CTLA-4 blockade boosts the expansion of tumor-reactive CD8+ tumor-infiltrating lymphocytes in ovarian cancer.

Scientific Reports
Christina FrieseÖ Met

Abstract

Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) can induce durable complete tumor regression in patients with advanced melanoma. Efforts are currently underway to expand this treatment modality to other cancer types. In the microenvironment of ovarian cancer, the engagement of co-inhibitory immune checkpoint molecules such as CTLA-4 can lead to the inactivation of TILs. Thus, approaches that directly manipulate co-inhibitory pathways within the tumor microenvironment might improve the expansion of tumor-reactive TILs. The initial expansion of TILs for ACT from tumor fragments provides a window of opportunity to manipulate an intact tumor microenvironment and improve CD8+ T-cell output and TIL tumor reactivity. To exploit this, we used a CTLA-4-blocking antibody, added during the initial TIL culture, and found that the blockade of CTLA-4 favored the propagation of CD8+ TILs from ovarian tumor fragments. Interestingly, adding the CTLA-4 blocking antibody in the initial phase of the TIL culture resulted in more potent anti-tumor TILs in comparison to standard TIL cultures. This phenotype was preserved during the rapid expansion phase. Thus, targeting CTLA-4 within the intact tumor microenvironment...Continue Reading

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Citations

Jun 20, 2020·Scandinavian Journal of Immunology·Emmanuelle BenardSébastien Wälchli
Jul 23, 2020·Frontiers in Immunology·Valentina BianchiGeorge Coukos
Dec 2, 2020·International Journal of Molecular Sciences·Kevinn Eddy, Suzie Chen
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Mar 7, 2021·Cancers·Aleksei TitovEmil Bulatov
Mar 31, 2021·British Journal of Cancer·Matteo MorottiAhmed A Ahmed
Oct 6, 2021·Journal for Immunotherapy of Cancer·Anders Handrup KvernelandInge Marie Svane

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Methods Mentioned

BETA
flow cytometry
FACS

Clinical Trials Mentioned

NCT02482090
NCT03287674

Software Mentioned

MiXCR
Excel
Graphpad Prism
CalcDiversityStats
VDJtools

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