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

Christina Friese,Özcan Met,Marco Donia,Marie Christine Wulff Westergaard,Inge Marie Svane,Troels Holz Borch,Magnus Pedersen,Anders Kverneland,Katja Harbst,Göran Jönsson

doi:10.1038/s41598-020-60738-4

Christina Friese, Özcan Met + Show 8 more

Open Access

https://doi.org/10.1038/s41598-020-60738-4

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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 of tumor fragments enriches tumor-reactive TILs and may improve clinical outcome of TIL-based ACT in ovarian cancer.

Highlights

Ovarian cancer is the eighth most common cause of cancer death in women worldwide[1]
The activity of tumor-infiltrating lymphocytes (TILs) can be impeded by antigen-presenting cells or tumor cells through immune checkpoints such as programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expressed on the T-cell surface, which can be blocked by checkpoint inhibitors such as ipilimumab, nivolumab and pembrolizumab[27]
TIL.27) had a tumor removed as part of the standard care, while the others underwent tumor removal as part of a clinical trial with adoptive cell therapy (GY1508 and GY1721 - NCT02482090 and NCT03287674)

Summary

Introduction

Ovarian cancer is the eighth most common cause of cancer death in women worldwide[1]. Checkpoint inhibitors have demonstrated clinical benefit in a small proportion of patients with ovarian cancer. Adoptive T-cell therapy (ACT) based on autologous TILs takes advantage of tumor-reactive T cells naturally present in the tumor lesions[14] and has shown overall response rates of around 50% with durable complete responses in 15–20% of the patients in metastatic melanoma[15,16,17,18,19,20]. The activity of TILs can be impeded by antigen-presenting cells or tumor cells through immune checkpoints such as programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expressed on the T-cell surface, which can be blocked by checkpoint inhibitors such as ipilimumab (anti-CTLA-4), nivolumab and pembrolizumab (both anti-PD-1)[27]

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