scholarly journals Lentiviral Vectors for T Cell Engineering: Clinical Applications, Bioprocessing and Future Perspectives

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1528
Author(s):  
Roman P. Labbé ◽  
Sandrine Vessillier ◽  
Qasim A. Rafiq
Keyword(s):  
T Cell ◽  
Critical Role ◽  
Lentiviral Vectors ◽  
Retroviral Vectors ◽  
Good Manufacturing Practice ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Fda Approval ◽  
T Cell Engineering

Lentiviral vectors have played a critical role in the emergence of gene-modified cell therapies, specifically T cell therapies. Tisagenlecleucel (Kymriah), axicabtagene ciloleucel (Yescarta) and most recently brexucabtagene autoleucel (Tecartus) are examples of T cell therapies which are now commercially available for distribution after successfully obtaining EMA and FDA approval for the treatment of blood cancers. All three therapies rely on retroviral vectors to transduce the therapeutic chimeric antigen receptor (CAR) into T lymphocytes. Although these innovations represent promising new therapeutic avenues, major obstacles remain in making them readily available tools for medical care. This article reviews the biological principles as well as the bioprocessing of lentiviral (LV) vectors and adoptive T cell therapy. Clinical and engineering successes, shortcomings and future opportunities are also discussed. The development of Good Manufacturing Practice (GMP)-compliant instruments, technologies and protocols will play an essential role in the development of LV-engineered T cell therapies.

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

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.

T cell engineering for adoptive T cell therapy: safety and receptor avidity

2019 ◽  
Vol 68 (10) ◽  
pp. 1701-1712 ◽  
Author(s):  
Elvira D’Ippolito ◽  
Kilian Schober ◽  
Magdalena Nauerth ◽  
Dirk H. Busch
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Cell Engineering ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
T Cell Engineering

scholarly journals Synthetic Antigen-Presenting Cells for Adoptive T Cell Therapy

2021 ◽  
Author(s):  
Shreyas N. Dahotre ◽  
Anna M. Romanov ◽  
Fang-Yi Su ◽  
Gabriel A. Kwong
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Presenting Cells ◽  
Adoptive T Cell Therapy ◽  
Target Antigen ◽  
T Cell Therapy ◽  
Promising Alternative ◽  
Cell Therapies ◽  
Antigen Presenting

AbstractAdoptive T cell therapies are transforming the treatment of solid and liquid tumors, yet their widespread adoption is limited in part by the challenge of generating functional cells. T cell activation and expansion using conventional antigen-presenting cells (APCs) is unreliable due to the variable quality of donor-derived APCs. As a result, engineered approaches using nanomaterials presenting T cell activation signals are a promising alternative due to their ability to be robustly manufactured with precise control over stimulation cues. In this work, we design synthetic APCs that consist of liposomes surface-functionalized with peptide-major histocompatibility complexes (pMHC). Synthetic APCs selectively target and activate antigen-specific T cell populations to levels similar to conventional protocols using non-specific αCD3 and αCD28 antibodies without the need for costimulation signals. T cells treated with synthetic APCs produce effector cytokines and demonstrate cytotoxic activity when co-cultured with tumor cells presenting target antigen in vitro. Following adoptive transfer into tumor-bearing mice, activated cells control tumor growth and improve overall survival compared to untreated mice. Synthetic APCs could potentially be used in the future to improve the accessibility of adoptive T cell therapies by removing the need for conventional APCs during manufacturing.

scholarly journals Engineering Strategies to Enhance TCR-Based Adoptive T Cell Therapy

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1485 ◽  
Author(s):  
Jan A. Rath ◽  
Caroline Arber
Keyword(s):  
T Cell ◽  
Cell Receptor ◽  
Clinical Results ◽  
Adoptive T Cell Therapy ◽  
Great Promise ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Challenges And Opportunities ◽  
The Impact ◽  
Insight Into

T cell receptor (TCR)-based adoptive T cell therapies (ACT) hold great promise for the treatment of cancer, as TCRs can cover a broad range of target antigens. Here we summarize basic, translational and clinical results that provide insight into the challenges and opportunities of TCR-based ACT. We review the characteristics of target antigens and conventional αβ-TCRs, and provide a summary of published clinical trials with TCR-transgenic T cell therapies. We discuss how synthetic biology and innovative engineering strategies are poised to provide solutions for overcoming current limitations, that include functional avidity, MHC restriction, and most importantly, the tumor microenvironment. We also highlight the impact of precision genome editing on the next iteration of TCR-transgenic T cell therapies, and the discovery of novel immune engineering targets. We are convinced that some of these innovations will enable the field to move TCR gene therapy to the next level.

scholarly journals Hypoxia in cancer chemo- and immunotherapy: foe or friend?

2019 ◽  
Author(s):  
Noemi Vitos ◽  
Shannon Chen ◽  
Shreya Mathur ◽  
Ibrahim Chamseddine ◽  
Katarzyna A. Rejniak
Keyword(s):  
T Cell ◽  
Oxygen Demand ◽  
Optimization Techniques ◽  
Adoptive T Cell Therapy ◽  
Tumor Resistance ◽  
Treatment Protocols ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Computational Optimization

AbstractHypoxia, a low level of oxygen in the tissue, is a feature of most solid tumors. It arises due to an imbalance between the oxygen supply from the abnormal vasculature and oxygen demand by the large number of tumor and stromal cells. Hypoxia has been implicated in the development of aggressive tumors and tumor resistance to various therapies. This makes hypoxia a negative marker of patients’ survival. However, recent advances in designing new hypoxia-activated pro-drugs and adoptive T cell therapies provide an opportunity for exploiting hypoxia in order to improve cancer treatment. We used novel mathematical models of micro-pharmacology and computational optimization techniques for determining the most effective treatment protocols that take advantage of heterogeneous and dynamically changing oxygenation in in vivo tumors. These models were applied to design schedules for a combination of three therapeutic compounds in pancreatic cancers and determine the most effective adoptive T cell therapy protocols in melanomas.

Effect of modulation of the hostile tumor microenvironment through adoptive transfer of IL-12 expressing MUC-16 targeted T cells on ovarian tumors in vivo.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2586-2586
Author(s):  
Alena A. Chekmasova ◽  
Samith Sandadi ◽  
David R. Spriggs ◽  
Renier J. Brentjens
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Model ◽  
Retroviral Vectors ◽  
Ovarian Tumors ◽  
Adoptive T Cell Therapy ◽  
Antitumor Efficacy ◽  
Ovarian Carcinomas ◽  
T Cell Therapy

2586 Background: T cells may be genetically modified to recognize tumor associated antigens (TAAs) through the introduction of genes encoding artificial T cell receptors termed chimeric antigen receptors (CARs). MUC16 (CA125) is an antigen over-expressed on ovarian carcinomas and a serum marker for the diagnosis of ovarian cancer. We have previously demonstrated enhanced antitumor efficacy of CAR+ T cells further modified to secrete IL-12. We therefore tested whether MUC-16 targeted T cells further modified to express IL-12 would exhibit an enhanced antitumor efficacy in a syngeneic immunocompetent tumor model of ovarian cancer. Methods: We have constructed SFG retroviral vectors encoding the second (4H11m28mz) generation CARs as well as IL-12 modified CAR (4H11m28mz/mIL12) targeted to the retained extra-cellular domain of MUC16, termed MUC-CD. We demonstrated an antitumor efficacy of these T cells in a syngeneic tumor model using the C57BL6 (B6) mice intraperitoneally (i.p.) injected with ID8(MUC-CD) tumor cells. Results: In our studies treatment of mice bearing established ID8(MUC-CD) ovarian tumor with MUC-CD specific T cells expressing IL-12 gene, in contrast to T cells targeted to MUC-CD alone, fully eradicate highly advanced intraperitoneal ovarian tumors. Significantly, we found that mice treated with 4H11m28mz/mIL12 T cells had increased number of modified T cells in the peritoneum at day 4 and 7 with increased recruitment of endogenous T cells to the site of the tumor when compared to controls and mice treated with 4H11m28mz T cells. The observed antitumor effect did not required prior lymphodepletion and was well tolerated in treated mice. Conclusions: CAR modified T cells targeted to the MUC-16 antigen efficiently eradicate orthotopic ovarian cancer in syngeneic immunocompetent mice with markedly enhanced antitumor efficacy seen in those mice treated with CAR+ T cells further modified to secrete IL-12. These data support future clinical trials utilizing adoptive T cell therapy in patients with relapsed ovarian cancer.

scholarly journals Nanoparticles for Enhanced Adoptive T Cell Therapies and Future Perspectives for CNS Tumors

2021 ◽  
Vol 12 ◽  
Author(s):  
Preethi Bala Balakrishnan ◽  
Elizabeth E. Sweeney
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Ex Vivo ◽  
Clinical Success ◽  
Hematologic Malignancies ◽  
Adoptive T Cell Therapy ◽  
Cns Tumors ◽  
T Cell Therapy ◽  
Cell Therapies

Adoptive T cell therapy has emerged as a revolutionary immunotherapy for treating cancer. Despite immense promise and clinical success in some hematologic malignancies, limitations remain that thwart its efficacy in solid tumors. Particularly in tumors of the central nervous system (CNS), T cell therapy is often restricted by the difficulty in intratumoral delivery across anatomical niches, suboptimal T cell specificity or activation, and intratumoral T cell dysfunction due to immunosuppressive tumor microenvironments (TMEs). Nanoparticles may offer several advantages to overcome these limitations of T cell therapy, as they can be designed to robustly and specifically activate T cells ex vivo prior to adoptive transfer, to encapsulate T cell stimulating agents for co-localized stimulation, and to be conjugated onto T cells for added functionality. This perspective highlights recent preclinical advances in using nanoparticles to enhance T cell therapy, and discusses the potential applicability and constraints of nanoparticle-enhanced T cells as a new platform for treating CNS tumors.

scholarly journals Inducible gene switches with memory in human T cells for cellular immunotherapy

2018 ◽  
Author(s):  
Deboki Chakravarti ◽  
Leidy D Caraballo ◽  
Benjamin H. Weinberg ◽  
Wilson W. Wong
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Activity ◽  
Adoptive T Cell Therapy ◽  
Cellular Immunotherapy ◽  
Antigen Receptors ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Gene Switches ◽  
Engineered T Cells

AbstractCell-based therapies that employ engineered T cells—including the expression of chimeric antigen receptors (CARs)—to target cancer cells have demonstrated promising responses in clinical trials. However, engineered T cell responses must be regulated to prevent severe side effects such as cytokine storms and off-target responses. Here we present a class of recombinase-based gene circuits that will enable inducible switching between two states of adoptive T cell therapy using an FDA-approved drug, creating a generalizable platform that can be used to control when and how strongly a gene is expressed. These circuits exhibit memory such that induced T cells will maintain any changes made even when the drug inducer is removed. This memory feature avoids prolonged drug inducer exposure, thus reducing the complexity and potential side effect associated with the drug inducer. We have utilized these circuits to control the expression of an anti-Her2-CAR, demonstrating the ability of these circuits to regulate CAR expression and T cell activity. We envision this platform can be extended to regulate other genes in T cell behavior for various adoptive T cell therapies.

scholarly journals Recent Advance in Antigen-Specific Immunotherapy for Acute Myeloid Leukemia

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Norimitsu Kadowaki ◽  
Toshio Kitawaki
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Specific Immunotherapy ◽  
Adoptive T Cell Therapy ◽  
Tumor Vaccines ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Dendritic Cell Vaccines ◽  
Acute Myeloid

Relapse after chemotherapy is inevitable in the majority of patients with acute myeloid leukemia (AML). Thus, it is necessary to develop novel therapies that have different antileukemic mechanisms. Recent advances in immunology and identification of promising leukemia-associated antigens open the possibilities for eradicating minimal residual diseases by antigen-specific immunotherapy after chemotherapy. Several methods have been pursued as immunotherapies for AML: peptide vaccines, granulocyte-macrophage colony-stimulating factor-secreting tumor vaccines, dendritic cell vaccines, and adoptive T cell therapy. Whereas immunogenicity and clinical outcomes are improving in these trials, severe adverse events were observed in highly avid engineered T cell therapies, indicating the importance of the balance between effectiveness and side effects in advanced immunotherapy. Such progress in inducing antitumor immune responses, together with strategies to attenuate immunosuppressive factors, will establish immunotherapy as an important armament to combat AML.

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