Engineering VHH-based Chimeric Antigen Receptor (CAR) T Cell Therapy for Solid Tumor Treatment PDF Download
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Author: Yushu Joy Xie
Publisher:
ISBN:
Category :
Languages : en
Pages : 154
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Book Description
Chimeric antigen receptor (CAR) T cells are a promising cancer therapeutic, as they can specifically redirect the cytotoxic function of a T cell to a chosen target of interest. CAR T cells have been successful in clinical trials against hematological cancers, but have experienced low efficacy against solid tumors for a number of reasons, including a paucity of tumor-specific antigens to target and a highly immunosuppressive solid tumor microenvironment. In chapter 2 of this thesis, we develop a strategy to target multiple solid tumor types through markers in their microenvironment. The use of single domain antibody (VHH)-based CAR T cells that recognize these markers circumvents the need for tumor-specific targets. Chapter 3 will describe methods to overcome the immunosuppressive microenvironment of solid tumors. Here, we have developed VHH-secreting CAR T cells that can modulate additional aspects of the tumor microenvironment, including the engagement of the innate immune system through secretion of a VHH against an inhibitor of phagocytosis. We show that this strategy of VHH-secretion by CAR T cells can lead to significant benefits in outcome. We also demonstrate that delivery of therapeutics by CAR T cells can improve the safety profile of the therapeutic. Chapter 4 of this thesis explores strategies to increase the targeting capacity of CAR T cells by building logic-gated CARs. Finally, chapter 5 will describe work in imaging CAR T cells specifically, longitudinally, and non-invasively through PET imaging. Our results demonstrate the flexibility of VHHs in CAR T cell engineering and the potential of VHH-based CAR T cells to target the tumor microenvironment, modulate the tumor microenvironment, and treat solid tumors.
Author: Yushu Joy Xie
Publisher:
ISBN:
Category :
Languages : en
Pages : 154
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Book Description
Chimeric antigen receptor (CAR) T cells are a promising cancer therapeutic, as they can specifically redirect the cytotoxic function of a T cell to a chosen target of interest. CAR T cells have been successful in clinical trials against hematological cancers, but have experienced low efficacy against solid tumors for a number of reasons, including a paucity of tumor-specific antigens to target and a highly immunosuppressive solid tumor microenvironment. In chapter 2 of this thesis, we develop a strategy to target multiple solid tumor types through markers in their microenvironment. The use of single domain antibody (VHH)-based CAR T cells that recognize these markers circumvents the need for tumor-specific targets. Chapter 3 will describe methods to overcome the immunosuppressive microenvironment of solid tumors. Here, we have developed VHH-secreting CAR T cells that can modulate additional aspects of the tumor microenvironment, including the engagement of the innate immune system through secretion of a VHH against an inhibitor of phagocytosis. We show that this strategy of VHH-secretion by CAR T cells can lead to significant benefits in outcome. We also demonstrate that delivery of therapeutics by CAR T cells can improve the safety profile of the therapeutic. Chapter 4 of this thesis explores strategies to increase the targeting capacity of CAR T cells by building logic-gated CARs. Finally, chapter 5 will describe work in imaging CAR T cells specifically, longitudinally, and non-invasively through PET imaging. Our results demonstrate the flexibility of VHHs in CAR T cell engineering and the potential of VHH-based CAR T cells to target the tumor microenvironment, modulate the tumor microenvironment, and treat solid tumors.
Author: Ken Young
Publisher: Frontiers Media SA
ISBN: 2889767914
Category : Medical
Languages : en
Pages : 153
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Book Description
Author: Andrew J Hou
Publisher:
ISBN:
Category :
Languages : en
Pages : 118
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Book Description
Adoptive T-cell therapy is a cancer treatment strategy where T cells from a cancer patient are harvested, modified ex vivo to target tumor cells, and subsequently reinfused back into the patient's body. Although remarkably successful against blood-based B-cell malignancies, efficacy has been limited against solid tumors, in large part due to the immunosuppressive tumor microenvironment (TME). Among the many inhibitory factors in the TME, transforming growth factor-beta (TGF-[Beta]) plays a prominent role in suppressing anti-tumor immunity through both direct inhibition of T-cell cytotoxicity, as well as recruitment and polarization of immunosuppressive cell types such as myeloid-derived suppressor cells and regulatory T cells. We therefore hypothesized that T-cell function in the solid TME could be potentiated by pairing tumor-targeting CARs with TGF-[Beta] CARs that program T-cell activation, rather than inhibition, in the presence of TGF-[Beta]. Wefirst verified that TGF-[Beta] CAR expression is neither counterproductive to cytotoxic T-cell function, nor does it pose a significant risk of toxicity. Pairing TGF-[Beta] CARs with tumor-specific TCRs or CARs did not significantly enhance therapeutic outcomes of adoptive T-cell transfer in preclinical models of melanoma and prostate cancer, warranting further engineering efforts. In models of glioblastoma, however, single-chain bispecific CAR-T cells targeting TGF-[Beta] and tumor antigen were not only more resistant to tumor-mediated dysfunction, but also remodeled the immune-cell composition of the tumor microenvironment to potentiate anti-tumor immunity.
Author: Eugenia Zah
Publisher:
ISBN:
Category :
Languages : en
Pages : 136
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Book Description
The recent FDA approval of CD19 chimeric antigen receptor (CAR) adoptive T-cell therapy for B-cell leukemias serves to highlight CAR-T cell therapy as a promising treatment approach for refractory cancers. More recently, adoptive transfer of T cells expressing CARs targeting B-cell maturation antigen (BCMA) has had numerous successes in clinical trial with 80-100% of multiple myeloma patients responding to treatment. However, CAR-T-cell therapy still faces several limitations including tumor antigen escape, a circumstance where tumor cells downregulate their surface antigen to avoid detection by CAR-T cells, and T-cell inhibition by cytokines such as transforming growth factor (TGF)- in the solid tumor environment. These factors can significantly limit the efficacy of CAR-T-cell therapy. To overcome antigen escape, we designed single-chain bispecific CARs (OR-gate CARs) capable of signaling in the presence of two antigens instead of one. Using rational design principles, we constructed and evaluated CD19-OR-CD20 CARs that are able to prevent tumor antigen escape by CD19- leukemia. We further demonstrate that unlike single-input CD19 CARs, CD19-OR-CD20 CARs also prevent the emergence of spontaneous CD19-downregulated tumors in vivo. In a second study, we describe the rapid design and characterization of BCMA-OR-CS1 CARs and demonstrate that BCMA-OR-CS1 CARs can be rationally engineered to prevent antigen escape by BCMA- as well as CS1- myeloma cells. Finally, we explore the utility of the TGF- CAR, a receptor capable of rewiring inhibitory TGF- signaling to an activating response, in improving CD20 CAR function in TGF- -rich environments. We evaluated three different bispecific targeting strategies, OR-gate CAR, DualCAR (co-expressing two receptors in one cells), and CARpool (pooling two different CAR-T cells), and demonstrate that TGF- CAR-T cells are able to shield neighboring CD20 CAR-T cells from the inhibitory effects of TGF- .
Author: Chi-Wei Man
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
Chimeric Antigen Receptor (CAR) T cell therapy is a revolutionary treatment option for cancer therapy, demonstrating widespread clinical success in treating hematological malignancies such as acute lymphoblastic leukemia and certain lymphomas. Despite its widespread success treating hematological malignancies, CAR T cells still struggle to treat solid tumors. One reason for this is the immunosuppressive tumor microenvironment. Expressed in certain tumors, Programmed Death-Ligand 1 (PD-L1) actively suppresses T cell activation and function. To both neutralize this immunoinhibitory effect and eliminate tumor cells, I used yeast display mediated directed evolution to engineer PDbody, derived from the monobody scaffold, to bind to PD-L1. I then employed PDbody as a SynNotch-gated CAR receptor to eliminate a triple-negative breast cancer model in vitro and slow tumor growth in vivo. CAR T cell therapy can also fail when tumors do not homogenously express the CAR target antigen. To combat this problem, I developed heat-inducible Cis-activated CAR (CisCAR) to allow CAR T cells to self-present their target antigen. I then used CisCAR to eliminate antigen-negative leukemic and breast cancer cells in vitro, demonstrating the universal applicability of this treatment strategy. Overall, this dissertation presents new methods that enhance CAR T cell therapy, enabling them to more effectively target a wider range of diseases.
Author: Alexandra E. Grier
Publisher:
ISBN:
Category :
Languages : en
Pages : 102
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Book Description
Adoptive T-cell therapy, particularly chimeric antigen receptor (CAR) therapy, is a revolutionary and quickly-evolving means of treating cancer patients who can no longer be helped by standard therapies. In multiple clinical trials, including our own at Seattle Children’s Hospital, CD19 CAR therapy for B-cell leukemia and lymphoma has achieved a complete remission rate of >90%. Unfortunately, in its present form, CAR therapy has had limited success against solid tumors. It is also not currently an option for patients who lack sufficient numbers of their own T-cells due to their disease or prior treatments. Thus, genome engineering strategies to overcome these limitations could be of great benefit to patients. We chose a two-pronged approach to achieve this goal: knock-out of the endogenous TCR and multiplex knock-out of the T-cell inhibitory checkpoints PD-1, Tim3, Lag3, and TIGIT. Knocking out these inhibitory checkpoint proteins specifically in the CAR T-cells will maintain the synergistic effects recently seen in combination monoclonal antibody therapy without the serious, sometimes fatal, immune-mediated side effects seen with systemic antibody therapy. To this end, we first developed a linear mRNA expression vector with a long, encoded poly(A) tail to allow transient delivery of nucleases such as TALENs or CRISPR to primary human cells in a consistent, clinically applicable, and scalable fashion. We then used IVT mRNA made from this vector to deliver a TALEN pair targeting the TCR locus to CD19 CAR T-cells, and demonstrated that removal of the endogenous TCR does not hinder CAR T-cell function in vitro or in vivo in a murine xenograft tumor model. Knockout of the endogenous TCR will facilitate production of an allogeneic CAR T-cell product to be used as a bridge to HSCT in patients who cannot receive autologous CAR therapy. Removal of the endogenous TCR will also add a measure of safety when creating CAR T-cells lacking inhibitory checkpoint proteins by preventing GvHD while retaining anti-tumor effects. These technologies and methods may allow a wider variety of patients to benefit from the recent advances in CAR T-cell therapy.
Author: Gert-Jan L. Kaspers
Publisher: CRC Press
ISBN: 9783718653874
Category : Medical
Languages : en
Pages : 458
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Book Description
The last ten years have seen the publication of a vast amount of data regarding cellular resistance to drugs in cancer cells. Recent studies have demonstrated that drug resistance assays appear to be predictive of clinical response and suggest that clinicians should now be considering the potential applications of these assays in the treatment of patients with hematological neoplasms. This collection of papers from the International Symposium on the Clinical Value of Drug Resistance Assays in Leukemia and Lymphoma, Amsterdam, 1992, provides a state-of-the-art discussion on drug resistance assays and their role in the design and individualization of treatment protocols.
Author: Ulrich Rothbauer
Publisher: MDPI
ISBN: 3036503781
Category : Science
Languages : en
Pages : 300
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Book Description
Nanobodies have become outstanding tools for biomedical research, diagnostics and therapy. Recent advances in the identification and functionalization of target-specific nanobodies now make nanobody-based approaches broadly available to many researches in the field. This book provides a compilation of original research articles and comprehensive reviews covering important and up to date aspects of research on nanobodies and their applications for immunoassays, proteomics, protein crystallization and in vitro and in vivo imaging.
Author: Muthupandian Saravanan
Publisher: Springer Nature
ISBN: 3030743306
Category : Medical
Languages : en
Pages : 362
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Book Description
Nanotechnology is an interdisciplinary research field that integrates chemistry, engineering, biology, and medicine. Nanomaterials offer tremendous opportunity as well as challenges for researchers. Of course, cancer is one of the world's most common health problems, responsible for many deaths. Exploring efficient anticancer drugs could revolutionize treatment options and help manage cancer mortality. Nanomedicine plays a significant role in developing alternative and more effective treatment strategies for cancer theranostics. This book mainly focuses on the emerging trends using nanomaterials and nanocomposites as alternative anticancer material’s. The book is divided into three main topic areas: how to overcome existing traditional approaches to combat cancer, applying multiple mechanisms to target the cancer cells, and how nanomaterials can be used as effective carriers. The contents highlight recent advances in interdisciplinary research on processing, morphology, structure, and properties of nanostructured materials and their applications to combat cancer.Cancer Nanotheranostics is comprehensive in that it discusses all aspects of cancer nanotechnology. Because of the vast amount of information, it was decided to split this material into two volumes. In the first volume of Cancer Nanotheranostics, we discuss the role of different nanomaterials for cancer therapy, including lipid-based nanomaterials, protein and peptide-based nanomaterials, polymer-based nanomaterials, metal-organic nanomaterials, porphyrin-based nanomaterials, metal-based nanomaterials, silica-based nanomaterials, exosome-based nanomaterials and nano-antibodies. In the second volume, we discuss the nano-based diagnosis of cancer, nano-oncology for clinical applications, nano-immunotherapy, nano-based photothermal cancer therapy, nano-erythrosomes for cancer drug delivery, regulatory perspectives of nanomaterials, limitations of cancer nanotheranostics, the safety of nano-biomaterials for cancer nanotheranostics, multifunctional nanomaterials for targeting cancer nanotheranostics, and the role of artificial intelligence in cancer nanotheranostics.
Author: Hilal Arnouk
Publisher:
ISBN: 9781839688690
Category : Cancer
Languages : en
Pages : 0
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Book Description
Recent advances in precision medicine and immuno-oncology have led to highly specific and efficacious cancer therapies such as monoclonal antibodies and immune checkpoint inhibitors (ICIs). This book provides an up-to-date overview of advances in the field of immuno-oncology. Chapters cover such topics as ICIs and how they mount a robust immune response against cancer cells as well as the response of ICIs to treatment predictive biomarkers and their potential immune-related adverse events (irAEs). Additionally, the book includes a comprehensive review of the powerful FDA-approved therapeutic agent doxorubicin, highlighting the molecular mechanisms behind doxorubicin's drug resistance and critical side effects.
