Combination of anti‐CD4 antibody treatment and donor lymphocyte infusion ameliorates graft‐versus‐host disease while preserving graft‐versus‐tumor effects in murine allogeneic hematopoietic stem cell transplantation

• Published in: Cancer science 2017-10, Vol.108 (10), p.1967-1973
• Main Authors: Ueha, Satoshi, Yokochi, Shoji, Ishiwata, Yoshiro, Kosugi‐Kanaya, Mizuha, Shono, Yusuke, Shibayama, Shiro, Ito, Satoru, Matsushima, Kouji
• Format: Article
• Language: English
• Subjects: Allogeneic hematopoietic stem cell transplantation; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacology; CD4; CD4 Antigens - immunology; Cell Line, Tumor; Colonic Neoplasms - therapy; Combined Modality Therapy; Disease Models, Animal; donor lymphocyte infusion; Graft vs Host Disease - immunology; Graft vs Host Disease - therapy; graft‐versus‐host disease; graft‐versus‐tumor; Hematopoietic Stem Cell Transplantation - mortality; Immunotherapy, Adoptive - methods; Lymphocyte Transfusion - methods; Mice; Original; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous - mortality; Treatment Outcome
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13346

Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is not only a well‐established immunotherapy for hematologic malignancies, but is potentially useful for treating solid tumors refractory to available therapies. However, application of allo‐HSCT to solid tumors is limited, despite the beneficial antitumor effects, by the risk of graft‐versus‐host disease (GVHD). CD4+ T cells have been implicated in several aspects of GVHD, and suppress antitumor CD8+ T‐cell responses. In the present study, we investigated clinically applicable allo‐HSCT protocols designed to maximize antitumor effects while reducing the risk of GVHD. We used a mouse model of allo‐HSCT with s.c. tumors. We found that myeloablative conditioning was associated with better inhibition of tumor growth but with severe acute GVHD. Early treatment with anti‐CD4 mAb substantially ameliorated GVHD while preserving antitumor effects, leading to improved survival in myeloablative allo‐HSCT. Late treatment with anti‐CD4 mAb also ameliorated GVHD to some extent. Donor lymphocyte infusion in GVHD mice treated with anti‐CD4 mAb further suppressed tumor growth without exacerbating GVHD. Collectively, our results suggest that myeloablative allo‐HSCT followed by anti‐CD4 mAb treatment and donor lymphocyte infusion could be a potent and safe immunotherapy for patients with cancers refractory to available therapies. Early anti‐CD4 mAb treatment ameliorates GVHD, while preserving anti‐tumor effects, leading to improved survival in myeloablative allo‐HSCT. DLI in GVHD mice treated with anti‐CD4 mAb augments anti‐tumor effects without exacerbating GVHD.