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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 -
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 -
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 -
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 -
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 -
EBioMedicine Mar 2022Chimeric antigen receptor (CAR) T cell therapy has emerged as a cancer treatment with enormous potential, demonstrating impressive antitumor activity in the treatment of... (Review)
Review
Chimeric antigen receptor (CAR) T cell therapy has emerged as a cancer treatment with enormous potential, demonstrating impressive antitumor activity in the treatment of hematological malignancies. However, CAR T cell exhaustion is a major limitation to their efficacy, particularly in the application of CAR T cells to solid tumors. CAR T cell exhaustion is thought to be due to persistent antigen stimulation, as well as an immunosuppressive tumor microenvironment, and mitigating exhaustion to maintain CAR T cell effector function and persistence and achieve clinical potency remains a central challenge. Here, we review the underlying mechanisms of exhaustion and discuss emerging strategies to prevent or reverse exhaustion through modifications of the CAR receptor or CAR independent pathways. Additionally, we discuss the potential of these strategies for improving clinical outcomes of CAR T cell therapy.
Topics: Humans; Immunotherapy; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes; Tumor Microenvironment
PubMed: 35301179
DOI: 10.1016/j.ebiom.2022.103941 -
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 -
Nature Reviews. Immunology Mar 2012Immunotherapy based on the adoptive transfer of naturally occurring or gene-engineered T cells can mediate tumour regression in patients with metastatic cancer. Here, we... (Review)
Review
Immunotherapy based on the adoptive transfer of naturally occurring or gene-engineered T cells can mediate tumour regression in patients with metastatic cancer. Here, we discuss progress in the use of adoptively transferred T cells, focusing on how they can mediate tumour cell eradication. Recent advances include more accurate targeting of antigens expressed by tumours and the associated vasculature, and the successful use of gene engineering to re-target T cells before their transfer into the patient. We also describe how new research has helped to identify the particular T cell subsets that can most effectively promote tumour eradication.
Topics: Animals; Genetic Engineering; Humans; Immunotherapy, Adoptive; Neoplasms; T-Lymphocytes
PubMed: 22437939
DOI: 10.1038/nri3191 -
Nature Medicine Jun 2022Despite success in hematologic malignancies, the treatment landscape of chimeric antigen receptor (CAR) T cell therapy for solid tumors remains limited. Claudin18.2...
Despite success in hematologic malignancies, the treatment landscape of chimeric antigen receptor (CAR) T cell therapy for solid tumors remains limited. Claudin18.2 (CLDN18.2)-redirected CAR T cells showed promising efficacy against gastric cancer (GC) in a preclinical study. Here we report the interim analysis results of an ongoing, open-label, single-arm, phase 1 clinical trial of CLDN18.2-targeted CAR T cells (CT041) in patients with previously treated, CLDN18.2-positive digestive system cancers ( NCT03874897 ). The primary objective was safety after CT041 infusion; secondary objectives included CT041 efficacy, pharmacokinetics and immunogenicity. We treated 37 patients with one of three CT041 doses: 2.5 × 10, 3.75 × 10 or 5.0 × 10 cells. All patients experienced a grade 3 or higher hematologic toxicity. Grade 1 or 2 cytokine release syndrome (CRS) occurred in 94.6% of patients. No grade 3 or higher CRS or neurotoxicities, treatment-related deaths or dose-limiting toxicities were reported. The overall response rate (ORR) and disease control rate (DCR) reached 48.6% and 73.0%, respectively. The 6-month duration of response rate was 44.8%. In patients with GC, the ORR and DCR reached 57.1% and 75.0%, respectively, and the 6-month overall survival rate was 81.2%. These initial results suggest that CT041 has promising efficacy with an acceptable safety profile in patients with heavily pretreated, CLDN18.2-positive digestive system cancers, particularly in those with GC.
Topics: Claudins; Cytokine Release Syndrome; Humans; Immunotherapy, Adoptive; Stomach Neoplasms; T-Lymphocytes
PubMed: 35534566
DOI: 10.1038/s41591-022-01800-8 -
Science Advances Feb 2023T cell engineering has changed the landscape of cancer immunotherapy. Chimeric antigen receptor T cells have demonstrated a remarkable efficacy in the treatment of B... (Review)
Review
T cell engineering has changed the landscape of cancer immunotherapy. Chimeric antigen receptor T cells have demonstrated a remarkable efficacy in the treatment of B cell malignancies in hematology. However, their clinical impact on solid tumors has been modest so far. T cells expressing an engineered T cell receptor (TCR-T cells) represent a promising therapeutic alternative. The target repertoire is not limited to membrane proteins, and intrinsic features of TCRs such as high antigen sensitivity and near-to-physiological signaling may improve tumor cell detection and killing while improving T cell persistence. In this review, we present the clinical results obtained with TCR-T cells targeting different tumor antigen families. We detail the different methods that have been developed to identify and optimize a TCR candidate. We also discuss the challenges of TCR-T cell therapies, including toxicity assessment and resistance mechanisms. Last, we share some perspectives and highlight future directions in the field.
Topics: Humans; Immunotherapy, Adoptive; Neoplasms; Receptors, Antigen, T-Cell; Antigens, Neoplasm; Cell- and Tissue-Based Therapy
PubMed: 36791198
DOI: 10.1126/sciadv.adf3700