Dataset Information

A long way to the battlefront: CAR T cell therapy against solid cancers.

ABSTRACT: Chimeric antigen receptors (CARs) are engineered synthetic receptors that redirect and reprogram T cells to tumor surface antigens for subsequent eradication. The unprecedented efficacy of CD19-CAR T cells against B-cell malignancies has inspired oncologists to extend these efforts for the treatment of solid tumors. However, limited success has been achieved so far, partially due to some of the formidable challenges, e.g. suppression of full activation, inhibition of T cell localization, lacking of ideal targets, inefficient trafficking and infiltration, immunosuppression of microenvironment, and the probability of off targets and associated side effects. Significant progresses have being made recently. Thus, an updated summary is urgently needed. Here in this review, we discuss the advantages and some of the key hurdles encountered by CAR T cell therapy in solid tumors as well as the strategies adopted to improve therapeutic outcomes of this approach. Continuing efforts to increase therapeutic potential and decrease the adverse effects of adaptive cell transfer are suggested as well.

SUBMITTER: Wang Z

PROVIDER: S-EPMC6603378 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A long way to the battlefront: CAR T cell therapy against solid cancers.

Wang Zhicai Z Chen Wei W Zhang Xing X Cai Zhiming Z Huang Weiren W

Journal of Cancer 20190602 14

Chimeric antigen receptors (CARs) are engineered synthetic receptors that redirect and reprogram T cells to tumor surface antigens for subsequent eradication. The unprecedented efficacy of CD19-CAR T cells against B-cell malignancies has inspired oncologists to extend these efforts for the treatment of solid tumors. However, limited success has been achieved so far, partially due to some of the formidable challenges, e.g. suppression of full activation, inhibition of T cell localization, lacking ...[more]

PMID: 31289581

Similar Datasets

Project description:CAR T cell research in solid tumors often lacks spatiotemporal information and therefore, there is a need for a molecular tomography to facilitate high-throughput preclinical monitoring of CAR T cells. Furthermore, a gap exists between macro- and microlevel imaging data to better assess intratumor infiltration of therapeutic cells. We addressed this challenge by combining 3D µComputer tomography bioluminescence tomography (µCT/BLT), light-sheet fluorescence microscopy (LSFM) and cyclic immunofluorescence (IF) staining. Methods: NSG mice with subcutaneous AsPC1 xenograft tumors were treated with EGFR CAR T cell (± IL-2) or control BDCA-2 CAR T cell (± IL-2) (n = 7 each). Therapeutic T cells were genetically modified to co-express the CAR of interest and the luciferase CBR2opt. IL-2 was administered s.c. under the xenograft tumor on days 1, 3, 5 and 7 post-therapy-initiation at a dose of 25,000 IU/mouse. CAR T cell distribution was measured in 2D BLI and 3D µCT/BLT every 3-4 days. On day 6, 4 tumors were excised for cyclic IF where tumor sections were stained with a panel of 25 antibodies. On day 6 and 13, 8 tumors were excised from rhodamine lectin-preinjected mice, permeabilized, stained for CD3 and imaged by LSFM. Results: 3D µCT/BLT revealed that CAR T cells pharmacokinetics is affected by antigen recognition, where CAR T cell tumor accumulation based on target-dependent infiltration was significantly increased in comparison to target-independent infiltration, and spleen accumulation was delayed. LSFM supported these findings and revealed higher T cell accumulation in target-positive groups at day 6, which also infiltrated the tumor deeper. Interestingly, LSFM showed that most CAR T cells accumulate at the tumor periphery and around vessels. Surprisingly, LSFM and cyclic IF revealed that local IL-2 application resulted in early-phase increased proliferation, but long-term overstimulation of CAR T cells, which halted the early added therapeutic effect. Conclusion: Overall, we demonstrated that 3D µCT/BLT is a valuable non-isotope-based technology for whole-body cell therapy monitoring and investigating CAR T cell pharmacokinetics. We also presented combining LSFM and MICS for ex vivo 3D- and 2D-microscopy tissue analysis to assess intratumoral therapeutic cell distribution and status.

Dataset Information

A long way to the battlefront: CAR T cell therapy against solid cancers.

Publications

A long way to the battlefront: CAR T cell therapy against solid cancers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets