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Blood Cancer Journal Apr 2021Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary new pillar in cancer treatment. Although treatment with CAR-T cells has produced remarkable clinical... (Review)
Review
Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary new pillar in cancer treatment. Although treatment with CAR-T cells has produced remarkable clinical responses with certain subsets of B cell leukemia or lymphoma, many challenges limit the therapeutic efficacy of CAR-T cells in solid tumors and hematological malignancies. Barriers to effective CAR-T cell therapy include severe life-threatening toxicities, modest anti-tumor activity, antigen escape, restricted trafficking, and limited tumor infiltration. In addition, the host and tumor microenvironment interactions with CAR-T cells critically alter CAR-T cell function. Furthermore, a complex workforce is required to develop and implement these treatments. In order to overcome these significant challenges, innovative strategies and approaches to engineer more powerful CAR-T cells with improved anti-tumor activity and decreased toxicity are necessary. In this review, we discuss recent innovations in CAR-T cell engineering to improve clinical efficacy in both hematological malignancy and solid tumors and strategies to overcome limitations of CAR-T cell therapy in both hematological malignancy and solid tumors.
Topics: Animals; Hematologic Neoplasms; Humans; Immunotherapy, Adoptive; Neoplasms; Receptors, Chimeric Antigen; T-Lymphocytes; Tumor Microenvironment
PubMed: 33824268
DOI: 10.1038/s41408-021-00459-7 -
Nature Jul 2023Engineering a patient's own T cells to selectively target and eliminate tumour cells has cured patients with untreatable haematologic cancers. These results have... (Review)
Review
Engineering a patient's own T cells to selectively target and eliminate tumour cells has cured patients with untreatable haematologic cancers. These results have energized the field to apply chimaeric antigen receptor (CAR) T therapy throughout oncology. However, evidence from clinical and preclinical studies underscores the potential of CAR T therapy beyond oncology in treating autoimmunity, chronic infections, cardiac fibrosis, senescence-associated disease and other conditions. Concurrently, the deployment of new technologies and platforms provides further opportunity for the application of CAR T therapy to noncancerous pathologies. Here we review the rationale behind CAR T therapy, current challenges faced in oncology, a synopsis of preliminary reports in noncancerous diseases, and a discussion of relevant emerging technologies. We examine potential applications for this therapy in a wide range of contexts. Last, we highlight concerns regarding specificity and safety and outline the path forward for CAR T therapy beyond cancer.
Topics: Humans; Hematologic Neoplasms; Immunotherapy, Adoptive; Neoplasms; Receptors, Chimeric Antigen; T-Lymphocytes; Autoimmune Diseases; Infections; Fibrosis; Aging; Heart Diseases
PubMed: 37495877
DOI: 10.1038/s41586-023-06243-w -
Frontiers in Immunology 2021Chimeric antigen receptor T (CAR-T) cell therapy achieved extraordinary achievements results in antitumor treatments, especially against hematological malignancies,... (Review)
Review
Chimeric antigen receptor T (CAR-T) cell therapy achieved extraordinary achievements results in antitumor treatments, especially against hematological malignancies, where it leads to remarkable, long-term antineoplastic effects with higher target specificity. Nevertheless, some limitations persist in autologous CAR-T cell therapy, such as high costs, long manufacturing periods, and restricted cell sources. The development of a universal CAR-T (UCAR-T) cell therapy is an attractive breakthrough point that may overcome most of these drawbacks. Here, we review the progress and challenges in CAR-T cell therapy, especially focusing on comprehensive comparison in UCAR-T cell therapy to original CAR-T cell therapy. Furthermore, we summarize the developments and concerns about the safety and efficiency of UCAR-T cell therapy. Finally, we address other immune cells, which might be promising candidates as a complement for UCAR-T cells. Through a detailed overview, we describe the current landscape and explore the prospect of UCAR-T cell therapy.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen
PubMed: 34691052
DOI: 10.3389/fimmu.2021.744823 -
International Journal of Biological... 2019Cancer immunotherapy by chimeric antigen receptor-modified T (CAR-T) cells has shown exhilarative clinical efficacy for hematological malignancies. Recently two CAR-T... (Review)
Review
Cancer immunotherapy by chimeric antigen receptor-modified T (CAR-T) cells has shown exhilarative clinical efficacy for hematological malignancies. Recently two CAR-T cell based therapeutics, Kymriah (Tisagenlecleucel) and Yescarta (Axicabtagene ciloleucel) approved by US FDA (US Food and Drug Administration) are now used for treatment of B cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) respectively in the US. Despite the progresses made in treating hematological malignancies, challenges still remain for use of CAR-T cell therapy to treat solid tumors. In this landscape, most studies have primarily focused on improving CAR-T cells and overcoming the unfavorable effects of tumor microenvironment on solid tumors. To further understand the current status and trend for developing CAR-T cell based therapies for various solid tumors, this review emphasizes on CAR-T techniques, current obstacles, and strategies for application, as well as necessary companion diagnostics for treatment of solid tumors with CAR-T cells.
Topics: Cytokine Release Syndrome; Cytokines; Humans; Immunotherapy, Adoptive; Neoplasms; Treatment Outcome; Tumor Microenvironment
PubMed: 31754328
DOI: 10.7150/ijbs.34213 -
Nature Feb 2023The remarkable clinical activity of chimeric antigen receptor (CAR) therapies in B cell and plasma cell malignancies has validated the use of this therapeutic class for... (Review)
Review
The remarkable clinical activity of chimeric antigen receptor (CAR) therapies in B cell and plasma cell malignancies has validated the use of this therapeutic class for liquid cancers, but resistance and limited access remain as barriers to broader application. Here we review the immunobiology and design principles of current prototype CARs and present emerging platforms that are anticipated to drive future clinical advances. The field is witnessing a rapid expansion of next-generation CAR immune cell technologies designed to enhance efficacy, safety and access. Substantial progress has been made in augmenting immune cell fitness, activating endogenous immunity, arming cells to resist suppression via the tumour microenvironment and developing approaches to modulate antigen density thresholds. Increasingly sophisticated multispecific, logic-gated and regulatable CARs display the potential to overcome resistance and increase safety. Early signs of progress with stealth, virus-free and in vivo gene delivery platforms provide potential paths for reduced costs and increased access of cell therapies in the future. The continuing clinical success of CAR T cells in liquid cancers is driving the development of increasingly sophisticated immune cell therapies that are poised to translate to treatments for solid cancers and non-malignant diseases in the coming years.
Topics: Humans; Cell- and Tissue-Based Therapy; Genetic Therapy; Immunotherapy, Adoptive; Neoplasms; T-Lymphocytes; Tumor Microenvironment; B-Lymphocytes; Receptors, Chimeric Antigen
PubMed: 36813894
DOI: 10.1038/s41586-023-05707-3 -
Current Hematologic Malignancy Reports Apr 2023Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy that has resulted in tremendous progress in the treatment of patients with B cell malignancies.... (Review)
Review
PURPOSE OF REVIEW
Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy that has resulted in tremendous progress in the treatment of patients with B cell malignancies. However, the remarkable efficacy of therapy is not without significant safety concerns. Herein, we will review the unique and potentially life-threatening toxicities associated with CAR-T cell therapy and their association with treatment efficacy.
RECENT FINDINGS
Currently, CAR-T cell therapy is approved for the treatment of B cell relapsed or refractory leukemia and lymphoma, and most recently, multiple myeloma (MM). In these different diseases, it has led to excellent complete and overall response rates depending on the patient population and therapy. Despite promising efficacy, CAR-T cell therapy is associated with significant side effects; the two most notable toxicities are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The treatment of CAR-T-induced toxicity is supportive; however, as higher-grade adverse events occur, toxicity-directed therapy with tocilizumab, an IL-6 receptor antibody, and steroids is standard practice. Overall, a careful risk-benefit balance exists between the efficacy and toxicities of therapies. The challenge lies in the underlying pathophysiology of CAR-T-related toxicity which relies upon the activation of CAR-T cells. Some degree of toxicity is expected to achieve an effective response to therapy, and certain aspects of treatment are also associated with toxicity. As progress is made in the investigation and approval of new CARs, novel toxicity-directed therapies and toxicity-limited constructs will be the focus of attention.
Topics: Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Immunotherapy, Adoptive; Multiple Myeloma; Cell- and Tissue-Based Therapy
PubMed: 36763238
DOI: 10.1007/s11899-023-00687-7 -
Expert Review of Anti-infective Therapy Jun 2021: Chimeric antigen receptor T-cell therapy (CAR-T cell therapy) is a novel immunotherapy with promising results in the treatment of relapsed or refractory B cell... (Review)
Review
: Chimeric antigen receptor T-cell therapy (CAR-T cell therapy) is a novel immunotherapy with promising results in the treatment of relapsed or refractory B cell malignancies. Patients undergoing CAR-T cell therapy are at increased risk of infection due to prior immunosuppression, lymphodepleting chemotherapy, treatment of unique toxicities with tocilizumab and/or steroids, on-target effects of hypogammaglobulinaemia, and prolonged cytopenias.: A narrative review of infections (PubMed, August 2020) occurring in patients undergoing CAR-T cell therapy is described, and the evidence for infection prevention strategies is presented.: The rapid adoption of CAR-T cell therapy into clinical practice presents many challenges for the diagnosis, management, and prevention of infection. Ongoing surveillance of the spectrum of infectious complications and effectiveness of prophylaxis is required to support safe and effective patient care.
Topics: Antibodies, Monoclonal, Humanized; Hematologic Neoplasms; Humans; Immunotherapy; Immunotherapy, Adoptive; Infections; Receptors, Chimeric Antigen
PubMed: 33249873
DOI: 10.1080/14787210.2021.1855143 -
Archivum Immunologiae Et Therapiae... Aug 2022Despite advances in surgery and chemotherapy, ovarian cancer remains one of the most lethal malignancies. Hence, the implementation of novel treatment approaches is... (Review)
Review
Despite advances in surgery and chemotherapy, ovarian cancer remains one of the most lethal malignancies. Hence, the implementation of novel treatment approaches is required to improve the outcomes of the disease. Immunotherapy has been proven to be effective in many tumors and has already been incorporated into clinical practice. In this review, we describe key strategies in immunotherapy of ovarian cancer and summarize data from clinical studies assessing immunological prospects which could improve ovarian cancer treatment approaches in the future. The most notable current strategies include checkpoint blockade agents, the use of vaccines, adoptive cell transfer, as well as various combinations of these methods. While several of these options are promising, large controlled randomized studies are still needed to implement new immunotherapeutic options into clinical practice.
Topics: Cancer Vaccines; Female; Humans; Immunotherapy; Immunotherapy, Adoptive; Ovarian Neoplasms
PubMed: 35941287
DOI: 10.1007/s00005-022-00655-8 -
International Journal of Molecular... Jun 2020CAR-T therapy has revolutionized the treatment of select hematological malignancies, namely, acute lymphoblastic leukemia and large B-cell lymphomas [...].
CAR-T therapy has revolutionized the treatment of select hematological malignancies, namely, acute lymphoblastic leukemia and large B-cell lymphomas [...].
Topics: Animals; Antigens, Neoplasm; Disease Management; Humans; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Treatment Outcome
PubMed: 32560285
DOI: 10.3390/ijms21124303 -
Frontiers in Immunology 2023Chimeric antigen receptor (CAR) T cell therapy represents a major breakthrough in cancer care since the approval of tisagenlecleucel by the Food and Drug Administration... (Review)
Review
Chimeric antigen receptor (CAR) T cell therapy represents a major breakthrough in cancer care since the approval of tisagenlecleucel by the Food and Drug Administration in 2017 for the treatment of pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia. As of April 2023, six CAR T cell therapies have been approved, demonstrating unprecedented efficacy in patients with B-cell malignancies and multiple myeloma. However, adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity pose significant challenges to CAR T cell therapy. The severity of these adverse events correlates with the pretreatment tumor burden, where a higher tumor burden results in more severe consequences. This observation is supported by the application of CD19-targeted CAR T cell therapy in autoimmune diseases including systemic lupus erythematosus and antisynthetase syndrome. These results indicate that initiating CAR T cell therapy early at low tumor burden or using debulking strategy prior to CAR T cell infusion may reduce the severity of adverse events. In addition, CAR T cell therapy is expensive and has limited effectiveness against solid tumors. In this article, we review the critical steps that led to this groundbreaking therapy and explore ongoing efforts to overcome these challenges. With the promise of more effective and safer CAR T cell therapies in development, we are optimistic that a broader range of cancer patients will benefit from this revolutionary therapy in the foreseeable future.
Topics: United States; Young Adult; Humans; Child; Immunotherapy, Adoptive; Neurotoxicity Syndromes; Lymphocytes; Multiple Myeloma
PubMed: 37256141
DOI: 10.3389/fimmu.2023.1188049