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

BMC Med. 2024 May 20;22(1):207. doi: 10.1186/s12916-024-03420-0.

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.

Keywords: Gynecologic malignancies; Interleukin-2; Lymphodepletion; Tumor-infiltrating lymphocyte.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Female
  • Genital Neoplasms, Female / drug therapy
  • Genital Neoplasms, Female / therapy
  • Humans
  • Immune Checkpoint Inhibitors / administration & dosage
  • Immune Checkpoint Inhibitors / therapeutic use
  • Interleukin-2* / administration & dosage
  • Interleukin-2* / therapeutic use
  • Lymphocytes, Tumor-Infiltrating* / drug effects
  • Lymphocytes, Tumor-Infiltrating* / immunology
  • Mice
  • Middle Aged
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Treatment Outcome

Associated data

  • ClinicalTrials.gov/NCT04766320