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Posted on Tuesday, Feb 12, 2013

Mesothelioma Research Roundup: Redirecting T Cells

Ricki Lewis, Geneticist

Rick Lewis, science writer with a PhD in genetics, writes about the science of redirecting T Cells.

An ingenious technique that has vanquished leukemia in a handful of patients is also being applied to mesothelioma. The strategy combines parts of the immune system in a way that targets cancer cells.

The New York Times reported two of the leukemia cases. “An Immune System Trained to Kill Cancer” tells the story of the first patient treated, William Ludwig. He was 65 and had chronic lymphocytic leukemia when he enrolled in 2010 in a clinical trial at the Perelman School of Medicine, University of Pennsylvania. Chemotherapy no longer worked, but the experimental treatment did, and he’s still in remission. An article in The New England Journal of Medicine describes the technology.

The second New York Times article, “In Girl’s Last Hope, Altered Immune Cells Beat Leukemia,” is about Emma Whitehead, a 6-year-old who was near death from acute lymphoblastic leukemia in April 2012 – yet by fall was back in school, her hair regrown and energy back.

Chimeric Antigen Receptors from Altered T Cells Destroy Cancer

The researchers took blood from Emma and Mr. Ludwig, separated T cells (a type of lymphocyte, which in turn is a class of white blood cells) and gave the cells segments of genes that encode key immune system proteins that extend from the membranes of the cells. One gene bit produces part of a T cell receptor; the other produces part of an antibody. About a billion of the doctored cells were then infused into the patients.

The engineered protein that juts from the altered T cells, called a chimeric antigen receptor (CAR), finds and binds a molecule called CD19, which is more abundant on the cancer cells that were in Emma and Mr. Ludwig. Like a flare revealing a military target, bound CAR attracted other components of the immune system to destroy the cancer cells.

The researchers send the DNA encoding the CARs into the T cells as part of a disabled form of HIV, which can carry a large payload and naturally goes to T cells. The approach is a form of gene therapy, and the HIV (aka “lentivirus”) is the vector that delivers the genes. Dr. Zelig Eshhar, at the Weizmann Institute of Science, came up with the CAR idea in the 1980s. Ironically, the approach of using disabled HIV to deliver a CAR is also being used, so far after more than a decade successfully, to treat HIV.

That’s a lot of jargon, so here’s a primer.

The human immune system is a mobile army of about 2 trillion cells, the biochemicals they release, and the organs where these components are made and stored. T and B cells are white blood cells called lymphocytes. T cells secrete proteins called cytokines (which make us sick when we get the flu) that have general effects in cell-cell signaling, and B cells secrete antibody proteins, which are more specific. Antibodies have parts that fit molecules on the surfaces of pathogens. That’s how they protect us from infectious disease.

In the case of cancer, antibodies can bind molecules on cell surfaces and call in other immune chemicals to neutralize cells that have too many of a particular molecule. (A molecule or part of one that evokes an immune response is called an antigen. Many antigens protrude from cell membranes.) Many cancer cells are festooned with specific antigens that are less common on healthy cells. Prostate-specific antigen (PSA) is an example of a tumor antigen that is also on healthy cells, and so low levels are normal.

Modified T Cells in the Treatment of Mesothelioma

The approach of redesigning T cells is both specific yet versatile, like the immune system itself. “We have a platform now. We can swap out the antibody domain for any antibody directed against any tumor antigen,” says Bruce Levine, PhD, Associate Professor of Pathology and Laboratory Medicine at the Abramson Cancer Center of the University of Pennsylvania, and part of the team that treated Emma. The treatment is individualized because each patient has his or her T cells modified, although it could use donor cells. Many research groups are using the approach, and the first clinical trials, in 2006, reported testing in ovarian and kidney cancer.

The technique doesn’t yet have a catchy name that I’m aware of. An editorial in the New England Journal of Medicine calls it “Redirecting T Cells” and The New York Times calls it “reprogramming the patient’s immune system.” (I dislike the negative connotations of “engineering” when it follows “genetic,” no offense to engineers.)

The clinical trial to treat mesothelioma doesn’t use HIV like in the leukemia trial, but sends in the genetic information as an RNA molecule. The RNA is short-lived, giving the researchers a window to assess toxicity without causing permanent harm should something go wrong. And instead of CAR, it’s called a chimeric immune receptor (CIR).

The doctored T cells are directed against mesothelin, a protein that is sparse on normal cells lining the lungs, abdominal cavity, and heart. But certain cancer cells – mesothelioma and ovarian and pancreatic adenocarcinomas – have excess mesothelin emerging from their surfaces like flags. The idea is that T cells led to the mesothelioma cells will attract an immune response. The phase 1 clinical trial is recruiting patients.

Novartis and Penn Medicine Partnership

Engineering T cells to fight cancer is so promising that Novartis is building a $20 million center at Penn to pursue the technology. A recent paper discusses another approach using RNA interference and/or microRNAS to “silence” mesothelin on cancer cells.

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Ricki Lewis is a PhD, geneticist and author. She received her PhD in genetics from Indiana University. Her ninth book, The Forever Fix: Gene Therapy and the Boy Who Saved It, narrative nonfiction, was just published by St. Martin’s Press.  Ricki’s blog for the Public Library of Science is at DNA Science Blog and she tweets at @rickilewis.