Durable Remission of Renal Cell Carcinoma in Conjuncture with Graft versus Host Disease following Allogeneic Stem Cell Transplantation and Donor Lymphocyte Infusion: Rule or Exception?

et al. (2014) Durable Remission of Renal Cell Carcinoma in Conjuncture with Graft versus Host Disease following Allogeneic Stem Cell Transplantation and Donor Lymphocyte Infusion: Rule or Exception? PLoS ONE 9(1): e85198. doi:10.1371/journal.pone.0085198 Durable Remission of Renal Cell Carcinoma in Conjuncture with Graft versus Host Disease following Allogeneic Stem Cell Transplantation and Donor Lymphocyte Infusion: Rule or Exception? Cornelis A. M. van Bergen 0 Elisabeth M. E. Verdegaal 0 M. Wilhelmina Honders 0 Conny Hoogstraten 0 A. Q. M. Jeanne Steijn-van Tol 0 Linda de Quartel 0 Joan de Jong 0 Maaike Meyering 0 J. H. Frederik Falkenburg 0 Marieke Griffioen 0 Susanne Osanto 0 Yoshiki Akatsuka, Fujita Health University, School of Medicine, Japan 0 1 Department of Hematology, Leiden University Medical Center , Leiden , The Netherlands , 2 Department of Clinical Oncology, Leiden University Medical Center , Leiden , The Netherlands Allogeneic stem cell transplantation (alloSCT) followed by donor lymphocyte infusion (DLI) can be applied as immunotherapeutic intervention to treat malignant diseases. Here, we describe a patient with progressive metastatic clear cell renal cell carcinoma (RCC) who was treated with T cell depleted non-myeloablative alloSCT and DLI resulting in disease regression accompanied by extensive graft versus host disease (GVHD). We characterized the specificity of this immune response, and detected a dominant T cell population recognizing a novel minor histocompatibility antigen (MiHA) designated LB-FUCA2-1V. T cells specific for LB-FUCA2-1V were shown to recognize RCC cell lines, supporting a dominant role in the graft versus tumor (GVT) reaction. However, coinciding with the gradual disappearance of chronic GVHD, the anti-tumor effect declined and 3 years after alloSCT the metastases became progressive again. To re-initiate the GVT reaction, escalating doses of DLI were given, but no immune response could be induced and the patient died of progressive disease 8.5 years after alloSCT. Gene expression studies illustrated that only a minimal number of genes shared expression between RCC and professional antigen presenting cells but were not expressed by non-malignant healthy tissues, indicating that in patients suffering from RCC, GVT reactivity after alloSCT may be unavoidably linked to GVHD. - Funding: This work was supported by the Dutch Cancer Society grant no. UL-2004-3013 (www.kwfkankerbestrijding.nl). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Allogeneic stem cell transplantation (alloSCT) is a highly effective treatment for many hematological malignancies [1]. Following HLA-matched alloSCT, the curative graft versus tumor (GVT) reactivity is mediated by donor-derived T cells recognizing minor histocompatibility antigens (MiHA) expressed by the malignant patient cells. MiHA are polymorphic peptides presented by HLA-molecules and are the result of genomic single nucleotide polymorphisms (SNP) that are disparate between patient and donor. The repertoire of patient specific MiHA can act as non-self antigens to infused donor T cells [2]. If MiHA are co-expressed by malignant cells and normal non-hematopoietic tissues, alloreactive donor T cells may induce both GVT reactivity and graft versus host disease (GVHD). Donor T cells recognizing MiHA exclusively expressed by normal and malignant hematopoietic cells from the patient can mediate GVT reactivity in the absence of GVHD. Since hematopoiesis after alloSCT is of donor origin, complete elimination of patient hematopoiesis does not impair normal hematopoiesis and immunological function. T cell depletion of the graft reduces the risk of GVHD, but increases relapse rates by abrogating therapeutic GVT reactivity. Postponed donor lymphocyte infusion (DLI) can be applied to prevent or treat disease recurrence [2,3]. Clinical beneficial effects of alloSCT for treatment of nonhematopoietic tumors were mainly observed in patients with metastatic renal cell cancer (RCC) [4,5] and metastatic breast cancer [6]. In RCC, alloSCT resulted in an overall response rate ranging between 2040% [7]. In the majority of these cases, however, GVT reactivity was associated with development of clinically significant GVHD. The concurrence of GVT reactivity and GVHD indicates that tumor controlling donor T cells often recognize MiHA that are co-expressed by tumor cells and by normal tissue cells. Specific GVT reactivity and concurrent prevention of GVHD by replacement of the normal patient counterpart by donor cells, comparable to achievement of full donor chimerism in bone marrow and peripheral blood of hematological patients after alloSCT, is obviously not possible in patients with solid tumors. For development and expansion of a primary donor-derived immune response after DLI, it may be essential that MiHA are presented by recipient-derived dendritic cells (DC) [8]. DC of patient origin can present both endogenously derived MiHA, and cross present antigens that are generated from proteins taken up from surrounding damaged tissue cells. In patients with hematological malignancies, the hematopoietic origin of DC may explain relative skewing of the T cell response towards hematopoietic cells, and targeting of hematopoiesis restricted MiHA can result in GVT reactivity in the absence of GVHD [9,10]. Solid tumor cells and DC however, originate from different lineages and successful targeting of these malignancies may often involve MiHA that are broadly expressed not only on DC and malignant cells, but also on the normal counterpart of tumor cells. In this study, we describe a patient with clear cell RCC who showed tumor regression and prolonged survival after alloSCT followed by DLI. Extensive chronic GVHD coincided with durable disease control but the disease became progressive when GVHD resolved. Subsequent administration of escalating doses of DLI could not re-induce the GVT reaction. We identified a strong T cell response targeting a novel MiHA (LB-FUCA2-1V) presented by HLA-B*07:02, and induction of LB-FUCA2-1V specific T cells coincided with tumor control and GVHD. Broad recognition of GVHD target tissues by LB-FUCA2-1V specific T cells correlated with a broad expression profile of the FUCA2 gene. Gene expression profile studies showed that, in contrast to leukemic cells, only a limited number of genes is selectively coexpressed by RCC and DC, and not by cells representing normal tissue cells. GVT reactivity may therefore be unavoidably correlated with GVHD after alloSCT and DLI for treatment of RCC. Materials and Methods Sample collection and preservation Peripheral blood samples and skin biopsies were collected from patient, donor, and third party individuals after approval by the Leiden University Medical Center institutional review board ac (...truncated)