Adoptive T-cell therapy Sample Clauses

Adoptive T-cell therapy. Adoptive T-cell therapy is an immunotherapeutic strategy that involves the ex vivo expansion of tumour-reactive T-cells followed by their adoptive transfer into patients to combat cancer. Different modalities of adoptive cell therapy have been investigated involving the use of tumour-infiltrating lymphocytes (TILs), antigen-specific autologous T-cell clones and genetically engineered human lymphocytes. Immunotherapy using TIL cells was pioneered by Xxxxxx Xxxxxxxxx at the National Institute of Health (NIH) who demonstrated that autologous TILs infused after lymphodepleting chemotherapy could induce regression of metastases in vivo71. In the first human study, the researchers showed that a single infusion of TILs could cause disease regression in up to 60% of patients with metastatic melanoma72,73. However, generation of TILs is time consuming (approximately 5-6 weeks) and labour intensive74,75. Moreover, TIL adoptive cell therapy is not applicable to many other tumour types because of low tumour immunogenicity and minimal TIL infiltration76. With improvements in gene transfer technology, genetically encoded receptors could be introduced to re-direct T-cells against tumours thereby broadening the applicability of adoptive cell therapy. With this approach, polyclonal T-cells with specificity for a tumour associated antigen (TAA) are rapidly generated. Two classes of receptors are commonly used for this purpose, namely antigen specific αβ T-cell receptors (TCR) or chimeric antigen receptors (CAR). An early report of gamma retroviral vector TCR gene transfer described the treatment of a patient with melanoma by targeting MART-1 with a TAA specific TCR77. Since then, T-cells have been successfully re-targeted using TCRs directed against several antigens such as p5378,79, glycoprotein-100 (gp100)80, Wilm’s tumour antigen-1 (WT-1)81, carcinoembryonic antigen (CEA)82,83 and others. The testis TAA NY-ESO-1 has been a particularly promising target as it is present in multiple cancer types and is highly immunogenic. In early-phase clinical trials NY-ESO-1 TCR engineered T-cells were used to treat multiple myeloma and synovial sarcoma, reporting response rates of 80% and 50% respectively84,85. A major restriction of TCR therapy is that a limited number of patients with the appropriate HLA alleles can receive treatment, owing to the need to match the TCR to the patient’s HLA haplotype. To date, the vast majority of TCRs in clinical trial are restricted by HLA-A*0201, w...
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