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.

128 Development of an M1-polarized, non-viral chimeric antigen receptor macrophage (CAR-M) platform for cancer immunotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A141-A141
Author(s):  
Yumi Ohtani ◽  
Kayleigh Ross ◽  
Aditya Dandekar ◽  
Rashid Gabbasov ◽  
Michael Klichinsky
Keyword(s):  
Cancer Immunotherapy ◽  
Chimeric Antigen Receptor ◽  
Scale Up ◽  
Antigen Receptor ◽  
Innate Immune ◽  
List Type ◽  
M1 Phenotype ◽  
The Impact ◽  
Anti Tumor Activity ◽  
Immunosuppressive Factors

BackgroundWe have previously developed CAR-M as a novel cell therapy approach for the treatment of solid tumors.1 CAR-M have the potential to overcome key challenges that cell therapies face in the solid tumor setting – tumor infiltration, immunosuppression, lymphocyte exclusion – and can induce epitope spreading to overcome target antigen heterogeneity. While macrophages transduced with the adenoviral vector Ad5f35 (Ad CAR-M) traffic to tumors, provide robust anti-tumor activity, and recruit and activate T cells, we sought to identify a robust non-viral method of macrophage engineering in order to reduce the cost of goods, manufacturing complexity, and potential immunogenicity associated with viral vectors.MethodsAs innate immune cells, macrophages detect exogenous nucleic acids and respond with inflammatory and apoptotic programs. Thus, we sought to identify a means of mRNA delivery that avoids recognition by innate immune sensors. We screened a broad panel of mRNA encoding an anti-HER2 CAR comprising multiplexed 5’Cap and base modifications using an optimized and scalable electroporation approach and evaluated the impact of interferon-β priming on CAR-M phenotype and function.ResultsWe identified the optimal multiplexed mRNA modifications that led to maximal macrophage viability, transfection efficiency, intensity of CAR expression, and duration of expression. Non-viral HER2 CAR-M phagocytosed and killed human HER2+ tumor cells. Unlike Ad CAR-M, mRNA CAR-M were not skewed toward an M1 state by mRNA electroporation. Priming non-viral CAR-M with IFN-β induced a durable M1 phenotype, as shown by stable upregulation of numerous M1 markers and pathways. IFN-β priming significantly enhanced the anti-tumor activity of CAR but not control macrophages. IFN-β primed mRNA CAR-M were resistant to M2 conversion, maintaining an M1 phenotype despite challenge with various immunosuppressive factors, and converted bystander M2 macrophages toward M1. Interestingly, priming mRNA CAR-M with IFN-β significantly enhanced the persistence of CAR expression, overcoming the known issue of rapid mRNA turnover. RNA-seq analysis revealed that IFN-β priming affected pathways involved in increasing translation and decreasing RNA degradation in human macrophages.ConclusionsWe have established a novel, optimized non-viral CAR-M platform based on chemically modified mRNA and IFN-β priming. IFN-β priming induced a durable M1 phenotype, improved CAR expression, improved CAR persistence, led to enhanced anti-tumor function, and rendered resistance to immunosuppressive factors. This novel platform is amenable to scale-up, GMP manufacturing, and represents an advance in the development of CAR-M.ReferenceKlichinsky M, Ruella M, Shestova O, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol 2020;38(8):947–953.

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

Chimeric antigen receptor T-cell therapy beyond cancer: current practice and future prospects

Immunotherapy ◽  
2020 ◽  
Vol 12 (13) ◽  
pp. 1021-1034
Author(s):  
Peng-Fei Zhang ◽  
Dan Xie ◽  
Qiu Li
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Adoptive Cell Therapy ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Clinical Investigations ◽  
Car T Cell Therapy ◽  
Car T

Adoptive cell therapy with chimeric antigen receptor T (CAR-T) cells has achieved remarkable efficacy in the treatment of hematological malignancies, which has inspired researchers to expand the application of CAR-T-cell therapy to other medical conditions. Here, we review the current understanding and development of CAR-T-cell therapy for infectious diseases, autoimmune diseases and allotransplantation. The limitations and challenges of CAR-T-cell therapy in the treatment of these diseases and potential solutions to overcome these shortcomings are also discussed. With the development of novel designs of CARs and preclinical/clinical investigations, CAR-T-cell therapy is expected to be a potential cure option in a wide array of disease settings in the future.

scholarly journals Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data

Pharmaceutics ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 194 ◽  
Author(s):  
Gils Roex ◽  
Tom Feys ◽  
Yves Beguin ◽  
Tessa Kerre ◽  
Xavier Poiré ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Hematological Malignancies ◽  
Adoptive Cell Therapy ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T

Chimeric antigen receptor (CAR)-T-cell therapy is an innovative form of adoptive cell therapy that has revolutionized the treatment of certain hematological malignancies, including B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL). The treatment is currently also being studied in other B-cell neoplasms, including multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). CD19 and B-cell maturation antigen (BCMA) have been the most popular target antigens for CAR-T-cell immunotherapy of these malignancies. This review will discuss the efficacy and toxicity data from the pivotal clinical studies of CD19- and BCMA-targeted CAR-T-cell therapies in relapsed/refractory B-cell malignancies (NHL, ALL, CLL) and MM, respectively.

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
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