A phase II trial of chimeric monoclonal antibody G250 for advanced renal cell carcinoma patients

Bleumer, I.; Knuth, Alexander; Oosterwijk, Egbert; Hofmann, Rainer; Varga, Zoltán; Lamers, Cor H.J.; Kruit, Wim; Melchior, Sebastian; Mala, C.; Ullrich, Stephen E.; Mulder, Pieter De; Mulders, Peter F.A.; Beck, Joachim

doi:10.1038/sj.bjc.6601617

Cited by 158 publications

(85 citation statements)

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“…Some of these, such as G250, are cell surface proteins that have been identified by murine Mab (Oosterwijk et al, 1986). Clinical trials are already underway utilising a number of immunotherapeutic modalities targeting the G250 protein in RCC (Lamers et al, 2002;Bleumer et al, 2004).…”

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confidence: 99%

Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy

et al. 2005

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The 5T4 oncofoetal antigen is a heavily glycosylated cell surface protein found on human placental trophoblast and on diverse types of human cancer but is not expressed at significant levels on adult human tissues in health. It therefore satisfies the criteria for a tumour-associated antigen and is an ideal target for the immunotherapy of cancer. We report here that 5T4 is strongly expressed on the majority of renal cell carcinomas and therefore this population of patients is suitable for trials of 5T4-targeted therapies. In particular, we have shown that T cells from renal cell carcinoma patients can be genetically modified to kill 5T4 expressing renal cancer cell lines by introduction of a chimeric-signalling protein. This protein consists of a single chain antibody fragment capable of binding antigen directly at the cell surface and then activating the T cell by virtue of a CD3z-signalling domain. This is a powerful tool that bypasses a number of mechanisms that allow tumours to escape T-cell killing and can be readily scaled up for clinical use.

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confidence: 99%

Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy

et al. 2005

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“…[12][13][14][15] Application of IL-2, [16][17][18][19][20] IFN-a [21][22][23][24] or the combination of IL-2 plus IFN-a [25][26][27][28] also together with fluorouracil and vinblastine 29 have been reported to significantly improve the 3-year survival rate. Besides application of chemokines, application of antibodies, particularly anti-G250, 30 which is expressed by >95% of RCCs, 31 should be mentioned. The antibody becomes internalized, 32 and application of 125 I-coupled G250 has been reported to retard tumor progression.…”

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confidence: 99%

Generation of RAGE‐1 and MAGE‐9 peptide‐specific cytotoxic T‐Lymphocyte lines for transfer in patients with renal cell carcinoma

Oehlrich

Devitt

Linnebacher

et al. 2005

Intl Journal of Cancer

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Renal cell carcinomas (RCCs) are supposed to be immunogenic, and several clinical trials of immunotherapy using tumor lysatepulsed dendritic cells (DCs) have been performed. We report on the generation of RAGE-1 and MAGE-9 peptide-specific CTL lines. RAGE-1 and MAGE-9 are expressed in 56% and 38% of RCCs. Seven MAGE-9-and 13 RAGE-1-derived peptides were found to be immunogenic in the context of the HLA-A*0201 MHC. CTLs were generated by coculture with peptide-pulsed, activated B cells, which were easily generated in great quantities and displayed functional activity for a prolonged period of time. MAGE-9 and RAGE-1 peptide-specific CTL lines were strictly peptide-specific and displayed high cytotoxic activity not only against peptide-loaded T2 cells but also against HLA-A*0201-positive RCC lines, which naturally express MAGE-9, RAGE-1 or both. Thus, B cells are well suited as APCs for the generation of large numbers of tumor peptide-specific CTLs for adoptive transfer. MAGE-9 as well as RAGE-1 may well provide suitable targets for immunotherapy of RCC. ' 2005 Wiley-Liss, Inc.Key words: human renal cell carcinoma; antigen-presenting cell; peptide-specific cytotoxic T lymphocyte With 1-2% of solid tumors, RCCs are less frequent than prostate and bladder carcinomas.1 However, the prognosis of patients with RCC is poor as one-third of patients already have metastatic disease at the initial presentation and 30-40% develop distant metastases after resection of the primary tumor.2,3 Median survival time of metastatic RCC is only 6-8 months, and the 5-year survival rate is <5%. As >80% of RCCs express the phenotype of multidrug resistance, chemotherapy is rarely efficient. [4][5][6] However, RCCs are supposed to be immunogenic; 7-11 hence, immunotherapeutic strategies are dominant. should be mentioned. The antibody becomes internalized, 32 and application of 125 I-coupled G250 has been reported to retard tumor progression. 33-35Cell-mediated immunotherapeutic protocols in RCC have been based on tumor lysate-loaded DCs.36-39 Vaccination-induced remissions and an increase in the 5-year survival rate to 70% have been observed. [40][41][42] Application of tumor antigen cDNA 43 or of DC transduced with tumor antigen mRNA or cDNA 44,45 has been reported also to improve survival time, albeit to a minor degree. For antigen-specific vaccination in RCC, 46,47 so far MUC1, HSP96 and MN/CAIX have been used. Yet, the therapeutic efficacy remains below expectation. [48][49][50][51] We previously observed, by SSH, expression of MAGE-9 in RCC.52 As RAGE-1 has been described as an immunogenic RCC-associated antigen, [53][54][55] we explored the frequency of MAGE-9 expression in RCC and identified HLA-A*0201-restricted immunogenic MAGE-9 peptides in comparison to RAGE-1. We also report on the efficacy of B cells in peptide presentation and stimulation of peptide-specific CTLs. Material and methods Tumor linesHuman RCC lines 769-p, 56 Caki-1 and Caki-2, 57 ACHN, KTCTL-28, KTCTL-30, KTCTL-53 and KTCTL-111 (tumor bank,

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“…Results of phase II studies, where G250 was combined with IFN-alpha and IL-2, did not show increase in toxicity, and a promising rate of SD and PR (45). A large randomized phase 3 trial of G250 in the adjuvant setting has just completed enrollment.…”

Section: Wx-g250 (Rencarex® Wilex Germany)mentioning

confidence: 99%

Metastatic renal cell carcinoma management

et al. 2009

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Purpose: To assess the current treatment of metastatic renal cell carcinoma, focusing on medical treatment options. Material and Methods:The most important recent publications have been selected after a literature search employing PubMed using the search terms: advanced and metastatic renal cell carcinoma, anti-angiogenesis drugs and systemic therapy; also significant meeting abstracts were consulted. Results: Progress in understanding the molecular basis of renal cell carcinoma, especially related to genetics and angiogenesis, has been achieved mainly through of the study of von Hippel-Lindau disease. A great variety of active agents have been developed and tested in metastatic renal cell carcinoma (mRCC) patients. New specific molecular therapies in metastatic disease are discussed. Sunitinib, Sorafenib and Bevacizumab increase the progression-free survival when compared to therapy with cytokines. Temsirolimus increases overall survival in high-risk patients. Growth factors and regulatory enzymes, such as carbonic anhydrase IX may be targets for future therapies. Conclusions: A broader knowledge of clear cell carcinoma molecular biology has permitted the beginning of a new era in mRCC therapy. Benefits of these novel agents in terms of progression-free and overall survival have been observed in patients with mRCC, and, in many cases, have become the standard of care. Sunitinib is now considered the new reference first-line treatment for mRCC. Despite all the progress in recent years, complete responses are still very rare. Currently, many important issues regarding the use of these agents in the management of metastatic renal cancer still need to be properly addressed.

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A phase II trial of chimeric monoclonal antibody G250 for advanced renal cell carcinoma patients

Cited by 158 publications

References 19 publications

Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy

Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy

Generation of RAGE‐1 and MAGE‐9 peptide‐specific cytotoxic T‐Lymphocyte lines for transfer in patients with renal cell carcinoma

Metastatic renal cell carcinoma management

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