T-cell receptor gene therapy in human melanoma-bearing immune-deficient mice: human but not mouse T cells recapitulate outcome of clinical studies.
Hum Gene Ther
; 23(2): 187-201, 2012 Feb.
Article
en En
| MEDLINE
| ID: mdl-21958294
ABSTRACT
Adoptive cell therapy using T-cell receptor (TCR)-engineered T cells is a clinically feasible and promising approach to target tumors, but is currently faced with compromised antitumor efficacies in patients. Here, we extensively validated immune-deficient mice to facilitate further development of the therapeutic potential of TCR-engineered T cells. Treatment of human melanoma-bearing SCID or NSG mice with high doses of human T cells transduced with an hgp100/HLA-A2-specific TCR did not result in antitumor responses irrespective of chemotherapeutic preconditioning. Imaging of human green fluorescent protein-labeled T cells demonstrated significant T-cell accumulation in intratumoral vasculature directly upon T-cell transfer, which was followed by loss of T cells within 72 hr. Peripheral persistence of human T cells was highly compromised and appeared related to T-cell differentiation. On the contrary, adoptive transfer (AT) of relatively low numbers of hgp100/HLA-A2 TCR-transduced mouse T cells resulted in rapid clearance of large established human melanomas. Unexpectedly and in contrast to reported studies with chimeric antibody receptor-engineered T cells, antitumor activity and homeostatic expansion of T cells were independent of TCR transgene as evidenced in two SCID strains and using two different human melanoma cell lines. Interestingly, the xeno-reactive melanoma response of mouse T cells appeared to be dictated by CD4(+) tumor-infiltrating lymphocytes and did not require in vitro T-cell activation, retroviral gene transfer, or subcutaneous interleukin-2 support. Taken together, AT of human but not mouse T cells in human melanoma-bearing immune-deficient mice is in close accordance with clinical studies.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Receptores de Antígenos de Linfocitos T
/
Terapia Genética
/
Antígeno HLA-A2
/
Inmunoterapia Adoptiva
/
Antígeno gp100 del Melanoma
/
Melanoma
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Hum Gene Ther
Asunto de la revista:
GENETICA MEDICA
/
TERAPEUTICA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Países Bajos