Spatiotemporally Controlled T-Cell Combination Therapy for Solid Tumor

Meixi Hao; Ying Zhou; Sijia Chen; Yu Jin; Xiuqi Li; Lingjing Xue; Mingxuan Shen; Weishuo Li; Can Zhang

doi:10.1002/advs.202401100

Spatiotemporally Controlled T-Cell Combination Therapy for Solid Tumor

Adv Sci (Weinh). 2024 Apr 17:e2401100. doi: 10.1002/advs.202401100. Online ahead of print.

Authors

Meixi Hao^{1

2}, Ying Zhou^{1

2}, Sijia Chen^{1

2}, Yu Jin^{1

2}, Xiuqi Li^{1

2}, Lingjing Xue^{1

2}, Mingxuan Shen^{1

2}, Weishuo Li³, Can Zhang^{1

2}

Affiliations

¹ State Key Laboratory of Natural Medicines, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, China.
² Chongqing Innovation Institute of China Pharmaceutical University, Chongqing, 401135, China.
³ Center for Molecular Metabolism, School of Environmental and Biological Engineering, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing, 210094, China.

PMID: 38634209
DOI: 10.1002/advs.202401100

Abstract

Due to multidimensional complexity of solid tumor, development of rational T-cell combinations and corresponding formulations is still challenging. Herein, a triple combination of T cells are developed with Indoleamine 2,3-dioxygenase inhibitors (IDOi) and Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). To maximize synergism, a spatiotemporally controlled T-cell engineering technology to formulate triple drugs into one cell therapeutic, is established. Specifically, a sequentially responsive core-shell nanoparticle (SRN) encapsulating IDOi and CDK4/6i is anchored onto T cells. The yielded SRN-T cells migrated into solid tumor, and achieved a 1st release of IDOi in acidic tumor microenvironment (TME). Released IDOi restored tryptophan supply in TME, which activated effector T cells and inhibited Tregs. Meanwhile, 1st released core is internalized by tumor cells and degraded by glutathione (GSH), to realize a 2nd release of CDK4/6i, which induced up-regulated expression of C-X-C motif chemokine ligand 10 (CXCL10) and C-C motif chemokine ligand 5 (CCL5), and thus significantly increased tumor infiltration of T cells. Together, with an enhanced recruitment and activation, T cells significantly suppressed tumor growth, and prolonged survival of tumor-bearing mice. This study demonstrated rationality and superiority of a tri-drug combination mediated by spatiotemporally controlled cell-engineering technology, which provides a new treatment regimen for solid tumor.

Keywords: T‐cell therapy; core‐shell structured nanoparticle; site‐specific drug release; spatiotemporally controlled cytopharmaceutical; triple drug combination.

Abstract

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