Expansion of Natural Killer cells as a complementary approach for adoptive cell therapy in advanced Colorectal Cancer’ NKAT-CRC

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The potential of natural killer cells in pancreatic cancer : from exploring tumorinfiltrating lymphocytes to novel CAR-NK cell therapy

Publication . Maia, Andreia; Castillo-Martin, Mireia; Maeurer, Markus; Borrego, Luís Miguel

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality rates due to challenges in diagnosis and limited effective treatments. Natural killer (NK) cells have emerged as a promising adoptive cell therapy for PDAC. These cells possess high cytotoxic function, can recognize tumors independently of major histocompatibility complex class I (MHC-I), and carry a low risk of toxicities, thus holding the potential to improve cancer treatment. Despite their promise, NK cell-based therapy faces challenges, such as limited in vivo persistence, reduced tumor infiltration, and low cell numbers. Additionally, the suppressive tumor microenvironment (TME) of solid tumors, particularly of pancreatic cancer, leads to the dysfunction of both T and NK cells. To address this, strategies exploring tumor-infiltrating lymphocytes (TILs) and developing novel chimeric antigen receptor (CAR)-cells are being investigated. This study characterized TIL-NK cells from central and peripheral tumor regions and peripheral blood mononuclear cells (PBMCs) of patients diagnosed with PDAC. A distinct distribution of NK cell infiltration within the TME was observed, with higher numbers infiltrating peripheral regions. However, NK cells from central tumor regions showed higher expansion rates than those infiltrating peripheral regions and PBMC. Moreover, NK cells stimulated with IL-2, IL-15, and short IL-12 showed superior expansion, activation, and cytotoxicity, indicating that the persistence and cytotoxicity of TIL-NK cells can be improved ex vivo. Genetic manipulation is another strategy to enhance NK cell function, including CARNK cells with superior persistence, cytotoxicity, and tumor-targeting capacities. Additionally, cytokine-induced memory-like (CIML) NK cells displayed increased cytotoxicity and prolonged persistence. In this study, we engineered the 'Buddy-CAR' system, consisting of CAR-CIML NK cells expressing IL7Rα and secreting IL-7 molecules. These engineered NK cells induced self-proliferation and activation, independent of exogenous IL-2 or IL-15, and promoted the proliferation of surrounding T cells. Overall, these findings represent significant advancements in NK cell-based therapies for solid tumors, particularly in the context of pancreatic cancer.

2024-09-23Tese de doutoramento

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Entidade financiadora

Fundação para a Ciência e a Tecnologia

Programa de financiamento

OE

Número da atribuição

SFRH/BD/144965/2019