scholarly journals CARs on the Highway: Chimeric Antigen Receptor Modified T Cells for the Adoptive Cell Therapy of Malignant Diseases

10.5772/66496 ◽  
2017 ◽  
Author(s):  
Astrid Holzinger ◽  
Hinrich Abken
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Adoptive Cell Therapy ◽  
Antigen Receptor ◽  
Malignant Diseases

scholarly journals Generation of regulable EGFRvIII targeted chimeric antigen receptor T cells for adoptive cell therapy of glioblastoma

2018 ◽  
Vol 507 (1-4) ◽  
pp. 59-66 ◽  
Author(s):  
Yan Zheng ◽  
Ning Gao ◽  
Yu-Long Fu ◽  
Bing-Yong Zhang ◽  
Xiu-Ling Li ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Adoptive Cell Therapy ◽  
Antigen Receptor

Adoptive cell therapy for solid tumors: Chimeric antigen receptor T cells and beyond

2021 ◽  
Vol 59 ◽  
pp. 70-84
Author(s):  
Victor Moreno ◽  
Tatiana Hernandez ◽  
Maria de Miguel ◽  
Bernard Doger ◽  
Emiliano Calvo
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Adoptive Cell Therapy ◽  
Antigen Receptor

scholarly journals Manufacturing development and clinical production of NKG2D chimeric antigen receptor–expressing T cells for autologous adoptive cell therapy

Cytotherapy ◽  
2018 ◽  
Vol 20 (7) ◽  
pp. 952-963 ◽  
Author(s):  
Joana M. Murad ◽  
Susanne H. Baumeister ◽  
Lillian Werner ◽  
Heather Daley ◽  
Hélène Trébéden-Negre ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Adoptive Cell Therapy ◽  
Antigen Receptor

Immunotherapy with Chimeric Antigen Receptor Targeting Intracellular WT1 Gene Product Complexed with HLA-a*24:02 Molecule

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4292-4292 ◽  
Author(s):  
Hiroaki Ikeda ◽  
Yasushi Akahori ◽  
Motohiro Yoneyama ◽  
Yuki Orito ◽  
Yoshihiro Miyahara ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
B Cell ◽  
Cancer Patients ◽  
Chimeric Antigen Receptor ◽  
Potential Risk ◽  
Research Funding ◽  
Adoptive Cell Therapy ◽  
Antigen Receptor ◽  
Epitope Peptide

Abstract Adoptive cell therapy with lymphocytes transduced with chimeric antigen receptor (CAR) is a promising strategy to treat cancer patients. Recent success in the treatment of patients with B cell malignancy by CD19-CAR encourages the development of successive CAR therapy targeting other tumor-associated antigens. However, the search for the appropriate target molecule for CAR, other than B cell markers, is a serious question. The target of CAR is generally limited to the cellular surface molecules, making difficult to expand CAR therapy for broad range of cancer patients. Inspired by the physiological recognition of epitope peptide and MHC molecule (pMHC) by T cells, we have generated a series of antibodies that recognize the pMHC complexes with peptides derived from tumor antigens expressed intracellularly. We isolated an scFv antibody clone WT#213 that can specifically recognize WT1 p235-243 peptide (CMTWNQMNL) complexed with HLA-A*24:02 molecule by the screening of human antibody scFv phage display library. We have constructed retrovirus that encodes the CAR consists of WT#213 and intracellular signal transduction domains of CD3z and GITR (WT#213 CAR). We confirmed the specific recognition of endogenous WT1-expressing cells by the CAR-T cells with the intracellular cytokine staining and the 51Cr release cytotoxic assay. Utilizing NOG immunodeficient mice, we demonstrated the effectiveness of adoptive cell therapy with WT#213 CAR against the WT1 expressing HLA-A*24:02 positive human leukemia cells. To evaluate the safety of the WT#213 CAR, we predicted the potential property of WT#213 CAR to cross-react to normal tissues in humans. We conducted alanine scan analysis of WT1p235-243 peptide that was recognized by WT#213 CAR as well as the TCR derived from CTL clone TAK-1 which recognizes same epitope peptide in association with HLA-A*24:02 to define the amino acids that were critically important in the recognition by the WT#213 CAR or TAK-1-derived TCR. After BLAST search, we synthesized the normal protein-derived peptides with potential risk of cross-reactivity, and tested the recognition of these peptides by WT#213 CAR or TAK-1-derived TCR. Although the critical peptides, and therefore the peptides with potential risk, were quite different between the WT#213 CAR and TAK-1-derived TCR, none of these peptides showed the stimulation of WT#213 CAR or TAK-1-derived TCR. The results here suggest that the immunotherapy with WT#213 CAR will be effective for the treatment of the leukemia patients without the predicted risk at least in the evaluation we performed. Figure 1. Figure 1. Disclosures Ikeda: Takara Bio Inc.: Research Funding. Akahori:Takara Bio Inc.: Research Funding. Miyahara:Takara Bio Inc.: Research Funding. Amaishi:Takaa Bio Inc.: Employment. Okamoto:Takara Bio Inc.: Employment. Mineno:Takara Bio Inc.: Employment. Takesako:TAKARA BIO INC.: Employment. Fujiwara:Celgene: Honoraria, Other: Travel, Acomodations, Expenses.

scholarly journals Do CARs Need a Driver's License? Adoptive Cell Therapy with Chimeric Antigen Receptor-Redirected T Cells Has Caused Serious Adverse Events

2010 ◽  
Vol 21 (9) ◽  
pp. 1039-1042 ◽  
Author(s):  
Hildegard Büning ◽  
Wolfgang Uckert ◽  
Klaus Cichutek ◽  
Robert E. Hawkins ◽  
Hinrich Abken
Keyword(s):  
T Cells ◽  
Adverse Events ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Adoptive Cell Therapy ◽  
Antigen Receptor ◽  
Serious Adverse Events ◽  
Driver's License

scholarly journals 104 Development and characterization of human chimeric antigen receptor monocytes (CAR-Mono), a novel cell therapy platform

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A114-A114
Author(s):  
Daniel Blumenthal ◽  
Linara Gabitova ◽  
Brett Menchel ◽  
Patricia Reyes-Uribe ◽  
Andrew Best ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Solid Tumor ◽  
Adoptive Cell Therapy ◽  
Antigen Receptor ◽  
List Type ◽  
Differentiation Potential ◽  
Gm Csf ◽  
M1 Macrophage ◽  
Anti Tumor Activity

BackgroundEngineered cell therapies have demonstrated significant clinical activity against hematologic malignancies, but solid tumors remain an intractable challenge. We have previously developed a human chimeric antigen receptor macrophage (CAR-M) platform for adoptive cell therapy and shown potent anti-tumor activity in pre-clinical solid tumor models.1 CAR-M overcome critical solid tumor challenges such as tumor infiltration, immunosuppression within the tumor microenvironment, lymphocyte exclusion, and target antigen heterogeneity. Currently, CAR-M are generated in a week-long ex-vivo process in which peripheral blood monocytes are differentiated into macrophages prior to genetic manipulation. Here, we demonstrate the production feasibility, phenotype, pharmacokinetics, cellular fate, specificity, and anti-tumor activity of human CD14+ CAR monocytes.MethodsUsing the chimeric adenoviral vector Ad5f35, we engineered primary human CD14+ monocytes to express a CAR targeted against human epidermal growth factor receptor 2 (HER2) (CAR-mono). Using a partially automated approach, we established a process that allowed for same day manufacturing (from Leukopak to cryopreserved CAR-mono cell product).ResultsCAR expression and cell viability exceeded 90%, and cells efficiently differentiated into CAR-expressing macrophages. The adenoviral based gene modification method led to pre-conditioning of CAR-mono cells resulting in a strong M1 phenotype upon differentiation, and potent anti-tumor activity regardless of exposure to GM-CSF, M-CSF, or immunosuppressive factors. Treating CAR-mono cells with GM-CSF and IL-4 resulted in their differentiation to monocyte-derived CAR-DCs, indicating that these cells retain their myeloid differentiation potential. In vivo, CAR-mono treatment induced anti-tumor activity in various HER2+ solid tumor xenograft models. Following intravenous administration, CAR-mono demonstrated the ability to traffic to both GM-CSF < sup >high</sup > and GM-CSF< sup >low</sup >expressing tumors. Notably, CAR-mono showed long-term CAR expression and persistence (>100 days) in both NSG and NSG-S mouse models, demonstrating lasting persistence irrespective of human cytokine support.ConclusionsThe CAR-mono platform allows for a rapid, same-day manufacturing process while maintaining the key characteristics of CAR-M therapy. Ad5f35 engineered human monocytes are primed toward M1 macrophage differentiation and produce a cell population highly similar to our established CAR-M platform. Collectively, these findings provide strong pre-clinical support to advance the CAR-mono platform into clinical testing.ReferenceKlichinsky M, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nature Biotechnology March 2020.

scholarly journals Profile of Capillary-Leak Syndrome in Patients Received Chimeric Antigen Receptor T Cell Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5204-5204 ◽  
Author(s):  
Yongxian Hu ◽  
Jingjing Feng ◽  
Mi Shao ◽  
He Huang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Capillary Leak Syndrome ◽  
Capillary Leak ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

Abstract Background: Autologous T cells modified to express a chimeric antigen receptor (CAR-T) has demonstrated exciting efficacy in treating leukemia and there has been some reports about the toxicities recently. However, the spectrum of capillary-leak syndrome (CLS) associated with CAR-T cell therapy has not been systematically evaluated, which can be a life threatening complication as results of the cytokine release syndrome (CRS). Therefore, as the use of CAR-T therapy continues to expand to broader applications, it is prudent to characterize the profile of CLS to help providers guide safe management. Method: We reviewed all acute lymphoblastic leukemia (ALL) patients who had participated in the clinical trial from our center to receive CAR-T therapy between 2016-2018. Patients analyzed in the study received either CD19 CAR-T cells or CD19 plus CD22 CAR-T cells. The diagnosis of CLS includes edema, acute hypotension and hemoconcentration with hypoproteinemia or hypoalbuminemia. CRS grading was evaluated with Lee's criteria for CRS. Result: 42 ALL patients were included in this study with the mean age of 27(8-52) years old. 11(11/42, 26.2%) patients were diagnosed as CLS and 31 were not. It was observed that CLS was more common in patients who developed severe CRS. Patients with CLS was found to have high rate of hypotension and use of gamma globulin.(Table 1) Top level concentration of serum IL-6 in CLS patients was much higher than that in non-CLS patients (16438.7 vs 3292.7 pg/mL, p=0.0016), which is consistent with the well recognized concept of IL-6 as an indicator of CRS.(Figure 1) It is important to notice that CLS patients had lower levels of serum total protein (TP, 43.7 vs 52.8 g/L, p=0.0005) and serum albumin (ALB, 27.4 vs 33.8 g/L, p=0.0011), while the hemoglobin (HGB) concentration showed no difference, suggesting that TP and ALB might be better indicators for CLS than HGB, although hemoconcentration, hypoproteinemia and hypoalbuminemia are both important in diagnosis.(Figure 2) Moreover, there was no significant difference in age, gender, Ph type of ALL, type of CAR-T cells infused and death ratio.(Table 1) Although CRS has been reported to be related with disease burden before the therapy, our data showed no difference of it between the patients with and without CLS. Conclusion: In conclusion, we have evaluated a basic profile of CLS among CAR-T patients in our center and the study indicates that CLS warrants extra attention for patients who receive CAR-T therapy. Further investigations are required to elucidate best practices for prevention and management of CLS in CAR-T therapy. Disclosures No relevant conflicts of interest to declare.

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