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Adoptive cell therapy with tumor-infiltrating lymphocytes supported by checkpoint inhibition across multiple solid cancer types

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Background Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has shown remarkable results in malignant melanoma (MM), while studies on the potential in other cancer diagnoses are sparse. Further, the prospect of using checkpoint inhibitors (CPIs) to support TIL production and therapy remains to be explored. Study design TIL-based ACT with CPIs was evaluated in a clinical phase I/II trial. Ipilimumab (3 mg/kg) was administered prior to tumor resection and nivolumab (3 mg/kg, every 2 weeks ×4) in relation to TIL infusion. Preconditioning chemotherapy was given before TIL infusion and followed by low-dose (2 10e6 international units (UI) ×1 subcutaneous for 14 days) interleukin-2 stimulation. Results Twenty-five patients covering 10 different cancer diagnoses were treated with in vitro expanded TILs. Expansion of TILs was successful in 97% of recruited patients. Five patients had sizeable tumor regressions of 30%-63%, including two confirmed partial responses in patients with head-and-neck cancer and cholangiocarcinoma. Safety and feasibility were comparable to MM trials of ACT with the addition of expected CPI toxicity. In an exploratory analysis, tumor mutational burden and expression of the alpha-integrin CD103 (p=0.025) were associated with increased disease control. In vitro tumor reactivity was seen in both patients with an objective response and was associated with regressions in tumor size (p=0.028). Conclusion High success rates of TIL expansion were demonstrated across multiple solid cancers. TIL ACTs were found feasible, independent of previous therapy. Tumor regressions after ACT combined with CPIs were demonstrated in several cancer types supported by in vitro antitumor reactivity of the TILs. Trial registration numbers NCT03296137, and EudraCT No. 2017-002323-25.

OriginalsprogEngelsk
Artikelnummere003499
TidsskriftJournal for ImmunoTherapy of Cancer
Vol/bind9
Udgave nummer10
ISSN2051-1426
DOI
StatusUdgivet - 4 okt. 2021

Bibliografisk note

Funding Information:
1Department of Oncology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark 2National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark 3Department of Pathology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark 4Department of Clinical Genetics, Kennedy Center, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Glostrup, Denmark Acknowledgements We are deeply grateful for the patients’ willingness to participate and the support of their families. A special thanks to the technicians responsible for tumor-infiltrating lymphocyte expansion at the GMP facility at Herlev Hospital and to the Department of Oncology, including attending physicians and nurses. Thanks to Morten Hansen at the National Center for Cancer Immune Therapy for support and assistance regarding the flow cytometry. This research was funded by the Danish Cancer Society and Herlev Hospital. The funders played no role in study design, data collection, analysis, or preparation of this manuscript.

Funding Information:
Another interesting finding was the clear feasibility of TIL production in two HPV-associated cancers (patients 19 and 20). TILs from both patients showed remarkably high fold expansions in the REP (4748 and 4960), had a high percentage of CD103 + cells (4.9% and 8.0%) and demonstrated antitumor reactivity in vitro. The patient with HNSCC (patient 19) who achieved a PR was also HPV-associated, and the clinical potential of TIL expansion in HPV-associated epithelial cancer is supported by clinical results with HPV-reactive TILs from the National Cancer Institute.7 10

Publisher Copyright:
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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