[CANCER RESEARCH 51. 688-695. January 15. 1991] Direct Intralymphatic Injection of Radiolabelcd Inln-T101 in Patients with Cutaneous T-Cell Lymphoma1 James L. Mulshine,2 Jorge A. Carrasquillo, John N. Weinstein, Andrew M. Keenan,1 James C. Reynolds, Jean Herdt, Paul A. Bunn, Edward Sausville, Joyce Eddy, James D. Cotelingam, Patricia Perentesis, Carl Pinsky, and Steven M. Larson National Cancer Institute-Navy Medical Oncology Branch, Clinical Oncology Program, Division of Cancer Therapy, National Cancer Institute /J. L M., P. A. B., E. S., J. E.J, Department of Nuclear Medicine [J. A. C., A. M. K., J. C. K., P. P.] and Department of Radiology [J. H.J, Warren C. Magnuson Clinical Center, National Institutes of Health, and Laboratory of Mathematical Biology, National Cancer Institute [J. N. W.], National Institutes of Health, Bethesda, Maryland 20814: Division of Medical Oncology, University of Colorado Cancer Center and Health Service Center, Denver, Colorado 80262 [P. A. B.J; Department of Pathology, Naval Hospital, Bethesda, Maryland 20814 fj. D. C.J; and Biological Response Modifier Program, Frederick Cancer Research Center, Divisions of Cancer Treatment, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21701 ¡C.P./; Department of Nuclear Medicine, Memorial SIoan-Kettering Cancer Center, New York, New York 10021 ¡S.M. L.J ABSTRACT Direct intralymphatic administration of radiolabeled monoclonal anti body in targeting antigen-bearing lymphoma cells in regional lymph nodes of patients with cutaneous T-cell lymphoma was evaluated. Seven con secutive patients undergoing staging lymphangiography received intra lymphatic infusions of '"In-11(11 to evaluate lymph node involvement. This procedure was accomplished without significant complication. The '"In- IKtl rapidly distributed throughout the regional lymphatic com partment and passed into the systemic circulation. Tumor-bearing sites in the inguinal-femoral lymph nodes retained from 0.42 to 4.8% of the injected dose of radiolabeled antibody. Three patients were upstaged to Stage IVA based on tumor involvement found after radiolymphoscintig- raphy-directed biopsy of groin lymph nodes, selected because of intense radioactivity by gamma camera imaging. Compared with previously re ported s.c. antibody administration, there was a marked reduction in the radioactive exposure of normal tissues at the injection sites in the lower extremities. Direct intralymphatic delivery of "'In-11(11 appears to be a feasible, efficient method for delivering therapeutic doses of radiolabeled antibody. INTRODUCTION CTCL" is a distinctive subtype of lymphoma, possibly of retroviral etiology ( 1), which is rarely cured by existing therapies (2). T101 is a murine monoclonal antibody which binds to CDS, an M, 65,000 antigen, expressed on normal T-cells as well as on malignant T- and B-cells (3). Administration of the radi- oconjugate "'In-T101 i.v. for radioimmunoscintingraphy of both CTCL and chronic lymphocytic leukemia patients has resulted in reproducible imaging of tumor-involved sites (4-7). Biopsy of involved lymph nodes in patients with CTCL showed recovery of only a very small fraction of the injected dose (<0.02%/g), but this was approximately 10-100 times greater than previously reported delivery of radiolabeled monoclonal antibodies in solid tumors (4-8). Delivery of '"In-T101 i.v. Received 12/11/89; accepted 10/23/90. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Navy, the Department of Defense, or the Department of Health and Human Services. 2To whom requests for reprints should be addressed, at National Cancer Institute, NCI-Navy Medical Oncology Branch. Naval Hospital Bethesda. Bldg. 8. Rm. 5101. Bethesda. MD 20814. 3 Present address: Nuclear Medicine/Radiology Department. Hospital of the University of Pennsylvania. 3400 Spruce St. Philadelphia. PA 19104. 4 The abbreviations used are: CTCL, cutaneous T-cell lymphoma; Ti-T3. tumor stages 1-3. also resulted in >50% of the injected dose localizing in the liver and spleen. In a therapeutic trial, administration of large doses of unla- beled T101 did not result in significant clinical benefit despite a transient lowering of circulating tumor cell number (9, 10). To enhance the therapeutic effect, Rosen et al. (11) coupled iodine-131 to T101 for administration to patients with refrac tory CTCL. The five patients with CTCL treated with '"I- T101 experienced brief objective and subjective improvements, but bone marrow toxicity was dose limiting. One way to decrease nonspecific reticuloendothelial uptake, to improve the efficiency of lymph node imaging, and to reduce toxicity in therapeutic trials is to administer antibody s.c. for regional lymphatic uptake. Extensive animal studies have shown that s.c. delivery of monoclonal antibody results in highly efficient delivery to lymphoid target cells in the regional lym phatics with much less systemic uptake than is seen with i.v. injection (12-16). Delivery of'"In-TlOl s.c., into the web spaces of the foot of patients with CTCL also resulted in efficient delivery of the labeled antibody to normal and tumor-involved lymph nodes along the draining regional lymphatic vessels (17, 18). Com parison of biopsy data from patients receiving '"In-TlOl by s.c. administration showed a much greater percentage of in jected dose recovered from cancerous lymph nodes than previ ously reported with i.v. radiolabeled T101 administration (18). Since regional lymph nodes are thought to be an important proliferative compartment for malignant cells in CTCL (19, 20), this is a potentially important target for radiolabeled T101 therapy. After s.c. "'In-T101 antibody administration, a large fraction of the injected radioactive dose remained at the injec tion sites, which cleared with a half-life of 14-29 h. This local retention resulted in 136-280 rads/mCi, or a total of 34-70 rads, to each foot per study (17, 18). This radiation dose exposure did not result in clinical toxicity. However, the a- and 0-emitting isotopes required for therapeutic purposes would exceed limits of local tissue tolerance if delivered s.c. (21). In the present study, we infused radiolabeled monoclonal antibody directly into cannulated lymphatic vessels of the foot at the time of routine diagnostic lymphangiography. The tech nique of direct antibody injection in the lymphatics was pi oneered by Order et al. (22) using heteroantibody preparations directed against tumor-associated antigens. Further work with regional delivery of radiolabeled antibody in patients with car cinoma was reported by DeLand et al. (23). The goal of this approach would be to preserve the efficiency of tumor tissue 688 Research. on October 31, 2015. © 1991 American Association for Cancer cancerres.aacrjournals.org Downloaded from