Safety profile and anti-tumor effects of adoptive immunotherapy using gamma-delta T cells against advanced renal cell carcinoma: a pilot study.

PURPOSE: Although various types of immunotherapy have been used to improve the prognosis of patients with advanced renal cell carcinoma (RCC), adoptive immunotherapy using gamma-delta (gammadelta) T cells has not yet been tried. In this study, we designed a pilot study of adoptive immunotherapy using in vitro activated gammadelta T cells against advanced RCC to evaluate the safety profile and possible anti-tumor effects of this study. EXPERIMENTAL DESIGN: Patients with advanced RCC after radical nephrectomy were administered via intravenous infusion in vitro-activated autologous gammadelta T cells every week or every 2 weeks, 6-12 times, with 70 JRU of teceleukin. Adverse events, anti-tumor effects and immunomonitoring were assessed. The anti-tumor effects were evaluated according to tumor doubling time (DT) by computed tomography (CT) and immunomonitoring was performed by flow cytometric analysis. RESULTS: Seven advanced RCC patients were entered in this study. The most common adverse events were fever, general fatigue and elevation of hepatobiliary enzymes, but no severe adverse events were seen. Prolongation of tumor DT was seen in three out of five patients; these three patients showed an increase in the number of gammadelta T cells in peripheral blood and also a high response to the antigen in vitro. CONCLUSIONS: The results indicated that adoptive immunotherapy using in vitro-activated autologous gammadelta T cells was well tolerated and induced anti-tumor effects.

Favorable prognosis of renal cell carcinoma with increased expression of chemokines associated with a Th1-type immune response.

The potential role of chemokines in clinical tumors remains poorly understood. Recent investigations have shown the differential expression of chemokine receptors on lymphocytes mediating Th1- and Th2-type immune responses. We examined Th1- and Th2-associated cytokines and chemokines, as well as the expression of their receptors in tumor-infiltrating lymphocytes in renal cell carcinoma (RCC). Sixty-seven patients with sporadic RCC were analyzed for the expression of Th1- and Th2-associated genes using real-time polymerase chain reaction. Tumor infiltration by CXC chemokine receptor 3 (CXCR3)-positive and CC chemokine receptor 5 (CCR5)-positive cells was detected by immunohistochemistry and by flow cytometry. The expression of Th1-associated genes was significantly increased in tumors compared to normal kidney tissues. The expression of interferon-gamma correlated positively with that of Th1 chemokines. Tumors expressing higher Th1 chemokines did not recur after curative surgery. Multivariate analysis showed that increased monokine induced by interferon (IFN)-gamma (MIG) expression was an independent favorable prognostic factor. Immunohistochemistry showed that the degree of CXCR3-positive cell infiltration significantly correlated with IFN-gamma inducible protein 10, MIG and IFN-gamma-inducible T cell a chemoattractant expression (I-TAC). Flow cytometric analysis showed increased expression of CXCR3 and CCR5 in tumor-infiltrating T lymphocytes compared to that in peripheral blood T cells. These results suggest that upregulation of the Th1-type immune response in RCC tumors with a favorable prognosis may be mediated by Th1-associated chemokines. Integrity of the Th1-type immune response seems to be required for tumor regression, suggesting that detection and correction of a defect in the Th1-type response cascade would thus be one of the main targets for tailor-made immunotherapy and gene therapy in RCC.

High expression of chemokine gene as a favorable prognostic factor in renal cell carcinoma.

PURPOSE: The presence and potential role of chemokines in clinical tumors remain poorly understood. Chemokines are a large family of chemoattractant cytokines with several members that are also able to regulate angiogenesis. We hypothesized that chemokines may have an important role in regulating tumor growth in renal cell carcinoma (RCC). To begin to test this hypothesis chemokine gene expression and its influence on prognosis, cellular infiltration and angiogenesis in RCC were examined. MATERIALS AND METHODS: A total of 51 patients with sporadic RCC were analyzed for the expression of the 7 chemokine genes interleukin-8, gamma-interferon inducible protein-10 (IP-10), monokine induced by gamma-interferon (MIG), macrophage chemoattractant protein-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and regulated and activated normal T cells excreted and secreted (RANTES) using semiquantitative reverse transcriptasepolymerase chain reaction. Lymphocyte infiltration and microvessel density were determined immunohistochemically by staining CD8 and CD34 cells, respectively. RESULTS: : The expression of IP-10, MIG, MIP-1beta and RANTES was significantly increased in tumor compared to normal kidney tissues. The expression of IP-10, MIG and MIP-1beta showed an inverse correlation with tumor size. Stages 1 to 3 tumors expressing high levels of IP-10, MIG, MIP-1beta and RANTES did not recur after curative surgery. Intratumor expression of IP-10, MIG and MIP-1beta showed a positive correlation with the degree of CD8 cell infiltrating in the tumor and an inverse correlation with microvessel density. CONCLUSIONS: These results suggest that IP-10, MIG and MIP-1beta are expressed at high levels in tumors that rarely recur after surgery. The antitumorigenic effect of IP-10, MIG and MIP-1beta may result from the recruitment of lymphocyte infiltration and/or inhibition of angiogenesis in RCC. The amplification of chemokine expression by immunotherapy or gene therapy may be a practical and effective strategy to promote tumor regression.