scholarly journals Chimeric antigen receptor T cells targeting PD-L1 suppress tumor growth

2020 ◽  
Author(s):  
Le Qin ◽  
Ruocong Zhao ◽  
Dongmei Chen ◽  
Xinru Wei ◽  
Qiting Wu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Car T Cells ◽  
Car T

Abstract Background: Chimeric antigen receptor T cells (CAR-T cells) therapy has been well recognized for treating B cell-derived malignancy. However, the efficacy of CAR-T cells against solid tumors remains dissatisfactory, partially due to the heterogeneity of solid tumors and T cell exhaustion in tumor microenvironment. PD-L1 is up-regulated in multiple solid tumors, resulting in T cell exhaustion upon binding to its receptor PD-1. Methods: Here, we designed a dominant-negative form of PD-1 , dPD1z, a vector containing the extracellular and transmembrane regions of human PD-1, and a CAR vector against PD-L1, CARPD-L1z, a vector employs a high-affinity single-chain variable fragment (scFv) against human PD-L1. These two vectors shared the same intracellular structure, including 4-1BB and TLR2 co-stimulatory domains, and the CD3ζ signaling domain. Results: dPD1z T and CARPD-L1z T cells efficiently lysed PD-L1 + tumor cells and had enhanced cytokine secretion in vitro and suppressed the growth of non-small cell lung cancer (NSCLC), gastric cancer and hepatoma carcinoma in patient-derived xenograft (PDX). However, the combination of anti-mesothelin CAR-T cells (CARMSLNz T) with dPD1z T or CARPD-L1z T cells did not repress tumor growth synergistically in PDX, as CARMSLNz T cells upregulated PD-L1 expression upon activation and were subsequently attacked by dPD1z T or CARPD-L1z T cells. Conclusions: In conclusion, we demonstrate CAR-T cells targeting PD-L1 were effective for suppressing the growth of multiple types of solid tumors in PDX models though their safety needs to be carefully examined.

scholarly journals Chimeric antigen receptor T cells targeting PD-L1 suppress tumor growth

2020 ◽  
Author(s):  
Le Qin ◽  
Ruocong Zhao ◽  
Dongmei Chen ◽  
Xinru Wei ◽  
Qiting Wu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Car T Cells ◽  
Car T

Abstract Background: Chimeric antigen receptor T cells (CAR-T cells) therapy has been well recognized for treating B cell-derived malignancy. However, the efficacy of CAR-T cells against solid tumors remains dissatisfactory, partially due to the heterogeneity of solid tumors and T cell exhaustion in tumor microenvironment. PD-L1 is up-regulated in multiple solid tumors, resulting in T cell exhaustion upon binding to its receptor PD-1. Methods: Here, we designed a dominant-negative form of PD-1 , dPD1z, a vector containing the extracellular and transmembrane regions of human PD-1, and a CAR vector against PD-L1, CARPD-L1z, a vector employs a high-affinity single-chain variable fragment (scFv) against human PD-L1. These two vectors shared the same intracellular structure, including 4-1BB and TLR2 co-stimulatory domains, and the CD3ζ signaling domain. Results: dPD1z T and CARPD-L1z T cells efficiently lysed PD-L1 + tumor cells and had enhanced cytokine secretion in vitro and suppressed the growth of non-small cell lung cancer (NSCLC), gastric cancer and hepatoma carcinoma in patient-derived xenograft (PDX). However, the combination of anti-mesothelin CAR-T cells (CARMSLNz T) with dPD1z T or CARPD-L1z T cells did not repress tumor growth synergistically in PDX, as CARMSLNz T cells upregulated PD-L1 expression upon activation and were subsequently attacked by dPD1z T or CARPD-L1z T cells. Conclusions: In conclusion, we demonstrate CAR-T cells targeting PD-L1 were effective for suppressing the growth of multiple types of solid tumors in PDX models though their safety needs to be carefully examined.

scholarly journals Chimeric Antigen Receptor T Cell Exhaustion during Treatment for Hematological Malignancies

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Chunyi Shen ◽  
Zhen Zhang ◽  
Yi Zhang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Hematological Malignancies ◽  
Antigen Receptor ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Immunotherapy, especially based on chimeric antigen receptor (CAR) T cells, has achieved prominent success in the treatment of hematological malignancies. However, approximately 30-50% of patients will have disease relapse following remission after receiving CD19-targeting CAR-T cells, with failure of maintaining a long-term effect. Mechanisms underlying CAR-T therapy inefficiency consist of loss or modulation of target antigen and CAR-T cell poor persistence which mostly results from T cell exhaustion. The unique features and restoration strategies of exhausted T cells (Tex) have been well described in solid tumors. However, the overview associated with CAR-T cell exhaustion is relatively rare in hematological malignancies. In this review, we summarize the characteristics, cellular, and molecular mechanisms of Tex cells as well as approaches to reverse CAR-T cell exhaustion in hematological malignancies, providing novel strategies for immunotherapies.

scholarly journals Chimeric Antigen Receptor T Cell Therapy for Solid Tumors: Current Status, Obstacles and Future Strategies

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 191 ◽  
Author(s):  
Benjamin Heyman ◽  
Yiping Yang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Current Status ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

Chimeric antigen receptor T cells (CAR T Cells) have led to dramatic improvements in the survival of cancer patients, most notably those with hematologic malignancies. Early phase clinical trials in patients with solid tumors have demonstrated them to be feasible, but unfortunately has yielded limited efficacy for various cancer types. In this article we will review the background on CAR T cells for the treatment of solid tumors, focusing on the unique obstacles that solid tumors present for the development of adoptive T cell therapy, and the novel approaches currently under development to overcome these hurdles.

scholarly journals Galunisertib enhances chimeric antigen receptor-modified T cell function

2020 ◽  
Author(s):  
Zhixiong Wang ◽  
Qian Liu ◽  
Na Risu ◽  
Jiayu Fu ◽  
Yan Zou ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Cell Function ◽  
Antigen Receptor ◽  
Target Cells ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Chimeric antigen receptor (CAR) T cell therapy still faces the challenge of immunosuppression when treating solid tumors. TGF-β is one of the critical factors in the tumor microenvironment to help tumors escape surveillance by the immune system. Here we tried using the combination of a small molecule inhibitor of TGF-β receptor I, Galunisertib, and CAR T cells to explore whether Galunisertib could enhance CAR T cell function against solid tumor cells. In vitro experiments showed Galunisertib could significantly enhance the specific cytotoxicity of both CD133- and HER2-specific CAR T cells. However, Galunisertib had no direct killing effect on target cells. Galunisertib significantly increased the cytokine secretion of CAR T cells and T cells that do not express CAR (Nontransfected T cells). Galunisertib did not affect the proliferation of T cells, the antigen expression on target cells and CD69 on CAR T cells. We found that TGF-β was secreted by T cells themselves upon activation, and Galunisertib could reduce TGF-β signaling in CAR T cells. Our findings can provide the basis for further preclinical and clinical studies of the combination of Galunisertib and CAR T cells in the treatment of solid tumors.

scholarly journals Deletion of Cbl-b inhibits CD8+ T-cell exhaustion and promotes CAR T-cell function

2021 ◽  
Vol 9 (1) ◽  
pp. e001688
Author(s):  
Jitendra Kumar ◽  
Ritesh Kumar ◽  
Amir Kumar Singh ◽  
Elviche L Tsakem ◽  
Mahesh Kathania ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
T Cell Exhaustion ◽  
Sequencing Data ◽  
T Cell Therapy ◽  
Cell Exhaustion ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

BackgroundChimeric antigen receptor (CAR) T-cell therapy is an emerging option for cancer treatment, but its efficacy is limited, especially in solid tumors. This is partly because the CAR T cells become dysfunctional and exhausted in the tumor microenvironment. However, the key pathways responsible for impaired function of exhausted cells remain unclear, which is essential to overcome CAR T-cell exhaustion.MethodsAnalysis of RNA-sequencing data from CD8+ tumor-infiltrating lymphocytes (TILs) led to identification of Cbl-b as a potential target. The sequencing data were validated using a syngeneic MC38 colon cancer model. To analyze the in vivo role of Cbl-b in T-cell exhaustion, tumor growth, % PD1+Tim3+ cells, and expression of effector cytokines were analyzed in cbl-b+/+ and cbl-b–/– mice. To evaluate the therapeutic potential of Cbl-b depletion, we generated a new CAR construct, hCEAscFv-CD28-CD3ζ.GFP, that recognizes human carcinoembryonic antigen (CEA). cbl-b+/+ and cbl-b–/– CEA-CAR T cells were generated by retroviral transduction. Rag–/– mice bearing MC38-CEA cells were injected with cbl-b+/+ and cbl-b–/–; CEA-CAR T cells, tumor growth, % PD1+Tim3+ cells and expression of effector cytokines were analyzed.ResultsOur results show that the E3 ubiquitin ligase Cbl-b is upregulated in exhausted (PD1+Tim3+) CD8+ TILs. CRISPR-Cas9-mediated inhibition of Cbl-b restores the effector function of exhausted CD8+ TILs. Importantly, the reduced growth of syngeneic MC38 tumors in cbl-b–/– mice was associated with a marked reduction of PD1+Tim3+ CD8+ TILs. Depletion of Cbl-b inhibited CAR T-cell exhaustion, resulting in reduced MC38-CEA tumor growth, reduced PD1+Tim3+ cells and increased expression of interferon gamma, tumor necrosis factor alpha, and increased tumor cell killing.ConclusionOur studies demonstrate that deficiency of Cbl-b overcomes endogenous CD8+ T-cell exhaustion, and deletion of Cbl-b in CAR T cells renders them resistant to exhaustion. Our results could facilitate the development of efficient CAR T-cell therapy for solid tumors by targeting Cbl-b.

A chimeric antigen receptor with antigen-independent OX40 signaling mediates potent antitumor activity

2021 ◽  
Vol 13 (578) ◽  
pp. eaba7308
Author(s):  
Huihui Zhang ◽  
Fanlin Li ◽  
Jiang Cao ◽  
Xin Wang ◽  
Hai Cheng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Mouse Tumor ◽  
Great Success ◽  
Car T Cells ◽  
Car T

Although chimeric antigen receptor (CAR)–modified T cells have shown great success in the treatment of B cell malignancies, this approach has limited efficacy in patients with solid tumors. Various modifications in CAR structure have been explored to improve this efficacy, including the incorporation of two costimulatory domains. Because costimulatory signals are transduced together with T cell receptor signals during T cell activation, we engineered a type of CAR-T cells with a costimulatory signal that was activated independently from the tumor antigen to recapitulate physiological stimulation. We screened 12 costimulatory receptors to identify OX40 as the most effective CAR-T function enhancer. Our data indicated that these new CAR-T cells showed superior proliferation capability compared to current second-generation CAR-T cells. OX40 signaling reduced CAR-T cell apoptosis through up-regulation of genes encoding Bcl-2 family members and enhanced proliferation through increased activation of the NF-κB (nuclear factor κB), MAPK (mitogen-activated protein kinase), and PI3K-AKT (phosphoinositide 3-kinase to the kinase AKT) pathways. OX40 signaling not only enhanced the cytotoxicity of CAR-T cells but also reduced exhaustion markers, thereby maintaining their function in immunosuppressive tumor microenvironments. In mouse tumor models and in patients with metastatic lymphoma, these CAR-T cells exhibited robust amplification and antitumor activity. Our findings provide an alternative option for CAR-T optimization with the potential to overcome the challenge of treating solid tumors.

scholarly journals 125 Co-opting IL-8 to enhance efficacy of B7H3 CAR T cells against pediatric sarcoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A134-A134
Author(s):  
Jessica Lake ◽  
Kevin Winkler ◽  
Alexander Harrant ◽  
Ashley Yingst ◽  
Kristin Schaller ◽  
...  
Keyword(s):  
T Cells ◽  
Young Adults ◽  
T Cell ◽  
Cell Therapy ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

BackgroundThe 5-year disease-free survival for children and young adults with metastatic sarcoma at diagnosis or recurrent disease after front-line therapy is 20–30%.1 2 Cellular immunotherapy using chimeric antigen receptor (CAR) T cells has shown dramatic benefits in leukemia, but only limited success in solid tumors.3 4 One limitation of CAR T cell therapy has been poor trafficking into solid tumors.5–7 Chemokines are small, secreted, cytokine-like molecules that mediate lymphocyte homing and migration.8 In this study, we discovered that both osteosarcoma (OS) and rhabdomyosarcoma (RMS) cells significantly increase expression of the chemokine IL-8 after clinically achievable doses of radiation, but not at rest. Given that CAR T cells do not express the receptor for IL-8, we created a construct with an IL-8 receptor (CXCR2) and a B7H3 CAR in T cells to improve CAR T homing and to create an effective new immunotherapy for patients with sarcoma.MethodsMultiple OS and RMS cell lines were irradiated at 10 Gy and IL-8 was measured by ELISA. We created retroviral constructs, B7H3 CAR-T2a-CXCR2 and B7H3 CAR. Peripheral blood T lymphocytes were stimulated with IL-2 and anti-CD3/28 antibodies for 48 hours prior to transduction with the retroviral vectors. Surface expression of the scFv (by L protein) and CXCR2 (mAb) were assessed using flow cytometry. In vitro cytotoxicity assays using sarcoma tumor spheroids were conducted using Incucyte. INF-γ and IL-2 production were measured by ELISA. NSG mice injected orthotopically with an IL-8 overexpressing RMS cell line were treated 4–7 days later with the B7H3 CAR-CXCR2 T cells or B7H3 T cells (control) and followed weekly with bioluminescent imaging.ResultsIrradiated (10 Gy) sarcoma cells express 2-9x higher IL-8 than non-irradiated sarcoma. T cells were transduced with efficiencies of 60–90%. INF-γ production was equivalent between the B7H3 CAR-T2a-CXCR2 T cells and B7H3 CAR T cells, but IL-2 production was significantly higher in the dual expressing CAR T cells. In vitro cytotoxicity with sarcoma spheroids was measured by Incucyte and showed faster and greater killing by B7H3 CAR-T2a-CXCR2 T cells than B7H3 CAR T cells. Furthermore, when sarcoma tumor bearing mice were treated with B7H3 CAR-T2a-CXCR2 T cells, tumors resolved completely by 4–5 weeks and had long-lasting remission.ConclusionsChemokine receptor expressing CAR T cells showed superior cytokine production and T cell activation/cytotoxicity compared to a CAR T construct alone. These finding lead to better efficacy in animal models and suggest a promising approach for pediatric sarcoma.ReferencesLuetke A, Meyers PA, Lewis I, Juergens H. Osteosarcoma treatment - where do we stand? A state of the art review. Cancer Treat Rev 2014;40:523–32.Bleyer A, Barr R, Hayes-Lattin B, et al. The distinctive biology of cancer in adolescents and young adults. Nat Rev Cancer 2008;8:288–98.Buechner J, SA G, SL M, et al. Global Registration Trial of Efficacy and Safety of CTL019 in Pediatric and Young Adult Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL): Update to the interim analysis. 2017 European Hematology Association Annual Meeting: Madrid, Spain2017.Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med 2018;378:439–48.Gill S, Maus MV, Porter DL. Chimeric antigen receptor T cell therapy: 25 years in the making. Blood Rev 2016;30:157–67.Fousek K, Ahmed N. The Evolution of T-cell Therapies for Solid Malignancies. Clin Cancer Res 2015;21:3384–92.Newick K, Moon E, Albelda SM. Chimeric antigen receptor T-cell therapy for solid tumors. Mol Ther Oncolytics 2016;3:16006.Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 2017;17:559–72.Ethics ApprovalThe animal experiments discussed in the abstract were approved by the University of Colorado IACUC, protocol #00251.

scholarly journals Evaluation of chimeric antigen receptor T cell therapy in non-human primates infected with SHIV or SIV

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248973
Author(s):  
Nami Iwamoto ◽  
Bhavik Patel ◽  
Kaimei Song ◽  
Rosemarie Mason ◽  
Sara Bolivar-Wagers ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Chimeric Antigen Receptor ◽  
Viral Suppression ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

Achieving a functional cure is an important goal in the development of HIV therapy. Eliciting HIV-specific cellular immune responses has not been sufficient to achieve durable removal of HIV-infected cells due to the restriction on effective immune responses by mutation and establishment of latent reservoirs. Chimeric antigen receptor (CAR) T cells are an avenue to potentially develop more potent redirected cellular responses against infected T cells. We developed and tested a range of HIV- and SIV-specific chimeric antigen receptor (CAR) T cell reagents based on Env-binding proteins. In general, SHIV/SIV CAR T cells showed potent viral suppression in vitro, and adding additional CAR molecules in the same transduction resulted in more potent viral suppression than single CAR transduction. Importantly, the primary determinant of virus suppression potency by CAR was the accessibility to the Env epitope, and not the neutralization potency of the binding moiety. However, upon transduction of autologous T cells followed by infusion in vivo, none of these CAR T cells impacted either acquisition as a test of prevention, or viremia as a test of treatment. Our study illustrates limitations of the CAR T cells as possible antiviral therapeutics.

Chimeric Antigen Receptor T Cell Immunotherapy for Tumor: A Review of Patent Literatures

2019 ◽  
Vol 14 (1) ◽  
pp. 60-69
Author(s):  
Manxue Fu ◽  
Liling Tang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Limiting Factors ◽  
Car T Cells ◽  
Car T Cell ◽  
Cell Immunotherapy ◽  
Car T ◽  
T Cell Immunotherapy

Background: Chimeric Antigen Receptor (CAR) T cell immunotherapy, as an innovative method for tumor immunotherapy, acquires unprecedented clinical outcomes. Genetic modification not only provides T cells with the antigen-binding function but also endows T cells with better immunological functions both in solid and hematological cancer. However, the CAR T cell therapy is not perfect because of several reasons, such as tumor immune microenvironment, and autologous limiting factors of CAR T cells. Moreover, the safety of CAR T cells should be improved.Objective:Recently many patents and publications have reported the importance of CAR T cell immunotherapy. Based on the patents about CAR T cell immunotherapy, we conclude some methods for designing the CAR which can provide information to readers.Methods:In this review, we collect recent patents and publications, summarize some specific antigens for oncotherapy from patents and enumerate some approaches to conquering immunosuppression and reinforcing the immune response of CAR T cells. We also sum up some strategies for improving the safety of CAR T cell immunotherapy.Results:CAR T cell immunotherapy as a neotype cellular immunotherapy has been proved effective in oncotherapy and authorized by FDA. Improvements in CAR designing enhance functions of CAR T cells.Conclusion:This review, summarizing antigens and approaches to overcome defects of CAR T cell immunotherapy from patents and publications, might contribute to a broad readership.

scholarly journals HIV-1-Specific Chimeric Antigen Receptor T Cells Fail To Recognize and Eliminate the Follicular Dendritic Cell HIV Reservoir In Vitro

2020 ◽  
Vol 94 (10) ◽  
Author(s):  
Matthew T. Ollerton ◽  
Edward A. Berger ◽  
Elizabeth Connick ◽  
Gregory F. Burton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Follicular Dendritic

ABSTRACT The major obstacle to a cure for HIV infection is the persistence of replication-competent viral reservoirs during antiretroviral therapy. HIV-specific chimeric antigen receptor (CAR) T cells have been developed to target latently infected CD4+ T cells that express virus either spontaneously or after intentional latency reversal. Whether HIV-specific CAR-T cells can recognize and eliminate the follicular dendritic cell (FDC) reservoir of HIV-bound immune complexes (ICs) is unknown. We created HIV-specific CAR-T cells using human peripheral blood mononuclear cells (PBMCs) and a CAR construct that enables the expression of CD4 (domains 1 and 2) and the carbohydrate recognition domain of mannose binding lectin (MBL) to target native HIV Env (CD4-MBL CAR). We assessed CAR-T cell cytotoxicity using a carboxyfluorescein succinimidyl ester (CFSE) release assay and evaluated CAR-T cell activation through interferon gamma (IFN-γ) production and CD107a membrane accumulation by flow cytometry. CD4-MBL CAR-T cells displayed potent lytic and functional responses to Env-expressing cell lines and HIV-infected CD4+ T cells but were ineffective at targeting FDC bearing HIV-ICs. CD4-MBL CAR-T cells were unresponsive to cell-free HIV or concentrated, immobilized HIV-ICs in cell-free experiments. Blocking intercellular adhesion molecule-1 (ICAM-1) inhibited the cytolytic response of CD4-MBL CAR-T cells to Env-expressing cell lines and HIV-infected CD4+ T cells, suggesting that factors such as adhesion molecules are necessary for the stabilization of the CAR-Env interaction to elicit a cytotoxic response. Thus, CD4-MBL CAR-T cells are unable to eliminate the FDC-associated HIV reservoir, and alternative strategies to eradicate this reservoir must be sought. IMPORTANCE Efforts to cure HIV infection have focused primarily on the elimination of latently infected CD4+ T cells. Few studies have addressed the unique reservoir of infectious HIV that exists on follicular dendritic cells (FDCs), persists in vivo during antiretroviral therapy, and likely contributes to viral rebound upon cessation of antiretroviral therapy. We assessed the efficacy of a novel HIV-specific chimeric antigen receptor (CAR) T cell to target both HIV-infected CD4+ T cells and the FDC reservoir in vitro. Although CAR-T cells eliminated CD4+ T cells that express HIV, they did not respond to or eliminate FDC bound to HIV. These findings reveal a fundamental limitation to CAR-T cell therapy to eradicate HIV.

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