Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor-infiltrating lymphocytes from mice bearing minor histoincompatible tumor cells in the anterior chamber (AC) or subconjunctival (SCon) space of the eye have been shown to contain large numbers of tumor-specific precursor cytotoxic T cells. Because SCon tumors eventually acquire directly cytotoxic, tumor-specific T cells and are rejected by their hosts and because AC tumors never acquire cytotoxic effector cells and are not rejected, we have examined tumor-infiltrating lymphocytes from both types of ocular tumors for the capacity to secrete lymphokines in response to in vitro stimulation with tumor cells. The results indicate that T "helper" cells were able to infiltrate both SCon and AC tumors. In the former, T cells capable of secreting IL-2 and IL-4 were found whereas in the latter only IL-2-secreting T cells were detected. These findings implicate a defect in local delivery of appropriate T cell help as the reason why AC tumors are not rejected. The failure of AC tumor-bearing mice to destroy their tumors correlates not only with defective delivery of local help but with a systemic inability to produce tumor-specific T cells that can secrete IL-2 and IL-4. Because these mice also generate down-regulatory T cells that suppress the expression of tumor-specific delayed hypersensitivity, they appear to have an immunologically mediated block in T helper cell differentiation which renders them unable to generate either T helper 1 or T helper 2 cells. This immunologic abnormality is discussed in terms of tumor rejection and the phenomenon of immunologic privilege.
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PMID:Local T helper cell signals by lymphocytes infiltrating intraocular tumors. 153 48

Tumor-infiltrating lymphocytes (TIL) were obtained from a mouse melanoma cell line (CL 62) transfected with the gene for the human melanoma Ag p97. TIL were cultured with anti-CD3 antibody and IL-2 for up to 38 days. Flow cytometry identified these TIL as Thy-1.2 + ve/CD4-ve/CD8 + ve cells. A heteroconjugated antibody 500A2 x 96.5, specific for both the CD3 Ag on TIL and the p97 Ag on CL 62 melanoma cells, was prepared using N-succinimidyl-3-(2-pyridyldithio)-propionate as a linking agent. TIL alone demonstrated low levels of cytotoxicity against autologous CL 62 tumor and also against the parental K1735 tumor and an allogeneic murine melanoma (B16). The addition of 500A2 x 96.5 heteroconjugated antibody enhanced TIL-mediated lysis of CL 62 tumor, but not of the K1735 or B16 tumors. This enhanced cytotoxicity was elicited at E:T ratios as low as 0.4:1, and in TIL cultured for 7 to 38 days. These results suggest that hetero-conjugated antibody may enhance the anti-tumor effect of TIL in vivo.
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PMID:Enhancement of in vitro tumor-infiltrating lymphocyte cytotoxicity by heteroconjugated antibodies. 153 18

Anti-CD3 antibody induced non-MHC-restricted cytolytic activity in murine spleen cells within 4 hr of incubation in vitro and within 8 hr in vivo after intraperitoneal injection. Interstitial lung leukocytes acquired the capacity to kill both NK-sensitive and -resistant targets within 24 hr after anti-CD3 injection. In vivo-stimulated spleen cells produced significantly more IL-2 and TNF than unstimulated cells. When these cells were restimulated with anti-CD3 in vitro, a potentiation of TNF production was seen. Interstitial lung leukocytes doubled their TNF production ex vivo after anti-CD3 injection, and the suppressed TNF production which was seen in lung cells from tumor-bearing animals was restored after anti-CD3 stimulation. The TNF production by alveolar macrophages was augmented 5-fold 48 hr after injection of antibody. Anti-CD3 antibody also induced significant accumulation of both TNF alpha and TNF beta mRNA in spleen and lung leukocytes. Pre-treatment with anti-TNF antibodies, both in vitro and in vivo, did not eliminate the cytolytic activation of lung and spleen cells. Our data indicate that anti-CD3 antibodies can induce rapid activation of both cytolytic activity and cytokine production in lung lymphocytes and macrophages.
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PMID:Anti-CD3 antibody-treated mice: in vivo induction of cytolytic activity and TNF production by lung leukocytes. 153 2

Peritumoral injection of human IL-2-activated natural killer cells into nude mice consistently induced regression of xenografts of human squamous cell carcinoma of the head and neck (SCCHN). To determine the mechanisms responsible for the tumor regression, the lymphoid cells infiltrating the tumor stroma at 24 to 48 h after adoptive immunotherapy were examined by in situ hybridization for the presence of mRNA for cytokines or IL-2R. Numerous lymphoid cells expressing cytokine or IL-2R genes were observed in these tumors, whereas the cultured IL-2-activated NK cells used for therapy were negative. Thus, it appeared that the transferred NK cells became activated in situ after coming into proximity with the tumor cells. To analyze this phenomenon, fresh or cultured human NK cells were coincubated in vitro with irradiated human SCCHN cell line, PCI-1, with or without the presence of IL-2. Expression of mRNA for IL-2R, perforin, and various cytokines was observed within 5 h. Contact with the tumor cells stimulated NK cells to proliferate, secrete IFN-gamma, TNF-alpha, and soluble IL-2R, up-regulate cell surface expression of IL2R p55 and p75 as well as CD16 Ag, and mediate higher levels of antitumor activity in 51Cr-release assays. In addition, supernatants of in vitro-activated NK cells significantly inhibited proliferation of SCCHN cell lines. By examining the effects of neutralizing mAb to various cytokines, this inhibitory activity was shown to be partially attributable to IFN-gamma. To determine the possible in vivo role of soluble factors produced by activated human NK cells, the supernatants (0.2 ml) or rIFN-gamma (10(5) U) were injected perilesionally each day for 2 wk into 3-day SCCHN established in immunosuppressed nude mice. These treatments caused significant (p less than 0.02) inhibition of tumor growth. The results of our studies indicate that human NK cells are strongly activated by SCCHN cells and that the consequent release of cytokines contribute to the regression of SCCHN growing in nude mice.
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PMID:Role of cytokines in the adoptive immunotherapy of an experimental model of human head and neck cancer by human IL-2-activated natural killer cells. 153 88

The generation of specific antitumor cytotoxic T-lymphocytes (CTL) via 2-fold immunization in vivo and subsequent cultivation without tumor cells (in monoculture) was previously described. The spleen cells from B10 mice bearing progressively growing MX-11 sarcoma suppressed the maturation of CTL specific to MX-11 but not to EL-4 lymphoma in monoculture. It was observed, that the suppression was not the result of the inhibitory effect of suppressor cells upon the IL-2 production, because suppression took place in the presence of the exogenous IL-2 in monoculture. Since the treatment of the spleen cells with MoAb against both L3T4 and Lyt2.2 antigens plus C' considerably decreased the suppressive activity, it was suggested, that two distinct subsets of T-lymphocytes were required for suppression. It might be possible, that the presence of anti-idiotype on the effector suppressors was the cause of the suppressive specificity in the absence of tumor antigens in vitro.
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PMID:[T-suppressors from tumor-bearing mice inhibit antitumor cytotoxic T-lymphocytes in monoculture]. 153 35

Although IL-2 infusion enhances cell-mediated cytotoxicity in patients with neoplastic disease, administration is paradoxically associated with a modest fall in total serum IgG and an increased risk of infection. We now show that the adverse effects of IL-2 infusion on the humoral immune system are substantial. Although IL-2 induces the B cell growth and differentiating factors IL-4 and IL-6, infusion abrogates primary antibody responses entirely and reduces secondary antibody responses 50-fold following antigen challenge. There is no evidence of the generation of cells with suppressive activity on B cells but IL-2 increases the ratio of circulating virgin:memory cells. These results may help to explain the increased rate of bacterial infection in patients receiving IL-2. As IL-2 plays a central role in the generation of an immune response, the finding that it is also sufficiently immunosuppressive to inhibit primary- and secondary-type antibody responses suggests that exploration of the underlying mechanisms may provide insights into immune system homeostasis and may offer new approaches to therapeutic immunosuppression.
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PMID:IL-2 infusion abrogates humoral immune responses in humans. 154 35

The observation that malignant cells express antigens that may be recognized by immunocytes and that immune effector mechanisms have the capability of destroying tumor cells has increased our appreciation of the biology of cancer and its relationship to immune function as well as offered new options for therapeutic intervention. Clinical trials are in progress to evaluate several different approaches to modifying the host's immune response against tumor. One approach is to administer agents that have direct activity against the malignancy. For example, antibody conjugates bring cytotoxic molecules of chemotherapy, radioisotopes, or toxins directly to the tumor. A second approach is to administer agents that modulate the host's own antitumor response such as IFN-alpha and IFN-gamma. Adoptive cellular immunotherapy aimed at isolating and expanding the host's own tumor-specific lymphocytes and inducing activation and proliferation with lymphokines such as IL-2 has shown encouraging results. Even though clinical data are still quite premature, it is reasonable to assume that in the future immunomodulation including the stimulation of immune effector mechanisms to eradicate tumor, the reconstitution of immune deficiency in diseases such as AIDS, the suppression of immune function to avoid graft rejection and GVHD, and the isolation and insertion of genes encoding tumor antigens into recombinant vectors to immunize the host to the tumor antigen will be commonly and successfully employed.
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PMID:The role of the immune system in the pathogenesis of cancer. 154 19

Polyethylene glycolated (pegylated) interleukin-2 (PEG IL-2) was administered as a weekly i.v. bolus to patients with metastatic cancer in a phase-I trial. Efficacy, toxicity and pharmacokinetics have been described previously. To explore mechanism of IL-2 action and discover predictors of efficacy, the levels of several lymphokines were measured in pharmacokinetic serum samples. IL-1 beta and IL-6 were elevated in many patients before PEG IL-2 administration, forming a continuous, log-normal distribution among patients. The levels of the two lymphokines were strongly correlated. However, no significant correlation could be found between these levels, clinical chemistry, or tumor regression seen after PEG IL-2 administration. Three hours after PEG IL-2 administration, IL-1 beta and IL-6 levels, if elevated, fell to normal. In all patients, independent of initial levels, IL-6 and IFN-gamma, but not IL-1 beta, increased 4 to 6 h after the injection and then fell rapidly, even though PEG IL-2 levels were high and often changed only slightly during this period. This suggests an active shut down of lymphokine synthesis, or an increase in elimination rate. After the fourth administration of PEG IL-2, the peak level of IFN-gamma was 2 to 20 times higher than after the first, while the peak level of IL-6 did not change in a consistent direction. Responding patients had typical peak levels of IL-6 and IFN-gamma. Low levels of TNF and IL-4 were occasionally seen before and after PEG IL-2 administration, but no consistent pattern was evident.
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PMID:Suppression and transient induction of lymphokines in cancer patients after administration of polyethylene glycolated interleukin-2. 154 19

Interleukin-7 (IL-7) is a 25-kDa cytokine that was initially described as a pre-B cell growth factor and more recently has been shown to cause T cell proliferation. We have investigated the in vitro effects of IL-7 on mature T cells to include the generation and further expansion of allospecific and antitumor CTL. B6 anti-DBA allospecific CTL were generated in the presence of IL-7, IL-2, the combination IL-7 plus IL-2, or no cytokine. IL-7 alone or when combined with IL-2 enhanced the generation of allospecific CTL. To evaluate the proliferative effects of IL-7, 4-day B6 anti-DBA cultures were cultured in IL-7, IL-2, or no cytokine. Cell proliferation and duration of growth of cells cultured in IL-7 were significantly greater than cells cultured in IL-2 or in the absence of cytokine. Allospecific cytolytic activity was maintained during proliferation in IL-7 to a maximum of 60 days. In contrast with the ability of IL-2 to generate LAK cells, murine splenocytes cultured at varying doses of IL-7 (1 to 10,000 ng/ml), resulted in minimal LAK cell activity. The effect of IL-7 in the generation of CTL with antitumor activity was also studied. Seven days after footpad injection of MCA 203 or 205 sarcoma, draining lymph nodes (DLN) were harvested and restimulated in vitro with MCA 203 or 205, respectively, and maintained in culture with either IL-7, IL-2, the combination of IL-7 plus IL-2, or no cytokine. After 10 days in culture, cells generated in IL-7 or IL-2 exhibited similar cytotoxicity against the syngeneic autologous MCA tumor. IL-7 generated cells, however, showed specificity when tested by 51Cr release which was not seen with IL-2-generated cells. Cells generated in IL-7 plus IL-2 were more cytolytic than cells cultured with either cytokine alone. To further define the mechanism of action of IL-7 in antitumor CTL cultures, a monoclonal antibody, S4B6.1, capable of blocking murine-specific IL-2 was employed. The partial inhibition by this mAb of the generation of antitumor CTL demonstrated that IL-7 acted, in part, by an IL-2-dependent mechanism. Finally, IL-7 cultures restimulated at Day 11 with autologous MCA 203 showed greater proliferation than IL-2 cultures and remained lytic at Day 21 of culture.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Interleukin-7 mediates the generation and expansion of murine allosensitized and antitumor CTL. 155 57

During the past 5 years publications from the NIH (Rosenberg et al.) and other centers have reported encouraging results in the treatment of metastatic renal cell carcinoma. Adoptive immunotherapy was applied, using lymphocytes activated by interleukin-2 (LAK cells) plus high doses of interleukin (IL-2) systemically. The mean clinical response rate was 20-35%. Severe lifethreatening adverse reactions to high doses of IL-2 were noted, although they were all of short duration. Laboratory findings of Novogrodsky et al. from Beilinson Medical Center, Israel showed that oxidizing mitogens can induce lymphocyte activation (PLAK cells). Further studies suggested that a combination of such activated cells with low doses of IL-2 could produce effective toxicity to tumor cells without the need for high doses of IL-2 which could be very toxic for the patient. In the past year we treated 7 patients with PLAK cells and IL-2. 4 completed the treatment, of whom 1 responded partially (regression of more than 50% of lung metastases), 1 is stable and in 1 liver metastases regressed but metastases in lumbar vertebrae and in the pelvis progressed. 1 patient died a month after discharge from hospital, probably due to rapid progression of the disease. Our protocol follows that of the Phase II clinical study of 40 patients treated at the Rogosin Institute, New York Hospital--Cornell Medical Center. The mean clinical response rate was 23.6%. Toxicity of IL-2 is dose-dependent. In this protocol, the low doses of IL-2 gave significantly fewer adverse reactions.
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PMID:[Immunotherapy for metastatic renal cell carcinoma: treatment with PLAK cells and low-dose interleukin-2]. 157 61


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