Current Status Of Tumor Immunotherapy

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Current immunotherapy approaches include adoptive transfer of T cells, peptides, recombinant viruses, autologous or allogeneic tumor cells, and dendritic cell (DC)-based vaccines [7]. All of these strategies have shown therapeutic responses and evidence of systemic immunity in preclinical murine models and in selected patients enrolled on early-phase clinical trials [8-11]. There is emerging evidence that measurement of immune responses can be used to predict clinical responses with these agents. In studies using recombinant poxviruses expressing T cell costimula-tory molecules with or without tumor antigens, objective clinical response and disease stabilization have been associated with an increase in antigen-specific T cell precursors detected by ELISpot assay [8]. Adoptive T cell immunotherapy has shown great promise, especially after nonmyeloablative but lymphodepleting chemotherapy, with objective clinical responses in 50% of patients [12,13]. Adoptively transferred T cell clones persisted in responding patients and preferentially localized to tumor sites and mediated antigen-specific immune responses that could be detected by ex vivo T cell analysis [14]. Perhaps the best example is the correlation of anti-human papilloma virus (HPV) antibody titers in women receiving an HPV virus-like particle (VLP) vaccine with prevention of cervical cancer [15,16]. These examples suggest that immune monitoring might be useful in predicting clinical responses for cancer patients receiving immunotherapy.

Despite intense efforts to increase the frequency of tumor antigen-specific T cells by various vaccines, a strict correlation has not always been seen and clinical responses are rare [17]. Careful monitoring, however, has provided critical insight into the reasons for the low responses in some trials [19,20]. For example, in cancers such as ovarian and melanoma, the presence of CD4+CD25+ regulatory T (Treg) cells in tumor is a predictor of poor patient survival [18]. These Tregs have also been shown to inhibit T cell responses following vaccine treatment in murine studies [20]. The role of Tregs in blocking effective antitumor immunity was based on careful immune monitoring and has led to proposals for combining vaccines with Treg blockade to improve the therapeutic activity of tumor vaccines [19]. Furthermore, combining immunotherapy with chemotherapy, radiation, and/or antiangiogenic therapy are currently being actively pursued in the clinic the basis of on immune monitoring data supporting an improved response with specific combinations of these strategies [20,21].

While the future of immunotherapy for the treatment of cancer is promising, it is difficult at present to directly compare the various immunotherapeutic approaches because monitoring assays have not been standardized with respect to technical or analytic methodology. Most of the currently used assays have focused on monitoring adaptive immune responses, such as antibody titers and T cells, although innate immune responses may also be important in immunosurveillance and therapeutic responses in cancer patients. Nonetheless, the focus on T cell immunity is probably important in terms of data from preclinical studies and analyses of the tumor microenvironment in cancer patients. The ideal T cell assay should be sensitive, specific, reliable, and reproducible. The assay should be easy to perform and reflect the status of the immune response in vivo. In addition, the assay should demonstrate a close correlation with clinical outcomes. The assays currently used to measure immune response can be divided into those assays that are performed directly in patients and those that are performed in vitro using patient-derived blood or tissue samples. Examples of direct in vivo assays are the delayed-type hypersensitivity response, imaging of lymph nodes and tumors, and whole-body scans. The more commonly employed in vitro T cell assays include the enzyme-linked immunospot assay (ELISpot), tetramer assay, intracellular cytokine flow cytometry (CFC), quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), microarray/proteomics, proliferation assay, and standard cytotoxicity assay. Humoral immunity is typically determined by enzyme-linked immunosor-bant assay (ELISA). The choice of an assay for monitoring of tumor vaccines needs must be based on a complete understanding of the characteristics and limitations of the assay, the proposed mechanism of action for the vaccine or regimen under investigation, the availability of pretreatment and posttreatment samples, and the skill of the immunologists doing the assays.

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