BMC Medicine (May 2024)

IL-2-free tumor-infiltrating lymphocyte therapy with PD-1 blockade demonstrates potent efficacy in advanced gynecologic cancer

  • Jing Guo,
  • Chunyan Wang,
  • Ning Luo,
  • Yuliang Wu,
  • Wei Huang,
  • Jihui Zhu,
  • Weihui Shi,
  • Jinye Ding,
  • Yao Ge,
  • Chunhong Liu,
  • Zhen Lu,
  • Robert C. Bast,
  • Guihai Ai,
  • Weihong Yang,
  • Rui Wang,
  • Caixia Li,
  • Rong Chen,
  • Shupeng Liu,
  • Huajun Jin,
  • Binghui Zhao,
  • Zhongping Cheng

DOI
https://doi.org/10.1186/s12916-024-03420-0
Journal volume & issue
Vol. 22, no. 1
pp. 1 – 13

Abstract

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Abstract Background Tumor-infiltrating lymphocyte (TIL) therapy has been restricted by intensive lymphodepletion and high-dose intravenous interleukin-2 (IL-2) administration. To address these limitations, we conducted preclinical and clinical studies to evaluate the safety, antitumor activity, and pharmacokinetics of an innovative modified regimen in patients with advanced gynecologic cancer. Methods Patient-derived xenografts (PDX) were established from a local recurrent cervical cancer patient. TILs were expanded ex vivo from minced tumors without feeder cells in the modified TIL therapy regimen. Patients underwent low-dose cyclophosphamide lymphodepletion followed by TIL infusion without intravenous IL-2. The primary endpoint was safety; the secondary endpoints included objective response rate, duration of response, and T cell persistence. Results In matched patient-derived xenografts (PDX) models, homologous TILs efficiently reduced tumor size (p < 0.0001) and underwent IL-2 absence in vivo. In the clinical section, all enrolled patients received TIL infusion using a modified TIL therapy regimen successfully with a manageable safety profile. Five (36%, 95% CI 16.3–61.2) out of 14 evaluable patients experienced objective responses, and three complete responses were ongoing at 19.5, 15.4, and 5.2 months, respectively. Responders had longer overall survival (OS) than non-responders (p = 0.036). Infused TILs showed continuous proliferation and long-term persistence in all patients and showed greater proliferation in responders which was indicated by the Morisita overlap index (MOI) of TCR clonotypes between infused TILs and peripheral T cells on day 14 (p = 0.004) and day 30 (p = 0.004). Higher alteration of the CD8+/CD4+ ratio on day 14 indicated a longer OS (p = 0.010). Conclusions Our modified TIL therapy regimen demonstrated manageable safety, and TILs could survive and proliferate without IL-2 intravenous administration, showing potent efficacy in patients with advanced gynecologic cancer. Trial registration NCT04766320, Jan 04, 2021.

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