Current status of radioimmunotherapy

Nucl. Med. Biol.Vol. 21, No. 5. pp. 7X5-792,1994 Copyright c, 1994Elsevier Science Ltd Printed in Great Britain. All rights reserved 0969~8051(93)EOO35-4 0969-8051194

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Status of Radioimmunotherapy

STEVEN M. LARSON,* CHAITANYA R. DIVGI, ANDREW SCOTT, GEORGE SGOUROS, MARTIN C. GRAHAM, LALE KOSTAKOGLU, DAVID SCHEINBERG, NAI-KONG V. CHEUNG, JEFFREY SCHLOM and RONALD D. FINN Memorial Sloan-Kettering

Cancer Center, 1275 York Avenue, New York, NY 10021, U.S.A.

Radioimmunotherapy with radiolabeled monoclonal antibodies is increasingly effective for hematopoietic tumors, with a number of investigators reporting persistent major responses. Radioimmunotherapy for solid tumors has been more difficult and only an occasional major response has been reported and these have so far not been persistent. Toxicity is predominantly hematopoietic, with platelets being most sensitive to the effects of radiation. Even at ultra-high doses (up to 28 mCi/kg of “‘I), second organ toxicity has not been reached. Rational approaches to dose planning are becoming possible with improvements in dosimetry, based on quantitative SPECT and PET imaging. Current therapeutic indices for tumor/marrow, the most radiosensitive organ, are in the range of 5-10 to I. This is probably still too low for curative treatment of solid tumors, and further refinements, perhaps based on novel antibody formulations. are needed

Introduction About 50% of oncology patients can expect to be cured of their disease. In most curative cases, the patient’s tumor is detected sufficiently early so that it can be removed surgically. In a smaller number of patients, particularly children and especially for hematopoietic tumors, chemotherapy can be curative. Despite these advances, there is still a large group of unfortunate patients, with a variety of common tumors, who will die of their disease. Radioimmunotherapy is a recently developed form of therapy that offers the potential for anti-cancer activity in patients with these common tumors. At this stage, therapy is largely experimental but progress is being made in developing useful clinical agents, particularly in the hematopoietic malignancies. The basic principle was first proposed and developed by Pressman and Korngold (1953), and early clinical trials were initiated by Bayles and Spar (Spar et al., 1967). Only in more recent times has the feasibility of this mode of therapy been demonstrated, however. Several reviews have been published on this subject (Larson et ul., 1991; Kramer and Larson, 1991). Current problems to be overcome include: (1) the relatively small fraction of the dose which concentrates in tumor, (2) the toxicity, which is largely hematopoietic and (3) the fact that murine monoclonal antibodies induce an immune response, which

*Author for correspondence.

alters biodistribution through formation of complexes of human antimouse antibody (HAMA). Like conventional radiotherapy, the success of radioimmunotherapy depends on delivering a large radiation dose to tumor, in comparison to marrow radiosensitive tissues. A variety of methods have been developed to estimate the amount of energy deposited in tissues, and this is usually expressed in centiGray (cGy). Internally administered radioisotopes and the radiation absorbed dose from their use is computed by the MIRD schema, a method for obtaining whole body and organ radiation doses (Loevinger et al.. 1988). This method is suitable for estimating doses when distribution of radioisotopes is relatively homogeneous throughout volumes in the order of a few grams or greater. Recently, modifications to this scheme have been developed to take into account the “short-range” dosimetry, when distribution is heterogeneous at a microscopic and sub-microscopic level. These methods are suitable for y-decay and B-decay, but different dosimetry methods have been developed for alpha decay and electron capture decay, to take into account high LET effects (Kassis et cd.. 1985).

Summary of Clinical Trials Solid tumors

Radiolabeled polyclonal and monoclonal antibodies have been used in the treatment of patients with hepatoma (Order et al., 1985), intrahepatic cholangiocarcinoma (Kang-Da et ul., 1988) melanoma (Carrasquillo et al., 1984; Larson et al., 1983), ovarian carcinoma (Stewart et al.. 1989) 785

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peritoneal carcinomatosis (Larson et al., 1991), neuroblastoma (Larson er al., 1991) and glioma (Kalofonos et al., 1989; Brady et al., 1990). In these trials, dose-limiting toxicity was hematopoietic, with platelets and white cells being most sensitive to the radiation effects. Iodine-131 was the label most commonly used. Of the various routes of injection, the administration of radiolabeled antibody into a closed space seemed to offer the greatest potential in these early trials (Courtenay-Luck et al., 1984). In a report of a Phase I trial in ovarian cancer, using ‘3’I-labeled anti-human milk fat globulin injected i.p. (Stewart et al., 1989), there was a 13% (2/15) response rate in tumors measuring less than 2 cm, and in patients who had malignant cytology only but no measurable tumor, 50% (3/6) had disappearance of malignant cells from the peritoneal fluid. In patients receiving intravenously administered radiolabeled antibodies, responses have been few and relatively short lived. Brady et al. documented one complete response in a patient with malignant glioma receiving intra-arterial “‘I-labeled EGF-425 (Brady et al., 1990). Even though melanoma is a radioresistant tumor, a therapeutic trial was begun using Fab fragments labeled with 13’1in patients who had exceptional uptake of a diagnostic dose of radiolabeled antibody. One of 10 patients (10%) responded to therapy with a good partial response. This patient’s tumor received approx. 11,000 centiGray (Carrasquillo et al., 1984). Preliminary reports have begun to appear which employ yttrium-90-labeled antibody (Stewart et al., 1988) or rhenium-186 (Breitz et al., 1992), but it is really too early to tell whether this approach will offer any practical advantages in comparison to iodine131. Targeting of yttrium-90 to bone cortex appears to significantly increase the hematopoietic suppression associated with radioimmunotherapy. Chelation treatment to increase renal excretion of the yttrium90 may reduce the dose delivered to bone marrow (Stewart et al., 1990). LymphomalJeukemia

Radioimmunotherapy of patients with cutaneous T-cell lymphoma (Rosen et al., 1987), chronic lymphocytic leukemia (DeNardo et al., 1988) nonHodgkin’s lymphoma (DeNardo et al., 1988) and Hodgkin’s disease (Vriesendorp et al., 1991) with radiolabeled antibody has been studied in clinical trials. In general, responses have been frequent, even in disease which is refractory to chemotherapy. A successful strategy has been developed by Press et al. (Press et al., 1989, 1991; Eary er al., 1990), which has resulted in a significant number of persistent complete responses (CRs) in patients with chemoresistant non-Hodgkin’s lymphoma. Patients were preselected with a tracer dose of radiolabeled iodine131 anti-CD37 (MBl) antibody, and in those patients with favorable dosimetry, very high dose therapy (up

to 800mCi 13’1)has been implemented with autologous marrow rescue being carried out when required. To date, this approach has resulted in the highest frequency and most durable CR’s seen with radioimmunotherapy. Encouraging results were also seen at non-marrow ablative doses using iodine-131 MB1 (Kaminski et al., 1992) in which one carefully selected patient had a persistent CR.

Radioimmunotherapy at Memorial SloanKettering Cancer Center To a certain extent further progress in radioimmunotherapy depends on the step-wise application of newly established biologic principles in the fields of radiation biology, immunology and hematopoiesis, to ongoing clinical protocols. At Memorial SloanKettering Cancer Center, applications of iodine-131labeled Ml95 (against CD33) in leukemia; 3F8 (against GD2) in neuroblastoma; and CC49 (against TAG-71) in colorectal carcinoma, illustrate the current problems and promise of radioimmunotherapy. Monoclonal antibody (Mab) Ml95

(anti-CD33)

Monoclonal antibody Ml95 (antXD33) is an IgG2a murine monoclonal antibody that reacts with most myeloid leukemic cells, monocytes and hematopoietic progenitors. This antibody does not react with the pluripotent stem cell. Iodine-131 Ml95 is being studied as a therapeutic agent in acute and chronic leukemia. Initial phase I studies were performed in 10 patients (Scheinberg et al., 1991). There was prompt targeting to tumor elements in the bone marrow, and relatively low doses of antibody (46 mg) appeared to be optimal for targeting (see Fig. 1). In a subsequent radioactivity dose escalation trial in 24 patients, iodine-131 M 195 showed antileukemic activity with 96% of patients achieving significant reduction in peripheral cell counts, and 83% of patients showing decreased marrow blasts, with >99% of blasts destroyed in some patients (Schwartz et al., 1993). Pancytopenia was profound at doses greater than 135 mCi/m2, and was of at least 12 days duration. Eight patients had sufficient marrow cytoreduction to proceed to bone marrow transplantation, and 3 of these patients were disease free on subsequent bone marrow biopsies. HAMA occurred in 52% of patients in these first 2 trials. No non-hematopoietic toxicity was seen in these initial studies. Thus, these trials demonstrated safe and saturable targeting of leukemic cells. Leukemic cytoreduction, both in the peripheral blood (Fig. 2) and of the bone marrow blasts (Fig. 3), was possible even in multiple relapsed or refractory patients with large tumor burdens. Based on these findings, new therapeutic trials have been implemented with iodine-l 3 1-labeled murine

Current status of radioimmunotherapy

Fig. 1. Whole body anterior and posterior planar images of a patient with AML obtained on day 0 following infusion with ‘3’I-M195 monoclonal antibody. The targeting of sites of known disease in the bone marrow (throughout the skeleton), and in both liver and spleen, is clearly apparent. The ITlinimai blood pool activity at this early time post-infusion is characteristic of this high affinity antibc>dy.

M195. Patients with CML in relapse are being treated as a part of preparation for a second bone marrow transplant. This study is designed in order to develop a methodology to estimate radiation absorbed dose to marrow and other organs during the course of this therapy (Sgouros et n[., 1994). Another group of patients being studied are in clinical remission from acute promyelocytic leukemia following treatment with all-trans retinoic acid in whom the status of the marrow is being followed with a polymerase chain reaction (PCR) technique designed to detect the particular gene translocation

[t( 15; 17)] associated with APL. Early disease-free survival appears to be improved by the use of the 13’I-M 195 at non-marrow ablative doses (50 mCi/m*) to eliminate minimal disease. In relapsed patients with acute myelocytic leukemia, for first transplants, patients are being prepared for bone marrow transplant with “‘I-Ml95 cytoreduction, instead of whole body radiation therapy. All 6 patients studied to date have achieved CR (initial doses are 120mCi/m*, and the dose is escalating). However, it is too early to evaluate duration of response.

STEVEN M. LARSON et al.

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Fig. 2. Changes in peripheral white blood cell counts over time in a patient infused with two separate doses of ‘-“I-M195 monoclonal antibody is shown. The marked anti-leukemic effect of the therapy is demonstrated by the changes in counts following infusion. The patient had failed conventional chemotherapy prior to infusion with ‘3%M195 monoclonal antibody.

In addition, a trial has just been completed utilizing humanized Ml95 (huGl-M195) (Co et al., 1992; Caron et al., 1992), designed to avoid neutralizing HAMA and to provide humanized Ml95 immunologic effector function. Humanized Ml95 consists of the murine complementarity-determining regions (CDRs) grafted onto a human IgGl backbone by genetic engineering methodology. Affinity of the humanized variant is about an order of magnitude higher than the murine monoclonal M195. In initial studies biodistribution of the ‘311-huG1-M195 appears to be similar to 13’I-M195, and HAMA development has been absent. CC49 therapy Antibodies to TAG-72, a mucin antigen present in colorectal, pancreas, prostate, ovarian, breast and ovarian cancer are among the most widely studied of all antibodies for diagnosis and therapy of human tumors (Colcher et al., 1991). A strategy for development of steadily improved forms of this versatile class of antibodies has been implemented by Dr Schlom and his colleagues at the National Cancer Institutes (NCI) in collaboration with a number of researchers around the world (Larson, 1993). B72.3 radiolabeled with iodine-131 was the prot type antibody used in clinical trials (Schlom et al., 1989), and as an indium-11 l-labeled antibody, this is the first diagnostic preparation to be approved by the US FDA for clinical use (Oncoscint CR-OV, Cytogen Corp., Princeton, N.J.) (Nabi and Doerr, 1992). Second generation antibodies to TAG-72 have increased affinity, and show improved localization in colorectal cancer patients (Scott et al., 1992a, b). Additional innovative approaches that are under development include the use of cytokines to increase antigen expression on tumor cells, and the development of antibody forms of smaller molecular weight which are more favorable for rapid targeting to tumors in uiuo (Schlom et al., 1990).

We have recently conducted a Phase 1 trial with i3’I-labeled CC49 monoclonal antibody in patients with metastatic colorectal cancer selected by immunohistochemistry for high expression of TAG-72 antigen (Scott et al., 1992a, b). All patients had measurable disease, had failed conventional therapy, had no significant prior radiotherapy and were in reasonable physical condition. We initially treated 24 patients at escalating dose levels of “‘I-labeled CC49 (20 mg Ab dose) from 15 to 90 mCi/m’ over an 18 month period. There was one patient who achieved a partial response, and 4 patients had stable disease at 10 weeks post-therapy. Tumor targeting was identified by gamma camera imaging in 95% of known lesions. All patients were HAMA positive 4 weeks after infusion. Six patients were retreated; in 5 there was faster clearance due to HAMA. Thrombocytopenia was the major toxicity, with 3 patients having Grade III to IV toxicity at the 90 mCi/m’ level. All patients with Grade IV toxicity had been heavily pretreated with chemotherapy, particularly nitrosoureas and mitomycin. Lymphocytopenia was seen in some patients, and reached a nadir after the fall in platelet counts. No second organ toxicity was seen. Based on this data, the maximum tolerated dose (MTD) for heavily pretreated patients was 75 mCi/m2. We have subsequently continued the trial in patients who have received only one or two courses of chemotherapy, excluding patients who had received prior nitrosoureas and mitomycin. In the 6 patients subsequently treated (3 at 90 mCi/m’ and 3 at 105 mCi/m’) there have been only two Grade IV thrombocytopenias (1 at 90 mCi/m’ and 1 at 105 mCi/m2). We are currently accruing further patients at the high dose level. A Phase II trial in patients with metastatic colorectal cancer has recently been initiated at MD Anderson Cancer Center, Tex., at the 75mCi/m2 level, based on our data. As expected, the 14 patients

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Isotope Dose Level Fig. 3. Changes in bone marrow blast numbers in response to increasing dose levels of “‘1-M 195 monoclonal antibody is shown. Greater than 90% decrease in blast numbers was found at dose levels greater than 135 mCi/m*.

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Current status of radioimmunotherapy treated to date have manageable toxicity and the trial isproceeding(Murray et al., 1992). An additional group of 15 patients was treated at the 75 mCi/m2 level in prostate cancer, in Phase II, and pain relief was seen in 2/3 of symptomatic patients (Meredith et al., 1993). Anti-GDZ 3F8 monoclonal antibody 3F8 is a murine IgG3 monoclonal antibody selective for the ganghoside Go,. ‘3’I-3F8 localized to primary and metastatic neuroblastomas in patients. The toxicities of ‘3’I-3F8 were defined in a dose escalation phase 1 study. Twenty-three patients (1 I M and 21 F, 0.3-24.2 years of age at diagnosis) with refractory neuroblastoma (22 stage IV, 1 stage IIIU), were treated with ‘3’I-3F8 at 7 dose levels, namely 6, 8, 12, 16,20,24 and 28 mCi/kg. Radiation dose to the blood was calculated based on blood clearance; total body dose was based on total body clearance; and the tumor/organ dose on regions of interest calculations from serial gamma imagings. Twenty one of 23 patients were rescued with autologous bone marrow; one patient received granulocyte macrophage-colony stimulating factor (GM-CSF) alone; one died of progressive disease before marrow reinfusion. Marrow was infused when blood radioactivity decreased to co.01 pCi/mL in the first 18 patients and to < 1 pCi/mL in the last 4 patients. Acute toxicities of 13’I-3F8 treatment included pain (19/23) during the infusion, fever (19/23), hyperbilirubinemia (6/23) and diarrhea. All patients developed grade 4 myelosuppression with sepsis in 7/23 patients (5 fungal, 2 bacterial), disseminated zoster in 1, and pneumocystis in 1. Despite orally administered saturated solution of potassium iodide, 3 patients developed hypothyroidism. Subsequently 14 patients were treated with synthroid or Cytomel for thyroid protection. No other extramedullary toxicities have been encountered in patients followed past 20 months (50 + ,40 + , 30+, 26+, 23 +, mos) from the time of 13’1-3F8 treatment. Fourteen patients have died, 1 I of disease and 3 from infections during the cytopenic period, and in 4 patients follow-up is still short. Responses were seen in both soft tissue masses and bone marrow. Average tumor dose was 150 rad/mCi/kg. When 13’1-3F8 was administered intravenously (6-28 mCi/kg), significant toxicities were encountered including myelosuppression and their infectious complications, pain, fever and hypothyroidism. Autologous marrow rescue could reverse marrow aplasia and thyroid supplement was essential to prevent thyroid damage. Although severe extramedullary toxicities were not seen, assessment of the late effects of this treatment modality requires longer follow-up. Part of the study has been previously summarized (Larson et al., 1991). Improvements in dosimetry in radioimmunotherapy of solid tumors

In order to make further improvements in radioimmunotherapy, accurate dosimetry calculations will be

essential in order to evaluate therapeutic efficacy in relationship to radiation dose delivered. This is particularly important in radiolabeled monoclonal antibody trials in solid tumors, where the determination of dose to normal and tumor tissue is complicated by the non-specific uptake of radiolabeled antibody in normal tissues. Standard techniques for dosimetry calculation using the S-factor based MIRD formalism also do not adequately address the problems of spatial distribution of dose to tumor and adjacent normal tissues. At Memorial Sloan-Kettering Cancer Center we have adopted a dosimetry approach that incorporates quantitation of dose, and the spatial distribution of dose, through fusion techniques. Following infusion of radiolabeled antibody, patients are imaged by conjugate planar view methods on at least 4 occasions over a 2 week period. Regions of interest are drawn around the whole body, specific organs of interest as well as identified tumor sites and quantitated by reference to standards included in each image. CT scans are used to provide tissue depth measurements for attenuation correction, as well as volume measurements of tumor and organs of interest. The dose contribution to tumor and surrounding normal tissue from distant organs is then obtained using DOSCAL, a program that implements the MIRD formalism (Sgouros et al., 1988). Contributions to the tumor dose from distant organs are obtained in this program by replacing tumor in the “source to tumor” S-factor with a tissue that is adjacent to or that contains the tumor. The final calculations include both photon and electron dose for the tumor and normal organs. Red marrow dose is derived from multiple blood samples using the American ASSOCIation of Physicist in Medicine (AAPM) recommendations, modified to account for differences in patient hematocrit. For the determination of spatial distribution of dose, SPECT studies are obtained at appropriate time points, and then fused with CT or MRI images to allow precise anatomic localization of areas of uptake. A novel 3-D dose calculation program based on a 3-D radiation treatment planning system is then used to calculate the spatially varying absorbed cumulated dose. which is displayed in a “colorwash” (see Fig. 4). This technique can also be used to determine the differences in spatial distribution of dose with other radionuchdes attached to the same antibody, assuming similar biodistribution (Sgouros et al., 1990, 1993). By combining 3-D and MIRD based techniques in this manner, accurate dosimetry can be performed for clinical trials of radioimmunotherapy. Summary

Improved methods for therapy of common human tumors are needed and radioimmunotherapy offers potential for delivery of high dose radiation in a

STEVEN M. LARSONet al.

Fig. 4. A display of combined photon and electron dose to tumor and normal organs of a patient infused with 90 mCi/m2 of “‘I-CC49 monoclonal antibody is shown. The patient had two metastatic lesions in the medial aspect of the right lobe of the liver, and a SPECT image obtained 7 days post-infusion is shown “fused” with an MRI slice precisely matching the SPECT image. The scale is derived from quantitation of tumor and organ uptake (see text for details), and the spatial distribution of dose is displayed across the entire abdomen.

References

Miyamoto C., Steplewski Z. and Koprowski H. (1990) Treatment of malignant gliomas with iodine-125 labeled monoclonal antibody against epidermal growth factor receptor. Antibody Immunoconj. Radiopharm. 3, 169-179. Breitz H. B., Weiden P. L., Vanderheyden J. L., Appelbaum J. W., Bjorn M. J., Fer M. F., Wolf S. B., Ratliff B. A., Seiler C. A. and Foisie D. C. (1992) Clinical experience with rhenium-I86-labeled monoclonal antibodies for radioimmunotherapy: results of phase I trials. J. Nucl. Med. 33, 1099-l ,39. Caron P. C., Co M-S., Bull M. K., Avdalovic N. M., Queen C. and Scheinberg D. A. (1992) Biological and immunological features of humanized Ml95 (anti-CD33) monoclonal antibodies. Cancer Res. 52, 6761-6767. Carrasquillo J. A., Krohn K. A., Beaumier P. L., McGuffin R. W., Brown J. P., Hellstrom K. E., Hellstrom I. and Larson S. M. (1984) Diagnosis and therapy of solid tumors with radiolabeled antibodies and immune fragments. Cancer Treat. Rep. 68, 317-328. Co M. S., Avdalovic N. M., Caron P. C., Avdalovic M. V. and Scheinberg D. A. (1992) Chimeric and humanized antibodies with specificity for the CD33. J. Immunol. 148, 1149-I154. Colcher D. C., Milenic D. E., Ferroni P., Roselli M. and Schlom J. (1991) In vivo and in vitro clinical applications of monoclonal antibodies against TAG-72. Nucl. Med.

Brady L. W., Woo D. V., Markoe A., Dadparvar S., Karlsson U., Rackover M., Peyster R., Emrich J.,

Courtenay-Luck N. S., Epenetos A. A., Halnan K. E., Hooker G. R., Hughes J. M. B., Krausz T., Lambert J.,

that is tumor selective without injury to radiation sensitive tissue. There have been a number of practical problems in achieving the goal of curing human tumors, such as the development of immunity against murine monoclonals and associated hematopoietic toxicity. However, significant progress has been made. Long term CRs are now being seen in selected patients with non-Hodgkin’s lymphoma treated with high dose iodine-l 3 1 radioantibody and bone marrow transplant. Progress is being made in other important human cancers as well; especially in Hodgkin’s lymphoma and leukemias. Solid tumors offer a greater challenge but novel methods of dosimetry, and new antibody forms promise to increase the number of CRs and potentially cures. Advances in genetic engineering have resulted in the production of clinic ready humanized antibodies which will be less immunogenic and are in a form better suited for in oiuo localization in tumors. manner

Biol. 18, 395401.

Current status of radioimmunotherapy Lavender P. J., MacGregor W. G., McKenzie C. J., Munro A. J., Myers M. J., Orr J. S., Pearse E. E., Snook D. E., Webb B., Burchell J., Durbin H., Kemshead J. and Taylor-Papadimitriou J. (1984) Antibody-guided irradiation of malignant lesions: three cases illustrating a new method of treatment. A report from the Hammersmith Oncology Group and the Imperial Cancer Research Fund. Lancer 1441-1443. DeNardo S. J., DeNardo G. L. and O’Grady L. F. (1988) Pilot studies of radioimmunotherapy of B cell lymphoma and leukemia using Iodine-131 Lym-1 monoclonal antibody. Antibody Immunoconj. Radiopharm. 1, 17-33. Eary J. F.. Press 0. W., Badger C. C., Durack L. D. and Richter K. Y. (1990) Imaging and treatment of B-cell lymphoma. J. Nucl. Med. 31, 125771268. Kalofonos H. P., Pawlikowska T. R., Hemingway A., Courtenay-Luck N. S., Dhokia B., Snook D. E., Sivolapenko G. B., Hooker G. R., McKenzie C. G., Lavender P. J., Thomas D. G. T. and Epenetos A. A. (1989) Antibody guided diagnosis and therapy of brain gliomas using radiolabeled monoclonal antibodies against epidemral growth factor receptor and placental alkaline phosphatase. J. Nucl. Med. 30, 16361645. Kaminski M. S., Fig L. M., Zasadny K. R., Koral K. F., DelRosario R. B., Francis I. R., Hanson C. A., Normoile D. P., Mudgett E. and Liu C. P. (1992) Imaging, dosimetry, and radioimmunotherapy with iodine 131-labeled anti-CD37 antibody in B-cell lymphoma. J. C/in. Oncol. 10, 16961711. Kang-Da L., Zhao-You T. and Ji-Zhen L. (1988) Radiotherapy for hepatocellular carcinoma (HCC) USING i-131 anti-HCC isoferritin IgG. Preliminary results of experimental and clinical studies. Inf. J. Radial. Oncol. Biol. Phys. 16, 319-323.

Kassis A. I., Sastry K. S. R. and Adelstein S. J. (1985) Intracellular localization of auger electron emitters: biophysical dosimetry. Radial. Prot. Dosim. 13, 233-236. Krdmer E. L. and Larson S. M. (1991) Tumor targeting with radiolabeled antibody for diagnosis and therapy. In Human Cancer 1mmunolog.y II. Immunology and Allergy Clinics of North America (Edited by Oettgen H. F.). 11th Edn, pp. 301.-339. Saunders, Philadelphia, Pa.

Larson S. M. (1993) A model for others: a strategy for improving diagnosis and therapy of human malignancies using monoclonal antibodies targeting the TAG-72 oncofetal antigen. Cancer fmest. 11, 235-238. Larson S. M., Leibel S. A. and Cheung N-K. V. (1991) Radioisotope conjugates. In Biologic Therapy of Cancer (Edited by DeVita V. T., Hellman S. and Rosenberg S. A.), pp. 469-51I. Lippincott, Philadelphia, Pa. Larson S. M., Carrasquillo J. A., Krohn K. A., Brown J. P., McGuffin R. W.. Ferens 3. M., Graham M. M., Hill L. D., Beaumier P. L., Hellstrom K. E. and Hellstrom I. (1983) Localization of Iodine-131-p97 specific Fab fragments in human melanoma as a basis for radiotherapy. J. Clin. Invesf. 72, 2101L2114.

Larson S. M., Carrasquillo J. A., Colcher D. C., Yokoyama K., Reynolds J. C.. Bacharach S. A., Raubitschek A. A., Pace I_..,Finn R. D., Rotman M., Stabin M., Neumann R. D.. SUmrbdker P. and Schlom J. (1991) Estimates of radiation absorbed dose for intraperitoneally administered Iodine- 131 radiolabeled B72.3 monoclonal antibody in patients with peritoneal carcinomatosis. J. Nucl. Med. 32, 1661-1667.

Loevinger R., Budinger T. F. and Watson E. E. (1988) MIRD Primer for Absorbed Dose Calculations. Society of Nu&ar Medicine, New York. Meredith R., Khazaeli M. B., Plott G. et al. (1993) Phase 11 trial of I-131 labeled high affinity anti-TAG-72 antibody for metastatic prostate cancer. Antibody Immunoconi. Radiopharm. 6, 89 (abstract). Murray J. L., Podoloff D., Kasi L. et al. (1992) Phase II radioimmunotherapy trial of I-131 CC49, a high affinity

791

second generation monoclonal antibody (MAB) against TAG-72, in refractory colon cancer. Antibody Immunoconj. Radiopharm. 5, 343 (abtract). Nabi H. A. and Doerr R. J. (1992) Radiolabeled monoclonal antibody imaging (immunoscintigraphy) of COIorectal cancers: Current status and future perspectives. Am. J. Surg. 163, 448456.

Order S. E., Stillwagon G. B. and Klein J. L. (1985) Iodine-131 antiferritin, a new treatment modality for hepatoma: a radiation oncology group study. J. Ckn. Oncol. 3, 1573-l 582.

Press 0. W., Eary J. F., Badger C. C.. Martin P. J., Appelbaum F. R.. Nelp W. B., Levy R., Miller R., Fisher D. and Matthews D. (1991) Radiolabeled antibody therapy of human B cell lymphomas. Adr. Exp. Med. Bio(. 303, 91-96.

Press 0. W., Eary J. F., Badger C. C.. Martin P. J., Appelbaum F. R., Levy R. N., Miller R. A., Brown S. J., Nelp W. B., Krohn K. A., Fisher D. R., DeSantes K.. Porter B., Kidd P., Thomas E. D. and Bernstein I. D. (1989) Treatment of refractory non-Hodgkin’s lymphoma with radiolabeled MB-I (Anti-CD37) antibody. J. C/in. Oncol. 7, 1027-~1038.

Pressman D. and Korngold L. (1953) The in-tioo localization of anti-Wagner osteogenic sarcoma antibodies. Cancer 6, 619-623.

Rosen S. T., Zimmer M. A. and Goldman-Leikin R. (1987) Radioimmunodetection and radioimmunotherapy of cutaneous T cell lymphomas using an Iodine-131 labeled monoclonal antibody. J. Clin. Oncol. 4, 562-573. Scheinbcrg D. A., Lovett D.. Divgi C. R., Graham M. C.. Berman E., Pentlow K. S., Feirt N., Finn R. D., Clarkson B. D.. Gee T. S., Larson S. M., Oettgen H. F. and Old L. J. (1991) A phase I trial of monoclonal antibody Ml95 in acute myelogenous leukemia: specific bone marrow targeting and internalization of radionuclide. J. Clin. Oncol. 9, 478~490. Schlom J., Colcher D. C., Roselli M., Carrasquillo J. A. and Reynolds J. C. (1989) Tumor targeting with monoclonal antibody B72.3. Nucl. Med. Biol. 16, 137 142. Schlom J., Hand P. H., Greiner J. W.. Colcher D. C.. Shrivastav S., Carrasquillo J. A., Reynolds I. C., Larson S. M. and Raubitschek A. A. (1990) Innovations that influence the pharmacology of monoclonal antibody guided tumor targeting. Cancer Res 50 (Suppl.), 820~s827s. Schwartz M. A., Lovett D. R.. Redner A.. Finn R. D.. Graham M. C., Divgi C. R., Dantis L., Gee T. S., Andreeff M., Old L. J., Larson S. M. and Scheinberg D. -A. (1993) Dose-escalation trial of Ml95 labeled with Iodine-l 31 for cytoreduction and marrow ablation in relapsed and refractory myeloid leukemias. J. Clin. Onwf. 11, 294-303.

Scott A. M.. Divgi C. R., Kemeny N. el ul. (1992a) Radioimmunotherapy with Iodine-131 labeled monoclonal antibody CC49 in colorectal cancer. Eur. J. NW/. Med. 19, 709 (abstract). Scott A. M., Divgi C. R., McDermott K. er al. (1992b) Comparative radiolocalizafion of monoclonai antibodies (MAB) 872.3 and CC49 in oatients with colorectal cancer. Akibo
Sgouros G., Chiu

DOSCAL: a tumor-incorporating mean absorbed dose calculation program. J. Nucl. Med. 29, X74.

792 Sgouros

STEVEN

M. LARSONet al.

G., Barest G., Thekkumthala J. et al. (1990) Treatment olannine for internal radionuclide theraov: three-dimensional - dosimetry for nonuniformiy radionuclides. J. distributed ivucl. Med. 31, 18861891. Spar 1. L., Bale W. F., Marrack D., Dewey W. C., McCardle R. J. and Harper P. V. (1967) Iodine-131 labeled antibodies to human fibrinogen: diagnostic studies and therapeutic trials, Cancer 20, 865-870. Stewart J. S., Hird V., Snook D., Dhokia B., Sivolapenko G., Hooker G., Papadimitriou J. T., Rowlinson G., Sullivan M. and Lambert H. E. (1990) Intraperitoneal yttrium-904abeled monoclonal antibody in ovarian cancer. J. C/in. Oncol. 8, 1941-1950.

Stewart J. S. W., Hird V., Snook D. E., Sullivan M., Myers M. J. and Eoenetos A. A. (1988) Intraoeritoneal “‘I- and 90Y-labelled~monoclonal antibodies for ovarian cancer: pharmacokinetics and normal tissue dosimetry. ht. J. Cancer (Suppl.) 3, 71-76. Stewart J. S. W., Hird V., Sullivan M., Snook D. E. and Epenetos A. A. (1989) Intraperitoneal radioimmunother;;;_k; ovarian cancer. Br. J. Obstet. Gynecol. 96, Vriesendorp H. M., Herpst J. M., Germack M. A., Klein J. L., Leichner P. K., Loudenslager D. M. and Order S. E. (1991) Phase I-II studies of yttrium-labeled antiferritin treatment for end-stage Hodgkin’s disease, including radiation therapy oncology group 87-01. 1. Clin. Oncol. 9, 918-928.