RESUMEN
Since malignant cells are derived from normal cells, many tumour-associated antigens are also expressed in normal tissues. For examples, WT1 is expressed at elevated levels in most leukaemias, but it is also expressed at reduced levels in normal CD34+ haematopoietic stem cells and in progenitor cells of other tissues. Antigen expression in normal tissues is likely to trigger immunological tolerance and thus blunt T cell responses. This could explain the observation that WT1 vaccination in mice frequently fails to stimulate high avidity cytotoxic T cell responses. In order to circumvent tolerance, we have isolated from HLA-A2-negative donors high avidity CTL specific for HLA-A2-presented peptide epitopes of WT1. These allorestricted CTL efficiently kill HLA-A2-positive leukaemia cells but not normal CD34+ haematopoietic stem cells. However, adoptive cellular therapy with allorestricted CTL could only be performed in leukaemia patients rendered tolerant to the infused CTL by prior allogeneic stem cell transplantation. In order to circumvent this limitation, we propose to exploit the TCR of allorestricted CTL as therapeutic tool. TCR gene transfer can be used to take advantage of the specificity of allorestricted CTL and transfer it to patient CTL, while avoiding the transfer of immunogenic alloantigens from the donor CTL to the patient.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Inmunoterapia Adoptiva , Leucemia/terapia , Linfocitos T Citotóxicos/trasplante , Proteínas WT1/inmunología , Animales , Epítopos de Linfocito T/inmunología , Antígeno HLA-A2/inmunología , Humanos , Leucemia/inmunología , Ratones , Péptidos/inmunología , Linfocitos T Citotóxicos/inmunologíaRESUMEN
It is well established that antigen-specific T lymphocytes can inhibit tumor growth in humans and in mice, leading to complete tumor elimination in some cases. However, in many cases T cell immunity is unable to successfully control tumor progression. Since tumors are derived from normal tissues, most antigens are shared with normal tissues, although expression levels are usually elevated in malignant cells. Nevertheless, low-level expression in normal cells can be sufficient to render autologous T cells tolerant and thus unable to mount effective immune responses against tumors. Here, we review how allogeneic T cells can be used to isolate T cells that effectively recognise and kill tumor cells, but not normal cells with low level of antigen expression. The TCR of allogeneic T cells can be introduced into patient T cells to equip them with anti-tumor specificity that may not be present in the autologous T cell repertoire.
Asunto(s)
Inmunoterapia Adoptiva , Leucemia/terapia , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T Citotóxicos/inmunología , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/terapia , Efecto Injerto vs Leucemia/inmunología , Antígenos HLA/inmunología , Humanos , Leucemia/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Citotóxicos/trasplante , Trasplante Homólogo/inmunología , Proteínas WT1/inmunologíaRESUMEN
The majority of T cell-recognized tumour antigens in humans are encoded by genes that are also present in normal tissues. Low levels of gene expression in normal cells can lead to the inactivation of high-avidity T cells by immunological tolerance mechanisms. As a consequence, low-avidity T cell responses in patients are often inadequate in providing tumour protection. Recently, several technologies have been developed to overcome tolerance, allowing the isolation of high-affinity, HLA-restricted receptors specific for tumour-associated peptide epitopes. Furthermore, transfer of HLA-restricted antigen receptors provides an opportunity to empower patient T cells with new tumour-reactive specificities that cannot be retrieved from the autologous T cell repertoire.