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Cancer Immunotherapy Continued: Non-transgenic T Cell Therapy

A number of adoptive T cell therapies are being examined for cancer treatment including isolation and culturing tumor infiltrating lymphocytes (TILs), isolating and expanding a specific T cell or clone, and generating novel T cells with chimeric receptors designed to target tumor cells and provide robust activation signals to the T cell. 1,2

Recently, I wrote a short essay about CAR T Cell therapy and how this therapy uses genetically modified T Cells to generate a large number of your own cells, capable of targeting tumors bearing a known antigen (e.g. CD19 as a Lymphoma marker).

T Cells are one of the immune system’s specific attackers, capable of recognizing cells bearing specific antigen only. They are engaged and activated via interactions with APCs presenting antigen bound to MHC molecules as well as other ‘secondary’ signals.  For a more complete description, see

In the case when the T Cell recognizes the antigen, it proliferates and activates if provided sufficient secondary signals in addition to TCR stimulation. In the absence of recognition, the T Cells will not stably bind the APC and therefor not receive sufficient signaling to activate.

T Cells ‘see’ antigen through presentation in the context of MHC molecules on the surface of Antigen Presenting Cells (APCs)

T Cells ‘see’ antigen through presentation in the context of MHC molecules on the surface of Antigen Presenting Cells (APCs)

Some benefits to that therapy include incorporation of a well-designed chimeric antigen receptor capable of providing normal T Cell Receptor (TCR) signals as well as signals from co-receptors required to generate mature effector cells. Because this construct targets the CD19 molecule directly, it does not require processing and presentation of antigen via MHC I by the tumor cells (important because one strategy tumor cells use to evade immune detection is to down-regulate MHC I). Using the patient’s own cells also means that immunosuppressive drugs aren’t required to prevent the body from rejecting the therapy.

One drawback though, is that the construct is made synthetically and can only include antibody binding regions specific to known cell surface antigens. So, if you know the cells you want to get rid of, and you can make an antibody to bind those cells preferentially, CAR T Cells are a good therapy for you.

Using Non-Transgenic T cells, similar effects can be obtained with an inverse set of pros and cons. Because this therapy does not utilize chimeric receptors, cells specific for a known  antigen aren’t singularly generated. Rather, a diverse array of cells is generated against tumor targets without requiring the isolation and characterization of one particular antigen. As opposed to the CAR T Cells these cells can only interact with target cells that present antigen via their MHC I molecules, which can be a drawback in situations where the tumor cells have downregulated antigen presentation molecules.

The Non-transgenic cells used may be generated in several ways. One method includes the harvest of tumor tissue from the patient, followed by killing these cells and re-injecting them (possibly in the presence of an adjuvant) to illicit a targeted immune response. 7-10 days later, peripheral T Cells enhanced for target specificity by the vaccine can be harvested and amplified outside of the body. In this way, cells can be amplified to numbers far outpacing what might be found in the patient, while also providing additional activation signals to promote effector cell development.

A second way of utilizing non-Transgenic T Cells in therapy is to isolate only those T Cells found to be actively invading the tumor. This biases toward cells already selected for by the immune system that may simply not be able to keep pace with the tumor’s growth. Ex vivo amplification can provide these cells the boost in numbers required to tip the balance in favor of the patient.

Screen Shot 2015-11-15 at 12.08.22 PM

Coupling any of these therapies with other treatments, such as the human monocloncal antibody anti-CTLA-4 (ipilimumab) 4, can further support T Cell efficacy – in this case by blocking checkpoints used to dampen the immune response following a period of activation. In healthy patients, these checkpoints allow the immune system to revert to a state of homeostasis once pathogens have been cleared. In cancer patients, the tumor may not yet be eradicated before checkpoint molecules begin to dampen the response. By interrupting these, the window during which T Cells are most effective is widened — at least in some patients.

This article has been cross-posted on Medium

A Few References:
1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315690/
2. https://depts.washington.edu/tumorvac/research/t-cell-therapy
3. My Medium Post
4. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1951510/

 
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Posted by on November 15, 2015 in Uncategorized

 

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Back from the Dead

Halloween seems like a good time to resurrect old blog posts that haven’t seen the sunlight for several years. Creeping out of the tomb is my first blog post about Genes, DNA, Memes, and GMO foods. Rather than post it here, I decided to post it over on my Medium site to see if it can catch some new eyes.

Take a look: Linked Memes

 
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Posted by on October 26, 2015 in Uncategorized

 

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Vaccines

To all my former students (as well as everyone else who reads this blog): please check out “Vaccines” a PBS documentary about the challenges faced by society revolving around maintaining society’s immunity against a number of vaccine-preventable diseases. Vaccines airs on PBS stations on August 26th at 9pm. You can also watch the film online here.

 
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Posted by on August 26, 2015 in Uncategorized

 

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HCV, briefly

Viral Hepatitis comes in a number of flavors, named HAV, HBV, HCV, HDV, and HEV (not to mention any subtypes). HCV, identified as recently as 1990, is a serious form of Hepatitis causing cirrhosis of the liver, chronic infection, and often hepatocellular cancer. Prior to 1990, the most common way to become infected was through transfusion with contaminated blood. However, after identifying the virus, tests became available to prevent this form of passage, leaving the primary mode of transmission being sharing of needles between IV drug users and sexual contact.
Unlike other viruses (HAV), few people ever clear HCV and, instead, become chronically ill. This may, in part, be due to the inability of the body to generate protective, neutralizing antibodies. Those antibodies that are produced are mostly usable only as markers of disease. Symptoms of disease include fatigue, nausea, vomiting, loss of appetite, abdominal pain, jaundice, dark urine, and clay colored feces. The CDC definition of a case is: (sorry this isn’t clearer)

acute-hcv-infection-cdc2012-case-definition.jpg

Serum alanine aminotransferase (ALT) levels greater than 400 IU/L indicate hepatocellular damage. This enzyme is normally found only in
liver cells, but is released into the blood when these cells are injured. Normal ALT should not exceed 60 IU/L, providing a fairly clear altmeasure of cell injury.This can be seen clearly below as serum levels of ALT spike with symptoms of disease and then return (however not down to normal, ‘healthy’ amounts) to lower levels following resolution of symptoms.

symptoms-acute-hepatitis-c-infection.jpg

There is no vaccine against HCV, so the best way to avoid it is to avoid contact with blood or other bodily fluids that may be contaminated.


Don’t forget to check out my comments on the novel ‘Rosemary’s Baby’ on my other blog. I highly recommend this book to anyone who enjoys thrillers / light horror (a la Stephen King).

 
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Posted by on April 12, 2015 in Uncategorized

 

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Diabetes and Kidney Failure

I wish my parents played Mozart when I was asleep because half the time I don't even know what the heck anyone's talking about!

I wish my parents played Mozart when I was asleep because half the time I don’t even know what the heck anyone’s talking about!

I don’t really think I’m that thick a guy (despite plenty of evidence to the contrary), but I do often encounter these blocks where I just don’t know what’s going on.

Most recently, it was in preparing to discuss the digestive system and how the pancreas participates in both the production of enzymes to digest food (Pancreatic Juice contains trypsin, chymotrypsin, elastase, etc) as well as hormones to aid the body in dealing with the coming wave of nutrients in the blood (i.e. how insulin and glucagon mediate blood glucose homeostasis).

The next unit we were getting into was the renal system – and in having our introductory discussion about the kidneys and their functions, the topic of kidney failure came up. That quickly led to a segue into diabetes (recalling the digestive system) and how many diabetics end up requiring dialysis due to chronic kidney failure.

‘So what’s the connection? Why do diabetics get kidney disease so often?’

I thought I knew – then, as my mouth started to open – I realized that I didn’t. I closed my mouth.

I think I asked my students to look into it, but … I couldn’t wait. So I jumped in.

diabetesFirst, a confirmation. A report from the 2007 US Department of Health and Human Services confirmed that not only is diabetes a common cause of kidney failure, it is the most common cause of kidney failure by a rather large margin.

Then, a quick reminder or the function of the kidney and the structure of its functional unit, the nephron – or which each kidney contains millions.

Briefly, the function of the kidney is to filter blood.

Peanut Gallery: ‘I thought the spleen did that!’

-well, the spleen does do that. But for an entirely different purpose. The spleen filters the blood for foreign particles, etc. as a function of the immune system. Lymph nodes filter the lymph for any foreign material brought back to the circulatory system as ‘run-off’, the spleen filters blood as it circulates through the body.

The Kidney also filters blood, but it does so in order to remove waste products that will otherwise build up and become toxic to the person / animal.

The way it does this filtration is by using a glomerulus. The glomerulus is a knot of capillaries with porous epithelia. The pores are large enough to permit the passage of water and other small molecules (urea), but small enough so that larger proteins and cells won’t leave the blood. Whatever material does filter through then either moves along and becomes urine, or is selectively reabsorbed into the blood.

[Image Removed as Requested by Artist]

The glomerulus looks a lot like this: (or at least it would if life were as cool as some people’s artistic impressions)

This is where blood comes in, at relatively high pressure, and the small molecules and water are pushed through fenestrations (windows) in the capillaries so they can drain into the renal tubule. The combination of capillary epithelial cells, basement membrane, and podocytes (cells that sit upon the capillaries) altogether called the Glomerular Filtration Barrier.This is the place where kidney function can really take a hit if there’s a problem – and if this breaks, the whole thing is broken.

Not surprisingly, it’s the glomerulus that fails in diabetes. The question is, ‘why?’

One prevailing theory has been that diabetics have generally higher amounts of glucose in their blood and it is known that glucose levels too high and too low are both dangerous. So, it’s not too much of a stretch to suspect that this is somehow to blame. The resulting injury is therefore called diabetic nephropathy.

However, more recently, the podocytes have been investigated as possible culprits. Rather than glucose itself, work published in 2010 suggested that it was insulin signaling – not glucose- that was involved in the damage to cells. Podocytes do have an insulin receptor that is engaged when glucose levels are high enabling the cell to restructure its cytoskeleton in a way that helps the cells to withstand the increased glomerular pressure that comes with filtering post-meal blood (incidentally, high blood pressure is another cause of kidney failure).

‘Knockout’ mice which specifically lack this insulin receptor on these podocytes (but otherwise express insulin receptors appropriately) were shown to suffer kidney damage very similar to that seen in diabetic nephropathy. Importantly, this damage occurred despite animals being otherwise normal (i.e. no abnormally high level of glucose in the blood). To be clear, without the insulin receptor, podocytes were unable to remodel cytoskeleton following meals, this lack of remodeling led to damage to the structure.

These results are also consistent with other animal models of diabetes (type I and type II) that exhibit a failure in glomerular insulin signaling early on in kidney disease.

Because these podocytes are terminally differentiated cells, they do not renew following damage meaning that kidney disease of this sort does not improve, but only progressively worsens.

This gives us a model that looks something like this

(ps – if anyone with deeper knowledge of this field reads this, I would certainly appreciate corrections)

Model

 
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Posted by on March 25, 2015 in Uncategorized

 

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The New Measles

leadApropos of class discussion about vaccine compliance and public policy, check out Adrienne LaFrance’s article from The Atlantic on how Measles is re-emerging in many countries – including the United States –  that have considered it eradicated for decades.

Click here to visit the article

The numbers in recent years are nothing like the devastation that Measles used to visit in the US, however, it is the trend that is disturbing. Prior to the introduction of the vaccine, cases numbered in the hundreds of thousands per year in the US. Globally, in 2013, there were 145 700 measles deaths compared to an estimated 2.6 million deaths each year prior to widespread immunization. (data from the WHO)

Measles cases in the US prior to and after the introduction of vaccine

Measles cases in the US prior to and after the introduction of vaccine Langmuir AD. Medical importance of measles. Am J Dis Child 1962;103:54-56

Some Data

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Measles Cases in the US 2001 – 2014

 
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Posted by on January 24, 2015 in Uncategorized

 

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One snake or two?

My wife and I had a conversation this afternoon that prompted this post.

This is a caduceus:

 Image

 

 

 

 

 

 

This is the staff of Asclepius (as part of the American Medical Association symbol):

Image

 

 

 

 

 

The caduceus is the staff carried by Hermes, the messenger of the gods.  As such, it is also a symbol associated with messengers and printers (considering that printing is a form of communication, and therefore within the realm of the messenger. It is also used today as a symbol of commerce.

 The rod of Asclepius is the symbol of the god of the same name, who is associated with healing and medicine. Today, this symbol retains its association with medicine and is often found incorporated in the signs of medical facilities.

Unfortunately, these two similar symbols are sometimes confused.

 Image

 For example, this student is clearly asking for donations so that he can afford the education to know the difference between a caduceus and a rod of Asclepius.

Maybe once he’s got that in order he can start studying medicine.

 

 

 

 

 

 

 

 

 

 

                      

 
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Posted by on January 5, 2014 in Uncategorized

 

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