Identification of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffolds as potent Lck inhibitors as anti-cancer agents.

Lymphocyte-specific protein tyrosine kinase (Lck) plays vital roles in the T-cell receptor- mediated development, function, and differentiation of T-cells. Given its substantial involvement in T cell signaling, irregularities in the expression and functionality of Lck may lead to various diseases, including cancer. In this study, we found that compound 12a exerted significant inhibitory potency against Lck with an IC50 value of 10.6 nM. In addition, 12a demonstrated high efficacy in various colon cancer cell lines as indicated by GI50 values ranging from 0.24 to 1.26 µM. Notably, 12a inhibited the phosphorylation of Lck in Colo201 cells. Overall, the anti-proliferative effects of 12a on diverse cancer cell lines highlights its potential application for the treatment of various cancer types.

Nanomaterials to improve cancer immunotherapy based on ex vivo engineered T cells and NK cells.

Recent clinical successes of chimeric antigen receptor (CAR) T cell therapy have led the booming of developments in cancer immunotherapy utilizing ex vivo engineered immune cells such as T cells and natural killer (NK) cells. However, a number of issues need to be resolved for this novel therapy to become widely applicable to cancer patients as current CAR-T cell therapies are only successful in treating some blood cancers, and economically not feasible for many patients. In this review, we describe various nanomaterial-based approaches developed to overcome current limitations in ex vivo engineered T/NK cells, along with key biological principles underlying each approach. First, nanomaterials developed to improve ex vivo expansion of T/NK cells and the basic principles of T/NK cell activation for designing nanomaterials are summarized. Second, nanomaterial-based gene delivery methods to generate genetically engineered T/NK cells are discussed with an emphasis on challenges in improving transfection efficacy. Third, nanomaterials loaded to T/NK cells to enhance their anti-tumor functions and to overcome tumor microenvironment are described with key biological characteristics of T/NK cells, which are essential for nanomaterial loading and drug release from the nanomaterials. In particular, we comment on similarities and differences of methods developed for T cells and NK cells based on the biological characteristics of each cell type.