Chemokine‐Based Injectable Navigation System for Enhancing CAR‐T Cell Therapy Against Solid Tumors

Abstract

AbstractChimeric antigen receptor (CAR)‐T cell therapy has demonstrated poor efficacy for solid tumors. The low number and poor functional persistence of CAR‐T cells in tumors are the main limiting factors. Here a Chemokine‐based Injectable platform for enhancing adoptive T cells’ Efficacy (CITE) is presented. CITE consists of peritumorally‐injected immunogel co‐loading chemotactic CXCL9 particles with PD‐1 antibody (aPD1) and intravenously‐infused tumor‐penetrating peptide iRGD. Immunogel formed drug depots and allowed sustained release of cargo peritumorally while iRGD facilitated tumor infiltration of gel‐released drugs, thus remarkably increasing the amount of CXCL9 and aPD1 in the tumor. CITE induced an effective chemotactic gradient to promote the tumor‐specific migration of CAR‐T cells and boosted the function of infiltrated T cells by blocking immunosuppression via a two‐in‐one approach. Consequently, CITE yielded a 218‐fold increase in the intratumoral number of transferred T cells and substantially improved the efficacies of transferred T cell receptor (TCR)‐T cells and CAR‐T cells in multiple syngeneic tumor models, including immunologically “cold” tumors, in immunocompetent mice. More importantly, CITE enhanced systemic antitumor immunity and elicited immune memory, enabling CITE to treat multimodal, metastatic, and recurrent tumors. CITE is broadly applicable to adoptive cell therapies involving CAR‐T or TCR‐T cells.