Abstract
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.
Highlights
Allogeneic stem cell transplantation is a highly effective treatment for many hematological malignancies [1]
Seven months after Allogeneic stem cell transplantation (alloSCT) postponed donor lymphocyte infusion (DLI) was administered at a single dose of 56106 T cells/kg, resulting in conversion to full donor chimerism, which persisted during the following years
We analyzed T cell responses elicited after alloSCT and DLI in a patient suffering from progressive clear cell renal cell carcinoma (RCC)
Summary
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. Postponed donor lymphocyte infusion (DLI) can be applied to prevent or treat disease recurrence [2,3]
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