Abstract:Introduction: Conventional CAR-T cells express a single chain antibody variable fragment that restricts recognition to one tumor antigen and a limited set of cancers. This study employs a novel CAR fusing full-length human NKG2D with the CD3z signaling domain. In autologous transduced CM-CS1 T cells, NKG2D CAR receives endogenous costimulation via DAP10 to target multiple NKG2D-ligands that are upregulated in solid and hematologic malignancies but absent or poorly expressed on healthy tissues.
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“…The results showed that 9 subjects treated in the first 3 cohorts completed their 28-day evaluation period without any DLTs. It is worth mentioning that there was no case of cell-related neurotoxicity, cytokine release syndrome (CRS), autoimmunity or CAR T cell-related death during treatment [ 48 ].…”
Currently, conventional therapies for acute myeloid leukemia (AML) have high failure and relapse rates. Thus, developing new strategies is crucial for improving the treatment of AML. With the clinical success of anti-CD19 chimeric antigen receptor (CAR) T cell therapies against B-lineage malignancies, many studies have attempted to translate the success of CAR T cell therapy to other malignancies, including AML. This review summarizes the current advances in CAR T cell therapy against AML, including preclinical studies and clinical trials, and discusses the potential AML-associated surface markers that could be used for further CAR technology. Finally, we describe strategies that might address the current issues of employing CAR T cell therapy in AML.
“…The results showed that 9 subjects treated in the first 3 cohorts completed their 28-day evaluation period without any DLTs. It is worth mentioning that there was no case of cell-related neurotoxicity, cytokine release syndrome (CRS), autoimmunity or CAR T cell-related death during treatment [ 48 ].…”
Currently, conventional therapies for acute myeloid leukemia (AML) have high failure and relapse rates. Thus, developing new strategies is crucial for improving the treatment of AML. With the clinical success of anti-CD19 chimeric antigen receptor (CAR) T cell therapies against B-lineage malignancies, many studies have attempted to translate the success of CAR T cell therapy to other malignancies, including AML. This review summarizes the current advances in CAR T cell therapy against AML, including preclinical studies and clinical trials, and discusses the potential AML-associated surface markers that could be used for further CAR technology. Finally, we describe strategies that might address the current issues of employing CAR T cell therapy in AML.
“…The most common adverse event was CRS (90% of the patients), including 14% grade 3/4 cases. Ongoing studies are investigating several other potential targets on MM plasma cell surface (196), including CD44v6 (197), Lewis Y (198), NKG2D ligands (199), CD229 (200), and integrin β7 (201). Selected clinical trial results in MM are summarized in Table 3.…”
Research on CAR T cells has achieved enormous progress in recent years. After the impressive results obtained in relapsed and refractory B-cell acute lymphoblastic leukemia and aggressive B-cell lymphomas, two constructs, tisagenlecleucel and axicabtagene ciloleucel, were approved by FDA. The role of CAR T cells in the treatment of B-cell disorders, however, is rapidly evolving. Ongoing clinical trials aim at comparing CAR T cells with standard treatment options and at evaluating their efficacy earlier in the disease course. The use of CAR T cells is still limited by the risk of relevant toxicities, most commonly cytokine release syndrome and neurotoxicity, whose management has nonetheless significantly improved. Some patients do not respond or relapse after treatment, either because of poor CAR T-cell expansion, lack of anti-tumor effects or after the loss of the target antigen on tumor cells. Investigators are trying to overcome these hurdles in many ways: by testing constructs which target different and/or multiple antigens or by improving CAR T-cell structure with additional functions and synergistic molecules. Alternative cell sources including allogeneic products (off-the-shelf CAR T cells), NK cells, and T cells obtained from induced pluripotent stem cells are also considered. Several trials are exploring the curative potential of CAR T cells in other malignancies, and recent data on multiple myeloma and chronic lymphocytic leukemia are encouraging. Given the likely expansion of CAR T-cell indications and their wider availability over time, more and more highly specialized clinical centers, with dedicated clinical units, will be required. Overall, the costs of these cell therapies will also play a role in the sustainability of many health care systems. This review will focus on the major clinical trials of CAR T cells in B-cell malignancies, including those leading to the first Cerrano et al. CART Research and Clinical Practice FDA approvals, and on the new settings in which these constructs are being tested. Besides, the most promising approaches to improve CAR T-cell efficacy and early data on alternative cell sources will be reviewed. Finally, we will discuss the challenges and the opportunities that are emerging with the advent of CAR T cells into clinical routine.
“…CAR‐T cells are also being investigated for use in generation of immune tolerance with solid organ transplant, autoimmune diseases (1 open CAR trial in lupus NCT03030976), and for infectious diseases . In conclusion, CAR T cell therapies targeting antigens and diseases beyond CD19 and B cell malignancies, respectively, have a bright future and are only beginning to emerge …”
CAR‐T cells have made dramatic inroads in targeting CD19‐positive B‐cell malignancies. This review focuses on application of CAR‐T cells in hematologic malignancies beyond targeting CD19, with specific attention to Hodgkin's lymphoma and acute myeloid leukemia.
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