IL-2-Free Tumor-Infiltrating Lymphocyte Therapy With PD-1 Blockade Demonstrates Potent Efficacy in Advanced Gynecologic Cancer

Authors

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

Publication Date

5-20-2024

Journal

BMC Medicine

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

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.

Keywords

Gynecologic malignancies, Tumor-infiltrating lymphocyte, Interleukin-2, Lymphodepletion

Comments

Trial Registration: NCT04766320, Jan 04, 2021.

Supplementary Materials

PMID: 38769543