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Successful ex vivo expansion of tumor infiltrating lymphocytes with systemic chemotherapy prior to surgical resection

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Abstract

Tumor infiltrating lymphocytes (TIL) have demonstrated efficacious clinical outcomes for many patients with various types of solid cancers, including melanoma, gastrointestinal cancer, lung cancer, and head and neck cancer. Currently, the majority of clinical trials require that patients did not receive systemic therapy right before tumor tissue resection to avoid the interference of chemotherapy in the ex vivo TIL expansion. The primary disadvantage of this strategy is limiting the accessibility of TIL therapy for many eligible cancer patients. Over the past decade, substantial progress has been made for ex vivo expansion technologies in T cells. In this study, we investigated the possibility of enrolling patients who underwent chemotherapy prior to surgical resection. We collected seventeen tumor tissues from treatment naive cases, and five from cases that underwent chemotherapies. Cancer indications enrolled in this study were colorectal and lung cancers from both primary and metastatic sites, such as liver and brain. TILs from these tumors were expanded ex vivo to 2.1E8 (total viable lymphocytes counts) on average, with an overall success rate of 90.9%. Subsequently, TIL phenotypes and cytokine production were analyzed using flow cytometry and ELISA, respectively. We demonstrated functional TIL expansion from tumor tissues despite chemotherapy prior to surgical resection. We observed no significant phenotypic or functional differences between groups with and without chemotherapy. TIL expansion rate and characteristics were similar regardless of chemotherapy prior to resection, thereby providing a possibility to recruit patients with the most recent chemotherapy history in TIL therapy trials.

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Acknowledgements

We acknowledge CHTN for tissue procurement. We thank all patients, staff and investigators at the CHTN network. We thank Drs. Fuli Yu and Imtiaz Yakub for technical assistance and Mrs. Jing Zhong for administrative coordination.

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JB, AR performed experiments, analyzed data, and wrote the manuscript. WX and HY contributed the bioinformatics analyses and revised the article. JM and AL performed experiments and analyzed data. SM developed the concept, analyzed data, managed the project, coordinated author activities, revised the article, and provided final approval of the version to be submitted.

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Correspondence to Satoko Matsueda.

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262_2023_3500_MOESM1_ESM.png

Supplemental Figure 1 Correlation between systemic therapy period and in vitro TIL expansion. A trend of negative correlation was observed between TIL numbers and treatment days prior to resection. Data points indicate individual patients (n=5). Spearman’s correlation coefficient analysis was conducted. n. s.: not significant (PNG 49 kb)

262_2023_3500_MOESM2_ESM.png

Supplemental Figure 2 Correlations among surface marker expressions and top PCs. A The Pearson correlation coefficients (− 1, 1) were calculated to measure the linear correlations between any pair of marker expressions. B The percentages of total variance were explained by each PC. C The Pearson correlation coefficients (− 1, 1) were calculated to measure the linear correlations between any marker expression with any of the top 3 PCs. (n=5, with chemotherapy; n=15, without chemotherapy) (PNG 182 kb)

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Balzeau, J., Ravindran, A., Wang, X. et al. Successful ex vivo expansion of tumor infiltrating lymphocytes with systemic chemotherapy prior to surgical resection. Cancer Immunol Immunother 72, 3377–3385 (2023). https://doi.org/10.1007/s00262-023-03500-9

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