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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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Vitamin Supplements: Vital? or Rubbish?

ImageIn class today, I was asked what I knew about vitamin supplements and whether it was a good idea to take them or not. To follow up on that conversation, I thought I would post a link to an article that addresses this question directly. This article, by Paul Offit, was published by the Atlantic magazine July 19 of this year and deals with some of the same material from his newest book, Do You Believe in Magic?

Vitamines are certainly required for healthy living, something reflected by their very name (vitamin = vital amine). The question is, how much of each of these do we need to add above and and beyond what we get from a well-balanced diet? It has been proposed that excessive doses of certain vitamins could be a panacea leading to elimination of many of life’s ailments.  From the Atlantic article…

In 1970, [Nobel Prize winning scientist, Linus] Pauling published Vitamin C and the Common Cold, urging the public to take 3,000 milligrams of vitamin C every day (about 50 times the recommended daily allowance). Pauling believed that the common cold would soon be a historical footnote. “It will take decades to eradicate the common cold completely,” he wrote, “but it can, I believe, be controlled entirely in the United States and some other countries within a few years. I look forward to witnessing this step toward a better world.” Pauling’s book became an instant best seller.

ImageThese pronouncements would have amounted to nothing coming from many other people, but Pauling was not just any other person. There’s a chance his pair of Nobel Prizes may have held some weight in people’s minds. 

 
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Posted by on November 14, 2013 in Uncategorized

 

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Poor Science Communication endangers public health

I have a pretty impressive stack of ‘Science’ and ‘Journal of Immunology’ journals stacked on my study desk. Well, they would be impressive if they were not in the ‘To Be Read’ pile.

I had an opportunity to make some headway into this pile today and started reading the 4 October 2013 issue of Science featuring a number of articles about science communication. So far, everything I’ve read has been good, but I just put down a fantastic article by Dan Kahan entitled “A Risky Communication Environment for Vaccines.”

Several aspects of this article make it one of the best I’ve read in some time.

1. Simple, clear writingImage

2. A clear mission of improving public health by insisting on the scientific community to do a better job of talking about its work with the public

3. A novel, data-supported argument exposing how misinformation among scientists leads to misinformation in the public

4. A level-headed explanation of how key decisions should be made in order to obtain the most desirable results (again, increased public health)

It’s widely recognized that Merck made a severe mistake in the marketing and legislative lobbying done to promote mandatory adoption of its HPV vaccine , Gardasil. However, Kahan goes further to illustrate how a very similar vaccine (against Hepatitis B) was previously introduced without a lobbying effort and resulted in widespread adoption of the vaccine without significant resistance from the public. Kahan writes:

Had the HPV vaccine taken this path, it would have followed the uneventful course that marked introduction of the hepatitis B virus (HBV) vaccine into the U.S. public health system. Hepatitis B, like HPV, is sexually transmitted and causes cancer (6). The CDC endorsed universal childhood HBV vaccination—for boys and girls, a much less jarring proposal—in the 1990s. There was no political controversy. Rather, states steadily added the HBV vaccine to mandatory vaccination schedules through the customary mechanism—not high-profile legislative enactments, but guidelines routinely promulgated by public health administrators operating outside the political realm (7).”

Also check out the Podcast Interview with the author, Dan Kahan at ScienceMag.com.

He then goes on to warn against aggressive promotion of vaccines as this can often backfire psychologically and provide fuel for the fire of an anti-vaccine movement. This is exactly what James Colgrove predicted in his Perspective article in the 2006 New England Journal of Medicine when he warned that, “Moves to make the vaccine compulsory are sure to ignite a new round of polarizing debates.” Yet, he goes on to reiterate the importance of (near) universal vaccination in protecting out most vulnerable:

Laws making vaccination compulsory raise unique ethical and policy issues. High levels of herd immunity protect all members of the community, including those who cannot receive vaccines because of medical contraindications. This protection provides a justification for compulsion. The availability of religious or philosophical exemptions mitigates concern about governmental intrusion on individual decision making. Opinions vary, however, about the permissible scope of exemptions. Data show that schools with exemption rates as low as 2 to 4% are at increased risk for disease outbreaks and that children who have been exempted from vaccine requirements have a much greater risk of acquiring infectious diseases than their vaccinated peers.1 Minors have a right to be protected against vaccine-preventable illness, and society has an interest in safeguarding the welfare of children who may be harmed by the choices of their parents or guardians.”

Luckily, these great articles about scientific communication are freely available on the website links above.

It’s embarrassing that a (admittedly fantastic) comic like Calvin and Hobbes can communicate more in one page that many scientists can over the course of their entire careers. Bill Waterson asks, “Is it sometimes valuable to give up just a little freedom if all society can work better because of it? …”

Ethicshobb

 
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Posted by on November 9, 2013 in Uncategorized

 

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Cell Division, Contact Inhibition and Cancer

imagesIn my general biology class we are now reading chapter 5 of Mader et al, on Cell Division. This chapter is a bridge between those chapters on descriptive cell biology and those describing the activities of the cell and how we explain the inheritance of traits from one generation to another.

We focused our attention on Mitosis and Meiosis of diploid Eukaryotic cells and followed how these two types of nuclear division manage the sorting of genetic material into daughter cells ensuring that each cell gets an appropriate set of instructions for life.

The body is comprised of somatic cells that include everything from skin to muscle and nerve cells. These are called somatic because soma comes from the greek word for body.

The other type of cell is the gametic cell, referring to germ-line, or sex, cells.

Each of these type of cells goes through its own type of division in order to end up with the correct amount of genetic material ( or ‘ploidy’) in the resulting cell or organism. Ploidy refers to the number of complete sets of genetic material a cell has. We, humans, are diploid organisms having two sets of genetic material in each cell.

Image

Mitosis in Diploid Cells

Somatic cells undergo mitosis in a way that maintains the diploid state of cells creating two exact replicas of the parent cell.

This mechanism makes sense, because one skin cell might replace a neighboring skin cell following its demise in order to maintain a confluent layer. We would expect every skin cell to be genetically identical to every other and mitosis delivers just that.

However, if we imagine sex cells that were made from mitosis, these would also be diploid (2n). Then a diploid sperm would fuse with a diploid egg and make a tetraploid offspring. Then that organism would have octaploid offspring and so on. This, of course, does not happen.

ImageSex cells are instead produced by a different kind of division called meiosis. Meiosis is merely a specialized form of mitosis in which the genetic material (ploidy) is ‘halved’. The resulting cells are then haploid (1n or n). As part of the specialization, meiosis occurs in two steps so instead of producing two cells, it produces four (at least theoretically). Also, instead of being identical, each of the resulting sex cells is unique.

But this discussion is supposed to be about cancer, so let’s ignore meiosis for now. I’ve discussed cancer before here, but I just found a couple of good animations that I wanted to include.

The first is an excellent animation on cell cycle and contact inhibition. See how cancer is defined here as the lack of respect for cell-cell signaling, that would otherwise result in a healthy monolayer of cells.

The second, discusses how cancer cells would need to alter their environment in order to get the nutrients they need to survive. It can be tempting to think that cancer cells don’t need these things, but they certainly do.

http://bcove.me/uc5vydod

Once cells mutate in a way that initiates cancer, the constant struggle with the immune system amounts to a selective pressure allowing only the strongest cells to survive. 😦 A brief article describing this battle can be found on the HHMI website. A more thorough treatment of the subject can be found in a freely available review by my friend Dr. Ezekiel Fuentes-Panana.

Here’s one last animation showing a tumor mass producing metastatic cells that leave the mass and migrate to new locations within the body. I’m not that fond of this video, but it does communicate the message I wanted to get across.

Alltogether, cancer cells are those that no longer obey the rules of polite cellular society and continue to reproduce through unchecked mitosis when such division is not in the best interest of the organism as a whole. One way these cells do this is to cease responding to contact inhibition signals. This results in the production of a tumor mass that will need to obtain energy and will often do so by sending out pro-angiogenic signals resulting in new blood vessel formation. As the tumor continues to grow, it may invade neighboring tissue and ultimately even metastasize into the blood or lymph leading to a number of secondary tumors throughout the body.

 
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Posted by on October 14, 2013 in Uncategorized

 

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