ImmYOUnology

More than just vaccines


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Training the immune system to kill cancer

Have you ever heard the term “cancer vaccine?”  Are there really vaccines to prevent cancer, and do they really work? The truth is, it’s kind of a misnomer. The vaccine against herpes papilloma virus (HPV) is often called a cancer vaccine, but it’s actually a vaccine to prevent an infection that can lead to cancer.  In other cases, the term “cancer vaccine” describes a treatment that trains immune cells to attack cancer cells.  There is one FDA-approved vaccine treatment for prostate cancer, but there are ongoing clinical trials for many other types of cancers. 

One recent clinical trial for patients with glioblastoma found that a cancer vaccine approach significantly extended the patients’ lives. Glioblastoma is the most common and most aggressive type of tumor that originates in the brain, and the average survival after treatment is about a year. This vaccine approach tested at Cedars-Sinai Medical Center in LA was so significant is because it gave half of the patients about five years.  The results of the study were reported at a meeting, but the details of the trial and initial findings were published in January.

Researchers collected large numbers of white blood cells (immune cells) from the volunteers through a process called leukapheresis, which separates immune cells and returns red blood cells and other blood components back to the donor.  They were after a rare cell type called monocytes that can morph into different cell types depending on their environment. Monocytes originally come from the bone marrow and remain round and smooth as they roll through the blood. Given the right signals, they can leave the blood for other tissues and change into macrophages or dendritic cells, both rugged spindly cells that poke out tiny arms to sense their environment.  

If you put white blood cells in a culture dish, as the scientists at Cedars-Sinai did,  the monocytes will stick to the bottom of the dish in just a couple of hours. Then you can wash away all of the other cells and keep just the monocytes. After about a week, they will morph on their own into macrophages—cells that eat up pathogens or other dead cells.  But if you add a couple of signaling proteins called cytokines, the monocytes will become dendritic cells.

Dendritic cells also eat up foreign material, but they are somewhat more refined at it. They break down everything that they eat and then present little pieces of it to educate other immune cells about what is going on in the body. T cells are their main pupils, and have receptors that sense what the dendritic cells are displaying.  Then both types of cells can make proteins to attack the foreign material (bacteria, cancer cells, infected cells) and signal other cells to start a cascading immune response.

Our bodies use this process to fight infection and to prevent cancers from developing. But once a tumor is formed, tumor cells are very effective at re-educating T cells and other immune cells.  Tumor cells can make proteins that lull and calm immune cells so that they can’t respond or don’t recognize the tumor cells as foreign. Technically, cancer cells aren’t foreign, but mutated and rebellious.  Proteins displayed on cancer cells can be distorted or can be made in excess, distinguishing them from normal cells.

File:Dendritic cell therapy.png

By Simon Caulton. This file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.

The idea behind cancer vaccines is to prepare dendritic cells outside of the body and put them back in where they can push immune system toward actively attacking tumors. The researchers at Cedars-Sinai coaxed monocytes into becoming active dendritic cells in culture. Then they gave the cells peptides, or pieces of proteins, that resembled the ones made in high abundance on glioblastoma cells.  Years of research went into simply identifying exactly which proteins were overproduced by these cancer cells and which would best activate the dendritic cells.  This study used six peptides to activate and train the dendritic cells.  Then the cells were sent back into the patients near their lymph nodes, which are full of T cells awaiting instructions.

Variations on this method are being tested for breast cancer, melanoma, leukemia and many other cancers. The outcomes will depend on which peptides are used, which peptides are made by each person’s tumor, how well one’s cells grow in culture and respond to activation and other variables. It’s a simple idea—to use the body’s own defenses to fight cancer—but there is a lot more to learn about this fascinating and promising treatment.

Sources:

The National Cancer Institute 

Vaccine promises longer survival for brain tumor patients, Belinda Weber Medical News Today, Nov 2013

Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma, Phuphanich S, Wheeler CJ, et al. Cancer Immunol Immunother. Jan 2013


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Getting a better a picture of human immunology

Most of our organs stay in place.  The immune system is different. It moves, it migrates, it ebbs and flows.  Our immune systems are made up of free agent cells that can go to almost any organ and release proteins and compounds that kill viruses, bacteria and infected cells.  Some of these free agents live in the spleen or the lymph nodes.  Some just troll around in the blood looking for pathogens or signals and will go back to these organs or die if they can’t find anything interesting.

There are two kinds of cells that can live a lot longer; even throughout your lifetime.  They start out as B cells or T cells. (B cells come from the bone marrow originally and T cells from the developing thymus.) B and T cells adapt themselves to specific parts of invading viruses and bacteria, so they’re called “adaptive immune cells.”  Some become memory cells after this adaptation, meaning they can respond with a vengeance if they see the same pathogen coming around a second time.  This is the basis for vaccination.

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Memory cells need a place to live.  Some live in the spleen and some B cells go back to their roots in the bone marrow to live out their days in peace.  It’s been thought that memory T cells just float around in the body as rouge patrollers and quickly arrive at an organ whenever a repeat offender like the flu rears its ugly head.  But recently, Donna Farber and her lab at Columbia University reported that those reacting memory T cells found at a site of re-infection had been there since the first infection.  They were residents of the lungs and they were very different from the memory T cells in the blood and spleen.

The idea makes sense. The most effective and well-adapted T cells are ready to meet the offending virus on its turf, in this case the lungs. This work, like much immunology, was done in mice, which raises the question, What does this mean for humans, or for vaccine development?  Scientists know so much about the “where and when” features of immune responses because we can pull out any mouse organ at any time and look for any type of cell.  We can count them, classify them, collect them and inject them into another mouse.  You name it, it can be done.

Human immunology, for obvious reasons, can’t be done this way.  Most work done on human immune cells is done with blood samples.  So if memory T cells in organs are fundamentally different from those in the blood, as Dr. Farber’s work suggests, we really only have half the picture.  And it may not even be a very accurate half.

Dr. Farber saw that if we mean to understand the human immune system, our methods have to change.  She initiated a collaboration with the New York Organ Donor Network and her lab has been able to process fresh samples from otherwise healthy brain-dead donors to study the true distribution of immune cells in the human body. The group initially described T cells in the lungs, intestines, spleens, lymph nodes and blood of 24 donors.  The study wasn’t important because of any complicated experiments or newly discovered drug targets, but because it lays out groundwork that has never before been possible.

Biopsy tissues from sick patients (often people with immune diseases) have been the mainstay for immunologists doing human work. The subjects in this study were mostly healthy because they were cleared to be organ donors. The care taken with the tissues and the speed with which they were processed allowed Farber and her group to do more than look at the tissues under a microscope; they were able to culture them and test their functionality. The arrangement also meant that this was the first time multiple tissues taken from the same donor at the same time could be used for immunology studies.

Dr. Farber’s work is providing physicians and immunologists with a picture of the steady state immune system that has never before been available.  And collaborations with other immunology specialists will address other subsets of immune cells in the same tissues. Recently, her group demonstrated that memory T cells against flu live in specific niches along the airways of human and mouse lungs.

The author of a commentary on Farber’s work brought up a 16th century physician named Vesalius, the first to promote post-mortem dissection in a time when the prevailing knowledge of human anatomy was based solely on animal dissection.  Even as our understanding of the mouse immune system grows and becomes more complex, there is huge value in stepping back and defining the basics of the human immune system.

Teijaro J.R., Turner D., Pham Q., Wherry E.J., Lefrancois L. & Farber D.L. (2011). Cutting Edge: Tissue-Retentive Lung Memory CD4 T Cells Mediate Optimal Protection to Respiratory Virus Infection, The Journal of Immunology, 187 (11) 5510-5514. DOI:

Sathaliyawala T., Kubota M., Yudanin N., Turner D., Camp P., Thome J.C., Bickham K., Lerner H., Goldstein M. & Sykes M. & (2013). Distribution and Compartmentalization of Human Circulating and Tissue-Resident Memory T Cell Subsets, Immunity, 38 (1) 187-197. DOI: