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Rational design of a SOCS1-edited tumor-infiltrating lymphocyte therapy using CRISPR/Cas9 screens
Abstract:
Cell therapies such as tumor-infiltrating lymphocyte (TIL) therapy have shown promise in the treatment of patients with refractory solid tumors, with improvement in response rates and durability of responses nevertheless sought. To identify targets capable of enhancing the antitumor activity of T cell therapies, large-scale in vitro and in vivo clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens were performed, with the SOCS1 gene identified as a top T cell-enhancing target. In murine CD8+ T cell-therapy models, SOCS1 served as a critical checkpoint in restraining the accumulation of central memory T cells in lymphoid organs as well as intermediate (Texint) and effector (Texeff) exhausted T cell subsets derived from progenitor exhausted T cells (Texprog) in tumors. A comprehensive CRISPR tiling screen of the SOCS1-coding region identified sgRNAs targeting the SH2 domain of SOCS1 as the most potent, with an sgRNA with minimal off-target cut sites used to manufacture KSQ-001, an engineered TIL therapy with SOCS1 inactivated by CRISPR/Cas9. KSQ-001 possessed increased responsiveness to cytokine signals and enhanced in vivo antitumor function in mouse models. These data demonstrate the use of CRISPR/Cas9 screens in the rational design of T cell therapies.
Insights
Scientists used CRISPR screens to find targets for improving T cell therapies. They identified SOCS1 as a key gene to enhance anti-tumor activity, leading to a new engineered therapy called KSQ-001.
Area of Science:
- Immunology
- Gene editing
- Cancer therapy
Background:
- Tumor-infiltrating lymphocyte (TIL) therapy shows promise for refractory solid tumors.
- Improving response rates and durability of TIL therapy is crucial.
- Identifying novel targets to enhance T cell-mediated anti-tumor activity is needed.
Purpose of the Study:
- To identify genes that can enhance T cell therapy efficacy using large-scale CRISPR screens.
- To investigate the role of SOCS1 in regulating T cell exhaustion and function.
- To develop an engineered TIL therapy with enhanced anti-tumor activity.
Main Methods:
- Performed in vitro and in vivo clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens to identify T cell-enhancing targets.
- Utilized murine CD8+ T cell-therapy models to study SOCS1 function.
- Conducted a comprehensive CRISPR tiling screen of the SOCS1-coding region to identify optimal sgRNAs.
- Manufactured KSQ-001, an engineered TIL therapy with CRISPR/Cas9-mediated SOCS1 inactivation.
Main Results:
- SOCS1 was identified as a top T cell-enhancing target.
- SOCS1 acts as a critical checkpoint, restraining T cell accumulation and exhaustion in tumors.
- sgRNAs targeting the SOCS1 SH2 domain were most potent.
- KSQ-001 demonstrated increased responsiveness to cytokine signals and enhanced in vivo anti-tumor function in mouse models.
Conclusions:
- CRISPR/Cas9 screens are effective for the rational design of T cell therapies.
- Inactivating SOCS1 can enhance the anti-tumor activity of TIL therapy.
- Engineered TIL therapy with SOCS1 inactivation represents a promising strategy for cancer treatment.
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