The controversial abscopal effect

CANCER TREATMENT REVIEWS (2005) 31, 159–172

www.elsevierhealth.com/journals/ctrv

CONTROVERSY

The controversial abscopal effect Joseph M. Kaminski a,b,c, Eric Shinohara a, James Bradley Summers Kenneth J. Niermann b, Allan Morimoto e, Jeffrey Brousal a

d,*

,

a

Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, USA Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA c Department of Radiology, Medical College of Georgia, Augusta, GA, USA d Department of Diagnostic Radiology, University of South Alabama, P.O. Box 16343, Mobile, AL 36616, USA e Department of Radiology, University of Utah, USA b

KEYWORDS

Summary The abscopal effect is potentially important for tumor control and is mediated through cytokines and/or the immune system, mainly cell-mediated immunity. It results from loss of growth stimulatory and/or immunosuppressive factors from the tumor. Until recently, the abscopal effect referred to the distant effects seen after local radiation therapy. However, the term should now be used interchangeably with distant bystander effect. Through analysis of distant bystander effects of other local therapies, we discuss the poorly understood and researched radiation-induced abscopal effect. Although the abscopal effect has been described in various malignancies, it is a rarely recognized clinical event. The abscopal effect is still extremely controversial with known data that both support and refute the concept. c 2005 Elsevier Ltd. All rights reserved.

Cancer; Distant bystander; Surgery; Radiation; Immune system




Introduction A potentially important but poorly understood method of tumor control is the abscopal effect.

* Corresponding author. Tel.: +1 251 639 3431; fax: +1 251 471 7882. E-mail address: [email protected] (J.B. Summers).




In 1953, R.H. Mole proposed the term ‘‘abscopal’’ which is derived from the Latin prefix ab- ‘‘position away from’’ and –scopos ‘‘mark or target for shooting at.’’ Abscopal effect was defined as an action at a distance from the irradiated volume but within the same organism. He emphasized that all cells in the body are interdependent and that damage to one cell affects the organism as a whole. Therefore, radiating one part of the body

0305-7372/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2005.03.004

160 would have an effect on all other aspects of the body. He then asked the questions, ‘‘How much of this abscopal effect occurs and how is it produced?’’ This paper will review the current body of knowledge about the abscopal effect and attempt to answer these fundamental questions posed by R.H. Mole more than 50 years ago.1 The abscopal effect apparently operates through mechanisms that are paralleled in gene therapy, local immunotherapy, hyperthermia, and post-surgical distant bystander effects. Recently, the definition of the abscopal effect has been broadened to include other forms of local therapy that have systemic effects, i.e., a distant bystander effect.2,3 Whether or not the definition should be extended to include other local therapies that have a distant effect is a matter of debate. However, to unravel the radiation abscopal effect, we feel it prudent to evaluate other directed therapies that are associated with systemic effects. Since the literal meaning is the same for abscopal and distant bystander, the terms should be used interchangeably to refer to any local therapy with a distant impact. Some clinicians underestimate the benefits of treatment if a clinically apparent response does not occur. However, many potential treatments may only have unrecognized cytostatic responses, and possibly only with certain malignant cells that constitute a portion of the malignancy. Furthermore, malignancies in various individuals are heterogeneous, and one form of treatment may have a detrimental or no net effect if we look only at the population as a whole. However, as we begin to understand and evaluate the population and intratumoral genetic variability of each malignancy through molecular ‘‘fingerprinting’’ and its host interactions, we will continue to realize that certain sub-populations do benefit from some treatments that might appear to have a poor effect on the whole treatment population. Furthermore, it has been shown that tumor-bearing hosts have impaired dendritic cell activity, because the abscopal effect may be immune mediated in many circumstances, that may lessen its clinical manifestation.4–6 Therefore, treatments aimed at stimulating the immune system may be warranted. Even though the abscopal effect is infrequently apparent after radiation therapy, one possible explanation is that it is a clinically under-recognized and under-reported phenomena. Through tailoring therapy to the patient’s specific malignancy characteristics, one may be able to harness the full potential of many therapies that would be discarded by today’s standards.

J.M. Kaminski et al.

Background Abscopal reactions are erroneously claimed to occur most frequently in lymphomas followed by various other malignancies, possibly because the mechanisms have not generally been elucidated in these malignancies.7–15 For example, an abscopal effect frequently occurs when the ovaries are irradiated or when an orchiectomy is performed for prostate cancer. In 1889, Schinzinger was possibly the first to suggest that an oophorectomy might treat breast cancer.16 However, it was George Beatson who was the first to publish a case report of a woman who underwent an oophorectomy for a recurrent advanced breast cancer.17 The woman exhibited a complete clinical response by the 8-month followup. Ovarian irradiation was first used for ovarian ablation in the 1920s in pre-menopausal women.18 However, the reduction of serum estrogen to post-menopausal levels is delayed, frequently incomplete or reversible, and dependent upon age, dose, and dosing schedule. Adrenalectomy19 and hypophysectomy were later utilized as treatment for breast cancer in post-menopausal women but have fallen out of favor along with oophorectomy in pre-menopausal women in lieu of hormonal therapy to suppress adrenal function (i.e., aromatase inhibitors), hypothalamic function (i.e., LHRH agonists), and estrogen receptor blockers (e.g., tamoxifen). Huggins and Hodges first proposed and tested orchiectomy for the treatment of prostate cancer. 20 Even though this practice has generally been replaced by hormonal therapy, orchiectomy is still considered a standard, and much less expensive, treatment for metastatic or high-risk prostate cancer. Radiation has never been considered acceptable due to the increased tolerance of Leydig cells, the potential side-effects of radiation therapy, and the simplicity of other treatments such as orchiectomy. The benefits of nephrectomy in patients with metastatic renal cell carcinoma have been debated for several decades.21 A recent randomized study by Flanigen et al. demonstrated a significantly longer survival interval in those who underwent nephrectomy followed by interferon therapy rather than patients receiving interferon alone, although measurable responses occurred infrequently in both groups.22 A few hypotheses possibly account for this finding (i.e., cytoreduction through removal of the primary cancer, altered immune responses, and/ or decreased production of cytokines) and will be discussed in further detail below.

The controversial abscopal effect Abscopal effects have been well documented in normal tissue.23–28 Distant effects can certainly be seen after head and neck radiation or thyroidectomy due to hypothyroidism if not appropriately addressed; or potential distant effects from orchiectomy or ovarian ablation resulting from decreased testosterone or estrogen after local therapies, respectively. We have known for over a century that local therapies have distant effects. The following discussion is not to belabor well-known phenomena but to explore abscopal effects that occur in the treatment of cancer where the mechanisms have not been fully described. From understanding well-established abscopal mechanisms and those that will be uncovered, therapeutic strategies can be developed for a variety of malignancies, including melanoma, renal cell cancer, prostate cancer, lymphoma, among others. And, although these distant effects may not always be apparent, they are likely to occur in all treated organisms to some extent. Elucidating the mechanisms of the abscopal effect could enable the development of effective benign treatment approaches to address metastatic disease.

Abscopal mechanisms A few major mechanistic categories have been proposed to account for the abscopal effect: immune system, cytokines (eliciting augmented tumor surveillance, tumor growth inhibition, and tumoricidal effects), and the pseudo-abscopal effect. This latter effect is relevant mainly to lymphomas and suggests that the distant effect observed is due to the circulation of lymphocytes through the field at the time of radiation. The distant bystander effect as it relates to the immune system is dependent on released cytokines in the local milieu that incite local and distant responses. Certain cytokines (e.g., angiogenesis inhibitors) have been described recently that affect distant tumor growth independent of the immune system. Elevated interleukin (IL)-6 serum levels and overexpression of the IL-6 receptor (IL-6R) have been associated with multiple types of malignancies and are frequently correlated with grade and stage of the tumor.29 IL-6 is an endogenous pyrogen and increases the serum levels of acute phase proteins, including C-reactive protein (CRP), by the liver.30–33 For example, IL-6 is expressed in most renal cell carcinomas and is necessary for proliferation.34–36 IL-6 produced in sufficient quantities by the primary tumor, acts as a growth stimulatory

161 cytokine on itself and distant metastatic sites, while also increasing tumor protective factors, e.g., superoxide dismutase.37 Therefore, removal of the primary cancer may slow tumor growth at distant sites and also induce cancer cell death (e.g., through apoptosis), thereby accounting for the infrequently identified abscopal effect seen after nephrectomy or percutaneous radiofrequency ablation.38 Additionally, IL-6 increases the expression of glutathione S-transferase; treating cells with anti-IL-6 or anti-IL-6R antibodies downregulates the glutathione S-transferase, thereby overcoming the normal cisplatin-resistant renal carcinoma cells.37 Blay and colleagues reported that higher pretreatment IL-6 and CRP levels in renal cell carcinoma are associated with a diminished response to cytokine therapy and poorer survival. Survival appeared better in those patients that had elevated CRP which decreased to normal levels after nephrectomy compared to those whose CRP did not decrease to normal. For those whose pre-treatment CRP was within normal limits, there was no difference in survival between those who did or did not undergo nephrectomy.33 Fujikawa et al. proposed that an IL-6 induced inflammatory response may inhibit the immune antitumor response. They proposed the following mechanism: in the setting of metastatic renal cell carcinoma and a primary tumor predominantly expressing IL-6, an associated drop in CRP following nephrectomy appears to curb the inflammatory response while simultaneously inducing immune activation.39 IL-1a (i.e, the secreted form) and IL-b, important inflammatory cytokines, are frequently expressed in a variety of cancer cell lines derived from carcinomas of the stomach, lung, ovary, breast, epithelium, and pancreas.40–47 IL-1a has been shown to augment metastasis of some cancers48,49 by increasing the expression of both adhesion molecules on vascular endothelial cells50,51 and proteases from tumor cell lines in vitro.52,53 Additionally, IL-1a concentrations have been reported to correlate with thymidine phosphorylase expression in both gastric and colon cancers.54,55 Tomimatsu and colleagues showed that patients undergoing curative resection for gastric carcinoma had a significantly higher incidence of liver metastasis when the primary tumors expressed IL-1a.56 Furthermore, these interleukins induce cyclooxygenase-2 (COX-2), which is frequently elevated in cancer.57–61 COX-2 derived prostaglandins participate in inflammation, immune response suppression, apoptosis inhibition, angiogenesis, carcinogenesis, tumor cell invasion, and metastasis.62

162 The loss of major histocompatibility complex (MHC) class I molecules allows tumors to escape recognition and destruction by cytotoxic T-cells.63 Thereby, natural killer (NK) cells lyse tumor cells that are MHC class I deficient, but they also require the expression of appropriate ligands on the target cell.64 However, this is an oversimplified model, and frequently different types of MHC class I deficient tumor immune escape variants exist within a specific tumor.63 These tumors are able to survive through various mechanisms; for example, aberrant expression of atypical MHC class I molecules (e.g., HLA-G). 65,66 Regardless, though, NK cells serve an important, early preventative role in the innate immunity to tumor proliferation. And a decline in NK cell function is associated with malignant proliferation, recurrence, and an increase risk of cause-specific mortality.67–71 Immunosuppressive acidic protein (IAP) is an acute phase reactant that exerts various immunosuppressive effects, e.g., suppression of NK cell activity, and is frequently increased in patients with inflammation and cancer.72–77 Ikuta and colleagues demonstrated a positive correlation between IL-6 and IAP levels.73 Furthermore, elevated levels of IL-6 and IAP have been associated with paraneoplastic syndromes, characterized by fever, elevated acute phase proteins (e.g., CRP), anemia, thromobocytosis, impaired immunity, and/or decreased serum albumin.73,78–80 Fujikawa and colleagues demonstrated that nephrectomy for renal cell carcinoma in patients with an elevated pretreatment serum CRP P1 ng/ml resulted in improved NK cell activity and decreased IAP. In those with a CRP 61 ng/ml, nephrectomy appeared to have little effect. CRP appears to be a marker for proliferative and immunosuppressive factors, such as IL-6, that are produced by the tumor. Thus, decreasing these tumor-based factors through nephrectomy may outweigh the effects of tumor proliferative factors that result from surgical manipulation perioperatively. Although cell-mediated immunity may fail to eradicate the primary tumor, it can frequently eliminate minimal residual disease. The cells that make up a tumor are heterogeneous and exist in a symbiotic state with each other. Thus, migrating or early colonizing tumor cells are theoretically more susceptible to elimination because they are outside the protective milieu of the primary tumor, and the levels of tumor-derived immunosuppressive cytokines are lower. The early metastasizing tumor cells are also greatly outnumbered by immune cells (e.g., NK cells), and escape mechanisms that are beneficial within the primary tumor may be detrimental for the metastatic cells (e.g.,

J.M. Kaminski et al. downregulation of MHC-1). Additionally, these tumor cells may depend upon cytokines that are produced by the tumor. Thus, suppression of the immune system contributes to the higher rates of metastasis. In addition to the specific cytokines mentioned above, a more general explanation of the mechanism of the abscopal effect may be the ‘‘danger’’ model of immunity originally proposed by Matzinger in 1994. 81,82 Matzinger postulates that the immune system rather than differentiating self from non-self, responds to ‘‘danger signals’’ which occur in response to tissue damage. Apoptosis and necrosis induced by environmental stress or pathogens can induce a milieu which elicits a ‘‘danger signal’’. T-cell activation in this hypothesis is based on three rules. The first rule is that T-cell activation requires binding of a peptide/MHC complex to the T-cell receptor and co-stimulation from an antigen presenting cell (APC). If T-cells receive only the peptide/MHC stimulation alone, they will die. Second, only APC are able to activate virgin T-cells. Third, once activated, T-cells are able to function with peptide/MHC stimulation alone, for a limited time, after which they die or return to a resting state at which time they must be activated again. Hence, during an inflammatory response to a viral infection, T-cells against self and viral proteins are made and once the infection is cleared, T-cells against virus move into circulation as T-memory cells. The T-memory cells against normal tissue from the area of inflammation circulate, encounter normal tissue, now without APC stimulation and die. By this theory, radiation may induce an inflammatory response locally, inducing T-cell activation against tumor antigens, which then circulate and may be responsible for the abscopal effects seen during radiation therapy. Of note a recent publication by Demaria et al. has shown that the abscopal effect induced in tumors treated with radiation appears to be immune mediated and it appears that T-cells are required for the distant effects.83 Cytotoxic T-cells have been shown to target tumor cells with great specificity and recent studies have tried to harness this by targeting antigens to dendritic cells.84,85 However, cancer poses a problem due to tolerance, which can be due to several factors. Part of the problem is that while some antigens are cancer specific such as bcr-abl or virus-derived, such as those related to HPV, the majority of cancer antigens are the same as those expressed on normal tissues, or slightly modified mutants.86 In addition to or perhaps because of this, cancer cells are often unable to activate naı¨ve T-cells independently because they lack costimula-

The controversial abscopal effect tory molecules.87,88 Furthermore, even when an immune response is induced there can be autoimmune effects as shown by patients with malignant melanoma who have been treated with melanosome-derived peptides developing vitiligo.89 Radiation may be an important way to enhance tumor immunogenicity by inducing an inflammatory response in tumor tissue leading to activation of the immune system. Activation of the immune system in response to radiation has been shown to happen in two ways. Radiation induces cell apoptosis and necrosis, and it has been shown that necrotic and apoptotic cells can induce a dendritic cell mediated antitumor immunity in vitro and in vivo.90–93 It has been suggested that this cell death leads to release of inflammatory cytokines which may be responsible for the abscopal effect after radiation therapy.94–96 It has been proposed that the direct effects of radiation are on tumor blood vessels or radiation induces increases in cytokine release which may cause increased permeability of tumor blood vessels leading to greater access for dendritic and T-cells to the tumor.97,98 The second mechanism by which radiation may induce an immune response is by causing radiation induced antigens to be expressed. Radiation has been shown to induce the expression of several proteins, including Death receptors (CD95), MHC class I expression, carcino-embryonic antigen, and a variety of adhesion molecules, such as ICAM-1.99–101 Recently, there have been studies by Brousal et al. attempting to target the increased expression of adhesion molecules using scFV. Both of these mechanisms are likely responsible for creating an inflammatory milieu in response to radiation. The equivalency of radiation or chemoradiation in the treatment of several malignancies, e.g., prostate and esophageal, respectively, compared to surgery may in part depend upon an abscopal mechanism. Radiation, with the probable exception of hematological malignancies, generally works through mitotic cell death; consequently, a gradual decline of the PSA level is seen over 2–3 years following treatment in those who are cured of their prostate cancer, unlike surgery where the nadir is achieved within two months and should be undetectable thereafter. Surgical treatment failures result from several possible mechanisms, including incomplete surgical excision, occult metastases, potential seeding from surgical manipulation,102–104 suppression of immunity due to surgical stress, decrease in antiangiogenic factors released by the tumor, and/or the release of growth factors (e.g., epidermal growth factor and transforming growth factor-b) necessary for wound healing that may also facilitate tumor prolifera-

163 tion.104 The extent of tissue damage, blood loss, transfusions, anesthetics (i.e., thiopental), hypothermia, pain, and/or anxiety that occur perioperatively result in a mainly cell-mediated immunosuppressive state.105,106 For example, in a mouse model, open cecectomy was associated with significantly more lung metastases than the control (i.e., anesthesia alone) or laparoscopic-assisted cecectomy. The authors proposed that surgery-related immune suppression or post-surgical tumor cell stimulation may account for this effect.107 Page and colleagues also demonstrated in a mouse model that surgery resulted in a 2–3.5-fold increase in lung tumor retention, and that indomethacin significantly reduced the tumor-promoting effects of surgery through restoration of NK cell activity and/or reduction of IL-6.108 And not infrequently, patients develop symptoms related to distant metastatic disease following surgery for other causes. For example, a 79-year old female, with a history of early stage breast cancer and a 21-year recurrence free interval, underwent bilateral knee arthroplasty. A couple of weeks after her orthopaedic surgery, she developed systemic symptoms, including fever, anorexia, and increasing back pain. A work-up revealed widely metastatic breast cancer consistent with her prior breast cancer pathology without evidence of a new primary breast cancer. This and other clinical examples support a belief that perioperative immunosuppression can increase the risk of metastatic disease or result in a ‘‘reawakening’’ of already-established distant metastases. Circulating cancer cells are frequently found, and the number or frequency of detection has been shown to increase following surgery.102,109 For example, Eschwege et al. reported that tumor ‘‘spillage’’ frequently occurs with prostatectomy and was seen in approximately 80% of patients after surgery, compared to 20% before surgery, whereas no prostate cells were detected in those undergoing prostatocystectomy for bladder cancer or prostatectomy for benign prostatic hypertrophy. Higher levels of cytosolic PSA from breast tumor extracts were significantly associated with smaller tumors, lower S-phase fraction, diploidy, younger patient age, and lower cellularity. Furthermore, recurrence and death were both significantly lower in PSA-positive patients (i.e., levels higher than the 30th percentile of PSA values) than in PSA-negative patients, and remained statistically significant in multivariate analysis.110 Fortier et al. subsequently demonstrated that PSA potently inhibited angiogenesis, blocked endothelial migration, and decreased the number of lung metastases from melanoma. Therefore, even if some neoplastic

164 cells are in the bloodstream during or after radiation, the cells may be prevented from implanting and surviving at distant sites due to the continued release of PSA (or other cytokine). This effect would be precluded by surgery. Additionally, the perioperative period is characterized by immunosuppression that may predispose the patient to metastatic spread. A surgically mediated decrease in NK cell activity through cytokines, such as IL-6 and IAP, has been implicated in perioperative immunosuppression.111–115 However, radiation therapy alone to a relatively small field appears to stimulate less immunosuppression,116 unlike chemoradiation where significant immune dysfunction occurs.117 Animal studies provide direct evidence confirming the importance of NK cells in controlling metastasis,118,119 and NK cell suppression resulting from surgery increases the risk of metastatic spread.120,121 Low NK cell activity during the perioperative period is associated with an increase in cancer recurrence and mortality in patients, e.g., with head and neck cancer,70,122 lung cancer,71 colorectal cancer,69,123 and breast cancer.68 Furthermore, recent studies have shown that when radiation is combined with dendritic cell growth factors, such as Flt-3 ligand, there is greater induction of an abscopal effect compared with either treatment alone, in certain tumor cell lines.83,124 There have also been a number of studies which have shown that radiation combined with cytokine therapy reduces risk of metastasis. Several groups have studied the effects of radiating lung followed by IL2 treatment on rate of lung metastasis from renal cancer. Results in animals were promising though one phase II trial did not show a difference in metastatic rates between patients treated with IL2 alone or with radiation.125–127 Further studies in mice showed that murine mammary and lymphoma grafts, when treated with radiation and IL2 showed a systemic antitumor effect with 90% complete response rate in the untreated bilateral tumor site.128 These findings support the role of the immune system in the abscopal effect. The immunosuppressive effects of surgery were shown to increase the risk of metastasis while treatments which potentiated the effects of the immune system appear to confer better control of metastasis, though this effect appears to be cell line dependent. Radiation provides local control and induces a local inflammatory response with less systemic suppression of the immune system seen in surgery. Therefore, we postulate that in certain tumors radiation may have an impact distantly, thereby offsetting any potential gain in local tumor control

J.M. Kaminski et al. by surgery. For some surgically resectable tumors, neoadjuvant radiation (or chemoradiation) followed by surgery has not been superior to traditional therapy (i.e., radiation, chemoradiation, or surgery alone), possibly for the same reasons as already described for surgery alone with the attendant morbidity and mortality associated with more aggressive approaches. In support of this hypothesis, Hartford and colleagues demonstrated in mice that irradiation of a primary tumor enhances inhibition of angiogenesis at a distal site, unlike surgery where distal angiogenesis tended to increase. Additionally, two days after irradiation, endostatin levels were twice as high as in the subjects undergoing surgical tumor resection.129 In another study, p53 appeared to mediate a radiation abscopal effect in mice that was dosedependent.130 Ohba et al. described a man who underwent radiation for a thoracic metastasis. Notably, a rise in the serum TNF-a after radiotherapy coincided with the regression of the primary hepatocellular carcinoma.12 TNF-a has a paradoxical role in cancer by promoting growth, invasion, and metastasis in some tumors, while having a reverse effect in other cancers through destruction of blood vessels and cell-mediated killing. An excellent review of TNF-a and cancer is found in the September 2003 issue of Lancet Oncology.131 Suicide gene therapy has been demonstrated to cause a distant bystander effect, which leads to regression of unmodified distant tumors, and is mediated through the immune system.132–138 For example, Chhikara et al. demonstrated in mice with prostate tumors transplanted subcutaneously that combined treatment with intratumoral injection of an adenoviral vector expressing herpes simplex-1 thymidine kinase (Ad-HSV-TK) and intraperitoneal gancyclovir, followed by radiation (5 Gy), resulted in decreased tumor growth and prolonged survival. Furthermore, the above combination therapy had an increased systemic bystander effect by reducing the number of lung nodules compared to Ad-HSV-TK therapy alone, while radiation alone had no effect distantly.137 Bi and colleagues demonstrated local and distant bystander effects when naı¨ve (i.e., non-modified) and HSV-TK expressing human squamous tumor cells were injected subcutaneously into one flank and only naı¨ve tumor cells were injected into the contralateral flank. The mixed tumor population demonstrated resolution, and the contralateral naı¨ve tumors either resolved or showed diminished growth rates following the administration of gancyclovir.138 Others have demonstrated that subcutaneous or intrahepatic injection of suicide-gene-modified tumor

The controversial abscopal effect cells induce a systemic antitumor effect which is mediated by NK cells132 or cytotoxic T-lymphocytes.134,136 Some data indicate that in situ destruction of the suicide-gene-modified tumor cells is necessary to elicit an appropriate antitumor response.139 Others have demonstrated a distant bystander effect or immunity to tumor challenge when cells (e.g., tumor or dendritic cells) were modified with transgenes expressing various cytokines, including IL-2,140–143 IL-4,144 TNF-a, 145 IL-12,146 IL-15,147 IL-18,146 Flt-3 ligand,133 IFN-b, 148 and GM-CSF,144 or combinations.145 For example, Dong et al. demonstrated that murine squamous tumor cells (B4B8) expressing the soluble form of Flt-3 ligand were able to induce a distant bystander effect in naı¨ve cells in the contralateral flank.133 Vartak and colleagues demonstrated in a mouse model that local hyperthermia of one leg at 41–43 °C for 40 min prior to transplantation of a fibrosarcoma reduced the tumor growth in the heated as well as the unheated contralateral leg.3 The mechanism of hyperthermia-induced distant bystander effect has not been fully elucidated. However, hyperthermia appears to enhance the immune response by increasing NK cell activity149 and cytokine production.150 Other groups have demonstrated distant bystander effects utilizing laser immunotherapy, involving intratumor administration of a laser-absorbing dye and an immunoadjuvant, followed by non-invasive laser irradadiation. In vivo experiments have demonstrated promising results through regression of the primary and metastases with long-term resistance to tumor rechallenge.151,152 Indeed, a paradoxical response may be seen in local therapy depending upon the tumor, i.e., sometimes therapies may exacerbate, inhibit, eliminate, or have no effect on metastasis. Therefore, it is essential for trials to measure many related parameters, such as the cytokines released before, during, and after therapy. Inflammatory effects following any form of local therapy appear to have, in many cases, an adverse impact on tumor control locally, if incompletely removed, and distantly. With cognizance of these negative effects, we can minimize these detrimental effects, while developing methods to stimulate the immune system and redirect the inflammatory response to suppress tumor growth and metastasis. Current day clinicians would be well served to look back at the basic immunotherapies employed in the 18th and 19th centuries and try to unravel the mechanisms of tumor suppression,153 even with the sobering realization that some of these therapies employed might be as effective as some current

165 therapies. A recent retrospective analysis compared patients from the Surveillance Epidemiology Ends Result Registry (1983) to patients treated with Coley’s toxins (1890–1960) for cancers of the ovaries, kidneys, breast, and soft tissue sarcomas. The study concluded that the risk of death within 10 years for any of the cancers studied was not significantly different.154

Conclusion The abscopal effect is mediated through cytokines and/or the immune system, mainly CMI, and results from loss of growth stimulatory and/or immunosuppressive factors from the tumor. To harness the full potential of the distant bystander effect, less immunosuppressive therapies should be developed that mitigate the non-directed inflammatory responses that can result from local therapies. In fact, it appears that potentiating the immune response may be of benefit in distant control. The development of safer, targeted therapies will be facilitated as we unravel the mechanisms underlying distant bystander effects.

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