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Current Treatment Options in Oncology Feb 2022The therapeutic armamentarium has significantly expanded since the approval of various CD19-targeting chimeric antigen receptor T cell (CAR-T) therapies in non-Hodgkin... (Review)
Review
The therapeutic armamentarium has significantly expanded since the approval of various CD19-targeting chimeric antigen receptor T cell (CAR-T) therapies in non-Hodgkin lymphoma (NHL). These CAR-Ts are patient-specific and require a complex, resource, and time-consuming process. While this appears promising, autologous CAR-Ts are limited due to the lack of accessibility, manufacturing delays, and variable product quality. To overcome these, allogeneic (allo) CARs from healthy donors appear appealing. These can be immediately available as "off the shelf" ready-to-use products of standardized and superior quality exempt from the effects of an immunosuppressive tumor microenvironment and prior treatments, and potentially with lower healthcare utilization using industrialized scale production. Allogeneic CARs, however, are not devoid of complications and require genomic editing, especially with αβ T cells to avoid graft versus host disease (GvHD) and allo-rejection by the recipient's immune system. Tools for genomic editing such as TALEN and CRISPR provide promise to develop truly "off the shelf" universal CARs and further advance the field of cellular immunotherapy. Several allogeneic CARs are currently in early phase clinical trials, and preliminary data is encouraging. Longer follow-up is required to truly assess the feasibility and safety of these techniques in the patients. This review focuses on the strategies for developing allogeneic CARs along with cell sources and clinical experience thus far in lymphoma.
Topics: Antigens, CD19; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; Lymphoma; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Tumor Microenvironment
PubMed: 35212892
DOI: 10.1007/s11864-021-00920-6 -
Seminars in Hematology Jul 2020The introduction of chimeric antigen receptor (CAR) T-cell therapy in acute lymphoblastic leukemia (ALL) has dramatically altered the landscape of treatment options... (Review)
Review
The introduction of chimeric antigen receptor (CAR) T-cell therapy in acute lymphoblastic leukemia (ALL) has dramatically altered the landscape of treatment options available to children and adults with ALL. With complete remission induction rates exceeding 70% in most trials and FDA approval of one CD19 CAR T-cell construct in ALL, CAR T-cell therapy has become a mainstay in the ALL treatment algorithm for those with relapsed/refractory disease. Despite the high remission induction rate, with growing experience using CAR T-cell therapy in ALL, a host of barriers to maintaining long-term durable remissions have been identified. Specifically, relapse after, resistance to, or loss of long-term CAR T-cell persistence may all hinder CAR T-cell efficacy. In this review, we provide an overview of the current limitations which inform the design of the next generation of CAR T-cells and discuss advances in CAR T-cell engineering aimed to improve upon outcomes with CAR T-cell-based therapy in ALL.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen
PubMed: 33256900
DOI: 10.1053/j.seminhematol.2020.07.002 -
Current Neurology and Neuroscience... Dec 2023To outline the spectrum of neurotoxicity seen with approved immunotherapies and in pivotal clinical trials including immune checkpoint inhibitors, chimeric antigen... (Review)
Review
PURPOSE OF REVIEW
To outline the spectrum of neurotoxicity seen with approved immunotherapies and in pivotal clinical trials including immune checkpoint inhibitors, chimeric antigen receptor T-cell therapy, vaccine therapy, and oncolytic viruses.
RECENT FINDINGS
There has been an exponential growth in new immunotherapies, which has transformed the landscape of oncology treatment. With more widespread use of cancer immunotherapies, there have also been advances in characterization of its associated neurotoxicity, research into potential underlying mechanisms, and development of management guidelines. Increasingly, there is also mounting interest in long-term neurologic sequelae. Neurologic complications of immunotherapy can impact every aspect of the central and peripheral nervous system. Early recognition and treatment are critical. Expanding indications for immunotherapy to solid and CNS tumors has led to new challenges, such as how to reliably distinguish neurotoxicity from disease progression. Our evolving understanding of immunotherapy neurotoxicity highlights important areas for future research and the need for novel immunomodulatory therapeutics.
Topics: Humans; Immunotherapy, Adoptive; Immunotherapy; Neoplasms
PubMed: 37938472
DOI: 10.1007/s11910-023-01315-w -
International Journal of Molecular... Jan 2022Despite significant progress in recent years, the therapeutic approach of the multiple different forms of human cancer often remains a challenge. Besides the... (Review)
Review
Despite significant progress in recent years, the therapeutic approach of the multiple different forms of human cancer often remains a challenge. Besides the well-established cancer surgery, radiotherapy and chemotherapy, immunotherapeutic strategies gain more and more attention, and some of them have already been successfully introduced into the clinic. Among these, immunotherapy based on natural killer (NK) cells is considered as one of the most promising options. In the present review, we will expose the different possibilities NK cells offer in this context, compare data about the theoretical background and mechanism(s) of action, report some results of clinical trials and identify several very recent trends. The pharmaceutical industry is quite interested in NK cell immunotherapy, which will benefit the speed of progress in the field.
Topics: Animals; Antigens, Neoplasm; Cell- and Tissue-Based Therapy; Disease Management; Disease Susceptibility; Genetic Engineering; Humans; Immunotherapy; Immunotherapy, Adoptive; Killer Cells, Natural; Neoplasms; Prognosis; Treatment Outcome
PubMed: 35054985
DOI: 10.3390/ijms23020797 -
Journal of Cellular and Molecular... Dec 2023Chimeric antigen receptor-T-cell (CAR-T-cell) therapy is a novel immunotherapy with encouraging results for treatment of relapsed/refractory haematologic malignancies.... (Review)
Review
Chimeric antigen receptor-T-cell (CAR-T-cell) therapy is a novel immunotherapy with encouraging results for treatment of relapsed/refractory haematologic malignancies. With increasing use, our understanding of immune-mediated side effects such as cytokine release syndrome and neurotoxicity has improved; nevertheless, prolonged haematologic toxicity (PHT), with a high incidence rate, remains underrecognized. Owing to heterogeneity in populations, the CAR-T cells used and diseases treated as well as differences in the definition of PHT, its rate, risk factors and management vary across studies. In this review, we provide a narrative of PHT occurring in patients following CAR-T-cell therapy; evidence of PHT treatment strategies is also presented, with the aim of contributing to systematic understanding of PHT.
Topics: Humans; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; Immunotherapy, Adoptive; Immunotherapy; Hematologic Neoplasms; Cell- and Tissue-Based Therapy
PubMed: 37702530
DOI: 10.1111/jcmm.17930 -
Frontiers in Immunology 2024Adoptive cell therapy (ACT) comprises different strategies to enhance the activity of T lymphocytes and other effector cells that orchestrate the antitumor immune... (Review)
Review
Adoptive cell therapy (ACT) comprises different strategies to enhance the activity of T lymphocytes and other effector cells that orchestrate the antitumor immune response, including chimeric antigen receptor (CAR) T-cell therapy, T-cell receptor (TCR) gene-modified T cells, and therapy with tumor-infiltrating lymphocytes (TILs). The outstanding results of CAR-T cells in some hematologic malignancies have launched the investigation of ACT in patients with refractory solid malignancies. However, certain characteristics of solid tumors, such as their antigenic heterogeneity and immunosuppressive microenvironment, hamper the efficacy of antigen-targeted treatments. Other ACT modalities, such as TIL therapy, have emerged as promising new strategies. TIL therapy has shown safety and promising activity in certain immunogenic cancers, mainly advanced melanoma, with an exciting rationale for its combination with immune checkpoint inhibitors. However, the implementation of TIL therapy in clinical practice is hindered by several biological, logistic, and economic challenges. In this review, we aim to summarize the current knowledge, available clinical results, and potential areas of future research regarding the use of T cell therapy in patients with solid tumors.
Topics: Humans; Melanoma; Immunotherapy, Adoptive; Lymphocytes, Tumor-Infiltrating; T-Lymphocytes; Cell- and Tissue-Based Therapy; Tumor Microenvironment
PubMed: 38550594
DOI: 10.3389/fimmu.2024.1352805 -
Cancer Control : Journal of the Moffitt... 2024Chimeric antigen receptor T cell therapy is used to treat hematological malignancies which are refractory to standard therapy. It is a form of immunotherapy in which a... (Review)
Review
Chimeric antigen receptor T cell therapy is used to treat hematological malignancies which are refractory to standard therapy. It is a form of immunotherapy in which a patient's T cells are programmed to act against tumor cells. We discuss the process of manufacturing CAR-T cells, the common side effects of therapy, and the recent emerging risk of T-cell malignancies after treatment.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes; Hematologic Neoplasms; Receptors, Antigen, T-Cell
PubMed: 38910268
DOI: 10.1177/10732748241263713 -
Expert Review of Pharmacoeconomics &... Dec 2019: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and is a clinically heterogeneous disease. Treatment pathways for DLBCL are diverse and... (Review)
Review
: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and is a clinically heterogeneous disease. Treatment pathways for DLBCL are diverse and integrate established and novel therapies.: We review the cost burden of DLBCL and the cost-effectiveness of DLBCL management including precision and cellular medicine. We utilized Medical Subject Heading (MeSH) terms and keywords to search the National Library of Medicine online MEDLINE database (PubMed) for articles related to cost, cost burden, and cost-of-illness of DLBCL and cost-effectiveness of DLBCL management strategies published in English as of June 2019.: Available and developing DLBCL therapies offer improved outcomes and often curative treatment at considerable financial expense, and the total cost burden for DLBCL management is substantial for patients and the healthcare system. In the era of personalized medicine, CAR T cells and targeted therapies provide exciting avenues for current and future DLBCL care and can further increase treatment cost. Determinations of cost and cost-effectiveness in DLBCL treatment pathways should continue to guide care providers and systems in identifying cost reduction strategies to provide appropriate therapies to the greatest number of patients in treating DLBCL.
Topics: Cost of Illness; Cost-Benefit Analysis; Humans; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Molecular Targeted Therapy; Precision Medicine
PubMed: 31623476
DOI: 10.1080/14737167.2019.1680288 -
Frontiers in Immunology 2023Chimeric antigen receptor (CAR) T cells therapy has emerged as a significant breakthrough in adoptive immunotherapy for hematological malignancies with FDA approval.... (Review)
Review
Chimeric antigen receptor (CAR) T cells therapy has emerged as a significant breakthrough in adoptive immunotherapy for hematological malignancies with FDA approval. However, the application of CAR-T cell therapy in solid tumors remains challenging, mostly due to lack of suitable CAR-T target antigens, insufficient trafficking and extravasation to tumor sites, and limited CAR-T survival in the hostile tumor microenvironment (TME). Herein, we reviewed the development of CARs and the clinical trials in solid tumors. Meanwhile, a "key-and-lock" relationship was used to describe the recognition of tumor antigen via CAR T cells. Some strategies, including dual-targets and receptor system switches or filter, have been explored to help CAR T cells matching targets specifically and to minimize on-target/off-tumor toxicities in normal tissues. Furthermore, the complex TME restricts CAT T cells activity through dense extracellular matrix, suppressive immune cells and cytokines. Recent innovations in engineered CARs to shield the inhibitory signaling molecules were also discussed, which efficiently promote CAR T functions in terms of expansion and survival to overcome the hurdles in the TME of solid tumors.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Neoplasms; Antigens, Neoplasm; Cell- and Tissue-Based Therapy; Tumor Microenvironment
PubMed: 36761757
DOI: 10.3389/fimmu.2023.1045024 -
International Journal of Cancer Nov 2023The clinical application of chimeric antigen receptor (CAR) T-cell therapy has rapidly changed the treatment options for terminally ill patients with defined blood-borne... (Review)
Review
The clinical application of chimeric antigen receptor (CAR) T-cell therapy has rapidly changed the treatment options for terminally ill patients with defined blood-borne cancer types. However, CAR T-cell therapy can lead to severe therapy-associated toxicities including CAR-related hematotoxicity, ON-target OFF-tumor toxicity, cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Just as CAR T-cell therapy has evolved regarding receptor design, gene transfer systems and production protocols, the management of side effects has also improved. However, because of measures taken to abrogate adverse events, CAR T-cell viability and persistence might be impaired before complete remission can be achieved. This has fueled efforts for the development of extrinsic and intrinsic strategies for better control of CAR T-cell activity. These approaches can mediate a reversible resting state or irreversible T-cell elimination, depending on the route chosen. Control can be passive or active. By combination of CAR T-cells with T-cell inhibiting compounds, pharmacologic control, mostly independent of the CAR construct design used, can be achieved. Other strategies involve the genetic modification of T-cells or further development of the CAR construct by integration of molecular ON/OFF switches such as suicide genes. Alternatively, CAR T-cell activity can be regulated intracellularly through a self-regulation function or extracellularly through titration of a CAR adaptor or of a priming small molecule. In this work, we review the current strategies and mechanisms to control activity of CAR T-cells reversibly or irreversibly for preventing and for managing therapy-associated toxicities.
Topics: Humans; Receptors, Chimeric Antigen; T-Lymphocytes; Receptors, Antigen, T-Cell; Neurotoxicity Syndromes; Immunotherapy, Adoptive; Neoplasms; Hematologic Neoplasms
PubMed: 37350095
DOI: 10.1002/ijc.34635