Abstract
Adoptive T cell therapy with T cell receptor (TCR)-modified T cells has shown promise in treating metastatic melanoma and other malignancies. However, studies are needed to improve the efficacy and durability of responses of TCR-modified T cells. Standard protocols for generating TCR-modified T cells involve activating T cells through CD3 stimulation to allow for the efficient transfer of tumor-reactive receptors with viral vectors. T cell activation results in terminal differentiation and shortening of telomeres, which are likely suboptimal for therapy. In these studies, we demonstrate efficient T cell transduction with the melanoma-reactive TIL1383I TCR through culturing with interleukin 7 (IL-7) in the absence of CD3 activation. The TIL1383I TCR-modified T cells generated following IL-7 culture were enriched with naïve (TN) and memory stem cell populations (TSCM) while maintaining longer telomere lengths. Furthermore, we demonstrated melanoma-reactivity of TIL1383I TCR-modified cells generated following IL-7 culture using in vitro assays and a superior response in an in vivo melanoma model. These results suggest that utilizing IL-7 to generate TCR-modified T cells in the absence of activation is a feasible strategy to improve adoptive T cell therapies for melanoma and other malignancies.
Highlights
The introduction of immunotherapies has dramatically improved the treatment of metastatic melanoma over the past two decades
We evaluated the phenotypes of TIL1383I T cell receptor (TCR)-modified T cells generated in the absence of activation to assess for potential therapeutic benefits
Adoptive T cell therapy remains a promising form of treatment for metastatic melanoma
Summary
The introduction of immunotherapies has dramatically improved the treatment of metastatic melanoma over the past two decades. A trial utilizing TIL in metastatic melanoma patients demonstrated a correlation between clinical response and longer telomere lengths in infused products[18]. Despite these data, current methods of generating both TCR-modified and CAR T cells involve activation through CD3 stimulation to allow for efficient viral gene transfer[19]. Culturing with IL-7 has been shown to allow for transduction of T cells with lentiviral vectors in the absence of a ctivation[22,23] In these studies, we show that utilizing IL-7 to generate TIL1383I TCR-modified T cells in the absence of activation results in a cellular product with lessdifferentiated subpopulations, longer telomere lengths, and antigen-reactivity in vitro and in vivo
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