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Basics of Chimeric Antigen Receptor (CAR) Immunotherapy

Basics of Chimeric Antigen Receptor (CAR) Immunotherapy
A Book

by Mumtaz Y. Balkhi

  • Publisher : Academic Press
  • Release : 2019-07-31
  • Pages : 92
  • ISBN : 0128197471
  • Language : En, Es, Fr & De
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Basics of Chimeric Antigen Receptor (CAR) Immunotherapy presents the latest on how T cell adoptive immunotherapy has progressed in its ultimate goal of curing metastatic malignant cancers. Recent clinical data obtained with checkpoint receptor blockade inhibitors and chimeric antigen receptor (CAR) therapy has been especially promising, thus generating renewed hope that we may be on the verge of finally curing cancer. Over the years, huge progress has been made in controlling several stage IV metastasized cancers through the clinical application of checkpoint receptor inhibitory drugs and CAR-Therapy that has seen unprecedented interest in the immunotherapy field. Presents the first book to provide a basic understanding of chimeric antigen receptor (CARs) design, production and clinical application protocols Provides unique authority as the editor has worked directly with CARs Discusses the challenges encountered in actual clinical trials and how these challenges can be overcome Includes a full chapter on various challenges researchers should expect to encounter in the CAR-therapy field

Part I- Understanding Cancer Immunotherapy: A brief Review. Part II- “What is Chimeric Antigen Receptor (CAR) T- Cell Therapy?” An Emerging Cancer Treatment Modality.

Part I- Understanding Cancer Immunotherapy: A brief Review. Part II- “What is Chimeric Antigen Receptor (CAR) T- Cell Therapy?” An Emerging Cancer Treatment Modality.
A Book

by Dr. Hakim Saboowala

  • Publisher : Dr.Hakim Saboowala
  • Release : 2020-05-12
  • Pages : 129
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Part I- Understanding Cancer Immunotherapy: A brief Review. Immunotherapy, also called biologic therapy, is a type of cancer treatment that boosts the body's natural defenses to fight cancer. It uses substances made by the body or in a laboratory to improve or restore immune system function. Immunotherapy may work by: Stopping or slowing the growth of cancer cells Stopping cancer from spreading to other parts of the body Helping the immune system work better at destroying cancer cells There are several types of immunotherapy, including: Monoclonal antibodies and tumor-agnostic therapies Non-specific immunotherapies Oncolytic virus therapy T-cell therapy Cancer vaccines Part II- “What is Chimeric Antigen Receptor (CAR) T- Cell Therapy?” An Emerging Cancer Treatment Modality. Chimeric antigen receptor (CAR) T-cell therapy is an emerging cancer treatment modality in which the patients’ own immune cells are collected, genetically engineered to recognize a tumor-related target, expanded in vitro, and then reinfused to produce responses and prevent progression in a variety of malignancies (ie, adoptive cell transfer) Several types of adoptive cell transfer(ACT) are under investigation, but CAR T-cell therapy is the first to enter clinical practice. Like other technologies, CAR-T cell therapy has undergone a long development process in the past. Chimeric antigen receptor- (CAR-) T cell therapy is one of the most recent innovative immunotherapies and is rapidly evolving. At present, CAR-T cell therapy is developing rapidly, and many clinical trials have been established on a global scale, which has great commercial potential. I have endeavored to compile this E- Booklet into Two Parts i.e. Part I & Part II for better understanding of Chimeric antigen receptor (CAR) T-cell therapy, an emerging cancer treatment modality. In Part I, an effort has been made to describe Cancer Immunotherapy briefly whereas in Part II know about of CAR T-Cell Therapy-the first to enter clinical practice- has been embodied. Further it is attempted to describe toxicity of CAR-T cell therapy briefly and future development and opportunities for immunotherapy. …Dr. H. K. Saboowala. M.B.(Bom) .M.R.S.H.(London)

Chimeric Antigen Receptor (CAR) T-cell Immunotherapy for MUC1-positive Breast Cancer

Chimeric Antigen Receptor (CAR) T-cell Immunotherapy for MUC1-positive Breast Cancer
A Book

by Artemis Gavriil

  • Publisher : Unknown Publisher
  • Release : 2018
  • Pages : 129
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Chimeric Antigen Receptor T-Cell Therapies for Cancer E-Book

Chimeric Antigen Receptor T-Cell Therapies for Cancer E-Book
A Practical Guide

by Daniel W. Lee,Nirali N. Shah

  • Publisher : Elsevier Health Sciences
  • Release : 2019-11-30
  • Pages : 244
  • ISBN : 0323755976
  • Language : En, Es, Fr & De
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From patient referral to post-therapy management, Chimeric Antigen Receptor (CAR) T-Cell Therapies for Cancer: A Practical Guide presents a comprehensive view of CAR modified T-cells in a concise and practical format. Providing authoritative guidance on the implementation and management of CAR T-cell therapy from Drs. Daniel W. Lee and Nirali N. Shah, this clinical resource keeps you up to date on the latest developments in this rapidly evolving area. Covers all clinical aspects, including patient referral, toxicities management, comorbidities, bridging therapy, post-CAR monitoring, and multidisciplinary approaches to supportive care. Includes key topics on associated toxicities such as predictive biomarkers, infections, and multidisciplinary approaches to supportive care. Presents current knowledge on FDA approved CAR T-cell products as well as developments on the horizon. Editors and authors represent leading investigators in academia and worldwide pioneers of CAR therapy.

Immunotherapy Using Chimeric Antigen Receptor Macrophage

Immunotherapy Using Chimeric Antigen Receptor Macrophage
A Book

by Peng Fei Huang

  • Publisher : Unknown Publisher
  • Release : 2019
  • Pages : 44
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Chimeric antigen receptor (CAR) T cell immunotherapy has become one of the most prominent and leading cancer therapies due to its remarkable success in targeting hematological malignancies. Unfortunately, CAR-T cell immunotherapy has not had the same amount of success in solid tumors due to the challenging tumor's immunosuppressive microenvironment. Therefore, we hypothesize the use of macrophages as a vessel for CAR immunotherapy due to their associate with tumors as TAMs and also the tumors ability to secrete various chemokines that can attract myeloid cells to the tumor site. THP-1 a monocytic cell line that represents a monocyte/macrophage model was transduced with an anti-CD19 scFv CAR construct. K562 a leukemia cell line that represents hematological malignancies and H460 a lung cancer cell line that represents solid tumors were transduced to overexpress the surface marker CD19. THP-1 clones expressing the anti-CD19 CAR construct were cocultured with the two tumor cell lines, which demonstrated the ability of the THP-1 CARs to specifically targeted and lysis the tumor cells that overexpressed the CD19 surface marker. Upon CAR activation, THP-1 cells were polarized towards the M1 classical activated phenotype due to the increase in expression of TNF-[alpha], IL-1[beta], IL-6, IL-12[beta], CXCl10, HLA-DR, and CD86. Additionally, THP-1 cells did not show any change in the M2 alternative activated markers of IL10, TFG[beta], CCL18, CCL22, CD206, and CD204 to suggest polarization towards the M2 phenotype. As a result, this study validates the proof of concept that macrophages could potentially be a vessel for CAR immunotherapy.

Defining Optimal T Cell Characteristics for Pediatric Chimeric Antigen Receptor (CAR) T Cell Trials

Defining Optimal T Cell Characteristics for Pediatric Chimeric Antigen Receptor (CAR) T Cell Trials
A Book

by Julie M. Rivers

  • Publisher : Unknown Publisher
  • Release : 2017
  • Pages : 23
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Background: Engineered chimeric antigen receptor (CAR) T cells have emerged as a powerful, highly personalized immunotherapy in pediatric cancer. Early phase clinical trials using CAR T cells targeting CD19 have resulted in complete response (CR) rates as high as 93% in children with relapsed and refractory acute lymphoblastic leukemia (ALL). Despite this success, there are many challenges that must be overcome before CAR T cell therapy can be used routinely in pediatric ALL or other malignancies. Objective: To develop novel biomarkers that will identify patients at high risk for poor product expansion, treatment failure and/or toxicity with current immunotherapy protocols and that may ultimately help improve manufacturing methods to produce safer and more effective CAR T cells. Design/Methods: Using flow cytometry, we evaluated T cell characteristics (memory phenotype, cytokine production, presence of markers of activation/exhaustion) of starting products in 43 patients enrolled and treated in a Phase I clinical trial, PLAT-02. Potential predictors of poor product expansion were assessed using the Wilcoxon Rank Sum Test. Results: A higher percentage of cells producing cytokines and expressing PD-1 in CD4 starting products was associated with poor expansion. Poor expansion was not associated with patient toxicities or outcomes. Discussion: Increased cytokine production and PD-1 expression suggest a more differentiated, effector-like phenotype of starting products that subsequently experience poor expansion, consistent with preclinical data, although numbers are limited. Conclusion: Ongoing correlative biology studies will be important in future immunotherapy trials as we seek to identify biomarkers that predict product expansion, toxicities and outcomes.

Fast Facts: CAR T-Cell Therapy

Fast Facts: CAR T-Cell Therapy
Insight into current and future applications

by R.J. Buka,A.J. Kansagra

  • Publisher : Karger Medical and Scientific Publishers
  • Release : 2021-01-26
  • Pages : 72
  • ISBN : 3318067423
  • Language : En, Es, Fr & De
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Chimeric antigen receptor (CAR) T cells are genetically engineered immune cells that can seek out and destroy cancer cells. The results from their use in cancer immunotherapy have been very promising, but treatment is often associated with frequent, serious short-term toxicities. 'Fast Facts: CAR-T Therapy' explains what CAR T cells are and how they were developed, discusses the results of clinical trials and the management of toxicities, and outlines future improvements and applications. It is ideal reading for any healthcare professional wanting to know more about this exciting therapeutic field. Table of Contents: • CAR T cells • Clinical application • Practical aspects • Future directions

NK Cell-Based Cancer Immunotherapy

NK Cell-Based Cancer Immunotherapy

by Francisco Borrego,Susana Larrucea,Rafael Solana,Raquel Tarazona

  • Publisher : Frontiers Media SA
  • Release : 2016-09-08
  • Pages : 129
  • ISBN : 2889199347
  • Language : En, Es, Fr & De
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Natural killer (NK) cells are innate lymphoid cells that have a significant role in regulating the defenses against cancer development and certain viral infections. They are equipped with an array of activating and inhibitory receptors that stimulate or diminish NK cell activity, respectively. Inhibitory receptors include, among others, the MHC class I ligands killer cell immunoglobulin-like receptors (KIR) in humans, and members of the Ly49 family of receptors in mice, and CD94/NKG2A. Activating receptors include cytokine and chemokine receptors, and those that interact with ligands expressed on target cells, such as the natural cytotoxicity receptors or NCRs (NKp30, NKp44 and NKp46), NKG2D, CD244 and DNAM-1. In addition, NK cells express Fc?RIIIA or CD16, the receptor that exerts antibody-dependent cell mediated cytotoxicity (ADCC). NK cells also express the death ligands FasL and TRAIL. The killing or sparing of target cells depends on the integration of distinct signals that originate from NK cell receptors. NK cells spare healthy cells that express normal levels of MHC class I molecules and low amounts of stress-induced self-molecules, whereas they kill target cells that down-regulate MHC class I molecules and/or up-regulate stress-induced self-molecules. The latter are common signatures of virus-infected cells and tumors. All the accumulated knowledge on NK cell biology, along with many clinical observations, is driving multiple efforts to improve the arsenal of NK cell-based therapeutic tools in the fight against malignant diseases. Indeed, NK cell-based immunotherapy is becoming a promising approach for the treatment of many cancers. It is well known that NK cells have a significant role in the anti-tumor effect of therapeutic antibodies that use ADCC as a mechanism of action. In addition to this, administration of autologous and allogeneic NK cells after activation and expansion ex vivo is used in the treatment of cancer. Moreover, adoptive transfer of NK cell lines has been tested in humans, and genetically modified NK cells expressing chimeric antigen receptors are being studied in preclinical models for potential use in the clinic.

Targeting and Elimination of T Cell Subpopulations by Chimeric Antigen Receptor-modified T Cells

Targeting and Elimination of T Cell Subpopulations by Chimeric Antigen Receptor-modified T Cells
A Book

by Stela Petkova

  • Publisher : Unknown Publisher
  • Release : 2021
  • Pages : 129
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Chimeric antigen receptors (CARs) demonstrated a high potential for the elimination of tumor cells in cancer immunotherapy. The first successful application of CAR-expressing T cells aimed at the elimination of B cells in hematological malignancies. However, despite being a breakthrough, which highlighted the potential of the CAR T cell technology, its application in targeting T cells currently has limitations. On the one hand, it is the limited choice of target molecules that are presented on malignant cells, but not on healthy cells. On the other hand, the design of the signaling componen...

Immunotherapy of Solid Tumors: Multimodal Imaging Strategies for Chimeric Antigen Receptor T Cell Tracking in the Tumor Microenvironment

Immunotherapy of Solid Tumors: Multimodal Imaging Strategies for Chimeric Antigen Receptor T Cell Tracking in the Tumor Microenvironment
A Book

by Janina Henze

  • Publisher : Unknown Publisher
  • Release : 2021
  • Pages : 129
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Immunotherapy is an emerging building block of modern oncology, after chimeric antigen receptor (CAR) T cells demonstrated groundbreaking survival rates in hematological malignancies. However, therapy success in more common solid tumors has not been achieved yet, due to a variety of obstacles, such as a limited availability of suitable targets and decreased CAR T cells trafficking to the tumor. One of these barriers is the tumor microenvironment (TME), which is most pronounced in pancreatic ductal adenocarcinoma (PDAC). Combinatorial 2D and 3D preclinical multimodal imaging and cell trackin...

Gene and Cellular Immunotherapy for Cancer

Gene and Cellular Immunotherapy for Cancer
A Book

by Armin Ghobadi

  • Publisher : Springer Nature
  • Release : 2022
  • Pages : 129
  • ISBN : 303087849X
  • Language : En, Es, Fr & De
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Fast Facts: CAR T-Cell Therapy

Fast Facts: CAR T-Cell Therapy
Insight into current and future applications

by Richard J. Buka,Ankit J. Kansagra

  • Publisher : Karger Medical and Scientific Publishers
  • Release : 2021-02-28
  • Pages : 72
  • ISBN : 3318067415
  • Language : En, Es, Fr & De
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Chimeric antigen receptor (CAR) T cells are genetically engineered immune cells that can seek out and destroy cancer cells. The results from their use in cancer immunotherapy have been very promising, but treatment is often associated with frequent, serious short-term toxicities. 'Fast Facts: CAR-T Therapy' explains what CAR T cells are and how they were developed, discusses the results of clinical trials and the management of toxicities, and outlines future improvements and applications. It is ideal reading for any healthcare professional wanting to know more about this exciting therapeutic field. Table of Contents: • CAR T cells • Clinical application • Practical aspects • Future directions

Global Epidemiology of Cancer

Global Epidemiology of Cancer
Diagnosis and Treatment

by Jahangir Moini,Nicholas G. Avgeropoulos,Craig Badolato

  • Publisher : John Wiley & Sons
  • Release : 2022-03-22
  • Pages : 656
  • ISBN : 1119817188
  • Language : En, Es, Fr & De
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GLOBAL EPIDEMIOLOGY OF CANCER Cancer is the second highest cause of death in the United States, and a leading cause of death globally. Our goals are to discuss the global epidemiology of various cancers, with detailed information on their prevalence, incidence, and clinical considerations. Epidemiology is the key to understanding the mortality and morbidity of cancer, and how we can prevent, diagnose, and treat the disease. Prevention of cancer is essential for saving lives. Prevalence and incidence of cancer are key factors that each government and population must be aware of. Advances in the study of cancer occur on a regular basis, and this book provides the latest insights about relationships between the disease and stem cells, tumorigenesis, molecular interactions, pathways, channels, and immunity. Global Epidemiology of Cancer: Diagnosis and Treatment meets the needs of readers by providing current information about epidemiology (including molecular epidemiology), diagnosis, and treatment. Providing logical, step-by-step information on various cancers, this book consolidates all of the most up-to-date information and data from verified studies on all different types of cancers in the United States and throughout the world. Chapters are presented so that each includes an overview, clinical manifestations, epidemiology, pathophysiology, etiology and risk factors, diagnosis, treatment, prevention, and prognosis. Global Epidemiology of Cancer: Diagnosis and Treatment will be invaluable to graduate and postgraduate students, including medical students; nurses; physician assistants; residents in oncology; public health students and allied health students.

Verzeichnis der Adressen unserer im Militärdienst stehenden Mitbrüder [der thüringischen Franziskanerprovinz].

Verzeichnis der Adressen unserer im Militärdienst stehenden Mitbrüder [der thüringischen Franziskanerprovinz].
A Book

by Anonim

  • Publisher : Unknown Publisher
  • Release : 1917
  • Pages : 46
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Genome Engineering to Expand Applications of Human T-cell Immunotherapy

Genome Engineering to Expand Applications of Human T-cell Immunotherapy
A Book

by Alexandra E. Grier

  • Publisher : Unknown Publisher
  • Release : 2017
  • Pages : 102
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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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.

Gene and Cellular Immunotherapy for Cancer

Gene and Cellular Immunotherapy for Cancer
A Book

by Armin Ghobadi,John F. DiPersio

  • Publisher : Humana
  • Release : 2021-12-20
  • Pages : 378
  • ISBN : 9783030878481
  • Language : En, Es, Fr & De
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Clinical and preclinical exploration of gene and cellular immunotherapy have seen rapid growth and interest with the development and approval of five Chimeric Antigen Receptor T-cell (CAR-T) products for lymphoma and myeloma and one Bispecific T-Cell Engager (BiTE) for acute lymphoblastic leukemia (ALL). These advances have dramatically improved the management of patients with relapsed refractory lymphoma, myeloma and leukemia. Gene and Cellular Immunotherapy for Cancer offers readers a comprehensive review of current cellular and gene-based immunotherapies. Divided into eighteen cohesive chapters, this book provides an in-depth and detailed look into cellular-based immunotherapies including CAR-T, TCR-T, TIL, Viral CTLs, NK cells in addition to T/NK cell engagers, focusing on their historical perspectives, biology, development and manufacturing, toxicities and more. Edited by two leading experts on gene and cellular immunotherapy, the book will feature chapters written by a diverse collection of recognized and up-and-coming experts and researchers in the field, providing oncologists, immunologists, researchers and clinical and basic science trainees with a bench to bedside view of the latest developments in the field.

Clinical Applications of Natural Killer Cells

Clinical Applications of Natural Killer Cells
A Book

by Yui Harada

  • Publisher : Unknown Publisher
  • Release : 2017
  • Pages : 129
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Natural killer (NK) cells are an essential component of the innate immune system, and they play a crucial role in immunity against malignancies. Recent advances in our understanding of NK cell biology have paved the way for new therapeutic strategies based on NK cells for the treatment of various cancers. In this section, we will focus on NK cell immunotherapy, including the enhancement of antibody-dependent cellular cytotoxicity, the manipulation of receptor-mediated activation, inclusion criteria based on killer cell immunoglobulin-like receptor (KIR) ligand mismatches, and adoptive immunotherapy with ex vivo expanded chimeric antigen receptor (CAR)-engineered or engager-modified NK cells. In contrast to T lymphocytes, donor NK cells do not attack any recipient tissues based on allogeneic human leukocyte antigens (HLAs), suggesting that NK-mediated antitumor effects may be achieved without the risk of graft-versus-host disease (GvHD). Despite reports of clinical efficacy, the application of NK cell immunotherapy is limited. Developing strategies for manipulating NK cell products, host factors, and tumor targets are thus current subjects of diligent study. Research into the biology of NK cells has indicated that NK cell immunotherapy has the potential to become the forefront of cancer immunotherapy in the coming years.

Endogenous Leukocyte Activation by Chimeric Antigen Receptor T Cell Immunotherapy

Endogenous Leukocyte Activation by Chimeric Antigen Receptor T Cell Immunotherapy
A Book

by Paul Spear

  • Publisher : Unknown Publisher
  • Release : 2013
  • Pages : 412
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Many protocols for adoptive T cell therapy (ACT) include preparative conditioning strategies to deplete host lymphocytes prior to T cell infusion. Total body irradiation and high-dose chemotherapy regimens not only relieve immunosuppression, but increase persistence of the transferred T cells in the host. These preconditioning regimens appear to correlate with improved clinical responses following adoptive T cell therapy. However, they can also result in the death of healthy cells and reduce the quality of life for patients. In addition, some clinical trials employing host conditioning strategies in combination with adoptive T cell transfer have demonstrated tumor persistence and relapse as a result of the outgrowth of antigenic variants. Harnessing endogenous lymphocytes is one method to broaden the tumor-specific T cell repertoire and eliminate tumor cells that have lost the targeted antigen following adoptive T cell therapy. Recent evidence suggests that transferred T cells may eradicate tumors without the need for prior conditioning, indicating that T cell therapies can enhance tumor elimination by relieving immunosuppression and promoting endogenous immunity. Collectively, the data presented in this thesis challenge the popular paradigm that lymphodepleting regimens are crucial for optimal efficacy of all ACTs. NKG2D chimeric antigen receptor (CAR) T cell therapy mounted robust anti-tumor immunity in unconditioned (immune intact) hosts, and this therapy harnessed endogenous macrophage and T cell anti-tumor immunity for superior elimination of ovarian tumors. Moreover, these data suggest that endogenous immunity broadens the specificity of the anti-tumor immune response and is critical for the control of antigenic tumor variants. The data also elucidate unique effector mechanisms employed by the transfused CD8 and CD4+ T cells in awakening endogenous macrophage and T cell immunity. These findings advance the T cell therapy field by improving the understanding of the mechanisms that are required for effective adoptive T cell therapy in unconditioned patients.

Harnessing Natural Killer Cell Receptors for Tumor Immunotherapy

Harnessing Natural Killer Cell Receptors for Tumor Immunotherapy
A Book

by Ming-Ru Wu

  • Publisher : Unknown Publisher
  • Release : 2015
  • Pages : 310
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Despite all the efforts and progress in cancer research, cancer remains a devastating disease. After more than 120 years of research, immunotherapy provides a realistic hope to cure cancer. Several formats of immunotherapy, such as immune-checkpoint-blockade antibodies and a bispecific T cell engager (BiTE) have been approved by the FDA. Immunotherapies that harness T cell effector functions will likely be the mainstream of cancer therapy in the near future. Chimeric antigen receptor (CAR) T cell therapies and BiTE therapies have shown curative and potential durable clinical efficacy in several clinical trials. However, the majority of pre-clinical and clinical development of CARs and BiTEs focuses on targeting hematological malignancies. CARs and BiTEs that can target solid tumors and have the potential to target multiple tumor types are rare. Furthermore, these pan-tumor targeting CARs and BiTEs in preclinical and clinical development generally target tumor associated antigens, which are also expressed by normal tissues and can potentially cause side effects. This thesis aims to describe studies of new CARs and BiTEs that can target multiple tumor types, including hematological malignancies and solid tumors, with high anti-tumor specificity. We aim to accomplish this goal by harnessing the pan-tumor recognition ability of natural killer (NK) cell receptors. Our data demonstrate that NK cell receptors can be harnessed for creating CARs and BiTEs. NKp30 based-, DNAM-1 based-, and B7H6-specific single-chain variable-fragment (scFv) based-CARs all exhibit the ability to recognize and kill multiple ligand+ tumor types in vitro and provide therapeutic efficacy in murine tumor models in vivo. A B7H6-specific BiTE also triggers T cells to kill multiple B7H6+ tumor types and mediates therapeutic efficacy in murine tumor models in vivo, including models of lymphoma, melanoma, and ovarian cancer. Harnessing NK cell receptors for creating CAR and BiTE therapies enables us to combine the best features of the two cell types, which are pan-tumor recognition of NK cells and potent effector functions of T cells, for designing effective immunotherapies. These approaches also demonstrate that bio-inspired engineering is efficient and effective. The CARs and BiTEs developed in this thesis have high translational values and have the potential to be further developed into clinical usage. In the future, by further harnessing the advances in genome engineering and synthetic biology, we will further enhance our ability to improve tumor immunotherapy and eventually unleash the full power of immunotherapy.

The Regulatory Landscape of CAR T Cell Dysfunction

The Regulatory Landscape of CAR T Cell Dysfunction
A Book

by David George Gennert

  • Publisher : Unknown Publisher
  • Release : 2021
  • Pages : 129
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Chimeric Antigen Receptor (CAR) T cells have emerged as a promising immunotherapy strategy to target cancer in a subset of patients. T cell exhaustion presents a significant barrier to the progress of CAR T cell therapy development and efficacy. We use a human CAR T cell model system, utilizing the non-exhausting CD19-targeting CD19-28z CAR T cells and the in vitro exhausting GD2-targeting HA-28z CAR T cells, to investigate the genetic interactions and regulation underlying CAR T cell exhaustion and dysfunction. We nominate regulatory transcription factors and enhancer loci that control the expression of exhaustion-associated and -promoting genes and perturb these regulatory networks to modulate the exhaustion phenotype and prevent T cells from exhibiting the hallmarks of exhaustion.