CAR T-Cell Therapy in Hematological Malignancies.
Ontology highlight
ABSTRACT:
SUBMITTER: Haslauer T
PROVIDER: S-EPMC8396650 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In the past decade, the emergence of chimeric antigen receptor (CAR) T-cell therapy has led to a cellular immunotherapy revolution against various cancers. Although CAR-T cell therapies have demonstrated remarkable efficacy for patients with certain B cell driven hematological malignancies, further studies are required to broaden the use of CAR-T cell therapy against other hematological malignancies. Moreover, treatment failure still occurs for a significant proportion of patients. CAR antigen loss on cancer cells is one of the most common reasons for cancer relapse. Additionally, immune evasion can arise due to the hostile immunosuppressive tumor microenvironment and the impaired CAR-T cells in vivo persistence. Other than direct antitumor activity, the adverse effects associated with CAR-T cell therapy are another major concern during treatment. As a newly emerged treatment approach, numerous novel preclinical studies have proposed different strategies to enhance the efficacy and attenuate CAR-T cell associated toxicity in recent years. The major obstacles that impede promising outcomes for patients with hematological malignancies during CAR-T cell therapy have been reviewed herein, along with recent advancements being made to surmount them.
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Project description:Opinion statementAlthough chimeric antigen receptor T cell immunotherapy has been successfully applied in patients with hematological malignancies, several obstacles still need to be overcome, such as high relapse rates and side effects. Overcoming the limitations of CAR-T cell therapy and boosting the efficacy of CAR-T cell therapy are urgent issues that must be addressed. The exploration of small-molecule compounds in combination with CAR-T cell therapies has achieved promising success in pre-clinical and clinical studies in recent years. Protein kinase inhibitors, demethylating drugs, HDAC inhibitors, PI3K inhibitors, immunomodulatory drugs, Akt inhibitors, mTOR inhibitors, and Bcl-2 inhibitors exhibited potential synergy in combination with CAR-T cell therapy. In this review, we will discuss the recent application of these combination therapies for improved outcomes of CAR-T cell therapy.
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Project description:Chimeric antigen receptor T (CAR-T) cells therapy has revolutionized the treatment paradigms for hematological malignancies, with multi-line therapy-refractory patients achieving durable complete remissions (CR) and relatively high objective response rate (ORR). So far, many CAR-T products, such as Kymriah, Yescarta and Tecartus, have been developed and got the unprecedented results. However, some patients may relapse afterwards, driving intense investigations into promoting the development of novel strategies to overcome resistance and mechanisms of relapse. Notable technical progress, such as nanobodies and CRISPR-Case9, has also taken place to ensure CAR-T cell therapy fully satisfies its medical potential. In this review, we outline the basic principles for the development and manufacturing processes of CAR-T cell therapy, summarize the similarities and differences in efficacy of different products as well as their corresponding clinical results, and discuss CAR-T immunotherapy combined with other clinical effects of drug therapy.
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Project description:Over the last decade, the emergence of several novel therapeutic approaches has changed the therapeutic perspective of human malignancies. Adoptive immunotherapy through chimeric antigen receptor T cell (CAR-T), which includes the engineering of T cells to recognize tumor-specific membrane antigens and, as a result, death of cancer cells, has created various clinical benefits for the treatment of several human malignancies. In particular, CAR-T-cell-based immunotherapy is known as a critical approach for the treatment of patients with hematological malignancies such as acute lymphoblastic leukemia (ALL), multiple myeloma (MM), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), and non-Hodgkin's lymphoma (NHL). However, CAR-T-cell therapy of hematological malignancies is associated with various side effects. There are still extensive challenges in association with further progress of this therapeutic approach, from manufacturing and engineering issues to limitations of applications and serious toxicities. Therefore, further studies are required to enhance efficacy and minimize adverse events. In the current review, we summarize the development of CAR-T-cell-based immunotherapy and current clinical antitumor applications to treat hematological malignancies. Furthermore, we will mention the current advantages, disadvantages, challenges, and therapeutic limitations of CAR-T-cell therapy.
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Project description:Chimeric antigen receptor (CAR) T cells have been successfully used for hematological malignancies, especially for relapsed/refractory B-cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma. Patients who have undergone conventional chemo-immunotherapy and have relapsed can achieve complete remission for several months with the infusion of CAR T-cells. However, side effects and short duration of response are still major barriers to further CAR T-cell therapy. To improve the efficacy, multiple targets, the discovery of new target antigens, and CAR T-cell optimization have been extensively studied. Nevertheless, the fact that the determination of the efficacy of CAR T-cell therapy is inseparable from the discussion of clinical application strategies has rarely been discussed. In this review, we will discuss some clinical application strategies, including lymphodepletion regimens, dosing strategies, combination treatment, and side effect management, which are closely related to augmenting and maximizing the efficacy of CAR T-cell therapy.
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Project description:AbstractRemarkable improvement relative to traditional approaches in the treatment of hematological malignancies by chimeric antigen receptor (CAR) T-cell therapy has promoted sequential approvals of eight commercial CAR T products within last 5 years. Although CAR T cells' productization is now rapidly boosting their extensive clinical application in real-world patients, the limitation of their clinical efficacy and related toxicities inspire further optimization of CAR structure and substantial development of innovative trials in various scenarios. Herein, we first summarized the current status and major progress in CAR T therapy for hematological malignancies, then described crucial factors which possibly compromise the clinical efficacies of CAR T cells, such as CAR T cell exhaustion and loss of antigen, and finally, we discussed the potential optimization strategies to tackle the challenges in the field of CAR T therapy.
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