EuropeanJournalof

Nuclear Medicine

Review article

A role for gamma scintigraphy in cancer immunology and immunotherapy Alan C. Perkins 1, Malcolm V. Pimm 2 1 Department of Medical Physics, University Hospital, Nottingham NG7 2UH, UK 2 Cancer Research Campaign Laboratories, University of Nottingham, Nottingham NG7 2RD, UK

Abstract. Facilities for radiolabelling and gamma scintigraphy are largely restricted to nuclear medicine departments or specialised research institutions and are therefore not widely available to workers in cancer research. Despite this, there is growing interest in gamma scintigraphy, which can provide information relevant to the entire field of cancer immunology. This review discusses the present and future roles of gamma scintigraphy in respect of antibody-targeted, cell-mediated and cytokine therapy. The authors aim to show that gamma scintigraphy is an investigative tool of great potential.

Key words: Gamma scintigraphy - Monoclonal antibodies

Cell-mediated therapy - Cytokines

Eur J Nucl Med (1992) 19:1054-1063

Antibody-targeted therapy The primary motivating factor behind the production of monoclonal antibodies has been the desire to target in vivo cell-killing agents to tumours. Fundamental to this approach is the necessity to produce a conjugate combining the antibody and the cell-killing moiety. To date there have been two main strategies for tumour immunotherapy: the use of antibody-radionuclide conjugates for radioimmunotherapy and the use of antibody-drug conjugates or toxin conjugates for chemotherapy. The radiolabelling of antibodies has been an integral component in the development and production of conjugates for radioimmunotherapy and has resulted in a diagnostic imaging technique in its own right (immunoscintigraphy). Imaging studies have played a crucial role in assessing in vivo biodistribution and radiation dosimetry from high dose radioimmunotherapy.

Radioimmunotherapy

Introduction Use of the gamma camera has now extended well beyond the boundaries of routine clinical diagnosis and in addition to providing basic physiological data it is proving to be a valuable tool in the design and development of pharmaceutical formulations (Wilson and Perkins 1992). Cancer is one of the commonest pathological conditions routinely investigated in nuclear medicine departments. Over the past decade interest and expertise have grown in the use of antibodies, particularly monoclonal antibodies for tumour imaging. Indeed, 1991 saw the approval'of the first immunoradiopharmaceutical (Oncoscint CR-103) for diagnostic use in oncology by the Committee of Proprietary Medical Products of the European Economic Community. We hope to show in this review that gamma scintigraphy has the potential to play yet other roles in the study of cancer immunology and immune-directed therapy, not all of which involve the use of monoclonal antibodies. Correspondence to: A.C. Perkins

In 1980 Order et al. described the use of antibodies raised against ferritin and carcinoembryonic antigen (CEA) for diagnostic scanning and also for cancer therapy. Gamma camera imaging was employed to determine the iodine 1-131 deposited in liver and tumour tissue. Since that time the main radionuclides which have been investigated are rhenium-186, yttrium-90 and iodine131, but there are a number of other candidate radionuclides. More recently there has been interest in the use of the radionuclides copper-67 and silver-111. Both these radionuclides have gamma energies suitable for imaging but at the present time they are expensive and availability is poor. The physical characteristics of the main radionuclides suitable for radioimmunotherapy are given in Table 1. Theoretical considerations of the dosimetric aspects of radioimmunotherapy are dealt with elsewhere (Humm et al. 1986; Britton ]991). Clinical results of the therapeutic application of these radionuclides conjugated to antibodies are, however, limited. As with treatment of thyrotoxicosis and thyroid cancer using 131I, imaging is a valuable means of monitoring uptake and estimating absorbed radiation dose. Diag-

© Springer-Verlag 1992

1055 1. Radionuclidesapplicable for radioimmunotherapy

Table

Radionuclide

Physical half-life(h)

Mode of decay (MeV)

Production process

6VCu 9oy 11lAg 131I t53Sm lS6Re

57.6 64 180 192 47 91

/3 (0.57) /3 (2.27) /3 (1.05) /3 (0.81) /3 (0.80) /3 (1.07)

67Zn (n, p) 9°Sr generator tl°Pd (n, 7,/3) la°Te (n, 7) 131Te->13tI 15ZSm(n, 7) lSVRe(n, 7)

nostic immunoscintigraphy using the same antibody and, if possible, radionuclide as intended for therapy should be performed before radioimmunotherapy. It is then possible to assess tumour uptake prior to administration of the therapeutic dose. In particular the quantification of organ uptake from images provides valuable data on kinetics and in vivo dosimetry (Baum et al. 1987, 1988), Dynamic imaging has been especially useful in assessing the kinetics of regionally administered antibodies such as by the intrahepatic artery or intraperitoneal route. An example of a study from PD Dr. Baum's laboratory at the University Hospital, Frankfurt, is given in Fig. 1. Dynamic images of radiolabelled antibody administered via an intrahepatic artery cannula into a patient with liver metastases secondary to colorectal carcinoma are shown. In this case the patient was given a dose of degradable starch microspheres in an attempt to increase the residence time of antibody in the liver. From the imaging study, essential data such as the accumulation of radiolabelled antibody in tumour, tumour: organ ratios, half-life and radiation burden may be assessed. Use of starch microspheres and infusion via the hepatic artery have not been found to increase the radiation dose to liver metastases. Unless resected surgical specimens are obtainable, the main method for estimating tissue uptake is whole body counting or imaging. A number of studies have included imaging together with the collection of excreted radioactivity and blood samples for the estimation of whole body, tumour and organ dose (Leichner et al. 1981; Hammond et al. 1984; Carrasquillo et ah 1984; Begent et al. 1989; Green et al. 1990; Leichner et al. 1990). Serial measurements using a whole body or shadow shield detector may be used to derive figures for whole body retention of administered radioactivity. In the absence of such equipment, probe detectors or the gamma camera with the collimator removed may be used for the estimation of whole body uptake. The gamma camera is the most convenient instrument for measuring organ biodistribution and uptake (Thomas et al. 1976). However, if the amounts of administered radioactivity are high, count rate saturation may occur. In such instances it may not be possible to undertake imaging until the activity has largely cleared from the body. This may prevent the accurate recording of serial images immediately after administration.

7 (48% 0.184) No 7 7 (6% 0.342) 7 (83% 0.365) 7 (28% 0.103) 7 (9% 0.137)

Conventional planar imaging is limited due to attenuation of gamma rays with tissue depth and may be unsatisfactory for measuring activity in tumours or organs deep within the body (Riggs et al. 1988; Begent et al. 1989). Accuracy may be improved using paired anterior and posterior images and obtaining the geometric mean of the count rates (Thomas etal. 1976; Order etal. 1980). Single photon emission tomography (SPECT) is considered to be the most accurate method of measuring in vivo dosimetry (Riggs et al. 1988; Begent et al. J989; Green et al. 1990; Macey et al. 1990). The careful choice of equipment and technique is mandatory for accurate estimation of dosimetry. The majority of clinical work has been carried out using therapy doses of antibody radiolabelled with 131i. However, the resolution characteristics of standard gamma camera collimators are poorly suited to SPECT imaging since the full width tenth maximum (FWTM) values are considerably larger than the full width half maximum (FWHM) values. As a consequence of this, low sensitivity collimators with thick septa and long bore holes have been advocated in order to reduce the effects of scatter (Clarke et al. 1985). Begent et al. (1989) measured the dosimetry in 16 patients receiving polyclonal anti-CEA antibody using a gamma camera fitted with a high resolution 400keV collimator having a FWHM of 2 mm at 10 mm in air. A high sensitivity 400-keV collimator with a FWHM of ] 4.1 mm was used for imaging at later times to compensate for clearance and decay of the activity. As with the studies of Order et al. (1980), to correct for photon attenuation a transmission whole body map of each patient was obtained prior to therapy using a flood source containing approximately 200 MBq 13~I. The source was fixed with respect to the camera head and rotated around the !6atient to obtain a transmission image. The image was subsequently used to correct for attenuation within each patient. The authors considered these procedures to be laborious but necessary for the accurate estimation of in vivo dosimetry. Imaging can be a time-consuming process and radiation doses to staff may be significant. Moving patients from the ward to the imaging suite requires careful planning. In addition the potential for error in estimating dosimetry from images is high. The accuracy of image quantification has been investigated in detail by Green et al. (1990). The use of scatter correction was found to improve accuracy

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1057 and the technique was validated for clinical studies for activities as low as 1 pCi/g which may typically be found in the blood 3 days after administration of 1.8 GBq (50 mCi) 131I-labelled antibody. An example of in vivo SPECT imaging of a therapeutic dose of 13q-labelled antibody is given in Fig. 2. This example demonstrates the value of three-dimensional information for estimating dosimetry and shows how the relative distribution between tumour and normal tissue changes with time. A program for radioimmunotherapy treatment planning has been used by Macey et al. (1990). In this case quantitative radionuclide imaging using SPECT is used to provide in vivo pharmacokinetic data, and radiation absorbed dose estimates for tumour and other organs are obtained from software run on a standard nuclear medicine computer system. The count rate detected from a source organ after background subtraction was converted to radionuclide content from the equation: R = (C/S). Acf, where R is the total amount of the radionuclide in the site, C is the geometric mean of the count rate detected from anterior and posterior images o f the site in counts per second, S is the sensitivity o f the imaging system and Acf is the attenuation correction factor. (Acf= Exp(u.d).where u is the linear attenuation coefficient of the tissues between the source and the camera and d is the effective depth.) A further alternative lies in the use of positron emission tomography (PET). The physical basis of PET allows for high resolution imaging and accurate quantification of dose. Instrumentation and facilities for experimental work are limited and studies are restricted to animal models at the present time. Westera et al. first reported the use of P E T imaging using iodine-124-monoclonal anti-CEA antibody in a mouse xenograft model in 1991.

Fig. 1 a-g. Images of a patient with liver metastases from a colorec-

tal carcinoma resected 1 year earlier. In this study the antibody infusions were carried out following administration of degradable starch microspheres, a 99mTc-colloid images demonstrating liver metastases 4.5 and 5.0 cm in diameter, b Whole body images recorded 22 h following administration of 99mTc-43t/26 anti-CEA antibody. An outline of the hepatic artery cannula and activity in the right renal tract can be seen. e Two-minute image during infusion of the therapeutic dose of 1311-431/26 antibody via the hepatic cannula. Initial high concentration can be seen in the metastases, d Ten-minute image showing rapid clearance from metastatic sites and high blood pool activity in the heart, e Regions of interest over metastases (1 and 2) and heart (3). f Time-activity curves showing rapid uptake and wash out of activity from the metastases (m) with more slowly rising blood activity (b) which gradually clears, g Image of 13~I antibody 7 days following administration demonstrating high uptake in liver metastases. (Previously unpublished data supplied by PD Dr. R.P. Baum, University Hospital, Frankfurt)

Fig. 2. Transverse SPECT images of a patient with liver metastases. The patient was given 1.7 MBq (45 mCi) 131I-labelled A5B7 antiCEA antibody. Top left: Tc-99m-colloid image showing metastatic site. Other images show increasing concentration of activity at the metastatic site up to 160 h post administration. (Images supplied by Dr. A.J. Green, CRC Targeting and Imaging Group, Royal Free Hospital, London)

Drug targeting The use of antibodies conjugated to drugs and plant toxins to selectively increase the delivery of drug to tumours whilst simultaneously reducing whole body toxicity has been assessed in a number of centres in both Europe and the United States. This approach is more sophisticated than that of radionuclide conjugation partly because the chemical linking of drug to antibody is more complex. The synthesis of immunoconjugates for clinical use necessitates detailed preliminary evaluation. The in vivo stability of the conjugates is especially important and furthermore the biodistribution even of stable conjugates may differ from that of the antibody alone; hence the distribution of both the antibody and the drug moieties requires critical evaluation. Biodistribution and localisation studies are necessary to demonstrate that the conjugate behaves in a similar manner to that of free antibody and, more importantly, that the drug is localising in the tumour. Such studies may be performed by dissection studies in animal models after radiolabelling the drug conjugate with either a gamma or beta emitter (e.g. iodine-125, hydrogen-3). Tumour localisation and whole body biodistribution may then be assessed by the assay of the tissue samples. The degree of specificity of the uptake of the antibody conjugate is commonly measured using human tumour xenografts which are antigen positive and compared with

1058 the localisation in antigen-negative xenografts. Using this approach the analysis of tissue levels of drugs has shown site-specific targeting of immunoconjugates of cytotoxic and cytostatic drugs such as methotrexate, daunomycin and neocarzinostatin (Pimm et al. 1990). In experimental models imaging has been found to be reliable and data have been correlated with dissection studies (Perkins and Pimm 1987). It also needs to be stressed that imaging offers a much more humane alternative for the quantification of in vivo biodistribution in experimental models. The assessment of pharmacokinetics over a period of time will require the sacrifice of possibly four or five animals at each time point, whereas the use of the gamma camera could provide quantitative data by the repeated imaging of a group of five subjects. The scintigraphic expertise developed during the use of radiolabelled antibodies for diagnosis has been successfully applied to the clinical examination of the biodistribution of drug conjugates. However, published studies utilising this method in patients have been limited. The first published study imaging the biodistribution and turnout localisation of an antibody drug conjugate was that of Ford et al. (1983). In this study the 131Ilabelled moiety of a vindesine-anti-CEA polyclonal antibody conjugate was imaged in patients with colorectal cancer. The first imaging studies of a monoclonal antibody conjugate were carried out in Nottingham using the monoclonal antibody 791T/36 conjugated to methotrexate and radiolabelled with 13~I. Imaging studies using la1I-(79]T/36-MTX) were first performed in mice with turnout xenografts and subsequently in patients with colorectal cancer (Perkins et al. 1987a). This work demonstrated the positive localisation of radiolabelled antibody conjugate in patients and imaged the uptake of tracer in tumour specimens removed at surgery following administration of the conjugate to patients. Tumour to normal mucosa ratios of 2.9:1 were measured in resected colonic and rectal specimens obtained from 14 patients undergoing surgery (Ballantyne et al. 1988). A fundamental deficiency of these studies is that they only imaged the distribution of the antibody part of the conjugate and hence there was no formal proof that the distribution of the drug was in parallel with that of the antibody. Examination of this is limited by the difficulty of labelling drugs with appropriate gamma emitters, at least to a high enough specific activity for external detection. Immunotoxins have been synthesised by the conjugation of antibody to plant toxins such as ricin and abrin (Wawrzynczak 1991). The ricin toxin A chain (RTA) is produced from the residue of the castor bean following the extraction of caster oil. The protein nature of these toxins means that they can be radiolabelled in just the same way as antibodies. It is feasible to prepare antibody immunoconjugates in which either the whole molecule or only the RTA or antibody moieties are labelled with radioiodine, or even in which both moieties are independently labelled with different radioiodines (Byers et al.

ii J

Fig. 3 a, b. Diagrams showing suitable sites for radiolabelling immunotoxins, a Both moieties radiolabelled with 131I. b Site-specific labelling of the toxin moiety by DTPA chelation with 11~In, after Perkins et al. (1990)

1987) Figure 3 shows possible sites for radiolabelling of the whole conjugate or selective labelling of the toxin moiety. However, because of the logistic problem of preparing and characterising such radiolabelled immunotoxins with radioiodines suitable for imaging within the constraints of the half-lives of their decay, most studies have been carried out with immunotoxins in which both moieties are labelled immediately prior to administration. Although this gives some indication of the biodistribution of the immunotoxins, it is not clear whether the emissions being imaged from the radioiodine are attached to intact immunotoxin, or free toxin, or free antibody released following breakdown of the immunotoxin. Preliminary imaging studies in a mouse model using 131i_(791T/36-RTA) have demonstrated the rapid hepatic uptake of intravenously administered immunotoxin (Perkins et al. 1987b). In this way time-activity curves

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Fig. 4. Left: Whole body image of a mouse following intravenous injection of ~31I-labelled immunotoxin. ROIs are shown over the heart, liver and urinary bladder. Right: Time-activity curves from the 60 min dynamic study. Rapid hepatic uptake of conjugate was seen within the first 10 min (upper curve). Blood activity declines steeply (middle curve)

could be created from regions of interest (ROIs) drawn over the heart, liver and urinary bladder (Fig, 4). Thus dynamic imaging with the gamma camera was capable of demonstrating biokinetics which occurred so quickly that it was not within the resolution of dissection analysis. Imaging was subsequently used to assess the effect of hepatic blocking agents such as mannosylated HSA on the blood survival and turnout-targeting properties of the immunotoxin. Despite such manoeuvres turnout localisation was poor. The rapid and high liver uptake of this immunotoxin prohibited systemic administration to cancer patients. As an alternative strategy the first clinical studies using immunotoxins in vivo, in Nottingham, were carried out in 1989 by the intraperitoneal administration to patients with recurrent ovarian cancer. In this patient group the disease is restricted to the peritoneal cavity and preliminary imaging studies using the same antibody as used for the immunotoxin had demonstrated sites of uptake into tumour deposits within the abdomen (Perkins et al. 1989). Images of the localisation of the immunotoxins 131I-(791T/36-RTA) and 131I-(791T/36RTA30) are shown in Figs. 5 and 6. In these patients the kinetics of radiolabelled materials were similar to those seen with antibody alone. In order to improve the quality of imaging and to demonstrate the targeting of the toxin component of the immunoconjugate there was a need for immunotoxins radiolabelled with gamma emitters more suitable than 131I and in which only the toxin moiety is radiolabelled. Consequently, Perkins et al. (1990)prepared an RTA-antibody immunotoxin in which only the R T A moiety was radiolabelled with indium-111 by diethylene triamine penta-acetic acid (DTPA) chelation (Fig. 3). Whole body biodistribution in mice with human turnout xenografts was measured by both dissection analysis and gamma camera imaging. There was a significantly greater uptake o f 111In into antigen-positive compared with antigen-negative xenografts, but the high liver uptake still remained a problem preventing effective imaging of subcutaneous xenografts.

Fig. 5. Serial images of a patient with recurrent ovarian carcinoma following the intraperitoneal injection of 131I-(791T/36-RTA) immunotoxin. Left column: abdomen; right column: pelvis. By 48 h release of radioiodine can be visualised with activity in the stomach and urinary bladder. (Previously unpublished data)

Fig. 6. Images of a patient with a large recurrent ovarian carcinoma following intraperitoneal injection of 131I-(791T/36-RTA30). Left: Within 60 min of injection showing activity pooling laterally within the peritoneum. Right: Uptake of conjugate within the main bulk of the tumour (shown by arrow). (Previously unpublished data)

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Cell-mediated therapy Granulocytes and mixed leucocytes labelled with g a m m a emitters are widely used in nuclear medicine for the detection of sites of inflammation and infection. 111Inindium oxine or technetium-99m hexamethylpropylene amine oxime is generally used as the tracer with the patient's own cells, prepared from peripheral blood, being radiolabelled in vitro before re-infusion. Localisation

of labelled cells at the sites of abscesses or inflammation depends on the normal physiological function of these cells to accumulate at such foci. Recently the use of such cell labelling in studying the biodistribution of specifically immune-activated cells has started to be investigated, particularly in the study of cancer. Such studies are not intended to be a diagnostic procedure, but rather to aid in the investigation of the possible therapeutic potential of this form of immunotherapy.

Fig. 7a-d. Kinetics of tumour localisation of 111In-labelled LAK cells. Serial images in a patient with an inguinal mass from metastatic melanoma, a 2.5 h, b 24 h, c 48 h post injection, d CT scan showing site of mass. [Images reproduced with kind permission of Dr. E. Schafer (Dept. of Nuclear Medicine, University of W/irzburg, FRG) and the publisher; from Schafer et al. 1991]

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Lymphokine-activated killer cells The in vitro culture of normal peripheral blood lymphoctes (PBLs) with the lymphokine interleukin-2 (IL-2) results in the generation of cells having broad anti-tumour cytotoxicity, i.e. the PBLs (or a subpopulation of them) acquire the property of destroying tumour cells both from the same (autologous) patient or from other patients. Expertise developed with conventionally labelled leucocytes is now being applied to studying the biodistribution of such lymphokine-activated killer (LAK) cells. For example Schafer et al. (1991) have used imaging to evaluate the pattern of biodistribution of autologous LAK cells, labelled with l~tIn-indium oxine, in patients with metastatic melanoma. Patients received about 1 x 108 to 5 x l0 s cells labelled with of the order of 5MBq l l~In. Re-infused cells distributed primarily to the lungs, spleen and liver. However, in four of six patients the images showed enrichment of the tracer at tumour sites in the lymph nodes, as visceral masses or in the bones. Tumour visualisation was mainly seen between 24 and 48 h following administration. An example of the work from this group is reproduced in Fig. 7. It is not yet whether anti-tumour effects of LAK cells are mediated by their direct attack on malignant cells or by indirect effects, such as the release of other lymphokines with systemic or local effects. The demonstration of some tumour accumulation of LAK cells in patients suggests that there may be some site-specific retention of such cells in malignant lesions. Scintigraphy appears to be a valuable technique to evaluate further this hypothesis. Furthermore, such imaging could allow a comparison between the degree of tumour uptake of LAK cells and the degree of any therapeutic effects in patients undergoing LAK cell therapy trials.

Specifically cytotoxic lymphocytes Although it is not generally proven that specific immune responses exist to all malignancies, at least in melanoma there is growing evidence of such responses. Recent attention has focused on lymphocytes already infiltrating tumour deposits as a source of immune cells for study and possible therapeutic application. An important component of such studies is the assessment of the biodistribution and tumour-homing properties of such tumourinfiltrating lymphocytes (TILs) re-infused into patients, and scintigraphy could have a role here. In studies by Griffith et al. (1989), lymphocytes isolated from melanoma tissue were cultures in vitro, radiolabelled with t ~1in and re-infused into the autologous patients. Imaging was carried out daily for up to 9 days. As a control, peripheral blood lymphocytes were prepared from the same patients, similarly radiolabelled with 1~~In and infused. At imaging tumour deposits were seen in 13 of 18 sequences in 17 patients (one receiving ~111n_TILs twice). Tumour

biopsies contained on average 0.0055% of the original 1111n_TIL count rate per gram of tissue between 1 and 10 days after infusion, while normal skin count rates were about ten-fold lower. With peripheral blood lymphocytes, only one of four patients showed transient uptake at one tumour site. Moreover, 111in count rate in resected tumour was only 0.001% fivefold lower than that seen with TILs.

Cytokine therapy The name "cytokines" is now given to a broad group of naturally occurring regulators of cell function which are of particular interest in immunology and in cancer research. Some act directly on malignant cells, whilst others modulate other responses which in turn impact on cells of the immune sytem, or malignant cells. They include various subgroups of materials such as the lymphokines, interleukins and interferons. Current techniques of genetic engineering mean that many of the materials now can be produced in pure form in the laboratory on a large scale and are therefore available for experimental study or therapeutic investigation. In general the cytokines exert their functions by acting locally at the site of their production, unlike antibodies and hormones, which act on distant sites. However, if they are to be used therapeutically they will often have to be given systemically and the study of their pharmacokinetics is therefore important. Although blood pharmacokinetics of cytokines can be assessed by assays on peripheral blood samples, other information on the biodistribution, particularly in humans, is only going to be obtainable by the use of imaging techniques. All of the cytokines are proteins and as such are amenable to radiolabelling with the same methods as are used for labelling other proteins such as antibodies. Although it has not been widely used, one can foresee an increased role for the gamma camera in the evaluation of the biodistribution and target levels of cytokines.

Interferon Interferon-c~ is currently being evaluated as an anti-tumour agent in several malignant diseases and a preliminary scintigraphic evaluation of its biodistribution in two patients with osteosarcoma has been reported by Diez et al. (1990). In this study interferon was labelled with iodine-123 using the chloramine T method widely used in antibody labelling. The liver was the major site of clearance of the tracer, about 30% being concentrated in the liver within the first 50 min. About 7% of the tracer was also localised in the kidneys at this time, but it was not clear whether this was due to renal clearance of the interferon or urinary excretion of 123I following breakdown of the material in the liver. In tumours in

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limbs a scintigraphic measurement was made of the uptake of the interferon and compared with the corresponding site in the contralateral limb. Uptake of tracer by the tumours was clearly delineated for up to 24 h, with target to non-target ratios of up to 5 : 1 which could not be accounted for by the quantity of labelled material simply surviving in the circulation. Thus this study showed that interferon was able to reach tumour deposits, a basic prerequisite for therapeutic effectiveness, and demonstrated the potential of gamma scintigraphy for further evaluation of the biodistribution of such cytokines.

Conclusion Facilities for radiolabelling and gamma scintigraphy are largely restricted to nuclear medicine departments or specialised research institutions and are therefore not widely available to workers in cancer research. However, there is growing interest in and a strong argument for the use of imaging studies, since these will increase the understanding of the in vivo behaviour of molecular and cellular anti-tumour agents and improve drug delivery systems. Gamma scintigraphy is now emerging as a powerful investigate tool capable of providing valuable information relevant to the whole field of cancer immunology.

Acknowledgements. Dr. M.V. Pimm is supported by the Cancer Research Campaign.

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Byers VS, Pimm MV, Pawluczyk IZAP, Lee HM, Scannon PJ, Baldwin RW (1987) Biodistribution of ricin toxin A chainmonoclonal antibody 791T/36 immunotoxin and influence of hepatic blocking agents. Cancer Res 47 : 5277-5283 Carrasquillo JA, Krohn KA, Beaumier P, McGuffin RW, Brown JP, Hellstrom KE, Hellstrom I, Larson SM (1984) Diagnosis of and therapy for solid tumours with radiolabeled antibodies and immune fragments. Cancer Treat Rep 68:317 328 Clarke LP, Saw CB, Leong LK, Serafini AN (1985) SPECT imaging of 1-131 (364keV): importance of collimation. Nucl Med Commun 6:41-47 Diez RA, Perdereau B, Pter M, Dorval T, Gongora R, Falcoff ET (1990) Scintigraphic study of radiolabelled interferon-c~ in osteosarcoma patients. Clin Pharmacokinet 18 : 82-89 Ford CHJ, Newman CE, Johnson JR, Woodhouse CS, Reeder TA, Rowland GF, Simmons RG (1983) Localisation and toxicity study of vindesine-anti-CEA conjugate in patients with advanced cancer. Br J Cancer 47:35-45 Green AJ, Dewhurst SE, Begent RHJ, Bagshawe KD, Riggs SJ (1990) Accurate quantification of 1-131 distribution by gamma camera imaging. Eur. J Nucl Med 16:361-365 Griffith KD, Read EJ, Carrasquillo JA, Carter CS, Yang JC, Fisher B, Aebersold P, Packard BS, Yu MY, Rosenberg SA (1989) In vivo distribution of adoptively transferred indium-ltl-labelled tumour infiltrating lymphocytes and peripheral blood lymphocytes in patients with metastatic melanoma. J Natl Cancer Inst 81 : 1709-1717 Hammond ND, Moldofsky P J, Beardsley MR, Mulhern CB (1984) External imaging techniques for quantification of distribution of I-131 F(ab')2 fragments of monoclonal antibody in humans. Med Phys 11 : 778-783 Humm JL (1986) Dosimetric aspects of antibodies for tumour therapy. J Nucl Med 27:1409-1479 Leichner PK, Klein JL, Garrison JB, Jenkins RE, Nickloff EL, Ettinger DS, Order SE 0981) Dosimetry of 1-131-1abeled antiferritin in hepatoma: a model for radioimmunoglobulin dosimetry. Int J Radiat Oncol Biol Phys 7:323 333 Leichner PK, Yang NC, Wessels BW, Hawkins WG, Order SE, Klein JL (1990) Dosimetry and treatment planning in radioimmunotherapy. Front Radiat Ther Oncol 24:109-120 Macey DJ, DeNardo GL, DeNardo SJ (1990) A treatment planning program for radioimmunotherapy. Front Radiat Ther Oncol 24:123-131 Order SE, Klein JL, Ettinger D, Alderson P, Siegelman S, Leichner P (1980) Use of isotopic immunoglobulin therapy. Cancer Res 40 : 3001-3007 Perkins AC, Pimm MV (1987) Validity of gamma scintigraphy for the quantification of radionuclide uptake in experimental animals. Med Sci Res 15:205-206 Perkins AC, Pimm MV, Ballantyne KC, Garnett MC, Clegg JA, Hardcastle JD, Baldwin RW (t987a) In vivo imaging of a monoclonal antibody drug conjugate (791T/36-methotrexate): experimental and clinical studies. In: Klapdor R (ed) New tumour markers and their monoclonal antibodies. Georg Thieme, Stuttgart, pp 554-562 Perkins AC, Pimm MV, Baldwin RW (1987b) Demonstration of the hepatic uptake of radiolabelled immunotoxins using gamma scintigraphy. Eur J Clin Oncol 23:1225-1227 Perkins AC, Pimm MV, Gie C, Marksman RA, Symonds EM, Baldwin RW (1989) Intraperitoneal 1-131 and In-lll-791T/36 monoclonal antibody in ovarian cancer: imaging and biodistribution. Nucl Med Commun 10:577-584 Perkins AC, Pimm MV, Reardan DT, Bernhard SL, Baldwin RW (1990) Biodistribution of monoclonal antibody immunotoxin

1063 conjugates by imaging the toxin moiety radiolabeled with In111. In: Klapdor R (ed) Recent results in tumour diagnosis and therapy. W. Zuckschwerdt, Munich, pp 484-490 Pimm MV (1990) Chemoimmunoconjugates for cancer treatment: possibilities and limitations. In: Baldwin RW, Byers VS, Mann RD (eds) Monoclonal antibodies and immunoconjugates. Partheneon, Carnforth, pp 105-125 Riggs SJ, Green AJ, Begent RHJ, Bagshawe KD (1988) Quantitation in 1-131 radioimmunotherapy using SPECT. Int J Cancer [Suppl 2] : 95-98 Schafer E, Dummer R, Eilles C, Borner W, Martin R, Rendl J, Burg G (1991) Imaging pattern of radiolabelled lymphokineactivated killer cells in patients with metastatic malignant melanoma. Eur J Nuct Med 18 : 10(~110

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A role for gamma scintigraphy in cancer immunology and immunotherapy.

Facilities for radiolabelling and gamma scintigraphy are largely restricted to nuclear medicine departments or specialised research institutions and a...
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