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Eradicating tumor in a recurrent cervical cancer patient with autologous tumor-infiltrating lymphocytes and a modified lymphodepleting regimen.

ABSTRACT: Tumor-infiltrating lymphocyte (TIL) therapy has shown promising results against several cancers. However, traditional lymphodepleting regimens are severe and represent a major limitation for a more widespread use of TIL. The modified pretreatment strategies may alleviate side effects and demonstrate the persistence of tumor-reactive T cells in the blood. Here, we report a case who was diagnosed recurrent cervical cancer with bladder metastasis. Omitting high dose of IL-2, she received intravenous dose of cyclophosphamide (20 mg/kg) for 3 days, approximately 48 hours before receiving the intravenous infusion of TILs. Half dosage (100 mg) of PD1 antibody was administered with purpose of neutralizing PD1 expressed on T cells surface. She achieved complete response 10 weeks after one-time TILs infusion. Adverse reactions were negligible and safely manageable in a general ward without the need for intervention from intensive care units. Time-course peripheral blood counts and TCR repertoire sequencing demonstrated a robust expansion and long-term persistence of the infused TILs. These results illustrated the potential value of modified lymphodepletion, followed by TILs for the treatment of patients with cervical cancer with local recurrence. Trial registration number, NCT04766320.

SUBMITTER: Guo J

PROVIDER: S-EPMC8860082 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Eradicating tumor in a recurrent cervical cancer patient with autologous tumor-infiltrating lymphocytes and a modified lymphodepleting regimen.

Guo Jing J Luo Ning N Ai Guihai G Yang Weihong W Zhu Jihui J Li Caixia C Chen Rong R Zhang Changbao C Liu Shupeng S Jin Huajun H Cheng Zhongping Z

Journal for immunotherapy of cancer 20220201 2

Tumor-infiltrating lymphocyte (TIL) therapy has shown promising results against several cancers. However, traditional lymphodepleting regimens are severe and represent a major limitation for a more widespread use of TIL. The modified pretreatment strategies may alleviate side effects and demonstrate the persistence of tumor-reactive T cells in the blood. Here, we report a case who was diagnosed recurrent cervical cancer with bladder metastasis. Omitting high dose of IL-2, she received intravenou ...[more]

PMID: 35177415

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Project description:BACKGROUNDAdoptive 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.METHODSTwenty-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.RESULTSTILs 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.CONCLUSIONTIL-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 REGISTRATIONClinicalTrials.gov NCT04443296.FUNDINGNational 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.

Project description:BackgroundTumor-infiltrating lymphocyte (TIL) therapy has shown efficacy in metastatic melanoma, non-small cell lung cancer, and other solid tumors. Our preclinical work demonstrated more robust CD8 predominant TIL production when agonistic anti-4-1BB and CD3 antibodies were used in early ex vivo TIL culture.MethodsPatients with treatment-refractory metastatic colorectal (CRC), pancreatic (PDAC) and ovarian (OVCA) cancers were eligible. Lymphodepleting chemotherapy was followed by infusion of ex vivo expanded TIL, manufactured at MD Anderson Cancer Center with IL-2 and agonistic stimulation of CD3 and 4-1BB (urelumab). Patients received up to six doses of high-dose IL-2 after TIL infusion. Primary endpoint was evaluation of objective response rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 with secondary endpoints including disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival (OS), and safety.Results17 patients underwent TIL harvest and 16 were treated on protocol (NCT03610490), including 8 CRC, 5 PDAC, and 3 OVCA patients. Median age was 57.5 (range 33-70) and 50% were females. Median number of lines of prior therapy was 2 (range 1-8). No responses were observed at 12 weeks. Ten subjects achieved at least one stable disease (SD) assessment for a DCR of 62.5% (95% CI 35.4% to 84.8%). Best response included prolonged SD in a patient with PDAC lasting 17 months. Median PFS and OS across cohorts were 2.53 months (95% CI 1.54 to 4.11) and 18.86 months (95% CI 4.86 to NR), respectively. Grade 3 or higher toxicities attributable to therapy were seen in 14 subjects (87.5%; 95% CI 61.7% to 98.4%). Infusion product analysis showed the presence of effector memory cells with high expression of CD39 irrespective of tumor type and low expression of checkpoint markers.ConclusionsTIL manufactured with assistance of 4-1BB and CD3 agonism is feasible and treatment is associated with no new safety signals. While no responses were observed, a significant portion of patients achieved SD suggesting early/partial immunological effect. Further research is required to identify factors associated with resistance and functionally enhance T cells for a more effective therapy.

Dataset Information

Eradicating tumor in a recurrent cervical cancer patient with autologous tumor-infiltrating lymphocytes and a modified lymphodepleting regimen.

Publications

Eradicating tumor in a recurrent cervical cancer patient with autologous tumor-infiltrating lymphocytes and a modified lymphodepleting regimen.

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