Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1994-06-06
1999-02-23
Draper, Garnette D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536234, 536 2352, 435 691, 435 695, 435 6952, 4353201, 435697, 4352523, 4353723, 435372, 435366, 435363, 514 44, 424 93R, 424 93A, 424 93B, 424 93U, 424 93V, C12N 1500, C12N 1524, C12N 1587, A61K 4800
Patent
active
058745564
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The invention relates to materials for use in immunotherapy, and more specifically to lymphocytes containing recombinant genes that when expressed, enhance growth or proliferation.
BACKGROUND
T lymphocytes are responsible primarily for protection against intracellular pathogens and malignancies. Individuals who are grossly deficient in T-cell immunity frequently succumb to overwhelming infections by organisms such as cytomegalovirus, Pneumocystis carinii, Candida, and other apparently "opportunistic" pathogens, including bacteria, viruses and fungi. These individuals may also succumb to malignancies such as B cell lymphomas, indicating the importance of T cell immunity in the suppression or elimination of certain tumors. Immunosuppression can result from a variety of causes, including viral infections (for example, with the RIV virus), as a result of chemical therapy, and malignancies (particularly of types that affect the hematopoietic system).
All mature T lymphocytes express the CD3 cell surface molecule, but consist of two basic subtypes based on their mutually exclusive expression of cell surface molecules CD4 and CD8. The functional distinction between CD4+ and CD8+ T cells is based on the ability of CD4+ cells to recognize antigen presented in association with class II MHC molecules, and CD8+ cells to recognize antigen presented in association with class I MHC molecules. CD8+ cells are involved in "effector" functions in immune responses, such as direct cytotoxic destruction of target cells bearing foreign antigens, and represent an important mechanism for resistance to viral infections and tumors. The CD8+ cells that mediate this lytic function are designated cytotoxic T lymphocytes (CTLs). CD4+ T cells are generally involved in "helper" functions in immune responses and secrete cytokine molecules, in particular IL-2, upon which the cytotoxic CD8+ T cells are dependent. CD4+ T cells are often referred to as T helper (TH) cells. Although most CTL are of the CD8+ phenotype, some CTL of the CD4+ phenotype have been described. Generally, individual CTLs (whether CD8+ or CD4+) are antigen-specific.
Classes of lymphocytes, for example CTLs, are dependent on helper T (TH) cell-derived cytokines, such as IL-2, for growth and proliferation in response to foreign antigens. (Zinkernagel and Doherty, Adv. Immunol. 27:51, 1979; Male et al., Advanced Immunology, Chap. 7, Gower Publ., London, 1987; Jacobson et al., J. Immunol. 133:754, 1984). IL-2, for example, is a potent mitogen for cytotoxic T lymphocytes (Gillis and Smith, Nature 268:154, 1977), and the combination of antigen and IL-2 cause proliferation of primary CD8+ T cells in vitro. The importance of IL-2 for the growth and maintenance of the CD8+ CTL in vivo has been documented in models of adoptive immunotherapy in which the therapeutic efficacy of transferred anti-retroviral CD8+ cells is enhanced on subsequent administration of IL-2 (Cheever et al., J. Exp. Med. 155:968, 1982; Reddehase et al., J. Virol. 61:3102, 1987). IL-4 and IL-7 are also capable of stimulating the proliferation of mature CD8+ CTL (Alderson et al., J. Exp. Med. 172:577, 1990).
Considerable research has been focused on the use of T cells in treating malignant tumors and viral infections. Cytotoxic T cells specific for a particular type of tumor can be isolated and administered to a patient having a tumor, with the effect that the CTLs ameliorate the tumor. It has been demonstrated, for example, that tumor-specific T cells can not only be generated to experimental tumors in mice, but also that T cells with apparent tumor specificity can be isolated from human tumors. Such human tumor infiltrating lymphocytes (TILs) have been expanded in vitro and used to treat cancer patients, generating significant enthusiasm for human adoptive immunotherapy with tumor-specific T cells (Rosenberg et al., N. Engl. J. Med. 319:1767, 1988).
Similar studies using cytotoxic T cells specific for viral antigens have also been conducted in animal models. Human HIV-specific CTL of both
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Allen James M.
Feldhaus Andrew L.
Lupton Stephen D.
Draper Garnette D.
Dylan Tyler M.
Targeted Genetics Corporation
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