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Bulletin Du Cancer Feb 2024Immunotherapy strategies have revolutionized the management of a significant number of patients in recent years, whether they are undergoing treatment for hematologic... (Review)
Review
Immunotherapy strategies have revolutionized the management of a significant number of patients in recent years, whether they are undergoing treatment for hematologic malignancies or solid tumors. This therapeutic class is extensive, ranging from antibodies targeting immune checkpoint molecules to adoptive cell therapy strategies, including bispecific antibodies and anticancer vaccines. All these strategies are currently in active development. Adoptive cell therapy involves the infusion of normal or genetically modified immune cells into a patient with the aim of restoring strong antitumor immunity, primarily associated with the cytotoxicity of T lymphocytes. Currently, there are three major adoptive cell therapy strategies: allogeneic hematopoietic stem cell transplantation, CAR-T cell therapy, and TCR-T cell therapy. The objective of this article is to describe the mechanisms of action of these three strategies as well as their current advantages, limitations and constraints.
Topics: Humans; Hematopoietic Stem Cell Transplantation; T-Lymphocytes; Hematologic Neoplasms; Immunotherapy, Adoptive; Cell- and Tissue-Based Therapy
PubMed: 38242769
DOI: 10.1016/j.bulcan.2024.01.001 -
Journal of Hematology & Oncology Dec 2023Brain metastases signify a deleterious milestone in the progression of several advanced cancers, predominantly originating from lung, breast and melanoma malignancies,... (Review)
Review
Brain metastases signify a deleterious milestone in the progression of several advanced cancers, predominantly originating from lung, breast and melanoma malignancies, with a median survival timeframe nearing six months. Existing therapeutic regimens yield suboptimal outcomes; however, burgeoning insights into the tumor microenvironment, particularly the immunosuppressive milieu engendered by tumor-brain interplay, posit immunotherapy as a promising avenue for ameliorating brain metastases. In this review, we meticulously delineate the research advancements concerning the microenvironment of brain metastases, striving to elucidate the panorama of their onset and evolution. We encapsulate three emergent immunotherapeutic strategies, namely immune checkpoint inhibition, chimeric antigen receptor (CAR) T cell transplantation and glial cell-targeted immunoenhancement. We underscore the imperative of aligning immunotherapy development with in-depth understanding of the tumor microenvironment and engendering innovative delivery platforms. Moreover, the integration with established or avant-garde physical methodologies and localized applications warrants consideration in the prevailing therapeutic schema.
Topics: Humans; Tumor Microenvironment; Immunotherapy; Brain Neoplasms; Melanoma; Brain; Immunotherapy, Adoptive
PubMed: 38104104
DOI: 10.1186/s13045-023-01518-1 -
European Journal of Haematology Jan 2024While cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome are well-recognized acute toxicities of chimeric antigen receptor (CAR) T cell... (Review)
Review
While cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome are well-recognized acute toxicities of chimeric antigen receptor (CAR) T cell therapy, these complications have become increasingly manageable by protocolized treatment algorithms incorporating the early administration of tocilizumab and corticosteroids. As CAR-T cell therapy expands to new disease indications and the number of long-term survivors steadily increases, there is growing recognition of the need to appropriately evaluate and manage the late effects of CAR-T cell therapy, including late-onset or persistent neurotoxicity, prolonged cytopenias, delayed immune reconstitution and infections, subsequent malignancies, organ dysfunction, psychological distress, and fertility implications. In this review, we provide a practical approach to the long-term survivorship care of the CAR-T cell recipient, with a focus on the optimal strategies to address the common and challenging late complications affecting this unique population.
Topics: Humans; Receptors, Chimeric Antigen; Survivorship; Immunotherapy, Adoptive; Cytokine Release Syndrome; Cell- and Tissue-Based Therapy; Receptors, Antigen, T-Cell
PubMed: 37767547
DOI: 10.1111/ejh.14100 -
Blood Mar 2024Despite newer targeted therapies, patients with primary refractory or relapsed (r/r) T-cell lymphoma have a poor prognosis. The development of chimeric antigen receptor...
Despite newer targeted therapies, patients with primary refractory or relapsed (r/r) T-cell lymphoma have a poor prognosis. The development of chimeric antigen receptor (CAR) T-cell platforms to treat T-cell malignancies often requires additional gene modifications to overcome fratricide because of shared T-cell antigens on normal and malignant T cells. We developed a CD5-directed CAR that produces minimal fratricide by downmodulating CD5 protein levels in transduced T cells while retaining strong cytotoxicity against CD5+ malignant cells. In our first-in-human phase 1 study (NCT0308190), second-generation autologous CD5.CAR T cells were manufactured from patients with r/r T-cell malignancies. Here, we report safety and efficacy data from a cohort of patients with mature T-cell lymphoma (TCL). Among the 17 patients with TCL enrolled, CD5 CAR T cells were successfully manufactured for 13 out of 14 attempted lines (93%) and administered to 9 (69%) patients. The overall response rate (complete remission or partial response) was 44%, with complete responses observed in 2 patients. The most common grade 3 or higher adverse events were cytopenias. No grade 3 or higher cytokine release syndrome or neurologic events occurred. Two patients died during the immediate toxicity evaluation period due to rapidly progressive disease. These results demonstrated that CD5.CAR T cells are safe and can induce clinical responses in patients with r/r CD5-expressing TCLs without eliminating endogenous T cells or increasing infectious complications. More patients and longer follow-up are needed for validation. This trial was registered at www.clinicaltrials.gov as #NCT0308190.
Topics: Humans; Immunotherapy, Adoptive; Neoplasm Recurrence, Local; T-Lymphocytes; Chronic Disease; Lymphoma, T-Cell; Antigens, CD19
PubMed: 38145560
DOI: 10.1182/blood.2023022204 -
Nature Biotechnology Dec 2023Chimeric antigen receptor (CAR) T cells are changing the therapeutic landscape for hematological malignancies. To date, all six CAR T cell products approved by the US... (Review)
Review
Chimeric antigen receptor (CAR) T cells are changing the therapeutic landscape for hematological malignancies. To date, all six CAR T cell products approved by the US Food and Drug Administration (FDA) are autologous and centrally manufactured. As the numbers of approved products and indications continue to grow, new strategies to increase cell-manufacturing capacity are urgently needed to ensure patient access. Distributed manufacturing at the point of care or at other local manufacturing sites would go a long way toward meeting the rising demand. To ensure successful implementation, it is imperative to harness novel technologies to achieve uniform product quality across geographically dispersed facilities. This includes the use of automated cell-production systems, in-line sensors and process simulation for enhanced quality control and efficient supply chain management. A comprehensive effort to understand the critical quality attributes of CAR T cells would enable better definition of widely attainable release criteria. To supplement oversight by national regulatory agencies, we recommend expansion of the role of accreditation bodies. Moreover, regulatory standards may need to be amended to accommodate the unique characteristics of distributed manufacturing models.
Topics: Humans; Immunotherapy, Adoptive; Hematologic Neoplasms
PubMed: 37884746
DOI: 10.1038/s41587-023-01981-8 -
Nature Cancer Nov 2023
Topics: Humans; Multiple Myeloma; T-Lymphocytes; Immunotherapy, Adoptive
PubMed: 37993694
DOI: 10.1038/s43018-023-00637-5 -
Current Treatment Options in Oncology Nov 2023Immunotherapy is an innovative approach to cancer treatment that involves using the body's immune system to fight cancer. The landscape of immunotherapy is constantly... (Review)
Review
Immunotherapy is an innovative approach to cancer treatment that involves using the body's immune system to fight cancer. The landscape of immunotherapy is constantly evolving, as new therapies are developed and refined. Some of the most promising approaches in immunotherapy include immune checkpoint inhibitors (ICIs): these drugs target proteins on the surface of T-cells that inhibit their ability to attack cancer cells. By blocking these proteins, checkpoint inhibitors allow T-cells to recognize and destroy cancer cells more effectively. CAR T-cell therapy: this therapy involves genetically modifying a patient's own T-cells to recognize and attack cancer cells. CAR T-cell therapy exhibits favorable response in many patients with refractory hematological cancers with growing clinical trials in solid tumors. Immune system modulators: these drugs enhance the immune system's ability to fight cancer by stimulating the production of immune cells or inhibiting the activity of immune-suppressing cells. While immunotherapy has shown great promise in the treatment of cancer, it can also pose significant cardiac side effects. Some immunotherapy drugs like ICIs can cause myocarditis, which can lead to chest pain, shortness of breath, and heart failure. Other cardiac side effects of ICIs include arrhythmias, pericarditis, vasculitis, and accelerated atherosclerosis. It is important for patients receiving immunotherapy to be monitored closely for these side effects, as prompt treatment can help prevent serious complications. Patients should also report any symptoms to their healthcare providers right away, so that appropriate action can be taken. CAR T-cell therapy can also illicit an exaggerated immune response creating cytokine release syndrome (CRS) that may precipitate cardiovascular events: arrhythmias, myocardial infarction, and heart failure. Overall, while immune modulating therapy is a promising and expanding approach to cancer treatment, it is important to weigh the potential benefits against the risks and side effects, especially in patients with high risk for cardiovascular complications.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy; Immunotherapy, Adoptive; Heart Diseases; Neoplasms; Heart Failure
PubMed: 37624557
DOI: 10.1007/s11864-023-01130-y -
Frontiers in Bioscience (Landmark... Sep 2023Adoptive chimeric antigen receptor (CAR) T cells designed to recognize specific tumor antigens have shown promising results in cancer therapy. While CAR T cell therapy... (Review)
Review
Adoptive chimeric antigen receptor (CAR) T cells designed to recognize specific tumor antigens have shown promising results in cancer therapy. While CAR T cell therapy has demonstrated notable clinical effectiveness for hematologic disease, efforts to develop therapies for solid tumors, including glioblastoma (GBM), have been hampered by heterogeneity, an immunosuppressive tumor microenvironment, and difficulty in trafficking. Several specific tumor antigens, such as IL13Rα2, EGFRvIII, and HER2, have been attempted in clinical trials; however, limited efficacy has been observed. In this review, we discuss the current status of CAR T therapy for GBM in clinical trials and highlight the potential target antigens for CAR T cells. Additionally, we summarize the mechanisms used to enhance their efficacy and explore the challenges and future prospects of CAR T cell therapy for GBM.
Topics: Humans; Immunotherapy, Adoptive; Glioblastoma; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; T-Lymphocytes; Brain Neoplasms; Antigens, Neoplasm; Cell- and Tissue-Based Therapy; Tumor Microenvironment
PubMed: 37796692
DOI: 10.31083/j.fbl2809206 -
International Immunopharmacology Jun 2024Immunotherapy has become a revolutionary method for treating tumors, offering new hope to cancer patients worldwide. Immunotherapy strategies such as checkpoint... (Review)
Review
Immunotherapy has become a revolutionary method for treating tumors, offering new hope to cancer patients worldwide. Immunotherapy strategies such as checkpoint inhibitors, chimeric antigen receptor T-cell (CAR-T) therapy, and cancer vaccines have shown significant potential in clinical trials. Despite the promising results, there are still limitations that impede the overall effectiveness of immunotherapy; the response to immunotherapy is uneven, the response rate of patients is still low, and systemic immune toxicity accompanied with tumor cell immune evasion is common. Ultrasound technology has evolved rapidly in recent years and has become a significant player in tumor immunotherapy. The introductions of high intensity focused ultrasound and ultrasound-stimulated microbubbles have opened doors for new therapeutic strategies in the fight against tumor. This paper explores the revolutionary advancements of ultrasound combined with immunotherapy in this particular field.
Topics: Humans; Neoplasms; Immunotherapy; Animals; Ultrasonography; Cancer Vaccines; Immune Checkpoint Inhibitors; Microbubbles; Immunotherapy, Adoptive; Combined Modality Therapy; Ultrasonic Therapy
PubMed: 38735256
DOI: 10.1016/j.intimp.2024.112233 -
Trends in Molecular Medicine Aug 2023Localized immunomodulation technologies are rapidly emerging as a new modality with the potential to revolutionize transplantation of cells and organs. In the past... (Review)
Review
Localized immunomodulation technologies are rapidly emerging as a new modality with the potential to revolutionize transplantation of cells and organs. In the past decade, cell-based immunomodulation therapies saw clinical success in the treatment of cancer and autoimmune diseases. In this review, we describe recent advances in engineering solutions for the development of localized immunomodulation techniques focusing on cellular and organoid transplantation. We begin by describing cell transplantation and highlighting notable clinical successes, particularly in the areas of stem cell therapy, chimeric antigen receptor (CAR)-T cell therapy, and islet transplantation. Next, we detail recent preclinical studies centered on genome editing and biomaterials to enhance localized immunomodulation. We close by discussing future opportunities to improve clinical and commercial success using these approaches to facilitate long-term immunomodulation technologies.
Topics: Humans; Immunomodulation; Immunotherapy, Adoptive; Gene Editing; Organoids; Stem Cell Transplantation
PubMed: 37301656
DOI: 10.1016/j.molmed.2023.05.008