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J S Weber

Publications and source records attributed to J S Weber.

43 records · Page 3Linked to original sources
PubMed1990

Effects of murine tumor class I major histocompatibility complex expression on antitumor activity of tumor-infiltrating lymphocytes.

Tumor-infiltrating lymphocytes (TILs) are T cells that can be grown from enzyme-digested murine or human tumors. When adoptively transferred to tumor-bearing hosts concurrent with the administration of recombinant interleukin-2 (rIL-2), TILs can mediate significant regression of tumor. To examine whether expression of class I major histocompatibility complex on tumor cells influenced the generation and antitumor activity of TILs, we used clones of murine B16BL6 melanoma either transfected with or lacking the class I gene Kb to generate TILs at a high dose (1,000 U/mL) or at a low dose (20 U/mL) of human rIL-2. TILs grew from both tumors in high-dose rIL-2, but they grew from the class I-expressing tumor only in low-dose rIL-2. TILs from the class I-deficient tumor did not lyse any target tested in vitro, nor did they demonstrate any therapeutic effect in vivo on established tumors that lacked or expressed class I. In contrast, TILs from the class I-expressing tumor specifically lysed the tumor of origin in vitro and caused it to regress in vivo. Further, these TILs demonstrated activity in vitro against the non-class I-expressing melanoma treated with the combination of murine recombinant interferon gamma and human recombinant tumor necrosis factor alpha; in vivo, when administered with recombinant interferon gamma and recombinant tumor necrosis factor alpha, TILs from the class I-expressing tumor mediated regression of non-class I-expressing pulmonary metastases, presumably by augmenting class I expression.

Animals↗
PubMed1990

In vitro and in vivo antitumor properties of a T-cell clone generated from murine tumor-infiltrating lymphocytes.

We have shown that a T-cell clone derived from murine tumor-infiltrating lymphocytes (TILs) can be established that mediates in vitro and in vivo antitumor effects. Utilizing this clone as a model, we examined the effect of cytokines on T-cell antitumor effector mechanisms in vitro and in vivo. This clone, termed BF-1, was generated by limiting dilution culture of a freshly excised MC-38 tumor, growing it in low levels of interleukin-2 (IL-2), and has been maintained for over 600 days. This clone became specifically cytotoxic for the MC-38 tumor during its first 100 days of culture. Pretreatment of the parental MC-38 tumor cell line with tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma) increased its susceptibility to lysis by the BF-1 TIL line, but not to lysis by lymphokine-activated killer cells, in in vitro cytotoxicity assays. This increased susceptibility of the cytokine-pretreated targets was restricted to the parental tumor (MC-38), since similar pretreatment of MCA-102, MCA-105, or MCA-106 tumors did not render them susceptible to lysis by BF-1 TILs. This increased sensitivity to lysis in vitro was not the result of a change in the expression of major histocompatibility complex class I molecules. In experiments testing the ability of TILs to treat established lung metastases, the combination of TNF, IFN-gamma, IL-2, and TILs was shown to increase significantly the antitumor properties of this therapy when compared to TILs and IL-2. This result demonstrates that combinations of lymphokines, which when administered alone do not affect micrometastatic tumor burdens (TNF, IFN-gamma), can synergize with cellular immunotherapy in the treatment of established tumor burdens and may have applicabilities to the treatment of cancer in humans.

Adenocarcinoma↗
PubMed1988

Modulation of murine tumor major histocompatibility antigens by cytokines in vivo and in vitro.

The capacity of different cytokines to upregulate major histocompatibility complex (MHC) expression on murine tumor cells in vitro, and on s.c. tumors or pulmonary metastases in vivo has been examined. Interleukins-1, -2, and -4 (IL-1, -2, -4), tumor necrosis factor-alpha (TNF-alpha), alpha-interferon (IFN-alpha), and gamma-interferon (IFN-gamma), were incubated with tissue culture lines of murine tumor cells displaying low (MCA-101), intermediate (MCA-102, -106), or high (MCA-105) Class I expression. IFN-alpha and IFN-gamma significantly increased Class I but not Class II antigens on all lines. TNF-alpha, IL-1, -2, and -4 had no significant effect on Class I or II expression in vitro. Mice bearing pulmonary metastases or s.c. lesions generated by MCA-101 and -102 were treated with IFN-alpha or IFN-gamma i.p. or i.v., or with a single dose of TNF-alpha i.v. Immunoperoxidase staining of lung metastases or subcutaneous tumors showed an increase in Class I but not Class II expression on MCA-102 tumors treated with IFN-alpha or IFN-gamma. IL-1, -2, or TNF-alpha had no effect on MHC Class I or II expression in vivo. None of the cytokines tested could upregulate MHC Class I or II expression on MCA-101 tumors in vivo. Flow cytometry analysis demonstrated an increase in Class I but not Class II expression on MCA-102 and MCA-106 tumor cells from s.c. tumor treated with IFN-alpha or IFN-gamma. A kinetic analysis of the flow cytometry data revealed that augmented MCA-102 Class I levels persisted for several days after cessation of in vivo therapy with IFN-alpha. Our data suggest one possible mechanism for the synergistic antitumor effects of IL-2 and IFN-alpha.

Animals↗
PubMed1987

Immunotherapy of a murine tumor with interleukin 2. Increased sensitivity after MHC class I gene transfection.

We have shown that two weakly immunogenic MCA sarcomas developed in our laboratory that are sensitive to high-dose IL-2 immunotherapy express class I MHC in vivo and in vitro. Two nonimmunogenic MCA sarcomas are relatively insensitive to IL-2 therapy and express minimal or no class I MHC molecules in vivo and in vitro. To study the role of MHC in the therapy of tumors with IL-2, a class I-deficient murine melanoma, B16BL6, was transfected with the Kb class I gene. Expression of class I MHC rendered B16BL6 advanced pulmonary macrometastases sensitive to IL-2 immunotherapy. 3-d micrometastases of CL8-2, a class I transfected clone of B16BL6, were significantly more sensitive to IL-2 therapy than a control nontransfected line. Expression of Iak, a class II MHC molecule, had no effect on IL-2 therapy of transfectant pulmonary micrometastases in F1 mice. By using lymphocyte subset depletion with mAbs directed against Lyt-2, therapy of class I transfectant macrometastases with high-dose IL-2 was shown to involve an Lyt-2 cell. In contrast, regression of micrometastases treated with low-dose IL-2 involved Lyt-2+ cells, but regression mediated by high doses of IL-2 did not. We hypothesize that both LAK and Lyt-2+ T cells effect IL-2-mediated elimination of micrometastases, but only Lyt-2+ T cells are involved in macrometastatic regression. Low doses of IL-2 stimulate Lyt-2+ cells to eliminate class I-expressing micrometastases, but high doses of IL-2 can recruit LAK cells to mediate regression of micrometastases independent of class I expression. Only high-dose IL-2, mediating its effect predominantly via Lyt-2+ cells, is capable of impacting on MHC class I-expressing macrometastases. Macrometastases devoid of class I MHC antigens appear to be resistant to IL-2 therapy.

Animals↗
PubMedDate not supplied

Carbon monoxide: a hazard to fire fighters.

Carbon monoxide levels were measured in twenty-five fires in the city of Los Angeles to obtain information about fire fighters exposure to carbon monoxide. Levels as high as 3,000 ppm were observed for some fires. In general, when carbon monoxide levels were significantly elevated (greater than 100 ppm) the smoke was quite heavy and noxious, but in some cases the smoke was heavy and carbon monoxide levels were minimal. In two-story structures, the highest concentrations of carbon monoxide were found on the second-floor level and were usually still elevated after the fire had been "knocked down" but was still smoldering. These data show that fire fighters are exposed to levels of carbon monoxide which could be a serious health hazard and may be related to the high incidence of heart disease in fire fighters.

Air Pollutants↗
PubMedDate not supplied

Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2.

OBJECTIVE: To determine the efficacy of treatment using high-dose bolus interleukin 2 (IL-2) in patients with metastatic melanoma or renal cell cancer. DESIGN AND SETTING: Consecutive series of all patients treated with high-dose IL-2 in the Surgery Branch of the National Cancer Institute from September 1985 through December 1992. PATIENTS: Two hundred eighty-three patients with metastatic melanoma or metastatic renal cell cancer who had failed standard treatment for their cancers. INTERVENTIONS: Patients received IL-2 at a dose of 720,000 IU/kg intravenously every 8 hours for a maximum of 15 doses per cycle. Two cycles constituted a treatment course, and patients with stable or responding disease received additional treatment courses. A total of 447 courses of treatment were administered. MAIN OUTCOME MEASURES: Regression of measurable tumor, durability of response to treatment, and survival. RESULTS: Nine patients (7%) with metastatic melanoma achieved complete regression of all disease and 14 patients (10%) had partial regression. Ten patients (7%) with metastatic renal cell cancer experienced complete regression and 20 patients (13%) had partial regression. Of the 19 patients with complete regression, 15 have remained in complete remission from 7 to 91 months after treatment. Three treatment-related deaths (1.1%) occurred early in this series, but as experience with the administration of this IL-2 regimen increased, no treatment-related deaths occurred in 214 patients treated during the last 5 years of the study. CONCLUSION: Biologic therapy with IL-2 can cause significant antitumor effects in patients with advanced metastatic melanoma or renal cell cancer. Because IL-2 does not have a direct effect on cancer cells but rather mediates its antitumor activity by altering host immune reactions, these data represent the best available evidence that immunologic therapy for cancer can be effective in selected patients.

Adolescent↗