High immune response rates and decreased frequencies of regulatory T cells in metastatic renal cell carcinoma patients after tumor cell vaccination

• Published in: Molecular medicine (Cambridge, Mass.) Mass.), 2013-02, Vol.18 (12), p.1499-1508
• Main Authors: Pohla, Heike, Buchner, Alexander, Stadlbauer, Birgit, Frankenberger, Bernhard, Stevanovic, Stefan, Walter, Steffen, Frank, Ronald, Schwachula, Tim, Olek, Sven, Kopp, Joachim, Willimsky, Gerald, Stief, Christian G, Hofstetter, Alfons, Pezzutto, Antonio, Blankenstein, Thomas, Oberneder, Ralph, Schendel, Dolores J
• Format: Article
• Language: English
• Subjects: Antigens; Biopsy; Cancer Vaccines - immunology; Carcinoma, Renal Cell - blood; Carcinoma, Renal Cell - immunology; Carcinoma, Renal Cell - pathology; Carcinoma, Renal Cell - prevention & control; Chemokines; Clinical trials; Cytokines; Cytokines - biosynthesis; Cytokines - blood; DNA methylation; Enzymes; Flow cytometry; Good Manufacturing Practice; Humans; Immunity - immunology; Immunotherapy; Kidney cancer; Kidney Neoplasms - blood; Kidney Neoplasms - immunology; Kidney Neoplasms - pathology; Kidney Neoplasms - prevention & control; Lymphocyte Count; Lymphocytes, Tumor-Infiltrating - immunology; Medical prognosis; Metastasis; Monoclonal antibodies; Myeloid Cells - immunology; Myeloid Cells - pathology; Neoplasm Metastasis; Neoplasm Staging; Patients; Peptides; Peptides - immunology; Response rates; Software; Survival Analysis; T-Lymphocytes, Regulatory - immunology; Th1 Cells - immunology; Th2 Cells - immunology; Time Factors; Treatment Outcome; Tumor necrosis factor-TNF; Tumors; Vaccination; Vaccines; Vascular endothelial growth factor
• ISSN: 1076-1551; 1528-3658
• DOI: 10.2119/molmed.2012.00221

Our previously reported phase I clinical trial with the allogeneic gene-modified tumor cell line RCC-26/CD80/IL-2 showed that vaccination was well tolerated and feasible in metastatic renal cell carcinoma (RCC) patients. Substantial disease stabilization was observed in most patients despite a high tumor burden at study entry. To investigate alterations in immune responses that might contribute to this effect, we performed an extended immune monitoring that included analysis of reactivity against multiple antigens, cytokine/chemokine changes in serum and determination of the frequencies of immune suppressor cell populations, including natural regulatory T cells (nTregs) and myeloid-derived suppressor cell subsets (MDSCs). An overall immune response capacity to virus-derived control peptides was present in 100% of patients before vaccination. Vaccine-induced immune responses to tumor-associated antigens occurred in 75% of patients, demonstrating the potent immune stimulatory capacity of this generic vaccine. Furthermore, some patients reacted to peptide epitopes of antigens not expressed by the vaccine, showing that epitope-spreading occurred in vivo. Frequencies of nTregs and MDSCs were comparable to healthy donors at the beginning of study. A significant decrease of nTregs was detected after vaccination (p = 0.012). High immune response rates, decreased frequencies of nTregs and a mixed T helper 1/T helper 2 (T(H)1/T(H)2)-like cytokine pattern support the applicability of this RCC generic vaccine for use in combination therapies.