Influence of CD80, Interleukin-2, and Interleukin-7 Expression in Human Renal Cell Carcinoma on the Expansion, Function, and Survival of Tumor-Specific CTLs

Frankenberger, Bernhard; Pohla, Heike; Noeßner, Elfriede; Willimsky, Gerald; Papier, Britta; Pezzutto, Antonio; Oberneder, R.; Blankenstein, Thomas; Schendel, Dolores J.

doi:10.1158/1078-0432.ccr-04-1883

Cited by 21 publications

(24 citation statements)

References 36 publications

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“…Partial HLA-mismatch of patients with vaccine cells is likely to increase activation of the immune system through induction of an alloresponse. 20 IL-7/CD80-transfected RCC26 cells were previously shown to be immunogenic 14,16,21 and the vaccine was tested for the expression of several RCC-associated tumor antigens. According to this antigen-expression profile, a number of peptides were selected for the use as surrogate markers for immune monitoring.…”

Section: Discussionmentioning

confidence: 99%

“…16 GMP production of the genetically-modified vaccine (RCC26/IL7/CD80) was performed in our GMP facility. External quality control of the master cell bank for viral contamination was performed by BioReliance (Stirling, Glasgow, Scotland).…”

Section: Allogeneic Tumor Cell Line and Vaccination Schedulementioning

confidence: 99%

“…14,15 Transfection with CD80 and cytokine genes led to increased immunogenicity of RCC26 cells. 16 The use of allogeneic tumor cells offers several advantages: the approach (1) circumvents the laborious and cost-intensive Good Manufacturing Practice (GMP) production of a patient-individualized vaccine, with variable efficiency of gene-modification and subsequent immunogenicity; (2) allows for the large-scale production of highly standardized and antigenically well-defined tumor cells, which are ready for clinical use in a large number of patients and (3) improves comparisons within a study through the use of cells from a single batch. The allovaccine can be used in partially human leukocyte antigen (HLA)-matched patients, particularly when the HLA-restriction of immunogenic antigenic peptides is known, but it can also be used across HLA-barriers as cross-priming through autologous antigen-presenting cells is likely to occur.…”

Section: Introductionmentioning

confidence: 99%

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Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study

et al. 2010

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Despite novel targeted agents, prognosis of metastatic renal cell cancer (RCC) remains poor, and experimental therapeutic strategies are warranted. Transfection of tumor cells with co-stimulatory molecules and/or cytokines is able to increase immunogenicity. Therefore, in our clinical study, 10 human leukocyte antigen (HLA)-A*0201 + patients with histologicallyconfirmed progressive metastatic clear cell RCC were immunized repetitively over 22 weeks with 2.5-40Â10 6 interleukin (IL)-7/CD80 cotransfected allogeneic HLA-A*0201 + tumor cells (RCC26/IL-7/CD80). Endpoints of the study were feasibility, safety, immunological and clinical responses. Vaccination was feasible and safe. In all, 50% of the patients showed stable disease throughout the study; the median time to progression was 18 weeks. However, vaccination with allogeneic RCC26/IL-7/ CD80 tumor cells was not able to induce TH1-polarized immune responses. A TH2 cytokine profile with increasing amounts of antigen-specific IL-10 secretion was observed in most of the responding patients. Interferon-g secretion by patient lymphocytes upon antigen-specific and non-specific stimulation was substantially impaired, both before and during vaccination, as compared with healthy controls. This is possibly due to profound tumor-induced immunosuppression, which may prevent induction of antitumor immune responses by the gene-modified vaccine. Vaccination in minimal residual disease with concurrent depletion of regulatory cells might be one strategy to overcome this limitation.

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Section: Discussionmentioning

confidence: 99%

Section: Allogeneic Tumor Cell Line and Vaccination Schedulementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study

et al. 2010

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“…We developed an allogeneic gene-modified RCC vaccine based on a well-characterized tumor cell line that showed improved immunogenicity through expression of CD80 and IL-2 (Frankenberger et al, 2005a). The original cell line (RCC-26) was derived from an HLA-A*0201-positive patient with stage I disease (pT1pN0M0G2) in whom only a single brain metastasis appeared after nephrectomy, following a disease-free interval of 9 years.…”

mentioning

confidence: 99%

Phase 1 Trial of Allogeneic Gene-Modified Tumor Cell Vaccine RCC-26/CD80/IL-2 in Patients with Metastatic Renal Cell Carcinoma

et al. 2010

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Preclinical studies showed that the allogeneic tumor cell line RCC-26 displayed natural immunogenic potential that was enhanced through expression of CD80 costimulatory molecules and secretion of interleukin-2. Here we report the study of RCC-26=CD80=IL-2 cells in a phase 1 vaccine trial of renal cell carcinoma patients with metastatic disease (mRCC). Fifteen patients of the HLA-A*0201 allotype, with at least one metastatic lesion, were included. Irradiated vaccine cells were applied in increasing doses of 2.5, 10, and 40Â10 6 cells over 22 weeks. Primary study parameters included safety and toxicity. Sequential blood samples were analyzed by interferon-g enzyme-linked immunospot assays to detect tumor antigen-associated (TAA) effector cells. The vaccine was well tolerated and the designated vaccination course was completed in 9 of 15 patients. Neither vaccine-induced autoimmunity nor systemic side effects were observed. Delayed-type hypersensitivity skin reactions were detected in 11 of 12 evaluated patients and were particularly strong in patients with prolonged survival. In parallel, vaccine-induced immune responses against vaccine or overexpressed TAA were detected in 9 of 12 evaluated patients. No tumor regressions occurred according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria; however, median time to progression was 5.3 months and median survival was 15.6 months, indicating substantial disease stabilization. We conclude that vaccine use was safe and feasible in mRCC. Clinical benefits were limited in these patients with advanced disease; however, immune monitoring revealed vaccine-induced responses against multiple TAAs in the majority of study participants. These results suggest that this vaccine could be useful in combination therapies and=or minimal residual disease.

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“…RCC cells have been modified to express the costimulatory molecule B7-1 as both allogeneic and syngeneic whole tumor cell vaccines and show increased immunogenicity in vitro (19), whereas the results in a phase I clinical trial could not be differentiated from the effect of IL-2 because of the small number of patients in the study (20,21). We and others have shown that the introduction of a single T-cell costimulatory molecule into carcinomas can enhance their immunogenicity (22,23).…”

mentioning

confidence: 99%

Combination Therapy of an Orthotopic Renal Cell Carcinoma Model Using Intratumoral Vector-Mediated Costimulation and Systemic Interleukin-2

Kudo-Saito¹,

Wansley²,

Gruys

et al. 2007

Clinical Cancer Research

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Purpose: Interleukin (IL)-2 therapy is currently used for therapy of renal cell carcinoma (RCC).However, it is only effective in approximately 10% to 15% of patients, showing a need for additional therapies. We have previously described a replication-defective fowlpox vector encoding three costimulatory molecules (B7-1, ICAM-1, and LFA-3), designated rF-TRICOM. Here, we show that intratumoral administration of rF-TRICOM in an orthotopic RCC model effectively enhances tumor immunogenicity and reduces tumor burden in mice and the combination of rF-TRICOM and IL-2 is more effective than either therapy alone. Experimental Design: RCC cells were implanted under the capsule of the kidney, and mice were given rF-TRICOM intratumorally 14 days later. We compared the effect of rF-TRICOM, rFgranulocyte macrophage colony-stimulating factor (GM-CSF), and two doses of IL-2 and combinations of the above on antitumor efficacy and survival. Host CD4 + and CD8 + T-cell responses were also evaluated. Results: The results show that (a) systemic IL-2 therapy was moderately effective in the reduction of tumor burden in an orthotopic RCC model; (b) a single intratumoral injection of rF-TRI-COM and rF-GM-CSF significantly reduced tumor burden; (c) the addition of systemic IL-2 to intratumoral rF-TRICOM/rF-GM-CSF administration resulted in further reduction of tumor burden, decrease in the incidence of metastasis, and extended survival in tumor-bearing mice above that seen with either treatment alone; and (d) CD8+ Tcells played a critical role in the antitumor effect seen with rF-TRICOM/rF-GM-CSF + IL-2 therapy. Finally, the addition of systemic recombinant IL-15 or intratumoral vector-delivered IL-15 to intratumoral rF-TRICOM/rF-GM-CSF administration resulted in substantially more tumor-free mice than either therapy alone. Conclusions: These studies show that intratumoral administration of rF-TRICOM admixed with rF-GM-CSF is effective at reducing tumor burden in mice and the addition of IL-2 further contributes to this effect. These studies thus form the rationale for combination immunotherapy clinical trials in patients with RCC.

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Influence of CD80, Interleukin-2, and Interleukin-7 Expression in Human Renal Cell Carcinoma on the Expansion, Function, and Survival of Tumor-Specific CTLs

Cited by 21 publications

References 36 publications

Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study

Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study

Phase 1 Trial of Allogeneic Gene-Modified Tumor Cell Vaccine RCC-26/CD80/IL-2 in Patients with Metastatic Renal Cell Carcinoma

Combination Therapy of an Orthotopic Renal Cell Carcinoma Model Using Intratumoral Vector-Mediated Costimulation and Systemic Interleukin-2

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