T Cells Expanded from PD-1⁺ Peripheral Blood Lymphocytes Share More Clones with Paired Tumor-Infiltrating Lymphocytes

Area of Science:

• Immunology
• Oncology
• Cellular Therapy

Background:

• Tumor-infiltrating lymphocytes (TILs) and PD-1⁺ peripheral blood lymphocytes (PBLs) contain tumor-reactive T cells.
• The relationship between TIL and PD-1⁺ PBL T-cell receptor repertoires is not fully understood.
• The therapeutic potential of T cells expanded from PD-1⁺ PBLs as TIL substitutes requires investigation.

Purpose of the Study:

• To investigate the T-cell receptor-β (TCRβ) repertoire overlap between TILs and T cells expanded from paired PD-1⁺ PBLs.
• To assess the feasibility of using T cells expanded from PD-1⁺ PBLs as a substitute for TILs in cancer therapy.
• To evaluate the clinical efficacy of expanded T cells from PD-1⁺ PBLs in patients resistant to anti-PD-1 therapy.

Main Methods:

• Development of an efficient protocol for expanding polyclonal T cells from PD-1⁺ PBLs.
• Functional T-cell assays and tetramer staining to identify tumor-reactive T cells.
• Deep TCRβ sequencing to compare repertoires of TILs and expanded T cells from PD-1⁺ PBLs.
• Clinical treatment of patients with advanced cancer using expanded autologous T cells and anti-PD-1 antibody.

Main Results:

• T cells expanded from PD-1⁺ PBLs were enriched for tumor-reactive T cells.
• Significant overlap in TCRβ clonotypes was observed between expanded T cells from PD-1⁺ PBLs and paired TILs (average 11.29% tumor-resident clonotypes).
• Three out of four patients with advanced cancer, refractory to multiple therapies, showed objective responses to treatment with expanded T cells and anti-PD-1.

Conclusions:

• T cells expanded from PD-1⁺ PBLs share a significant repertoire with TILs.
• Expanded T cells from PD-1⁺ PBLs represent a viable alternative to TILs for cancer immunotherapy.
• This approach holds promise as a therapeutic strategy for patients with cancer, including those resistant to current treatments.