Category Archives: Medicine in general

What about Long COVID?

A friend was happy to hear that the pandemic was winding down (see old post below the ****), but was still worried about ‘long COVID’.  He’d heard that it was very common and debilitating.  So I looked up the latest [Nature vol. 616 pp. 228 – 229 ’23, Science vol. 379 pp. 1174 – 1175 ’23].

There have been a variety of definitions of long COVID, but anyone still symptomatic 3 months after the initial infection probably has it.

The first strain of the virus was called alpha, and 46% of those affected were still symptomatic at 3 months.  So my friend was right.  It made the news as it should have, everyone being concerned and worried about where the new pandemic was taking us.  Alpha was replaced by the milder delta variant, and here long COVID dropped to 35%.  Then the Omicron strain took over, and the risk of long COVID dropped to 14%.  The paper noted that the risk of long COVID in 97,000 ‘healthy’ people infected with Omicron was 4.5%.  No headlines trumpeted this.  Good news just doesn’t sell.

Things are probably even better now as the new strain, XBB.1.16, is milder still and isn’t covered in the papers (it couldn’t be as it wasn’t around when the papers were written and submitted).

Now you don’t have to go to medical school to know that it takes longer to recover from a severe case (of anything) than a mild one.   So the decline in the incidence of long COVID is another piece of evidence that the pandemic is winding down and that successive variants are less virulent (or the populace is becoming immunologically immune due to asymptomatic infections).

The symptoms of long COVID and chronic fatigue syndrome are the same.As a neurologist I saw a lot of people who were chronically tired and fatigued, because neurologists deal with muscle weakness and diseases like myasthenia gravis which are associated with fatigue.  Once I ruled out neuromuscular disease as a cause, I had nothing to offer them (nor did medicine).  Some of these patients were undoubtedly neurotic, but there was little question in my mind that many others had something wrong that medicine just hadn’t figured out yet — not that it hasn’t been trying.

Infections of almost any sort are associated with fatigue, most probably caused by components of the inflammatory response.  Anyone who’s gone through mononucleosis knows this.    The long search for an infectious cause of chronic fatigue syndrome (CFS) has had its ups and downs — particularly downs — see

At worst many people with these symptoms are written off as crazy; at best, diagnosed as depressed  and given antidepressants.  The fact that many of those given antidepressants feel better is far from conclusive, since most patients with chronic illnesses are somewhat depressed.


The serious part of the pandemic is over, but the virus is here to stay

Massachusetts has some of the best statistics in the country on hospitalizations due to COVID-19.  Everybody admitted to the hospital gets tested for the virus so they won’t spread it.  However Massachusetts distinguishes people in the hospital withCOVID-19 from people in the hospital because of COVID-19.  Statistics come out every Thursday usually after 5 PM —

On 3 January ’23 there were 1,336 people hospitalized with COVID-19 and 437 hospitalized because of COVID-19.

On 9 May ’23 there were 172 people hospitalized with COVID-19 and 42 hospitalized because of COVID-19.

COVID-19 will always be with us, but it is acting differently than the season flu, as waves of high levels of mostly mild infections due to new variants (as shown by testing), without waves of hospitalization occur all year long,  so the new variants are milder.

The latest strain is XBB.1.16 which now accounts for 11% of USA cases (without a surge in hospitalizations or deaths).

The virus is still a killer, but you have to be old (like my wife and I) or seriously ill with something else to die from it.  That’s good news for just about everyone.

Remember when COVID-19 was being touted as a disease of the unvaccinated (by the CDC and everyone else) in an attempt to get people vaccinated.  All year long the percentage of ‘fully vaccinated’ people hospitalized with/for COVID-19 in Massachusetts has ranged from 60 to 71%.  Some humility is in order

The serious part of the pandemic is over, but the virus is here to stay

Massachusetts has some of the best statistics in the country on hospitalizations due to COVID-19.  Everybody admitted to the hospital gets tested for the virus so they won’t spread it.  However Massachusetts distinguishes people in the hospital with COVID-19 from people in the hospital because of COVID-19.  Statistics come out every Thursday usually after 5 PM —

On 3 January ’23 there were 1,336 people hospitalized with COVID-19 and 437 hospitalized because of COVID-19.

On 9 May ’23 there were 172 people hospitalized with COVID-19 and 42 hospitalized because of COVID-19.

COVID-19 will always be with us, but it is acting differently than the season flu, as waves of high levels of mostly mild infections due to new variants (as shown by testing), without waves of hospitalization occur all year long,  so the new variants are milder.

The latest strain is XBB.1.16 which now accounts for 11% of USA cases (without a surge in hospitalizations or deaths).

The virus is still a killer, but you have to be old (like my wife and I) or seriously ill with something else to die from it.  That’s good news for just about everyone.

Remember when COVID-19 was being touted as a disease of the unvaccinated (by the CDC and everyone else) in an attempt to get people vaccinated.  All year long the percentage of ‘fully vaccinated’ people hospitalized with/for COVID-19 in Massachusetts has ranged from 60 to 71%.  Some humility is in order

A neuron synapsing on an immune cell.

The immunologic synapse is well known.  It occurs between two types of immune cells (not between neurons), an antigen presenting cell and a T lymphocyte.  An effective immunologic synapse produces T cell activation and proliferation to kick off the immune response.

Neuroinflammation is equally well known.  Stimulate a neuron responding to painful stimuli and it releases inflammatory mediators locally and fires impulses back to the brain.  The best known example of a receptor for pain (nociceptor) is the TRPV1 channel, which responds to capsaicin, an active component of red hot chili peppers.  TRPV1 also responds to other obviously painful stimuli — heat, acid etc.  Neurons containing TRPV1 are called nociceptor neurons.

Activation of TRPV1 on nociceptor neurons results in the release of inflammatory mediators such as substance P, and other things (CCL2, CGRP).

Many immune cells have receptors for inflammatory mediators and direct contact with nociceptor neurons isn’t necessary.  I’ve always wondered if something like a synapse between a nerve cell and immune cell existed.

Finally a paper just cultured nociceptor neurons and a type of immune cell (the dendritic cell) together [Science vol. 379 pp. 1301 – 1302, 1315 eabm5658 pp. 1 –> 1 ’23 ].  Figure 3c on p. 4 of the paper, shows a dendritic cell plastered up along an axon, which is about as close to synapse as you are going to get.  However, the area of contact is much longer than the usual synapse.  Whether such things occur in vivo is unknown, but I’ve never seen a picture like this one.

Capsaicin was used to stimuli the neurons, and they were found to communicate wth  dendritic cells three ways

l. By producing the chemokine CCL2 which attract dendritic cells

2, By releasing Calcitonin Gene Related Peptide (CGRP) which causes dendritic cells to release another inflammatory mediator — interleukin 1 beta (IL1beta)

3. By direct electrical coupling triggering calcium flux into the dendritic cell along with membrane depolarization.  This potentiates the dendritic cell response to inflammatory stimuli.

The experimental system is far out, but anything we can learn about pain is worth having, as present therapy is far from ideal.

Lactic acid, the mitotic spindle killer

Nature vol. 616 pp. 790 – 797 ’23 is one of the most interesting papers I’ve read in the past year, both for its contents and for the two very large issues it raises (which the authors don’t really discuss).

Simply stated, the rise in cellular lactic acid levels from 6  milliMolar at mitosis onset, to 15 – 20 when mitosis is nearly over is what ’causes’ the breakdown of the mitotic spindle.

It’s now 100 years since Otto Warburg noted that tumors metabolize glucose by glycolysis producing 2 molecules of ATP per glucose (and two molecules of lactic acid) when, with plenty of oxygen around, they could get 38 molecules of ATP using their mitochondria.   This is called aerobic glycolysis.

Tumors are said to be energy hungry, so why do they use aerobic glycolysis? Simply because using oxygen to chew up glucose gives you lots of ATP along with CO2 and water, leaving you nothing to build new tumor cells with.  All 6 carbons remain present after glycolysis

The last stage of mitosis is called anaphase, where the mitotic spindle (made of microtubules) is broken down, among other things such as reformation of the nuclear membrane, and separation of the two daughter cells.

Well protein breakdown immediately brings ubiquitin to mind which, when added to most proteins, targets them to the proteasome, a huge molecular complex which breaks proteins down completely to their constituent amino acids.

APC/C is another huge multiprotein complex (at least 13 different protein subunits with a molecular mass of 1.2 megaDaltons) which acts to add ubiquitin to components of the mitotic  spindle (made mostly of microtubules).  So APC/C is a ubiquitin ligase, a dangerous thing to have around most of the time, which it is why it is usually inhibited so the cell doesn’t destroy itself.

One APC/C subunit is APC4, which has ubiquitinLike molecules (SUMO) attached to two of its lysines (#722 and #798) to activate the ubiquitin ligase activity of APC/C.    APC4 is held in check by yet another enzyme, SENP1, which removes the SUMOs.

Where does lactic acid fit in to all this?  It binds to the active site of SENP1 when coordinated with zinc ions, inhibiting SENP1’s ability to remove SUMO.

Byzantine enough for you?  Lactic acid inhibits SENP1 which inhibits APC4 allowing uninhibited APC4 to activate APC/C which breaks down the mitotic spindle.

Lactic acid, if thought of at all, was regarded as an important part of cellular metabolism, not an enzyme inhibitor.   This is an example of moonlighting, a lot of which goes on in the cell.  with its links will get you started.

Here is one of the larger issues the paper raises — how events in the cell at all levels of structure are linked to each other.  Phillip Anderson famously said “More is Different”.  The paper shows how something very small (lactic acid fits into a 5 Angstrom (.5 nanoMeters) sphere) and yet  is responsible for breaking down something 40,000 – 100,000 times larger  (the length of a microtubule in the mitotic spindle).

Here is the other (even larger) issue — Lactic acid was found as a player in cell metabolism, e.g., it is a member of the metabolome.  I was amazed to find out how large it is — some 42,000 for in the Human Metabolome DataBase — for details please see  Not only do we not know what they are doing, we don’t even know the structure of most of them. State of the art untargeted metabolomics studies still report ‘up to’ 40% unidentified, but potentially important metabolitcs which can be detected reproducibly. The unknown metabolites are only rarely characterized because of the extensive work required for de novo structure determination..

The science behind Cassava Sciences (SAVA) — the latest as of 23 April ’23

It’s time for an update on the science  behind Cassava Sciences’ anti-Alzheimer drug, Simufilam.  It is  based on an older post of mine and a review of the published literature and my decades of experience as a clinical neurologist.

Disclaimer:  My wife and I have known Lindsay Burns, one of the Cassava Sciences principals since she was a teenager and we were friendly with her parents when I practiced neurology in Montana.

But as H. L. Mencken said, “A Professor must have a theory as a dog must have fleas”, and the reason I’m excited about Simufilam has nothing to do with the theory of the science behind it.  Simply put, the results of Cassava’s open label trial have never  been seen with Alzheimer’s patients.  10% improved by nearly 50% at 1 year, and over half did not deteriorate.  As a clinical neurologist with decades of experience seeing hundreds of demented people, I never saw anything like this, especially significant improvement after a year).  For more detail please see

Here is the science behind the drug.  We’ll start with the protein the drug is supposed to affect — filamin A, a very large protein (2,603 amino acids to be exact).  I’ve known about it for years because it crosslinks actin in muscle, and I read everything I could about it, starting back in the day when I ran a muscular dystrophy clinic in Montana.

Filamin binds actin by its amino terminal domain.  It forms a dimerization domain at its carboxy terminal end.  In between are 23 repeats of 96 amino acids which resemble immunoglobulin — forming a rod 800 Angstroms long.  The dimer forms a V with the actin binding domain at the two tips of the V, making it clear how it could link actin filaments together.

Immunoglobulins are good at binding things and 90 different proteins are known to which filamin A binds.  This is an enormous potential source of trouble.

As one might imagine, filamin A could have a lot of conformations in addition to the V, and the pictures shown in

One such altered (from the V) conformation binds to the alpha7 nicotinic cholinergic receptor on the surface of neurons and Toll-Like Receptor 4 (TLR4) inside the cell.

Abeta42, the toxic peptide, has been known for years to bind tightly to the alpha7 nicotinic receptor — they say in the femtoMolar (10^-15 Molar) range, although I have my doubts as to whether such tiny concentration values are meaningful.  Let’s just say the binding is tight and that femtoMolar binding is tighter than picoMolar is tighter than nanoMolar is tighter than microMolar  binding etc., etc.

When aBeta42 binds to alpha7 on the outside of the neuronal plasma membrane  filamin A binds to alpha 7 on the inside making  aBeta42 binding even tighter.

The tight binding causes signaling inside the cell  to hyperphosphorylate the tau protein forming the neurofibrillary tangle, which is more directly correlated with dementia in Alzheimer’s disease than the number of senile plaques.

In more detail, the high affinity aBeta42-alpha7 nicotinic cholinergic receptor binding activates the MAPK cascade (Mitogen Activated Protein Kinase cascade), ending in activation of the protein kinases ERK2, and JNK1.  Activated protein kinases catalyze the addition of phosphate to proteins forming an ester with the free hydroxyl groups of serine and/or threonine.  Activating ERK2 and JNK1 allows them to phosphorylate the tau protein leading to the neurofibrillary tangle of  Alzheimer’s disease (which is just a mess of hyperphosphorylated tau protein).

But there is still more about the mechanism which isn’t clear.  Recall that MAPK stands for Mitogen Activated Protein Kinase where a mitogen binds to a receptor on the cell surface, and a mitogen is nowhere in sight here, so there are still a few missing steps between aBeta42 binding to the alpha7 nicotinic cholinergic receptor and MAPK activation.  The references do show that MAPK signaling, ERK2 and JNK1 are activated when aBeta42 binds to the alpha7 nicotinic acetyl choline receptor.

Also the mechanism is radical in the extreme. The nicotinic acetyl choline receptor is a receptor all right but for acetyl choline. It is an ion channel and   looks nothing like the receptors that proteins and peptides bind to which are usually G Protein Coupled Receptors (GPCRs) or Receptors with Tyrosine Kinase activity (RTKs).  Also aBeta42 is not a mitogen.

So what does Sumifilam actually do — it changes the ‘altered’ conformation of filamin A getting it away from the alpha7 acetyl choline receptor and “indirectly reducing the high femtoMolar binding affinity of aBeta42 for alpha7” (and however this binding triggers tau hyperphosphorylation)  How do they know the conformation of filamin A has changed?  They haven’t done cryoEM or Xray crystallography on the protein.  The only evidence for a change in conformation, is a change in the electrophoretic mobility (which is pretty good evidence, but I’d like to know what conformation is changed to what).

So there you have it, after a fairly deep dive into protein chemistry, cellular physiology and biochemistry, the current thinking of how Simufilam works.

But even if the theory is completely wrong, the data in the link above must be regarded with respect.  Clinical blinded studies are ongoing, and the soon to be released Cognition Maintenance Study should  give us more information –

The Cognition Maintenance Study of Simufilam

Addendum and revision 11 May ’23 — Cassava announced today that dosing inthe Cognition Maintenance Study (CMS) is complete —  All that remains is to analyze and report the data  which will happen in the third quarter of 2023. The link notes that “The CMS dataset remains locked and blinded. After unlocking, the dataset will be analyzed by outside biostatisticians.”   This could be a game changer and lead to early FDA approval as the CMS study is double blinded.  So it’s worth republishing an earlier (5/22) post on the subject to explain how this might occur.

Cassava’s Cognition Maintenance Study may prove Simufilam works

The FDA will approve less than perfect therapies if there is nothing useful for a serious condition.  Consider the following from Proc. Natl. Acad. Sci. vol. 119 e2120512119 ’22

“KRAS is the most frequently mutated oncogene in human cancer, with mutations detected across many lineages, particularly in the pancreas, colon, and lungs. Among the most commonly activating KRAS mutations at codons 12, 13, and 61, G12C occurs in ∼13% of lung and 3% of colorectal carcinomas and at lower frequencies in other tumors.

“In locally advanced or metastatic non–small-cell lung cancer (NSCLC) patients with KRASG12C mutations who have received at least one prior systemic therapy”  treatment with sotorasib resulted in the following “objective response  in 37.1% of the patients, with a median duration of response was 11.1 months.”   This is hardly a cure, but nonetheless “This promising anticancer activity has resulted in accelerated approval from the US Food & Drug Administration”

Which brings me to the current CMS study from Cassava Sciences.  I’ll let them speak for themselves.

Cognition Maintenance Study (CMS) – on-going
In May 2021, we initiated a Cognition Maintenance Study (CMS). This is a double-blind, randomized, placebo-controlled study of simufilam in patients with mild-to-moderate Alzheimer’s disease. Study participants are randomized (1:1) to simufilam or placebo for six months. To enroll in the CMS, patients must have previously completed 12 months or more of open-label treatment with simufilam. The CMS is designed to evaluate simufilam’s effects on cognition and health outcomes in Alzheimer’s patients who continue with drug treatment versus patients who discontinue drug treatment. The target enrollment for the CMS is approximately 100 subjects. Over 75 subjects have been enrolled in the CMS and 35 have completed the study.”

Even though the open label study was not randomized, this one will be.

Only someone who has actually taken care of  patients would know the following.  People who are getting no benefit from a drug will soon stop taking it.  This was particularly true for my experience with Cognex for Alzheimer’s disease.

Which is exactly why the fact that 75 patients who’ve been on Simufilam have decided to continue on in the CMS study.  Presumably they feel they are getting some benefit.

There are two possible hookers to this

l. The patients are being paid to enter CMS

2. The original cohort was 200, not all of whom have finished the 1 year.  So we don’t know how many could have been in CMS but chose not to.

As I discussed in an earlier post, the most impressive thing (to me at least) was that at 9 months 5/50 had significant improvement in their cognition — here’s a link —

The CMS study should give us an idea of how they fared at 1 year and  at 18 months.


l. gains in cognition were maintained on Simufilam

2. gains in cognition were lost off Simufilam

FDA approval should follow quickly.

Results on the 75 will be available this year.   Also available this year will be 1 year results on all 200 entering the open label study.

There are two other double blind studies in progress which will provide  more definitive answers, but they are far from full and will take much longer to complete.  So stay tuned.

How herpes viruses use the cell’s machinery to shut themselves off

Herpes viruses (simplex — for fever blisters, Kaposi’s sarcoma, herpes zoster — shingles) persist in the body in a latent state where they don’t don’t reproduce, don’t make many of their proteins and don’t make trouble.   Every now and then they reproduce and cause disease, as anyone with recurrent fever blisters will tell you.  Staying quiet allows them to avoid the immune system and essentially act as selfish DNA.

A recent paper [ PNAS vol. 120 e2212864120 ’23 ] shows that Kaposi’s Sarcoma Herpes Virus (KSHV) uses a circular RNA (circRNA) derived from a human oncogene called RELL1.  The circular RNA they induce is called hsa_circ-0001400.  In general circular RNAs are formed by back splicing of a 5′ splice to an upstream 3′ splice site.   One of their functions is to act as sponges for microRNAs as some contain multiple binding sites for them.  Some cells contain 25,000 of them.

Viruses are known to hijack cellular proteins to use for their own ends.  It isn’t clear how the herpes viruses stimulate formation of hsa_circ_0001400, but use it they do, as it promotes viral latency,  cell cycle genes and inhibits apoptosis.

This another example of the RNA world which supposedly existed before the DNA world, like DOS under the Windows operating system (forgotten but not gone)

Clinical reality comes to animal models of genetic disease

“So you’re going to be experimenting on me, doc?”  I heard that a fair amount practicing neurology in Montana.  There is no guarantee that any drug we use will always work, particularly drugs for epilepsy (anticonvulsants).  When one of them didn’t, it was always obvious.

Being honest with patients, I’d always say we’ll try drug X, it has a high chance of working.  And that was the (actually quite intelligent) response I sometimes got.

I’d then launch into some sort of explanation, saying that people aren’t cars and not all the same so they don’t respond the medications the same way (cue up rare side effects).  Of course in the 70’s and 80’s we had no idea just how different each of us actually is.

Now we do and this is even true for children in which the copies of their parents genomes is far from exact–

From the ENCODE study.  Some 2,976 parent child trios had their whole genomes sequenced.  There were 200,435 de novo mutations in the group (an average of 67 mutations/child).  The number of de novo mutations increases by 1.39% for each year of paternal age and .38% for each year of maternal age at the time of the birth of the child.  Earlier work with far less data implied that maternal age at conception was irrelevant to the mutation rate — this is clearly incorrect.

The same variation in genomes is another pitfall in understanding what effects a protein mutation has when studied in animals.  Up to now research has been done in very inbred animal strains which all have exactly the same genome, to cancel out the variability in response. Usually just one inbred strain is studied.  This is good.

No it’s bad !! [ Neuron vol. 111 pp. 539 – 556 ’23 ] studied one particular mutation in a protein called CHD8 which is associated with autism in man.  They put the mutated protein into 1,000 mice from 33 different strains and measured a variety of phenotypes (brain and body weights, cognition, activity, social behavior, exploratory activity in an open field, etc. etc.).

Guess what?  The same mutant in the same protein had a wide variety of phenotypes which depended on the strain and sex.  Some strains showed no phenotypic effects at all, while others showed many large effects.

So a lot of animal work on disease should be repeated (or at least taken with several grains of salt) on multiple strains.

So experimental animals are just like people responding to drugs that docs experiment with on them

Location bias

Location bias:  no this isn’t about real estate or red lining.  It’s about how drugs act differently depending on where they’re able to get.  If this sounds too abstract, location bias may explain why dimethyl tryptamine (DMT) is a hallucinogen (it is the main psychoactive component of ayahuasca) and why serotonin (5 hydroxy tryptamine) is not.

The psychoactive effects of many drugs (LSD, DMT) are explained by their binding to one of the many (> 13) subtypes of serotonin receptors, namely 5HT2AR.

Well serotonin certainly binds to 5HT2AR, so why doesn’t it produce hallucinations?  This is where [ Science vol. 379 pp. 700 – 706 ’23 ] (and local bias) comes in.

We tend to think of receptors for neurotransmitters (like serotonin) as being on the outer membrane of the cell (the plasma membrane).  This makes sense as neurotransmitters are released from neurons into the extracellular space.  However it is now known that some neurotransmitter receptors (such as 5HT2AR) are found inside the cell where they are found on endosomes and the Golgi apparatus.

The article claims that the hallucinogenic effects of DMT, LSD etc. etc. are due to their binding to 5HT2ARs found inside the cell, not those on the plasma membrane. Serotonin with its free OH and NH2 groups is simply too water soluble (hydrophilic) to pass through the lipids of the plasma membrane.   DMT and LSD are not.   Unfortunately we are a long way from understanding how activation of 5HT2ARs inside the cell leads to hallucinations, but if the authors are right, it’s time to look.

We don’t know if animals hallucinate, and use things like head twitch and effects on dendritic branching and size in tissue culture as markers for hallucinations as LSD, DMT produce these things,.

The authors do show that putting a serotonin transporter into neuronal cultures so serotonin gets inside, produces similar effects on dendritic branching and size.  While fascinating, these effects are  pretty far removed from clinical reality.

The authors do raise a fascinating point at the end of their paper.  Perhaps there are endogenous intracellular ligands for intracellular 5HT2AR which differ from serotonin.   Perhaps the hallucinations and mental distortions of schizophrenia and other psychiatric disease are due to too much of them.

The fact that not everyone responds to Simufilam is irrelevant to its eventual FDA approval

A very intelligent friend does not share my optimism about Simufilam.

“Is the data really that positive? ADAS-Cog mean scores changed minimally over 1 year in patients with mild-to-moderate Alzheimer’s disease.  47% of patients improved ADAS-Cog over 1 year by 4.7 points. But 23% of patients declined by <5 points. Mild patients responded better than patients with moderate Alzheimer’s.”

Why are these thoughts irrelevant to the eventual approval of Simufilam by the FDA?

First: no drug for anything works for everyone with the condition

Second: The assumption that Alzheimer dementia is a single disease is based on just that: an assumption.

An example: When I was running a muscular dystrophy clinic in MonrN (’71 – ’87), we saw something called limb girdle muscular dystrophy , in which the patients were weak primarily in muscles about the shoulders and hips. Now we know that there are at least 13 different genetic causes of the disorder.

If the clinical picture of Alzheimer’s disease is due to multiple causes, it is unsurprising that Simufilam doesn’t help all of them.

Also it is time for some humility about our knowledge about Alzheimer’s disease.  We have misunderstood what the senile plaque of Alzheimer’s disease really is for 111 years — see the following post written 12/22 —

Third (and probably the most relevant for FDA approval):  Less that perfect drugs will be approved if every other treatment is worse.

The example of immune checkpoint blockade therapy for cancer is particularly relevant.

Some absolutely spectacular results for the therapy has led to the approval of 6 different drugs in this class (all of them monoclonal antibodies against proteins involving the immune system).

One example [ Cell vol. 162 pp. 1186 – 1190 ’15 ]:  “20% of metastatic melanoma patients are cured with Ipilimumab, a fully humanized anti-CTLA4 monoclonal antibody.”

Would that results like this were the rule not the exception. Unfortunately — [ Nature vol. 565 pp. 43 – 48 ’19 ] “Most patients with cancer either do not respond to immune checkpoint blockade or develop resistance to it.”

So what.

Immune checkpoint blockade, despite being less than perfect,  is  still being offered to cancer patients, just the way Simufilam with its nearly 50% chance of improvement at 1 year should be offered to Alzheimer patients.