摘要:

The Society for Biological Therapy held a Workshop last fall devoted to immune monitoring for cancer immunotherapy trials. Participants included members of the academic and pharmaceutical communities as well as the National Cancer Institute and the Food and Drug Administration. Discussion focused on the relative merits and appropriate use of various immune monitoring tools. Six breakout groups dealt with assays of T-cell function, serologic and proliferation assays to assess B cell and T helper cell activity, and enzyme-linked immunospot assay, tetramer, cytokine flow cytometry, and reverse transcription polymerase chain reaction assays of T-cell immunity. General conclusions included: (1) future vaccine studies should be designed to determine whether T-cell dysfunction (tumor-specific and nonspecific) correlated with clinical outcome; (2) tetramer-based assays yield quantitative but not functional data (3) enzyme-linked immunospot assays have the lowest limit of detection (4) cytokine flow cytometry have a higher limit of detection than enzyme-linked immunospot assay, but offer the advantages of speed and the ability to identify subsets of reactive cells; (5) antibody tests are simple and accurate and should be incorporated to a greater extent in monitoring plans; (6) proliferation assays are imprecise and should not be emphasized in future studies; (7) the reverse transcription polymerase chain reaction assay is a promising research approach that is not ready for widespread application; and (8) there is a critical need to validate these assays as surrogates for vaccine potency and clinical effect. Current data and opinion support the use of a functional assay like the enzyme-linked immunospot assay or cytokine flow cytometry in combination with a quantitative assay like tetramers for immune monitoring. At present, assays appear to be most useful as measures of vaccine potency. Careful immune monitoring in association with larger scale clinical trials ultimately may enable the correlation of monitoring results with clinical benefit.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Antigen-specific T lymphocytes are attractive as potential anticancer agents. The generation of large numbers of antigen-specific T cells is possible through the use of gene therapy to express targeting receptors on the T lymphocyte. Activated T lymphocytes were transduced to express carcino-embryonic antigen or neural cell adhesion molecule targeted CD3ζ chimeric immune receptors. The chimeric receptors were expressed as homodimers and also as heterodimers with the native CD3ζ. T lymphocyte populations were expanded in the absence of selection for the modified cells and were shown to produce cytokines when cultured in the presence of immobilized purified protein antigen. These lymphocytes also responded by cytokine production and cytolytic activity when challenged with tumor-cell lines expressing the antigen recognized by the chimeric immune receptor. The cytolytic activity appears to be largely perforin mediated. Furthermore, soluble carcino-embryonic antigen did not interfere with the functional activity of the carcino-embryonic antigen-targeted lymphocytes. Long-term (5-day) stimulation of the modified lymphocytes by protein antigen resulted in reduced viability similar to that induced by anti-CD3 antibodies alone. Viability was improved by a costimulatory signal indicating that such signals may be vital in the maintenance of long-term functional activity of receptor modified T lymphocytes.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Dendritic cells (DC) are central to the control of adaptive immunity. Their ability to activate antigen-specific T cells depends on their maturation state. Many microbial and inflammatory products have stimulated DC maturation. This in vitro study used assays of phenotype and function to examine the potential of bacillus Calmette-Guérin, muramyl dipeptide, and CpG-rich oligodeoxynucleotides to stimulate DC maturation. A chemical fixation method was developed to reliably assess the functional potential of stimulated DC within a mixed lymphocyte reaction model. Using this method, it was shown that bacillus Calmette-Guérin provides a maturation signal as effective as the prototype DC stimulant interleukin-1&bgr;. Furthermore, weaker stimuli such as muramyl dipeptide and CpG-rich oligodeoxynucleotides also are able to induce functional maturation of DC. Using chemical fixation, it was possible to generate stable DC in an immature or a mature state. These observations have importance for our understanding of the regulation of adaptive immunity and for the design of DC-based immunotherapeutic strategies.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Rats vaccinated with attenuatedSalmonella typhimuriumtransformed with a vector containing the v2 exon of CD44 (SL-v2) were not protected and developed thymic metastases at a high rate. This was surprising because there was evidence for concomitant induction of a CD44v2-specific helper and cytotoxic T-cell response. The inefficacy of vaccination was partly caused by tumor escape and tumor-induced immunosuppression. More important were the facts that (i) BSp12v2 cells migrated from the intraperitoneal implantation site to the thymus and (ii) after vaccination with transformed attenuatedSalmonella typhimurium, a small number of dendritic cells, which had transcribed the cDNA insert, were detected in the thymus. In the thymic environment, these v2 presenting dendritic cells, as well as the BSp12v2 tumor cells, supported tolerance induction. Thus, vaccination with tumor-associated differentiation antigens, which in many instances have induced antitumor response, may deteriorate survival time and rate if vaccination is accompanied by presentation of the antigen during intrathymic T-cell selection.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The function of dendritic cells (DCs), antigen-presenting cells that can initiate and regulate cellular and humoral responses, is highly influenced by their level of maturation. Immature DCs may be harmful in anti-tumor immunotherapy, because they can induce immunotolerance rather than immunostimulation. In this study, the authors sought to determine the optimal culture conditions for obtaining fully mature DCs. When DCs were cultured in agonistic anti-CD40 monoclonal antibody-immobilized plates, they showed a higher expression of the maturation marker CD83 than DCs cultured without CD40 ligation or those cultured in medium supplemented with anti-CD40 monoclonal antibody. In addition, when interferon-gamma (IFN-&ggr;) was added to the medium, additive up-regulation of CD83 expression was observed. These DCs treated with both maturation signals showed a higher secretion of interleukin-12. To evaluate the capacity of antigen presentation, specific cytotoxic T lymphocytes were generated using autologous DC pulsed with a human lymphocyte antigen-A24–restricted peptide epitope derived from carcinoembryonic antigen. Interferon-gamma–secreting CD8+ T cells were analyzed by flow cytometry using the cellular affinity matrix technology. Dendritic cells, matured with CD40 ligation and IFN-&ggr;, were more efficient at eliciting an antigen-specific T-cell response in vitro than DCs stimulated with anti-CD40 monoclonal antibody or IFN-&ggr; alone. A cytotoxicity assay using carcinoembryonic antigen-expressing tumor cell lines also showed that DCs matured with both signals were more efficient at inducing cytotoxic T lymphocytes. These results demonstrate that DC culture in an anti-CD40 monoclonal antibody-immobilized plate in medium supplemented with IFN-&ggr; has a positive impact on DC maturation and may be optimal for eliciting an antigen-specific T-cell response without the need for CD4+ T-helper epitopes.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We evaluated 567 patients with metastatic melanoma who were treated with high-dose intravenous interleukin-2 (IL-2) to determine whether prior treatment with either alpha-interferon or low-dose IL-2 altered the rates of response to subsequent high-dose IL-2. Of the 567 patients treated, 46 patients had received low-dose IL-2 before, and 78 had received alpha-interferon before. The response rate for patients who had received IL-2 before compared with IL-2 naïve patients was 15% versus 21% respectively (p = 0.39). The response rate for patients who had received alpha-interferon before compared with patients who had not was 13% versus 21% (p = 0.084). Therefore, prior low-dose IL-2 therapy does not appear to prevent a subsequent response to high-dose IL-2. There is a trend for patients who received alpha-interferon before to have a lower-response rate to subsequent high-dose IL-2, but the number of patients evaluated in this study is too small to definitively answer this question.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID