Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Primate cell – per se
Patent
1995-11-01
2000-07-04
Saunders, David
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Primate cell, per se
424 9321, 424 9371, 435325, 435347, 435373, 530350, C12N 510, A61K 3514, C07K 14705
Patent
active
060837519
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The invention relates to the field of immunotherapy, more specifically to the introduction of genetic material encoding chimeric receptors into lymphocytes to generate cytotoxic T lymphocytes (CTLs) that are selectively-activatable and that have a lessened dependence on helper (T.sub.H) cells and/or growth factors supplied by T.sub.H cells.
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 HIV virus), as a result of chemical therapy, and malignancies (particularly of type that affect the hematopoietic system).
Mature T lymphocytes generally express the CD3 cell surface molecule, but consist predominantly of two basic subtypes based on their mutually exclusive expression of cell surface molecules CD4 and CD8. Most CD4+ T cells are involved in "helper" functions in immune responses and secrete cytokine molecules, in particular interleukin 2 (IL-2), upon which the cytotoxic CD8+ T cells are dependent. Such CD4+ T cells are often referred to as T helper (T.sub.H) cells. 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 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. The CD8+ cells that mediate this lytic function are designated cytotoxic T lymphocytes (CTLs). 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.
Lymphocytes are dependent upon a number of cytokines for proliferation. For example, CTLs are dependent on helper T (T.sub.H) 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 causes 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 by 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 at least a sub-population 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, generati
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Allison,
Feldhaus Andrew Lawrence
Jones Lori Ann
Saunders David
Targeted Genetics Corporation
Tung Mary Beth
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