Cutaneous T cell lymphoma (CTCL) represents a spectrum of disease which currently is not curable by conventional therapy once the disease advances beyond the localized plaque stage. This lack of adequate therapy indicates that new therapeutic and diagnostic approaches should be investigated which can detect this disease earlier and can cure patients when the disease has progressed beyond the local stages. The neoplastic T cells present in CTCL usually express the surface antigens CD3 and CD4, typical of mature T- helper cells, and the CD3-associated T cell antigen receptor (TCR). Studies in this laboratory initially demonstrated that the TCR expresses both a private idiotype, which is a tumor specific marker, and an epitope cross-reactive with normal T cells, which is only slightly less tumor specific than the private idiotype. This project will develop new monoclonal antibodies (mAbs) directed against the TCR expressed on either the actual neoplastic cells, in cases of Sezary syndrome, or cell lines derived from patients with CTCL. The antibodies will be selected for reactivity with the immunogen and a small percentage of normal human T cells. Most of these new mAbs should react with epitopes defined by the different TCR Vbeta or Valpha region genes or gene families. As these mAbs are developed, they will be used in immunofluorescence blocking experiments to confirm that the reagents detect different non-cross blocking epitopes on the TCR. The immunogen used to produce these cross-reactive anti-TCR mAbs will be characterized by a quantitative polymerase chain reaction to determine which V region gene family is expressed by the neoplastic clone. Taken together, these data will characterize the V region specificity of the new mAbs. As more mAbs are developed, they will be used to monitor the blood and bone marrow of patients with CTCL to determine the extent of disease involvement in these tissues and to evaluate whether a stage exists where marrow or blood involvement would preclude bone marrow harvest. Experiments also will be performed using these mAbs to purge normal bone marrow reconstituted with the immunizing cells or concordant cell line. After purging the reactive cells, the remaining marrow cells will be analyzed to demonstrate the depletion of anti-TCR reactive cells and to confirm that hematopoietic colony-forming cells are not depleted. These studies will determine whether transplantation of autologous bone marrow which was purged ex vivo using anti-TCR mAbs could become a clinically useful method to treat these patients. Experience with autologous bone marrow transplants in CTCL patients obtained in our department indicates that these patients can be successfully transplanted and survive the initial stage of leukopenia. Thus, over several years the production of these antibodies would provide a panel of anti-TCR reagents reactive with TCR Valpha and Vbeta gene families which should cover the entire T cell repertoire. One reagent from this panel should react with any individual patient's neoplastic clone and could then be used clinically for diagnostic or therapeutic purposes. Application of these studies to autologous bone marrow transplantation provides a new and potentially curative method to treat not only patients with CTCL but also patients with other T cell neoplasms, such as T-CLL, T cell non-Hodgkin's lymphoma, and some cases of T-ALL, all of which may express the TCR.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR040404-02
Application #
3160768
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1991-02-01
Project End
1996-11-30
Budget Start
1992-02-01
Budget End
1993-01-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Allegheny University of Health Sciences
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129
Vonderheid, E C; Zhang, Q; Lessin, S R et al. (1998) Use of serum soluble interleukin-2 receptor levels to monitor the progression of cutaneous T-cell lymphoma. J Am Acad Dermatol 38:207-20
Marks, D I; Vonderheid, E C; Kurz, B W et al. (1996) Analysis of p53 and mdm-2 expression in 18 patients with Sezary syndrome. Br J Haematol 92:890-9
Wasik, M A; Vonderheid, E C; Bigler, R D et al. (1996) Increased serum concentration of the soluble interleukin-2 receptor in cutaneous T-cell lymphoma. Clinical and prognostic implications. Arch Dermatol 132:42-7
Vonderheid, E C; Bigler, R D; Greenberg, A S et al. (1994) Extracorporeal photopheresis and recombinant interferon alfa 2b in Sezary syndrome. Use of dual marker labeling to monitor therapeutic response. Am J Clin Oncol 17:255-63
Esfahani, M; Bigler, R D; Alfieri, J L et al. (1993) Lipoproteins upregulate high affinity Fc receptors in human monocytes. Biochem Biophys Res Commun 191:610-6
Esfahani, M; Bigler, R D; Alfieri, J L et al. (1993) Cholesterol regulates the cell surface expression of glycophospholipid-anchored CD14 antigen on human monocytes. Biochim Biophys Acta 1149:217-23
Esfahani, M; Bigler, R D; Gressen, E (1993) Effect of lovastatin on cell surface expression of Fc receptors or CD14 antigen in human monocytes. Biochem Pharmacol 46:2333-6
Hubbell, H R; Vargas, H E; Tsujimoto, K L et al. (1992) Antitumor effects of interleukin-2 and mismatched double-stranded RNA, individually and in combination, against a human malignant melanoma xenograft. Cancer Immunol Immunother 35:151-7