War on cancer: harnessing the abscopal effect.
Article Type: Report
Subject: Cancer (Risk factors)
Cancer (Care and treatment)
Cancer (Research)
Radiotherapy (Health aspects)
Author: Moss, Ralph W.
Pub Date: 06/01/2008
Publication: Name: Townsend Letter Publisher: The Townsend Letter Group Audience: General; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2008 The Townsend Letter Group ISSN: 1940-5464
Issue: Date: June, 2008 Source Issue: 299
Topic: Event Code: 310 Science & research
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 217848131
Full Text: One of the most fascinating phenomena in cancer therapy is the so-called "abscopal effect." It is sometimes observed as a beneficial side effect of radiation therapy: when doctors irradiate one tumor site, they occasionally also get an unexpected "dividend" in the shrinkage or disappearance of tumors at non-irradiated sites. This phenomenon was first observed more than 50 years ago by Dr. R. H. Mole, of Britain's Medical Research Council. He coined the term "abscopal effect" to describe it. (The word "abscopal" is derived from the Latin prefix ab, meaning "away from," and the Greek word skopos, meaning "target.") CancerWeb has defined an abscopal effect as "a reaction produced following irradiation but occurring outside the zone of actual radiation absorption."

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The abscopal effect is admittedly rare and, in the past, was considered somewhat controversial, since it seemed to fly in the face of common sense. How could radiation, by definition a local treatment, make distant, non-irradiated tumors disappear? However, like spontaneous remissions, which they resemble, abscopal effects have occurred often enough over the years to demonstrate that they are indeed real.

Harnessing the Abscopal Effect Experimentally

What if it were possible to give cancer patients a substance that would actually make the abscopal effect a routine part of treatment? This would change radiation from being a strictly local treatment (i.e., a treatment that only has an effect in the area to which it is directly applied) to a systemic treatment (i.e., a whole-body treatment in which any distant metastases are also beneficially affected even though they are not in the area directly targeted by the treatment).

It appears that scientists in Japan are well on the way to making that happen. A group of ten radiologists at the University of Tokyo, with senior researcher Professor S. Kanegesaki, have induced the abscopal effect in mice by first administering a biologically active protein or "chemokine" called ECI301. EC1301 is an immune-modulating substance, an active variant of Macrophage Inflammatory Protein-1 {alpha}. (Chemokines are complex molecules that activate and attract white blood cells. They are closely involved in inflammatory responses.) ECI stands for "Effector Cell Institute," the company that Dr. Kanegesaki founded after he retired from the University of Tokyo (http://www.effectorcell.co.jp/).

It is not exactly a new finding that immune stimulants can trigger the abscopal effect. Other researchers, such as the surgical pathologist, Sandra Demaria, MD, of New York University, have in the past noted that the effect is mediated by the immune system (Demaria 2004).

But in a February 2008 article in Clinical Cancer Research, Prof. Kanegesaki and his Tokyo colleagues reported on their research, which was designed to show whether giving an intravenous dose of ECI301 after local irradiation could prevent any remaining local, as well as distant, tumors from growing.

Colon cancers were implanted and grown in both flanks of laboratory animals. Tumors on the right side were irradiated. Then ECI301 was injected intravenously daily over a course of three to five consecutive days following local radiation treatment. Tumor volume was measured every three days. In about half of the treated mice, the tumor was completely eradicated, not just at the site of irradiation but at distant sites as well.

EC1301 also worked in other experimental models of cancer besides colon cancer, including sarcomas and lung carcinoma. The researchers' most important finding was that tumor growth at non-irradiated sites was inhibited, which indicated that ECI301 may have enhanced the abscopal effect. The authors concluded that this study, "may offer a new concept for cancer therapy, namely chemokine administration after local irradiation, leading to development of novel therapeutics for the treatment of advanced metastatic cancer" (Shiraishi 2008).

Harnessing the Abscopal Effect in Human Subjects

There has already been at least one attempt to harness the abscopal effect in human patients. This involved combining heat treatment, i.e., hyperthermia, with a type of viral therapy called H101. H101 is a genetically modified adenovirus that, according to the US National Cancer Institute, was approved in 2006 for cancer treatment by the Chinese equivalent of the Food and Drug Administration (Garber 2006).

This research involved five patients in Shanghai, China, each of whom had inoperable and metastatic tumors. Two patients had nasopharyngeal cancers, one had lung cancer, one had a sarcoma, and one had bladder cancer. All these patients had previously failed to respond to conventional chemotherapy and radiotherapy. The patients were given 60 minutes of hyperthermia at 42[degrees]C (107.6[degrees]F) following intratumoral injections of H101 (i.e., the injections were given directly into the tumor). According to the sponsoring company, two of the patients "were cured with complete regressions of both injected and non-injected tumors and have survived for a long period up to date." (The article is only available in Chinese, and the English-language abstract does not indicate how long they survived. It also does not state what kind of heat therapy was given. I have written to the company to find this information.)

The three remaining patients initially responded to this unusual combination but died from their disease at 29, 15, and 13 months, respectively. The authors, led by Hu Fang, MD, the president of the sponsoring company, concluded: "The abscopal anti-tumor effect could be induced by the combination of H101 local intratumoral injection with heating" (Hu 2006). In European CAM clinics, hyperthermia is often combined with other immune-stimulating therapies, such as mistletoe extract injections.

More Intriguing Evidence

Meanwhile, researchers in the US are actively investigating other mechanisms whereby the abscopal effect could potentially be used to enhance cancer treatment. In particular, the p53 gene has become the focus of intense interest in this context.

The p53 gene is known to have a tumor-suppressor function--that is, it exerts a strong regulating influence on cell growth and division. More than 50% of human cancers exhibit mutations or deletions in the p53 gene, resulting in uncontrolled growth. A great deal of research points to the possibility that if p53 can be reactivated, or "switched" back on, tumor growth may be slowed or stopped entirely.

The p53 gene appears to have a crucial role in orchestrating the abscopal effect. A study carried out by researchers from the Radiation Oncology branch of the National Cancer Institute and published in the journal Cancer Research has suggested that the abscopal effect might, in fact, be mediated through p53 (Camphausen 2003).

The paper's authors propose that following radiation, p53 may actively trigger the production of cytokines in the irradiated field and that these cytokines, entering the general blood circulation, exert their effects distantly, leading to the observed abscopal effect. The authors further suggest that radiation may cause the release of substances called angiogenesis inhibitors, whose principal effect is to prevent the formation of new blood vessels--an effect that is also directly controlled by p53.

Role of the Primary Tumor in Controlling Metastases

The fact that a primary tumor is able to exert some form of control over the growth and behavior of distant metastases was first elucidated by the late Judah Folkman, MD, at Harvard University. Folkman showed that removing a primary tumor could sometimes "awaken" and trigger the growth of dormant distant metastases. He proposed that the primary tumor actively secretes angiogenesis inhibitors that operate as a brake on distant tumor growth, and that removing the primary tumor can diminish this natural form of tumor inhibition.

Other researchers in Folkman's laboratory, notably Michael Retsky, PhD, and Romano Demicheli, MD, have demonstrated convincingly that the primary tumor exerts a strong growth-retarding influence over the growth of distant metastases and that angiogenesis inhibition plays a pivotal role in this process. Their work in the field of breast cancer has produced some particularly intriguing results. In research published in 2004 in the journal Breast Cancer Research, Retsky and colleagues suggested that it might be of great benefit, particularly to younger (premenopausal) breast cancer patients if they were given intensive antiangiogenic therapy at the time of the surgical removal of their primary tumor (Retsky 2004).

The link between angiogenesis inhibition and the growth of metastases has been further explored by (among others) University of Chicago scientists, who have shown that when laboratory animals with tumors are given angiogenesis inhibitors at the same time as radiation, both local and distant tumor control is improved (Gorski 2003).

The notion that the primary tumor acts in effect like a "mother ship," exerting an abscopal influence over its distant "satellites" (metastases), has profound therapeutic implications. It is exciting that scientists are once again actively pursuing this promising field of research. I hope that someday soon it will be possible to improve the outcome and reduce the toxicity of cancer treatments such as radiation therapy by making use of the once-mysterious abscopal effect--an encouraging example of science harnessing and working in harmony with the body's own intrinsic wisdom.

References

Camphausen K, Moses MA, Menard C, et al. Radiation abscopal antitumor effect is mediated through p53. Cancer Research. 2003;63(8):1990-3.

Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, Formenti SC. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radial Oncol Biol Phys. 2004;58:862-870.

Retsky M, Bonadonna G, Demicheli R, el al. Hypothesis: Induced angiogenesis after surgery in premenopausal node-positive breast Cancer patients is a major underlying reason why adjuvant chemotherapy works particularly well for those patients. Breast Cancer Res. 2004;6(4):R372-4.

Garber K. China approves world's first oncolytic virus therapy for cancer treatment. JNCI. 2006;98:298-300.

Gorski DH, Mauceri HJ, Salloum RM, et al. Prolonged treatment with angiostatin reduces metastatic burden during radiation therapy. Cancer Res. 2003;63(2):308-11.

Hu F, Hu XH, Yu P, Zhang JX, Lou GG, Liu HL, Wu B, Zhao RH, Xia HQ, Wang Y, Chen J, Ben Y, Chen SY. [Abscopal effect on metastatic tumor induced by oncolytic virus of H101 combining with local heating]. Ai Zheng. 2006;25:919-24 [Chinese].

Shiraishi K, Ishiwata Y, Nakagawa K, Yokochi S, Taruki C, Akuta T, Ohtomo K, Matsushima K, Tamatani T, Kanegasaki S. Enhancement of Antitumor Radiation Efficacy and Consistent Induction of the Abscopal Effect in Mice by ECI301, an Active Variant of Macrophage Inflammatory Protein-1 {alpha}. Clin Cancer Res. 2008;14:1159-1166.

by Ralph W. Moss, PhD

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