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Tumor-Cell Death, Autophagy, and Immunity
By gdpawel at 2012-03-24 12:44
Tumor-Cell Death, Autophagy, and Immunity

A new finding in basic science should trigger a "change in thinking" about how cancer drugs might be developed and tested for maximum effectiveness, says Louis M. Weiner, M.D., director of the Georgetown Lombardi Comprehensive Cancer Center, in a "Clinical Implications of Basic Research" article titled Tumor-Cell Death, Autophagy, and Immunity published in the March 22, 2012 issue of the New England Journal of Medicine (NEJM).

An internationally known expert in immunotherapy research, Weiner was invited, along with Michael T. Lotze, M.D. from the University of Pittsburgh Cancer Institute, by NEJM editors to write an analysis of anticancer immune responses based on a recent report published in the journal Cell (Dec.16, 2011.)

The emerging science described in the cell report reveals how some dying cancer cells may trigger a lasting anti-cancer immune response that can prevent cancer relapses and improve the benefits of treatments. "This is a really exciting development, because we know that manipulating the body's immune system has proven to be the most powerful way to cure advanced cancer that cannot be cured by surgery or radiation treatments," Weiner says. "We now know that how cancer cells die matters, and so we should strive to manipulate that death in a way that primes the body to destroy any cancer that returns," he says. "This might vastly improve cancer care."

The recent Cell study, conducted primarily by researchers in France, focused on autophagy, which means, literally, "self eating."When cells die, the body cleans up the debris by using special cells that ingest and process the cell's component parts so that they can be recycled and used again. During this process, these parts are revealed so that roving protective cells of the immune system can determine if what was inside the cell was potentially harmful. If deemed dangerous, the immune system goes on permanent watch for these molecules so that they can be destroyed.

Cancer cells can die in several ways, Weiner says. One is a natural process called apoptosis, or programmed cell death, which is a way that the body keeps the cells growing within an organ or body in check. "This is a normal process, so the immune system ignores those cells," Weiner says. Many cancer drugs are designed to promote apoptosis.

The other way is autophagy, which can occur when cancer cells are distressed or under attack from toxic agents. Autophagy, which literally means "self-eating," involves the digestion of some parts of a cell to create energy and keep that cell alive. This process triggers the immune system to recognize the cells as a foreign invader that should be destroyed.

What hadn't been known until the Cell study was how the body's immune cells "see" cancer cells as foreign during autophagy – what is it within the cancerous cell that alerts those fighters to be on patrol for development of new cancer cells? "Cancer cells are derived from normal human cells, so something unusual alerts the immune system during autophagy," Weiner says.

In the Cell study, the French researchers discovered that when cancer cells are dying via autophagy, it is the release of energy in the cancer cell, in the form of the chemical ATP, that alerts immune cells to the existence of a big problem. This ATP activates toll-like immune cell receptors, which are a very primitive group of proteins that play a key role in the innate immune system by acting as alarms. (It is important to note that the two scientists who discovered the toll-like immune cell receptors shared the 2011 Nobel Prize in Medicine or Physiology).

The implication for cancer care, then, is to "look at how different drugs kill cancer, and find those that result in autophagy," he says. Additionally, drugs could be designed that force cancer cells to produce ATP when they are sick and dying, Weiner says. "That way, the immune system is primed to attack cancer that recurs."

In order for this strategy to be effective, researchers will have to develop ways to measure how effectively cancer drugs promote autophagy, he says. "So instead of looking at how many cancer cells a drug can kill, we should think about developing drugs that help cells die the way we want them to die," Weiner says. Still, there is a lot of work to do, Weiner says. "No tools exist today to measure which chemotherapy agent or combinations act by stimulating the immune system to control cancers."

Progress in this area will require a "change in thinking.""For many years, it has been thought that chemotherapy damages the immune system, lowering the levels of white blood cells that can fight invaders," he says. "But now researchers are beginning to realize that certain types of chemotherapy and other biologic and targeted treatments may be stimulating a powerful immune response.

"No doubt modern chemotherapeutic and targeted therapy have a powerful impact on the well-being of people with cancer," Weiner says. "But it is also true that we have a long way to go, and this new potential strategy is truly exciting."

Georgetown University Medical Center http://www.nejm.org/doi/full/10.1056/NEJMcibr1114526?query=TOC&



7 comments | 10106 reads

by gdpawel on Sun, 2012-03-25 04:13
Cells have their own recycling system: discarded cellular components, from individual proteins through to whole cellular organs, are degraded and the building blocks re-used in a different place. The scientific term for this recycling process is autophagy. In severely damaged cells, autophagy can also be a form of programmed cell death.

In this case, the cell uses the mechanism for complete self-decomposition. It is assumed that highly aggressive cancer cells use autophagy to resist tumor therapy. Investigations are leading to whether blocking the recycling system (autophagy) might be useful to support anti-cancer therapies. They are bascially rediscovering something reported 20 years ago (JNCI, 83:37-42, 1991).

This study had lead to the focus on the human tumor primary culture microspheroid (microclusters) platform. The functional profiling platform studies cancer response to drugs from actual human microspheroids (tumor microenvironment), enabling it to provide clinically relevant predictions to individual cancer patients.

This is why the functional profiling platform has recognized interplay between cells, stroma, fibroblasts, vascular elements, cytokines, macrophages, lymphocytes and other extracellular material like autophagy. This had lead to the focus on the human tumor primary culture microspheroid (microclusters), which contains all of these elements.

The functional profiling platform studies cancer response to drugs (from actual human microspheroids), within this microenvironment, enabling it to provide clinically relevant predictions to individual cancer patients. It is their capacity to study "human" tumor microenvironments that distinguishes it from other platforms in the field.

"No tools exist today to measure which chemotherapy agent or combinations act by stimulating the immune system to control cancers?" Dr. Larry Weisenthal, of the Weisenthal Cancer Group, had reported on a tumor immunotherapy study back in the early 90's. It was a concept of in situ cancer vaccination based upon studies of biologic response modifiers in an assay.

Preliminary results found a striking association between the activity of biologic response modifiers which activate macrophages and the prior treatment status of patients with breast and ovarian cancers. Effective chemotherapy produced a massive release and processing of tumor antigens, which led to a state in which the human immune system, via in situ cancer vaccination, responded to exogenous macrophage activation signals with potent and specific anti-tumor effects.

Because all research was prematurely abandon back then, Dr. Weisenthal had to refocus gears and today has brought us the latest technology called Functional Tumor Cell Profiling (recently known as Personalized Cancer Cytometrics). However, one of the themes at the 2012 American Association for Cancer Research (AACR) meeting held in Chicago was the growing development of meaningfully effective immune therapies. There was evidence of a renewed interest in tissue cultures as the best platform to study drug effects and interactions.

Literature Citation:

Weisenthal LM, Dill PL, Pearson FC (1991) Effect of prior cancer chemotherapy on human tumor-specific cytotoxicity in vitro in response to immunopotentiating biologic response modifiers. J Natl Cancer Inst 83: 37-42

Weisenthal LM (1991) Effect of prior chemotherapy on biologic response modifier activity. J Natl Cancer Inst 83: 790-791

Windbichler GH, Hausmaninger H, Stummvoll W, Graf AH, et al. (2000) Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase 3 trial. Br J Cancer 82:1138-1144, 2000.

[url]http://jnci.oxfordjournals.org/content/83/1/37.short
[url]http://www.wipo.int/patentscope/search/en/WO1989003995
[url]http://www.google.com/patents?hl=en&lr=&vid=USPAT4996145&id=waMaAAAAEBAJ &oi=fnd&printsec=abstract#v=onepage&q&f=false
[url]http://www.google.com/patents?hl=en&lr=&vid=USPAT5149527&id=vO4fAAAAEBAJ &oi=fnd&dq=weisenthal+immune&printsec=abstract# v=o nepage&q=weisenthal%20immune&f=false

by gdpawel on Fri, 2012-03-30 00:59
Larry Weisenthal, M.D., PhD.
Medical and Lab Director
Weisenthal Cancer Group; Huntington Beach, CA

Clinical trials are warranted to test macrophage-activating biologic response modifiers administered following chemotherapy of ovarian and breast cancers. This is based on (1) striking in vitro findings in fresh human tumor cell culture assays, (2) supportive data from pilot clinical trials, and (3) a sound mechanistic rationale. I would advocate sequential administration of (1) assay-directed chemotherapy, (2) "non-specific" immunotherapy (e.g. antigens derived from bacteria), and (3) more "specific" cytokine therapy (e.g. interferon gamma).

In 1991, my colleagues and I published a study (1,2) in the Journal of the National Cancer Institute which I hoped would receive scrutiny and follow-up. This was a tumor immunology study which grew out of a contract research project. Continuing this research was at the time not an option, as my priorities were to establish a clinical laboratory to provide cell culture drug resistance testing.

In the 1991 study, we presented the concept of "in situ vaccination," based upon our studies of biologic response modifiers in the DISC assay. We found that there was a striking association between the activity of biologic response modifiers which activate macrophages and the prior treatment status of patients with breast and ovarian cancers. Color photomicrographs illustrating method.

[url]http://weisenthal.org/jnci83_38_91f1.jpg

The following agents were dramatically more active in fresh tumor specimens from previously-treated breast and ovarian cancer patients than against specimens from untreated patients:

1. ImuVert (a potent macrophage activator derived from Serratia marcescens)
2. Interferon gamma, and
3. Tumor necrosis factor

This greater activity in specimens from treated versus non-treated patients was not observed in adenocarcinomas known to be relatively resistant to chemotherapy (colon cancer, non-small cell lung cancer, etc.). Graphs showing representative results.

[url]http://weisenthal.org/jnci83_39_91.jpg

This differential activity was also not observed in agents which are not potent macrophage activators (interleukin-2 and interferon alpha).

Based on these findings (and supported by anecdotal studies in the clinical trials literature), we proposed that effective chemotherapy produces massive release and processing of tumor antigens, which leads to a state in which the human immune system is primed (via "in situ vaccination") to respond to exogenous macrophage-activation signals with potent, specific antitumor effects.

In the above-quoted study (1), I reviewed a diverse clinical trials literature which supported this concept. More recently published was a randomized trial in previously untreated ovarian cancer (3) , in which cisplatin/cyclophosphamide was compared to the same chemotherapy plus interferon gamma, administered subcutaneously three times a week, every other week, for the duration of chemotherapy (6 plannned treatment cycles). The study was prematurely closed because chemotherapy standard treatment had changed from platinum/cyclophosphamide to platinum/Taxol, but, even with the low power of the small numbers of patients accrued to show a difference, there was a significant advantage to combined treatment in progression-free survival and a soft trend for improved overall survival. The authors quoted our earlier work1 in providing a mechanism for their positive results and called for follow-up clinical trials. Progression-free survival curves.

[url]http://weisenthal.org/bjc82_1138_00.jpg

As noted above, my preferred trial design would be (1) first complete (preferably assay-directed) chemotherapy, then (2) administer non-specific immunotherapy to responders, then (3) provide more specific cytokine therapy, e.g. interferon gamma.

Literature Citation:

1. Weisenthal LM, Dill PL, Pearson FC (1991) Effect of prior cancer chemotherapy on human tumor-specific cytotoxicity in vitro in response to immunopotentiating biologic response modifiers. J Natl Cancer Inst 83: 37-42

2. Weisenthal LM (1991) Effect of prior chemotherapy on biologic response modifier activity. J Natl Cancer Inst 83: 790-791

3. Windbichler GH, Hausmaninger H, Stummvoll W, Graf AH, et al. (2000) Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase 3 trial. Br J Cancer 82:1138-1144, 2000.

Method for detecting immune-mediated cytotoxicity

ABSTRACT

A method for detecting the sensitivity of tumor cells to immune effector substances by using an assay that distinguishes living tumor cells from dead cells in mixed populations of cells. Acquired resistance to immune effectors used in therapy may be determined and used to identify methods to circumvent such resistance using the method.

[url]http://www.google.com/patents/US4996145

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