RESUMEN
Monoclonal antibodies (mAbs) have an established role in current cancer therapy with seven approved for the treatment of a wide variety of tumors. The approved mAbs directly target tumor cells; however, it is becoming increasingly clear that as well as their direct effects, these mAbs can present antigens to the immune system. This stimulates long-lasting T-cell immunity, which may correlate with long-term survival. A more direct approach is to use mAbs to target antigens directly to antigen-presenting cells. One approach, ImmunoBody, which has just entered the clinic, stimulates antitumor immunity using mAbs genetically engineered to express tumor-specific T-cell epitopes. T cells not only respond via their T-cell receptors recognizing T-cell epitopes presented on MHC but are also influenced by stimulation of a wide variety of costimulatory molecules. mAbs targeting these molecules can also influence antitumor immunity. The main protagonist in this class of mAbs is ipilimumab, which has recently been shown to improve survival at 2 years in 23% of advanced melanoma patients. Combinations of mAbs targeting tumor antigens to activated antigen-presenting cells and mAbs targeting costimulatory receptors may provide effective therapy for a broad range of tumors.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Inmunidad Celular/fisiología , Inmunoterapia/métodos , Neoplasias/terapia , Anticuerpos Monoclonales/inmunología , Células Presentadoras de Antígenos/inmunología , Antígenos de Neoplasias/inmunología , Humanos , Inmunidad Celular/inmunología , Neoplasias/inmunología , Linfocitos T/inmunologíaRESUMEN
Stimulation of high-avidity CTL responses is essential for effective anti-tumor and anti-viral vaccines. In this study we have demonstrated that a DNA vaccine incorporating CTL epitopes within an Ab molecule results in high-avidity T-cell responses to both foreign and self epitopes. The avidity and frequency was superior to peptide, peptide-pulsed DC vaccines or a DNA vaccine incorporating the epitope within the native Ag. The DNA Ab vaccine was superior to an identical protein vaccine that can only cross-present, indicating a role for direct presentation by the DNA vaccine. However, the avidity of CTL responses was significantly reduced in Fc receptor gamma knockout mice or if the Fc region was removed suggesting that cross presentation of Ag via Fc receptor was also important in the induction of high-avidity CTL. These results suggest that generation of high-avidity CTL responses by the DNA vaccine is related to its ability to both directly present and cross-present the epitope. High-avidity responses were capable of efficient anti-tumor activity in vitro and in vivo. This study demonstrates a vaccine strategy to generate high-avidity CTL responses that can be used in anti-tumor and anti-viral vaccine settings.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/inmunología , Epítopos de Linfocito T/inmunología , Animales , Anticuerpos/inmunología , Afinidad de Anticuerpos , Humanos , Inmunoglobulina G/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Vacunas de ADN/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
gamma 1-Herpesviruses such as Epstein-Barr virus (EBV) have a unique ability to amplify virus loads in vivo through latent growth-transforming infection. Whether they, like alpha- and beta-herpesviruses, have been driven to actively evade immune detection of replicative (lytic) infection remains a moot point. We were prompted to readdress this question by recent work (Pudney, V.A., A.M. Leese, A.B. Rickinson, and A.D. Hislop. 2005. J. Exp. Med. 201:349-360; Ressing, M.E., S.E. Keating, D. van Leeuwen, D. Koppers-Lalic, I.Y. Pappworth, E.J.H.J. Wiertz, and M. Rowe. 2005. J. Immunol. 174:6829-6838) showing that, as EBV-infected cells move through the lytic cycle, their susceptibility to EBV-specific CD8(+) T cell recognition falls dramatically, concomitant with a reductions in transporter associated with antigen processing (TAP) function and surface human histocompatibility leukocyte antigen (HLA) class I expression. Screening of genes that are unique to EBV and closely related gamma 1-herpesviruses of Old World primates identified an early EBV lytic cycle gene, BNLF2a, which efficiently blocks antigen-specific CD8(+) T cell recognition through HLA-A-, HLA-B-, and HLA-C-restricting alleles when expressed in target cells in vitro. The small (60-amino acid) BNLF2a protein mediated its effects through interacting with the TAP complex and inhibiting both its peptide- and ATP-binding functions. Furthermore, this targeting of the major histocompatibility complex class I pathway appears to be conserved among the BNLF2a homologues of Old World primate gamma 1-herpesviruses. Thus, even the acquisition of latent cycle genes endowing unique growth-transforming ability has not liberated these agents from evolutionary pressure to evade CD8(+) T cell control over virus replicative foci.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Regulación de la Expresión Génica , Herpesvirus Humano 4/metabolismo , Secuencia de Aminoácidos , Animales , Linfocitos T CD8-positivos/metabolismo , Cercopithecidae , Clonación Molecular , Citometría de Flujo , Antígenos HLA/química , Antígenos HLA/metabolismo , Herpesviridae/metabolismo , Humanos , Sistema Inmunológico/metabolismo , Datos de Secuencia Molecular , Péptidos/química , Homología de Secuencia de AminoácidoRESUMEN
Antigen immunodominance is an unexplained feature of CD8+ T cell responses to herpesviruses, which are agents whose lytic replication involves the sequential expression of immediate early (IE), early (E), and late (L) proteins. Here, we analyze the primary CD8 response to Epstein-Barr virus (EBV) infection for reactivity to 2 IE proteins, 11 representative E proteins, and 10 representative L proteins, across a range of HLA backgrounds. Responses were consistently skewed toward epitopes in IE and a subset of E proteins, with only occasional responses to novel epitopes in L proteins. CD8+ T cell clones to representative IE, E, and L epitopes were assayed against EBV-transformed lymphoblastoid cell lines (LCLs) containing lytically infected cells. This showed direct recognition of lytically infected cells by all three sets of effectors but at markedly different levels, in the order IE > E >> L, indicating that the efficiency of epitope presentation falls dramatically with progress of the lytic cycle. Thus, EBV lytic cycle antigens display a hierarchy of immunodominance that directly reflects the efficiency of their presentation in lytically infected cells; the CD8+ T cell response thereby focuses on targets whose recognition leads to maximal biologic effect.