Blockade of Myeloid-Derived Suppressor Cells after Induction of Lymphopenia Improves Adoptive T Cell Therapy in a Murine Model of Melanoma

T lymphocytes function as major players in antigen-mediated cytotoxicity and have become powerful tools for exploiting the immune system in tumor elimination. Several types of T cell-based immunotherapies have been prescribed to cancer patients with durable immunological response. Such strategies include immune checkpoint inhibitors, adoptive T cell therapy, cancer vaccines, oncolytic virus, and modulatory cytokines. However, the majority of cancer patients still failed to take the advantage of these kinds of treatments. Currently, extensive attempts are being made to uncover the potential mechanism of immunotherapy resistance, and myeloid-derived suppressor cells (MDSCs) have been identified as one of vital interpretable factors. Here, we discuss the immunosuppressive mechanism of MDSCs and their contributions to failures of T cell-based immunotherapy. Additionally, we summarize combination therapies to ameliorate the efficacy of T cell-based immunotherapy.

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Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells

Blood ◽

10.1182/blood-2010-01-265041 ◽

2010 ◽

Vol 116 (19) ◽

pp. 3875-3886 ◽

Cited By ~ 178

Author(s):

James N. Kochenderfer ◽

Zhiya Yu ◽

Dorina Frasheri ◽

Nicholas P. Restifo ◽

Steven A. Rosenberg

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Cell Therapy ◽

Chimeric Antigen Receptor ◽

Murine Model ◽

Antigen Receptor ◽

Adoptive T Cell Therapy ◽

T Cell Therapy ◽

Self Antigen

Abstract Adoptive T-cell therapy with anti-CD19 chimeric antigen receptor (CAR)–expressing T cells is a new approach for treating advanced B-cell malignancies. To evaluate anti-CD19–CAR-transduced T cells in a murine model of adoptive T-cell therapy, we developed a CAR that specifically recognized murine CD19. We used T cells that were retrovirally transduced with this CAR to treat mice bearing a syngeneic lymphoma that naturally expressed the self-antigen murine CD19. One infusion of anti-CD19–CAR-transduced T cells completely eliminated normal B cells from mice for at least 143 days. Anti-CD19–CAR-transduced T cells eradicated intraperitoneally injected lymphoma cells and large subcutaneous lymphoma masses. The antilymphoma efficacy of anti-CD19–CAR-transduced T cells was critically dependent on irradiation of mice before anti-CD19–CAR-transduced T-cell infusion. Anti-CD19–CAR-transduced T cells had superior antilymphoma efficacy compared with the anti-CD19 monoclonal antibody from which the anti-CD19 CAR was derived. Our results demonstrated impressive antilymphoma activity and profound destruction of normal B cells caused by anti-CD19–CAR-transduced T cells in a clinically relevant murine model.

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Serial Low Doses of Sorafenib Enhance Therapeutic Efficacy of Adoptive T Cell Therapy in a Murine Model by Improving Tumor Microenvironment

PLoS ONE ◽

10.1371/journal.pone.0109992 ◽

2014 ◽

Vol 9 (10) ◽

pp. e109992 ◽

Cited By ~ 15

Author(s):

Hui-Yen Chuang ◽

Ya-Fang Chang ◽

Ren-Shyan Liu ◽

Jeng-Jong Hwang

Keyword(s):

T Cell ◽

Tumor Microenvironment ◽

Cell Therapy ◽

Murine Model ◽

Therapeutic Efficacy ◽

Adoptive T Cell Therapy ◽

Low Doses ◽

T Cell Therapy

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Adoptive T Cell Therapy in Patients With Recurrent Ovarian Cancer

Case Medical Research ◽

10.31525/ct1-nct04072263 ◽

2019 ◽

Author(s):

Keyword(s):

Ovarian Cancer ◽

T Cell ◽

Cell Therapy ◽

Recurrent Ovarian Cancer ◽

Adoptive T Cell Therapy ◽

T Cell Therapy

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Enhanced Sensitivity of Lymphoid Cells to Ethanol ADH Acetaldehyde Toxicity; Implications for GDEPT and Adoptive T Cell Therapy

Current Pharmacogenomics and Personalized Medicine ◽

10.2174/1875692116666180703151538 ◽

2018 ◽

Vol 16 (2) ◽

pp. 118-123

Author(s):

Philip Savage ◽

Claire Horlock ◽

Bryony Stott ◽

Justin Stebbing

Keyword(s):

T Cell ◽

Cell Therapy ◽

Lymphoid Cells ◽

Adoptive T Cell Therapy ◽

T Cell Therapy ◽

Enhanced Sensitivity

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'Off-the-shelf’ allogeneic antigen-specific adoptive T-cell therapy for the treatment of multiple EBV-associated malignancies

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001608 ◽

2021 ◽

Vol 9 (2) ◽

pp. e001608

Author(s):

Debottam Sinha ◽

Sriganesh Srihari ◽

Kirrliee Beckett ◽

Laetitia Le Texier ◽

Matthew Solomon ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Adoptive T Cell Therapy ◽

Nuclear Antigen ◽

T Cell Therapy ◽

In Vivo Models ◽

Hla Alleles ◽

Cell Therapies ◽

Wide Range

BackgroundEpstein-Barr virus (EBV), an oncogenic human gammaherpesvirus, is associated with a wide range of human malignancies of epithelial and B-cell origin. Recent studies have demonstrated promising safety and clinical efficacy of allogeneic ‘off-the-shelf’ virus-specific T-cell therapies for post-transplant viral complications.MethodsTaking a clue from these studies, we developed a highly efficient EBV-specific T-cell expansion process using a replication-deficient AdE1-LMPpoly vector that specifically targets EBV-encoded nuclear antigen 1 (EBNA1) and latent membrane proteins 1 and 2 (LMP1 and LMP2), expressed in latency II malignancies.ResultsThese allogeneic EBV-specific T cells efficiently recognized human leukocyte antigen (HLA)-matched EBNA1-expressing and/or LMP1 and LMP2-expressing malignant cells and demonstrated therapeutic potential in a number of in vivo models, including EBV lymphomas that emerged spontaneously in humanized mice following EBV infection. Interestingly, we were able to override resistance to T-cell therapy in vivo using a ‘restriction-switching’ approach, through sequential infusion of two different allogeneic T-cell therapies restricted through different HLA alleles. Furthermore, we have shown that inhibition of the programmed cell death protein-1/programmed death-ligand 1 axis in combination with EBV-specific T-cell therapy significantly improved overall survival of tumor-bearing mice when compared with monotherapy.ConclusionThese findings suggest that restriction switching by sequential infusion of allogeneic T-cell therapies that target EBV through distinct HLA alleles may improve clinical response.

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A modular and controllable T cell therapy platform for acute myeloid leukemia

Leukemia ◽

10.1038/s41375-020-01109-w ◽

2021 ◽

Author(s):

Mohamed-Reda Benmebarek ◽

Bruno L. Cadilha ◽

Monika Herrmann ◽

Stefanie Lesch ◽

Saskia Schmitt ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

T Cell ◽

Cell Therapy ◽

Myeloid Leukemia ◽

Tumor Antigens ◽

Adoptive T Cell Therapy ◽

Single Chain ◽

T Cell Therapy ◽

Acute Myeloid

AbstractTargeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33+ and CD123+ AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment.

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