Phase I study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer

Abstract

BACKGROUND. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has achieved remarkable clinical efficacy in metastatic cancers such as melanoma and cervical cancer (CC). Here we explored the safety, feasibility and preliminary tumor response and performed translational investigations of adjuvant immunotherapy using infusion of autogenous (auto)-TILs following concurrent chemoradiotherapy (CCRT) in CC patients with locally advanced disease. METHODS.Twenty-seven CC patients with stage III to IV disease were recruited in this single-center, phase I study. TILs were isolated from lesions in the uterine cervix and generated under good manufacturing practices (GMP) conditions and then infused after CCRT plus intramuscular interleukin (IL)-2 injections. RESTULTS.From 27 patients, TILs were successfully expanded from 20 patients, with a feasibility of 74.1%. Twelve patients received TILs following CCRT. Adverse events (AEs) were primarily attributable to CCRT. Only 1 (8.3%) patient experienced severe toxicity with a grade 3 hypersensitivity reaction after TIL infusion. No autoimmune AEs, such as pneumonitis, hepatitis, or myocarditis, occurred, and there was no treatment-related mortality. Nine of 12 patients (75.0%) attained complete response, with a disease control duration of 9 to 22 months. Translational investigation showed that the transcriptomic characteristics of the infused TIL products and some immune biomarkers in the tumor microenvironment and serum of CC patients at baseline were correlated with the clinical response. CONCULSION. TIL-based ACT following CCRT was safe in an academic center 4 setting, with potential effective responses in locally advanced CC patients. 'Hot' inflammatory immune environments are beneficial to the clinical efficacy of TIL-based ACT as adjuvant therapy. TRIAL REGISTRATION. ClinicalTrials.gov NCT04443296.

Evolving standards and future directions for systemic therapies in cervical cancer

“…Combinatorial trials of both drug classes are underway and may be planned across the different settings of cervical cancer ( Fig. 3 ) [ 42 ]. One such example in the first line for aCC is the ongoing arm H of the phase Ib/II innovaTV 205 (ENGOT-cx8/GOG-3024) trial wherein tisotumab vedotin-pembrolizumab combination is given in conjunction with carboplatin ± bevacizumab.…”

“… After successes in later lines in aCC, immunotherapies, mainly ICIs, have moved forward to the first line and for curative indications. Autologous TILs, a type of adoptive T cell therapy, has also made headway from metastatic disease into the LACC setting [ 42 ]. ADCs are likely to follow this path of drug development.…”

Current Landscape of Immunotherapy for Advanced Sarcoma

“…It has an exciting potential, being the only ACT-using cells with multiple TCR clones able to cover the antigenic heterogeneity of solid tumors in contrast to engineered TCRs and CAR T cells, which target specific antigens [ 182 ]. Up to date, TIL therapy has been mainly developed in melanoma with a positive phase III trial versus ipilimumab in the first-line setting [ 183 ] and has promising results in cervical cancer [ 184 , 185 , 186 ], non-small cell lung cancer [ 187 ], ovarian cancer [ 188 ], colorectal cancer [ 189 ], breast cancer [ 190 ] and cholangiocarcinoma [ 191 ].…”

Multiomics profiling reveals the benefits of gamma-delta (γδ) T lymphocytes for improving the tumor microenvironment, immunotherapy efficacy and prognosis in cervical cancer

“…Third, bulk transcriptome profiling, variations and clinical data were obtained from the CESC (cervical squamous cell carcinoma and endocervical adenocarcinoma) cohort of The Cancer Genome Atlas (TCGA) Research Network (release: July 27, 2022) through the National Cancer Institute Genomic Data Commons. 10 11 Fourth, the single-cell RNA sequencing (scRNA-seq) data of peripheral blood γδ T cells and tumor-infiltrating lymphocytes (TILs) of cervical cancer were obtained from Gene Expression Omnibus Series GSE128223 12 and GSE190075 13 respectively. Fifth, the MRI image data were obtained from The Cancer Imaging Archive (TCIA).…”