Mesothelin-targeted CAR-T cells for adoptive cell therapy of solid tumors.
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ABSTRACT:
SUBMITTER: Zhang GZ
PROVIDER: S-EPMC8425252 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:UnlabelledChimeric antigen receptors (CAR) are synthetic receptors that target T cells to cell-surface antigens and augment T-cell function and persistence. Mesothelin is a cell-surface antigen implicated in tumor invasion, which is highly expressed in mesothelioma and lung, pancreas, breast, ovarian, and other cancers. Its low-level expression in mesothelia, however, commands thoughtful therapeutic interventions. Encouragingly, recent clinical trials evaluating active immunization or immunoconjugates in patients with pancreatic adenocarcinoma or mesothelioma have shown responses without toxicity. Altogether, these findings and preclinical CAR therapy models using either systemic or regional T-cell delivery argue favorably for mesothelin CAR therapy in multiple solid tumors.SignificanceRecent success obtained with adoptive transfer of CAR T cells targeting CD19 in patients with refractory hematologic malignancies has generated much enthusiasm for T-cell engineering and raises the prospect of implementing similar strategies for solid tumors. Mesothelin is expressed in a wide range and a high percentage of solid tumors, which we review here in detail. Mesothelin CAR therapy has the potential to treat multiple solid malignancies.
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Project description:Non-small cell lung cancer (NSCLC) and mesothelioma are renowned for being diagnosed at a late stage and poor prognosis. Although surgery, chemotherapy, and radiotherapy have yielded successful outcomes, the improvement on the survival rate of NSCLC and mesothelioma have been less marked. Recently, adoptive immunotherapy, particularly chimeric antigen receptor T (CAR-T) cell therapy demonstrated promise for improving the survival of acute lymphoblastic leukemia with minimum toxicity. However, its application in solid tumors still warrants in-depth investigations and multiple consistent trial results, particularly in eliminating 'off-tumor' toxicity. To explore CAR-T therapy in NSCLC and mesothelioma, second-generation CAR-T cells were constructed targeting mesothelin (MSLN), which is abundant in NSCLC and mesothelioma but is under expressed in normal tissues. The second-generation design incorporated co-stimulatory CD28 and 4-1BB signaling domains to enhance the proliferation. Following the successful analysis of CAR-T cells by flow cytometry, cytotoxicity experiments were performed using the LDH kit to verify the killing effect of CAR-T cells on target cells. Otherwise, the in vivo killing tumor activity of MSLN CAR-T cells was verified by constructing a mouse model using tumor-derived cells from patients to inoculate the mice. When the effector-to-target ratio is >0.5:1, CAR-T MSLN cells exhibited significantly higher ability to kill tumor cells than T cells. In in vivo experiments, mice whose tail vein was injected with CAR-T MSLN cells demonstrated significantly slower tumor growth. Without continuous administration, both groups became gradually synchronized in growth of tumor size, which suggests that the persistence of CAR-T cells is an important issue in preclinical studies.
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Project description:Chimeric antigen receptor (CAR) T-cell therapy is an innovative form of immunotherapy wherein autologous T cells are genetically modified to express chimeric receptors encoding an antigen-specific single-chain variable fragment and various costimulatory molecules. Upon administration, these modified T cells traffic to, and recognize, cancer cells in an HLA-independent manner. CAR T-cell therapy has shown remarkable success in the treatment of CD-19-expressing B-cell acute lymphocytic leukemia. However, clinical gains to the same magnitude have not been reported in solid tumors. Several known obstacles to CAR T-cell therapy for solid tumors include target antigen identification, effective trafficking to the tumor, robust activation, proliferation, and in vivo cytotoxicity. Beyond these T-cell intrinsic properties, a complex and dynamic immunosuppressive tumor microenvironment in solid tumors hinders T-cell efficacy. Notable advancements in CAR design to include multiple costimulatory molecules, ligands, and soluble cytokines have shown promise in preclinical models, and some of these are currently in early-phase clinical trials. In this review, we discuss selected solid tumor malignancies and relevant preclinical data and highlight clinical trial results that are available. Furthermore, we outline some obstacles to CAR T-cell therapy for each tumor and propose strategies to overcome some of these limitations.
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Project description:PURPOSE OF REVIEW:This review will discuss the challenges facing adoptive cell techniques in the treatment of solid tumors and examine the therapies that are in development for specifically pediatric solid tumors. RECENT FINDINGS:Targeting solid tumors with adoptive cell therapy has been limited by the inhibitory tumor microenvironment and heterogeneous expression of targetable antigens. Many creative strategies to overcome these limitations are being developed but still need to be tested clinically. Early phase clinical trials in neuroblastoma with GD2 CAR T cells are promising but results need to be validated on a larger scale. Most research in other pediatric solid tumors is still in early stages. Adoptive cell therapy represents a useful tool to improve the outcomes of many pediatric solid tumors but significant study is still required. Several clinical trials are ongoing to test therapies that have shown promise in the lab.
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Project description:Chimeric antigen receptor (CAR) T (CAR-T) cell transfer has made great success in hematological malignancies, but only shown a limited effect on solid tumors. One of the major hurdles is the poor persistence of infused cells derived from ex vivo activation/expansion and repeated antigen encounter after re-infusion. Bcl-xL has been demonstrated to play an important role on normal T cell survival and function as well as genetically engineered cells. In the current study, we developed a retroviral CAR construct containing a second-generation carcinoembryonic antigen (CEA)-targeting CAR with the Bcl-xL gene and tested the anti-CEA CAR-T cell immunotherapy for colorectal cancer. In vitro, the anti-CEA CAR-T cells destroyed CEA-expressing tumor cells and sustained survival. In vivo, adoptive cell transfer of anti-CEA CAR-T cells significantly enhanced the ability of the CAR-T cells to accumulate in tumor tissues, suppress tumor growth and increase the overall survival rate of tumor-bearing mice in a murine model of colorectal cancer. These results demonstrate a novel CAR-T platform that has the ability to increase the persistence of CAR-T cells in solid tumors through exogenous expression of persistent genes. The data provide a potentially novel approach to augment CAR-T immunotherapy for solid tumors.
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Project description:Cellular immunotherapies represent a promising approach for the treatment of cancer. Engineered adoptive cell therapies redirect and augment a leukocyte's inherent ability to mount an immune response by introducing novel anti-tumor capabilities and targeting moieties. A prominent example of this approach is the use of T cells engineered to express chimeric antigen receptors (CARs), which have demonstrated significant efficacy against some hematologic malignancies. Despite increasingly sophisticated strategies to harness immune cell function, efficacy against solid tumors has remained elusive for adoptive cell therapies. Amongst cell types used in immunotherapies, however, macrophages have recently emerged as prominent candidates for the treatment of solid tumors. In this review, we discuss the use of monocytes and macrophages as adoptive cell therapies. Macrophages are innate immune cells that are intrinsically equipped with broad therapeutic effector functions, including active trafficking to tumor sites, direct tumor phagocytosis, activation of the tumor microenvironment and professional antigen presentation. We focus on engineering strategies for manipulating macrophages, with a specific focus on CAR macrophages (CAR-M). We highlight CAR design for macrophages, the production of CAR-M for adoptive cell transfer, and clinical considerations for their use in treating solid malignancies. We then outline recent progress and results in applying CAR-M as immunotherapies. The recent development of engineered macrophage-based therapies holds promise as a key weapon in the immune cell therapy armamentarium.
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Project description:Since the approval of chimeric antigen receptor (CAR) T cell therapy targeting CD19 by the FDA, CAR-T cell therapy has received increasing attention as a new method for targeting tumors. Although CAR-T cell therapy has a good effect against hematological malignancies, it has been less effective against solid tumors. In the present study, we selected mesothelin (MSLN/MESO) as a target for CAR-T cells because it is highly expressed by solid tumors but only expressed at low levels by normal tissues. We engineered a third generation MSLN-CAR comprising a single-chain variable fragment (scFv) targeting MSLN (MSLN-scFv), a CD8 transmembrane domain, the costimulatory domains from CD28 and 4-1BB, and the activating domain CD3ζ. In vitro, MSLN-CAR-T cells killed various solid tumor cell lines, demonstrating that it could specifically kill MSLN-positive cells and release cytokines. In vivo, we investigated the effects of MSLN-CAR-T cell therapy against ovarian, breast, and colorectal cancer cell-line-derived xenografts (CDX) and MSLN-positive colorectal and gastric cancer patient-derived xenografts (PDX). MSLN-CAR decreased the growth of MSLN-positive tumors concomitant with significantly increased T cells and cytokine levels compared to the control group. These results indicated that modified MSLN-CAR-T cells could be a promising therapeutic approach for solid tumors.
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