paper in the European Heart Journal recommending a much higher limit of about 5 grams per day.   They note (and I quote) that “Sodium is an essential nutrient. This implies that there must be a ‘U’-shaped relationship between dietary sodium intake and cardiovascular events, but there is no consensus of where the minimum risks lies.”

What that means is that we all have to stay alert and skeptical.   Our health demands eternal vigilance.   Doc Gumshoe promises to try to stay on top of these matters.   Best to all, Michael Jorrin

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