Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Patent
1995-12-08
1998-10-13
Schwadron, Ronald B.
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
424 931, 424 932, 424 9321, 424 9371, 424534, 424577, 435 2, 4352401, 4352402, 43524021, A01N 6300, C12N 508, C12N 500, C12N 522
Patent
active
058208569
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates generally to the preparation of a modified cytotoxic T lymphoblastic leukemia (T-ALL) cell line.
BACKGROUND OF THE INVENTION
Cytolytic T lymphocytes (CTL) and natural killer (NK) cells have complementary roles in providing defense against tumor cells, Young, Cancer Cells 2:138 (1990)!. CTL are CD3.sup.+ /T-cell receptor (TCR).alpha..beta..sup.+, CD8.sup.+, CD16.sup.- cells which recognize specific peptides in association with class I molecules of the major histocompatibility complex (MHC). NK cells are CD3.sup.- /TCR.sup.-, CD16.sup.+, CD56.sup.+ cells which are constitutively able to lyse virus-infected cells and some tumor cell lines (but not fresh tumor cells) without prior sensitization and without restriction by MHC antigens. The molecules specifically involved in target cell recognition by NK cells (the putative NK receptor) are as yet unknown.
Over the past decade, lymphokine-activated killer (LAK) activity has been defined as an additional type of MHC non-restricted killing. LAK cells are conventionally generated upon short-term culture of human peripheral blood cells in interleukin-2 (IL-2) and possess phenotypic characteristics of either NK (CD3.sup.- CD16.sup.+) or T (CD3.sup.+ CD16.sup.-) cells, thus constituting an heterogeneous (mixed) cell population. LAK cells are able to kill NK-resistant tumor cell lines, autologous and allogeneic fresh tumor targets, and virus-infected cells while remaining substantially S. Rosenberg, J. Natl. Can. Inst., 75:595 (1985)!.
A. Adoptive Immunotherapy of Cancer Using LAK Cells and CTL
The use of LAK cells as anti-cancer effectors in combination with recombinant human (rh) IL-2 in adoptive immunotherapy of cancer has resulted in the achievement of temporary remission in a variety of human New Engl. J. Med., 313:1485 (1985); S. A. Rosenberg et al., New Engl. J. Med., 316:889 (1987); W. H. West et al., New Engl. J. Med., 316:898 (1987)!. However, LAK cell therapy has had little success against major problems affect the efficiency of adoptively transferred LAK cells: one is the inadequate tumoricidal activity of these MHC non-restricted polyclonal killer cells; the second is the unavailability of sufficient numbers of activated effectors that retain both cytotoxic and tumor targeting capabilities. The high doses of rh IL-2 administered to the patients to circumvent these limitations have been associated with and Rosenberg et al., (1987), both cited above!.
Several alternate approaches have been proposed to improve cancer therapy, including the use of antigen-specific tumor infiltrating cytotoxic J. Immunol., 138:989 (1987)!, the use of LAK cells linked with antibodies and Nistico et al, J. Clin. Invest., 90:1093 (1992)!, and genetic engineering of tumor cells with cytokine genes (such as IL-2, TNF, IFN-.gamma., IL-4, IL-6, and IL-7), to promote enhanced anti-tumor al, Cancer Res., 50:7820 (1990); Hock et al, J. Exp. Med., 174:1291 (1991); Golumbeck et al, Science, 254:713 (1991); and Asher et al, J. Immunol., 146:3227 (1991)!. In particular, TIL expanded from tumor infiltrates in the presence of high doses of rh IL-2 (6000 U/ml) grow Cancer Res. 46:3011 (1986); Rosenberg, S. A., Ann. Surg. 208:121 (1988)! which can be transferred back into the tumor-bearing individuals (together with high doses of IL-2), where they migrate into tumor lesions and promote tumor regression. However, IL-2 therapy in combination with these specific CTL (TIL/IL-2 therapy) has yielded objective tumor regression in only 20-30% of patients with melanoma and carcinoma of the kidney cytokine-related toxicities (including the capillary leak syndrome and renal dysfunction) have precluded extended therapies in many patients 210:474 (1989); Lee, et al, J. Clin. Oncol. 7:7 (1989); and Lotze, et al. Hum. Immunol. 28:198 (1990)!.
B. Bone Marrow Purging and Consolidative Immunotherapy (LAK/IL-2 Therapy) in Patients with Leukemia
Autologous bone marrow transplantation (ABMT) has shown preliminary promising results both in children with acute myelobla
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Cesano Alessandra
Rovera Giovanni
Santoli Daniela
Schwadron Ronald B.
The Wistar Institute of Anatomy and Biology
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