Abstract
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 40 x 10(6) cells over 22 weeks. Primary study parameters included safety and toxicity. Sequential blood samples were analyzed by interferon-gamma 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.
Highlights
Up to 30% of patients with renal cell carcinoma (RCC) have metastatic disease at the time of diagnosis, and metastases develop metachronously in 20–40% of patients undergoing partial or radical nephrectomy for clinically localized tumors ( Janzen et al, 2003)
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)
Individualized RCC cell vaccines offer the possibility to target immune responses to a unique array of epitopes that arise through genetic mutation in tumor cells; a parallel compensation must be made to improve the inferior immune-stimulatory capacity of tumor cells
Summary
Up to 30% of patients with renal cell carcinoma (RCC) have metastatic disease at the time of diagnosis, and metastases develop metachronously in 20–40% of patients undergoing partial or radical nephrectomy for clinically localized tumors ( Janzen et al, 2003). Targeted molecular therapies have become available that can slow tumor progression, offering new hope for patients with metastatic RCC (mRCC). These therapies are directed primarily toward interruption of signaling pathways that foster angiogenesis (Longo et al, 2007). Cancer vaccines represent one treatment strategy to exploit this immunological potential because there is evidence that immunization against tumors can reduce or even eliminate some tumors and induce longlasting T cell memory responses with a capacity to control tumor relapse. Future treatment strategies that combine targeted molecular therapies with low-toxicity vaccination might enhance the development of effective immune responses and improve the long-term perspectives of patients with advanced disease
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