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A pilot study of autologous tumor lysate-loaded dendritic cell vaccination combined with sunitinib for metastatic renal cell carcinoma

BACKGROUND: Sunitinib, a tyrosine kinase inhibitor currently in use for the treatment of metastatic renal cell carcinoma (mRCC), has been reported to modulate immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in addition to exerting anti-angiogen...

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Autores principales: Matsushita, Hirokazu, Enomoto, Yutaka, Kume, Haruki, Nakagawa, Tohru, Fukuhara, Hiroshi, Suzuki, Motofumi, Fujimura, Tetsuya, Homma, Yukio, Kakimi, Kazuhiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331924/
https://www.ncbi.nlm.nih.gov/pubmed/25694811
http://dx.doi.org/10.1186/s40425-014-0030-4
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author Matsushita, Hirokazu
Enomoto, Yutaka
Kume, Haruki
Nakagawa, Tohru
Fukuhara, Hiroshi
Suzuki, Motofumi
Fujimura, Tetsuya
Homma, Yukio
Kakimi, Kazuhiro
author_facet Matsushita, Hirokazu
Enomoto, Yutaka
Kume, Haruki
Nakagawa, Tohru
Fukuhara, Hiroshi
Suzuki, Motofumi
Fujimura, Tetsuya
Homma, Yukio
Kakimi, Kazuhiro
author_sort Matsushita, Hirokazu
collection PubMed
description BACKGROUND: Sunitinib, a tyrosine kinase inhibitor currently in use for the treatment of metastatic renal cell carcinoma (mRCC), has been reported to modulate immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in addition to exerting anti-angiogenic effects. We conducted a clinical trial of dendritic cell (DC)-based immunotherapy together with sunitinib in mRCC patients in an effort to enhance immunotherapeutic efficacy by inhibiting immunosuppressive cells. METHODS: Patients aged ≥20 years with advanced or recurrent mRCC who underwent nephrectomy were eligible for this study. Autologous tumor samples were obtained by surgery under aseptic conditions and used for preparing autologous tumor lysate. About 4 weeks after surgery, leukapheresis was performed to isolate peripheral blood mononuclear cells (PBMCs). DCs were generated from adherent PBMCs in the presence of recombinant human granulocyte macrophage colony-stimulating factor (GM-CSF) (500 IU/ml) and recombinant human IL-4 (500 IU/ml). Autologous tumor lysate was loaded into mature DC by electroporation. Eight patients were enrolled in the study and received sunitinib at a dose of 50 mg p.o. daily for 28 days followed by 14 days of rest. Tumor lysate-loaded DCs were administered subcutaneously every two weeks, with concomitant sunitinib. RESULTS: No severe adverse events related to vaccination were observed. Sunitinib decreased the frequencies of MDSCs in peripheral blood of 5 patients and of Tregs in 3. Tumor lysate-reactive CD4 or CD8 T cell responses were observed in 5 patients, 4 of whom showed decreased frequencies of Tregs and/or MDSCs. The remaining 3 patients who failed to develop tumor-reactive T cell responses had high levels of IL-8 in their sera and did not show consistent reductions in MDSCs and Tregs. CONCLUSIONS: DC-based immunotherapy combined with sunitinib is safe and feasible for patients with mRCC. TRIAL REGISTRATION: UMIN000002136
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spelling pubmed-43319242015-02-19 A pilot study of autologous tumor lysate-loaded dendritic cell vaccination combined with sunitinib for metastatic renal cell carcinoma Matsushita, Hirokazu Enomoto, Yutaka Kume, Haruki Nakagawa, Tohru Fukuhara, Hiroshi Suzuki, Motofumi Fujimura, Tetsuya Homma, Yukio Kakimi, Kazuhiro J Immunother Cancer Research Article BACKGROUND: Sunitinib, a tyrosine kinase inhibitor currently in use for the treatment of metastatic renal cell carcinoma (mRCC), has been reported to modulate immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in addition to exerting anti-angiogenic effects. We conducted a clinical trial of dendritic cell (DC)-based immunotherapy together with sunitinib in mRCC patients in an effort to enhance immunotherapeutic efficacy by inhibiting immunosuppressive cells. METHODS: Patients aged ≥20 years with advanced or recurrent mRCC who underwent nephrectomy were eligible for this study. Autologous tumor samples were obtained by surgery under aseptic conditions and used for preparing autologous tumor lysate. About 4 weeks after surgery, leukapheresis was performed to isolate peripheral blood mononuclear cells (PBMCs). DCs were generated from adherent PBMCs in the presence of recombinant human granulocyte macrophage colony-stimulating factor (GM-CSF) (500 IU/ml) and recombinant human IL-4 (500 IU/ml). Autologous tumor lysate was loaded into mature DC by electroporation. Eight patients were enrolled in the study and received sunitinib at a dose of 50 mg p.o. daily for 28 days followed by 14 days of rest. Tumor lysate-loaded DCs were administered subcutaneously every two weeks, with concomitant sunitinib. RESULTS: No severe adverse events related to vaccination were observed. Sunitinib decreased the frequencies of MDSCs in peripheral blood of 5 patients and of Tregs in 3. Tumor lysate-reactive CD4 or CD8 T cell responses were observed in 5 patients, 4 of whom showed decreased frequencies of Tregs and/or MDSCs. The remaining 3 patients who failed to develop tumor-reactive T cell responses had high levels of IL-8 in their sera and did not show consistent reductions in MDSCs and Tregs. CONCLUSIONS: DC-based immunotherapy combined with sunitinib is safe and feasible for patients with mRCC. TRIAL REGISTRATION: UMIN000002136 BioMed Central 2014-08-19 /pmc/articles/PMC4331924/ /pubmed/25694811 http://dx.doi.org/10.1186/s40425-014-0030-4 Text en Copyright © 2014 Matsushita et al.; licensee BioMed Central http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Matsushita, Hirokazu
Enomoto, Yutaka
Kume, Haruki
Nakagawa, Tohru
Fukuhara, Hiroshi
Suzuki, Motofumi
Fujimura, Tetsuya
Homma, Yukio
Kakimi, Kazuhiro
A pilot study of autologous tumor lysate-loaded dendritic cell vaccination combined with sunitinib for metastatic renal cell carcinoma
title A pilot study of autologous tumor lysate-loaded dendritic cell vaccination combined with sunitinib for metastatic renal cell carcinoma
title_full A pilot study of autologous tumor lysate-loaded dendritic cell vaccination combined with sunitinib for metastatic renal cell carcinoma
title_fullStr A pilot study of autologous tumor lysate-loaded dendritic cell vaccination combined with sunitinib for metastatic renal cell carcinoma
title_full_unstemmed A pilot study of autologous tumor lysate-loaded dendritic cell vaccination combined with sunitinib for metastatic renal cell carcinoma
title_short A pilot study of autologous tumor lysate-loaded dendritic cell vaccination combined with sunitinib for metastatic renal cell carcinoma
title_sort pilot study of autologous tumor lysate-loaded dendritic cell vaccination combined with sunitinib for metastatic renal cell carcinoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331924/
https://www.ncbi.nlm.nih.gov/pubmed/25694811
http://dx.doi.org/10.1186/s40425-014-0030-4
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