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 TILs (auto-TILs) following concurrent chemoradiotherapy (CCRT) in patients with CC who had locally advanced disease. METHODS. Twenty-seven patients with CC with stage III–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 practice (GMP) conditions and then infused after CCRT plus i.m. IL-2 injections. RESULTS. TILs from 20 of the 27 patients were successfully expanded, 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 were no treatment-related mortalities. Nine of 12 patients (75.0%) attained a complete response, with a disease control duration of 9–22 months. Translational investigation showed that the transcriptomic characteristics of the infused TIL products and some immune biomarkers in the tumor microenvironment and serum of patients with CC at baseline were correlated with the clinical response. CONCLUSION. TIL-based ACT following CCRT was safe in an academic center setting, with potentially effective responses in patients with locally advanced CC. “Hot” inflammatory immune environments were beneficial to the clinical efficacy of TIL-based ACT as adjuvant therapy. TRIAL REGISTRATION. ClinicalTrials.gov NCT04443296. FUNDING. National Key R&D Program; Sci-Tech Key Program of the Guangzhou City Science Foundation; the Guangdong Province Sci-Tech International Key Program; the National Natural Science Foundation of China.

The aim of this study was to evaluate the inter- and intrafractional organs motions and dosimetric advantages of MRI guided online adaptive radiotherapy for cervical cancer. A total of 150 fractions treated on the 1.5 T Unity MR-Linac were included in this study. Each fraction, pre-treatment, position validation and post-treatment MRI scans were obtained. Structures including CTV, rectum and bladder were delineated by the same radiation oncologists on each MRI. The inter- and intrafractional changes of contours were assessed by Hausdorff distance (HD), dice similarity coefficient (DSC), relative volume difference (ΔV) and the relative positions of the geometric center. The non-ART plans and online adaptive plans were obtained by recalculating or re-optimizing from reference plans on daily MRI, respectively. CTV coverage and OARs constraints were evaluated between ART and non-ART plans. For each fraction, the interfractional changes of HD, ΔV and DSC for CTV, bladder and rectum were significant. Our study also examined the relationship of bladder and rectum filling on CTV position. For 150 non-ART plans, CTV coverage constraints (D_98% ≥ 45 Gy) were not met by 45 %, while 15 % were not covered by more than 5 % of the prescribed dose. Compared to the non-ART plans, the ART plans had higher CTV coverage and lower dose to the bladder and rectum (P < 0.05). During the treatment, the intrafractional changes of bladder, rectum and CTV may affect actual dose delivery. And we observed an intrafractional time trend in the motion of the CTV. There were 15 % fractions failing the CTV coverage constraints in post-MRI due to intrafractional motion. The adaptive plans optimized with 3 mm margin could cover CTV of post-MRI in 98 % fractions. Considerable inter- and intrafractional CTV and OARs changes were observed in cervical cancer patients treated on MR-Linac. MRI guided online ART has significant dosimetric advantages in cervical cancer and is an ideal approach for achieving individualized and precise radiotherapy.