ICG/LY@HES-PCL Nanomedicine Improving the Efficacy of CAR-T Therapy in Lymphoma

Abstract Background : The presence of tumor immunosuppressive microenvironment, abnormal vascular microenvironment, and the presence of a cross-linked matrix barrier may hinder the recruitment, proliferation, and activation of CAR-T to lymphoma tissue infiltration, which limit the efficacy of CAR-T in the treatment of lymphoma. The enhanced infiltration effect of ICG photothermal effect on CAR-T and the effect of LY on improving tumor immunosuppressive microenvironment have been confirmed. In this work, we have constructed LY/ICG@HES-PCL nanomedicine to improve the accumulation, proliferation and activation of CAR-T in lymphoma tissue, further improving the therapy efficacy of CAR-T in lymphoma. Methods: The effect of LY/ICG@HES-PCL on the proliferation and activation of CAR-T was studied by Transwell experiment. LY/ICG@HES-PCL was studied in vivo to investigate its improving the efficacy of CAR-T therapy in lymphoma. Biefly, 1×10 7 Raji human lymphoma cells were subcutaneously injected into both sides of each mouse. After ≈20 days, when the tumor volume reached ≈100 mm 3, mice were randomly assigned to 5 groups (n=6) and were treated by PBS, ICG@HES-PCL, ICG@HES-PCL+NIR, LY/ICG@HES-PCL, LY/ICG@HES-PCL+NIR, respectively. (4.0 mg/kg as ICG, 4.0 mg/kg as ICG). NIR groups were irradiated with an 808 nm laser at the power density of 0.3 W cm −2 for 10 mins. Two hours later, 1 × 10 7 CAR-T cells were intravenously injected into the mice. The tumor sizes were recorded by a digital caliper every 3 days. LY/ICG@HES-PCL in vivo was monitored using an in vivo bioluminescence imaging system. Lymphoma microenvironment was analyzed by immunofluorescence and FCM. Results: LY/ICG@HES-PCL increased CAR-T quantity by 3.7 times, IL-2 and IFN-λ release by 2.5 and 2.1 times in vitro, increased CAR-T accumulation in tumor tissue by 4.45 times within 3 days in vivo, achieving CAR-T activation, proliferation, and tumor accumulation enhancement. LY/ICG@HES-PCL improved CAR T efficacy in lymphoma by 3.4 times and CAR T longevity within 15 days by 1.6 times. Discussion: LY/ICG@HES-PCL co-delivered the photosensitifier ICG and TGF-β inhibitor LY to the lymphoma tissue. The photothermal effect of ICG decreased the density of lymphoma matrix and activated CD4+ T cells, CD8+ T cells and NK cells in tumor tissue. LY was used to inhibit PD-1 and CLTA-4 of CAR-T, so as to promotes CAR-T proliferation, improve CAR-T activity and longevity in vivo, and ultimately improve the anti-lymphoma efficacy of CAR-T cells. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.