摘要:

Summary:Disseminated tumors growing progressively in syngeneic hosts can be eradicated by combination therapy with cyclophosphamide and adoptive transfer of specifically immune T cells. Interleukin‐2 (IL‐2), which induces proliferation of T cells specifically activated by antigen, has substantial therapeutic potential as a reagent for increasing the magnitude of tumor‐specific T cell responses. The purpose of the present studies was to determine the effector mechanisms operative in tumor‐bearing hosts by which subpopulations of immune T cells can mediate tumor eradication, and to determine if thein vivoadministration of exogenous IL‐2 can augment these T cell effector functions. Disseminated leukemia was eradicated by adoptive therapy with the immune Lyt 1+2− noncytolytic T cell subpopulation, under experimental conditions in which cytolytic T lymphocytes could not participate. The Lyt 1+2− subset contains helper/amplifier cells that produce endogenous IL‐2 in response to tumor and effector cells that mediate delayed‐type hypersensitivity reactions. The administration of exogenous IL‐2 following transfer of immune T cells containing this noncytolytic subset failed to augment their therapeutic activity, implying that the amount of IL‐2 being produced endogenously did not limit the antitumor response. Adoptive therapy with purified cytolytic Lyt 1−2+ T cells produced a demonstrable but limited antitumor effect. Since this cytolytic subpopulation lacked helper T cells, the limited activity observed presumably reflected a requirement for an IL‐2‐producing cell. Administration of exogenous IL‐2 following cell transfer satisfied this requirement and markedly augmented the efficacy of adoptive therapy with Lyt 1−2+ T cells. Thus, infusions of exogenous IL‐2, which may have little activity in settings in which helper T cell function is intact, may be of significant benefit for augmenting cytotoxic responses in hosts that are relatively deficient in helper T cells.

ISSN:0732-6580    

出版商:OVID    

年代:1984

数据来源: OVID

摘要:

Summary:The purpose of the studies being described was to determine if interleukin‐2 (IL‐2) administeredin vivocan induce the growth and increase the number of antigen‐activated T cells, and thereby augment specific T cell functionin vivo.Initial experiments examined thein vivogrowth of adoptively transferred T cells previously cultured long term with IL‐2, sincein vitrosuch long‐term cultured T cells are exquisitely dependent on exogenous IL‐2 for proliferation and survival. To identify and quantify donor T cellsin vivo, experiments were performed with donor and host mice congenic for the T cell marker Thy 1. Host mice receiving congenic long‐term cultured immune T cells were inoculated daily with purified IL‐2 beginning on the day of cell transfer, and donor T cells within host ascites, spleen, and lymph nodes were enumerated at selected points in time. The experiments demonstrated that exogenous IL‐2 inducedin vivogrowth of long‐term cultured T cells proportional to the dose of IL‐2 administered. Similar IL‐2 regimens induced thein vivogrowth and augmented the function of donor T cells that had been activated to express IL‐2 receptorsin vitroby 5‐day culture with antigen but had not been cultured with exogenous IL‐2. Thus, prior adaptation to growth with exogenous IL‐2in vitrois not necessary to render T cells responsive to IL‐2in vivo. In contrast to long‐term cultured T cellsin vivo(which died rapidlyin vivowithout exogenous IL‐2), noncultured donor T cells proliferatedin vivoin response to antigen. This proliferation presumably reflected endogenous production of IL‐2 and the administration of exogenous IL‐2 failed to augment thein vivogrowth of noncultured donor T cells. Additionally, certain IL‐2 regimens appeared to decrease the magnitude of such antigen‐driven immune responses. Thus, there may be situationsin vivoin which the administration of IL‐2 negatively influences cell‐mediated immunity. Studies to examine the effect of IL‐2 on T cell functionin vivodemonstrated that IL‐2 regimens that induced growth of T cellsin vivoalso augmented the ability of adoptively transferred donor T cells to eradicate disseminated murine leukemia. Thus, the results suggest that IL‐2 may have significant therapeutic potential forin vivostimulation of T cell responses that are relatively deficient in the production of endogenous IL‐2.

ISSN:0732-6580    

出版商:OVID    

年代:1984

数据来源: OVID

摘要:

Summary:Precursors of antigen‐specific cytotoxic T cells from mice pretreated with immunosuppressive doses of cyclophosphamide can be expandedin vitroandin vivoby low doses of human interleukin‐2. The effector cells are Thy 1+ and are not elicited in the absence of antigen. High doses of human interleukin‐2in vitrocan expand both normal and cyclophosphamide‐resistant T cell precursors into effector cells capable of lysing both natural killer cell‐sensitive and ‐insensitive target cells in the absence of antigen.

ISSN:0732-6580    

出版商:OVID    

年代:1984

数据来源: OVID

摘要:

Summary:Twelve patients were treated in a Phase I trial of purified human interleukin‐2 (IL‐2) derived from the JURKAT cell line (E. I. duPont Corp., Glenolden, PA, U.S.A.). The serum half‐life, toxicity, andin vivoimmunologic effects of IL‐2 were studied in patients with cancer unresponsive to standard therapy and in patients with acquired immunodeficiency syndrome (AIDS). Patients received 0.25, 2.5, or 25 &mgr;g/kg IL‐2 by bolus or 24‐h continuous infusion on a weekly basis for 4 weeks. The serum half‐life of JURKAT IL‐2 in humans was ˜ 6 min. At higher doses of IL‐2 a second component of clearance with a half‐life of 30‐120 min was found. Acute toxicity was minimal and consisted of headache (6 of 12), nausea (4 of 12), malaise (6 of 12), and fever and chills (8 of 12). No evidence of pulmonary, hematologic, or renal toxicity or any evidence of autoimmune phenomena was detected. A transient hyperbilirubinemia was seen in two patients receiving 2 mg purified IL‐2. No demonstrable effect on tumors or chronic immunodeficiency (AIDS) was seen. No consistent chronic immunologic effects (natural killer or lymphokine‐activated killer activity, mitogen responsiveness, total lymphocyte counts, or change in the proportion of various mononuclear cell phenotypes as defined by monoclonal antibody) were seen on a week‐to‐week basis during or following therapy. Acute changes in lymphokine responsiveness, the ability to generate lymphokine‐activated killers, and an increase in macrophages in the mononuclear population were noted following administration of 1‐2 mg IL‐2.

ISSN:0732-6580    

出版商:OVID    

年代:1984

数据来源: OVID

摘要:

Summary:Fifteen patients with acquired immunodeficiency syndrome (AIDS), lymphoma and immunodeficiency, or severe combined immunodeficiency were treated with highly purified interleukin‐2 (IL‐2) prepared from human lymphocytes. All patients showed a defect in mitogen‐induced T cell proliferation which was partially corrected when IL‐2 was addedin vitro.IL‐2 was administered subcutaneously by daily injection or continuous infusion. The maximum daily dose was 20,000 U/m2, the maximum total dose 855,000 U/m2, and the maximum period of treatment 77 days. An increase in the platelet count was seen in one patient with AIDS, a decrease in the serum level of a monoclonal immunoglobulin in another patient with AIDS, and a minor tumor response in a patient with diffuse histiocytic lymphoma. As no toxicity was observed, further study of IL‐2 in the treatment of human immunodeficiency is indicated.

ISSN:0732-6580    

出版商:OVID    

年代:1984

数据来源: OVID

摘要:

Summary:The clinical effect of intralesional injection of interleukin‐2 (IL‐2)—cultured autologous lymphocytes was assessed in seven patients with cutaneous, recurrent tumor nodules (12 melanoma and 8 mammary cancer lesions). Each tumor nodule was injected 3‐10 times, once weekly, with IL‐2‐cultured lymphoid cells (CLC), 40‐400 million cells at each injection. Lymphoid cells obtained from buffy coats were separated on Ficoll‐Paque, cryopreserved in liquid nitrogen, thawed, and cultured for 1‐2 weeks in the presence of crude IL‐2 (containing phytohemagglutinin) before injection. CLC were tested for sterility, percent E‐rosette‐forming cells, and cytotoxicity against K562, allogeneic melanoma, and breast cancer cell lines and autologous tumor cells. Enhanced cytotoxicity was expressed by IL‐2 CLC, as compared with nonstimulated peripheral blood lymphocytes (PBL). Arrest of tumor growth (compared with untreated lesions) was observed in eight lesions and partial regression in three lesions. Moreover, complete regression was noted in one large melanoma lesion treated with low‐dose irradiation prior to intralesional administration of CLC and in three small intracutaneous melanoma lesions treated with CLC only. Histopathological findings of responding lesions showed infiltration with lymphoid cells and macrophages, with the tumor cells sparsely dispersed. No untoward side effects of CLC injections were observed. The present study points to the feasibility of trials of adoptive immunotherapy in cancer patients as indicated by the following: (a) response of lymphoid cells to IL‐2 adequate—although reduced—in patients with metastatic disease, including those after chemo‐ or radiotherapy; (b) possibility of cryopreservation of PBL and repeated culturing in IL‐2 after thawing, with cytotoxic activity unimpaired; (c) demonstrably enhanced cytotoxicityin vitroof IL‐2 CLC; (d) demonstrable—although limited—clinical response toin situtreatments with IL‐2 CLC; (e) good tolerance of treatment with CLC.

ISSN:0732-6580    

出版商:OVID    

年代:1984

数据来源: OVID

摘要:

Summary:The adoptive transfer of specifically immune lymphocytes is capable of mediating the regression of a variety of established experimental tumors. We have studied the factors responsible for successful adoptive immunotherapy. Following injection of FBL‐3 lymphoma into the footpad of syngeneic mice, this tumor forms a local nodule and is disseminated throughout the mouse within 5 days. Systemic administration of fresh immune lymphocytes on day 5, or ofin vitroboosted immune splenocytes, or immune lymphoid cells expanded in interleukin‐2 (IL‐2), is capable of mediating total regression of both local and disseminated tumor. The efficacy of this immunotherapy can be enhanced by the simultaneous administration of IL‐2. Because specifically immune cells can be difficult to obtain in many murine and human tumor systems, we have investigated the use of nonspecifically sensitized cells for use in adoptive immunotherapy. Lymphokine‐activated killer cells (LAK) can easily be generated by incubating fresh murine or human lymphocytes in IL‐2. Systemic injection of LAK cells can reduce the growth of established pulmonary metastases in murine tumor models when the LAK cells are administered in conjunction with IL‐2. A variety of methods for activating human lymphoid cells to become lytic for fresh human tumors have been developed, including activation by IL‐2, activation by lectins such as phytohemagglutinin and concanavalin A, and by allosensitization with pooled stimulator cells. The characteristics of these different activated killer cells have been defined. In a series of Phase I studies, we have demonstrated that activated killer cells can be safely administered to humans with advanced cancer. Studies are actively proceeding to develop an effective and practical method for the adoptive immunotherapy of cancer in humans, using both specifically activated and nonspecifically activated lymphoid cells.

ISSN:0732-6580    

出版商:OVID    

年代:1984

数据来源: OVID

摘要:

Summary:Twelve patients with acquired immunodeficiency syndrome were treated with a natural product, highly purified human interleukin‐2. Doses ranged from 250 to 250,000 units. No clinical responses were seen. Minimal toxicity was noted and consisted of mild prolongation of partial thromboplastin time and proteinuria. Immunologic changes during the study included a decrease in the number of circulating T8 lymphocytes, increased skin test reactivity, and a decline in serum immunoglobulin levels.

ISSN:0732-6580    

出版商:OVID    

年代:1984

数据来源: OVID

摘要:

Summary:The therapeutic efficacy of crude interleukin‐2 (IL‐2) preparations and of IL‐2‐propagated lymphocytes (cultured T cells; CTC) was assessed, with and without chemotherapy, in conventional mice and in athymic nude mice implanted with murine or human neoplasms. Treatment of conventional mice implanted with lung and mammary carcinomas by repeated administration of lowdose cyclophosphamide (CY), IL‐2, and tumor‐sensitized CTC resulted in delayed tumor onset, retarded tumor growth rate, prolonged survival, and a higher cure rate as compared with mice receiving only CY. In some experiments, nonsensitized CTC (but not fresh lymphocytes) were therapeutically effective almost to the same extent as tumor‐sensitized CTC. In most instances, the combination of chemo‐therapy and IL‐2 was significantly more curative than chemotherapy alone, and the addition of indomethacin improved the outcome of both chemotherapy and chemoimmunotherapy. Multiple administrations of IL‐2 into athymic mice, before or after implantation of human tumors, delayed or completely inhibited tumor growth. IL‐2 injections into normal, untreated, as well as X‐irradiated or CY‐treated mice, resulted in enhanced natural cytotoxicity and cytotoxic responsivenessin vitroto syngeneic tumors, greater proliferative response to phytohemagglutinin, and a tendency toward depressed proliferative responses to concanavalin A and to allogeneic leukocytes. It is concluded that the appropriate application of lymphokines and IL‐2‐propagated lymphocytes can be effective in the immunotherapy of experimental tumors and in immunorestoration of immunosuppressed mice. However, since crude lymphokine preparations have been employed in these studies, further analysis with purified lymphokines is required to confirm these observations.

ISSN:0732-6580    

出版商:OVID    

年代:1984

数据来源: OVID

ISSN:0732-6580    

出版商:OVID    

年代:1984

数据来源: OVID