Chimeric-antigen receptor T (CAR-T) cell therapy for solid tumors: challenges and opportunities

Xia, Anliang; Wang, X; Lu, Yijun; Lu, Xiao‐Jie; Sun, Beicheng

doi:10.18632/oncotarget.19361

Cited by 96 publications

(79 citation statements)

References 69 publications

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“…However, the development of T-cell based therapies for solid tumors remains challenging for several reasons, such as unknown cellular trafficking to the site of action, inadequate tumor infiltration, and immunosuppressive tumor microenvironments (Newick et al, 2017;Xia et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Measurement and Quantitative Characterization of Whole-Body Pharmacokinetics of Exogenously Administered T Cells in Mice

Khot

Matsueda

Thomas

et al. 2019

J Pharmacol Exp Ther

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Here we have investigated whole-body pharmacokinetics (PK) of exogenously administered T cells in a mouse model of melanoma and have developed a physiologically based pharmacokinetic (PBPK) model to quantitatively characterize the data. T cells were isolated from the spleen of tumor-bearing mice, activated, and labeled with chromium-51 to facilitate the quantification. Labeled T cells were injected in the tumor-bearing mice, and PK was measured in 19 different tissues. It was found that T cells disappear from the blood rapidly after administration and accumulate in the tissues to various extents. Spleen, liver, lung, kidney, bone, and lymph nodes accounted for more than 90% of T cells in the body. The distribution of T cells in solid tumors was found to be very low, hovering below 1%ID/g (percent of injected dose per gram of tissue) during the entire study. However, this observation may differ for targeted TCR-T and CAR-T cells. Observed PK profiles also suggest that T-cellbased therapies may be more successful in treating cancers of the lymphatic system and bone marrow metastases compared to solid tumors. A PBPK model was developed to characterize the whole-body PK of T cells, which incorporated key processes such as extravasation, elimination, and recirculation of T cells via lymph flow. Retention factors were incorporated into the spleen, liver, and kidney compartment to adequately capture the PK profiles. The model was able to characterize observed PK profiles reasonably well, and parameters were estimated with good confidence. The PK data and PBPK model presented here provide unprecedented insight into the biodistribution of exogenously administered T cells.

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Section: Introductionmentioning

confidence: 99%

Measurement and Quantitative Characterization of Whole-Body Pharmacokinetics of Exogenously Administered T Cells in Mice

Khot

Matsueda

Thomas

et al. 2019

J Pharmacol Exp Ther

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“…However, the same results were so far not observed in solid tumors [3,4]. In particular, the immunosuppressive tumor microenvironment in solid cancers is thought to negatively influence CAR-T-cell efficiency [3,4]. Another obstacle of CAR-T-cell therapy is the high rate of potential life-threatening side effects, including cytokine release syndrome (CRS), severe neurotoxicity, off-tumor on-target toxicities, and graft versus host disease (GvHD) caused by allogeneic cell therapy [5,6].…”

Section: Introductionmentioning

confidence: 55%

“…Promising results and response rates were also observed in patients suffering from refractory large B-cell lymphoma after the failure of conventional therapy [2]. However, the same results were so far not observed in solid tumors [3,4]. In particular, the immunosuppressive tumor microenvironment in solid cancers is thought to negatively influence CAR-T-cell efficiency [3,4].…”

Section: Introductionmentioning

confidence: 99%

The Generation of CAR-Transfected Natural Killer T Cells for the Immunotherapy of Melanoma

Simon

Wiesinger

März

et al. 2018

IJMS

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Natural killer T (NKT) cells represent a cell subpopulation that combines characteristics of natural killer (NK) cells and T cells. Through their endogenous T-cell receptors (TCRs), they reveal a pronounced intrinsic anti-tumor activity. Thus, a NKT cell transfected with a chimeric antigen receptor (CAR), which recognizes a tumor-specific surface antigen, could attack tumor cells antigen-specifically via the CAR and additionally through its endogenous TCR. NKT cells were isolated from peripheral blood mononuclear cells (PBMCs), expanded, and electroporated with mRNA encoding a chondroitin sulfate proteoglycan 4 (CSPG4)-specific CAR. The CAR expression on NKT cells and their in vitro functionality were analyzed. A transfection efficiency of more than 80% was achieved. Upon stimulation with melanoma cells, CAR-NKT cells produced cytokines antigen-specifically. Compared with conventional CAR-T cells, cytokine secretion of CAR-NKT cells was generally lower. Specific cytotoxicity, however, was similar with CAR-NKT cells showing a trend towards improved cytotoxicity. Additionally, CAR-NKT cells could kill target cells through their endogenous TCRs. In summary, it is feasible to generate CAR-NKT cells by using mRNA electroporation. Their CAR-mediated cytotoxicity is at least equal to that of conventional CAR-T cells, while their intrinsic cytotoxic activity is maintained. Thus, CAR-NKT cells may represent a valuable alternative to conventional CAR-T cells for cancer immunotherapy.

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“…The total effective rate was 66.6% for 1 year among 13 patients. It also proved CAR‐T to be safe and effective 9,10 …”

Section: Discussionmentioning

confidence: 91%

4SCAR‐GD2‐modified T‐cell therapy in neuroblastoma with MYCN amplification: A case report with over 4‐year follow‐up data

Zhao

Yue

et al. 2020

Pediatric Investigation

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Introduction Neuroblastoma (NB) is the most common extracranial solid tumor among children. The 5‐year event‐free survival rate for high‐risk (HR) NB is still poor, especially for patients with advanced NB with MYCN gene amplification. Chimeric antigen receptor T (CAR‐T) cell therapy is a new treatment for HR‐NB. Case presentation A 55‐month‐old boy with stage IV HR‐NB received 4th‐generation CAR‐T cells that target disialoganglioside GD2, as consolidation maintenance treatment after intensive chemotherapy, surgery, and autologous stem‐cell transplantation. As of February 2019, his CAR‐T follow‐up time was 37.5 months, indicating prolonged survival. Cranial MRI and ultrasound showed no mass; 123I‐metaiodobenzylguanidine (123I‐MIBG) scan was negative. Conclusion GD2‐CAR‐T cells may be an effective treatment option for NB patients with MYCN amplification.

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Chimeric-antigen receptor T (CAR-T) cell therapy for solid tumors: challenges and opportunities

Cited by 96 publications

References 69 publications

Measurement and Quantitative Characterization of Whole-Body Pharmacokinetics of Exogenously Administered T Cells in Mice

Measurement and Quantitative Characterization of Whole-Body Pharmacokinetics of Exogenously Administered T Cells in Mice

The Generation of CAR-Transfected Natural Killer T Cells for the Immunotherapy of Melanoma

4SCAR‐GD2‐modified T‐cell therapy in neuroblastoma with MYCN amplification: A case report with over 4‐year follow‐up data

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