In silico analysis of a novel protein in CAR T- cell therapy for the treatment of hematologic cancer through molecular modelling, docking, and dynamics approach

Mohanty, Rimjhim; Manoswini, Manoswini; Dhal, Ajit Kumar; Ganguly, Niladri

doi:10.1016/j.compbiomed.2022.106285

Computers in Biology and Medicine

2022

DOI: 10.1016/j.compbiomed.2022.106285

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In silico analysis of a novel protein in CAR T- cell therapy for the treatment of hematologic cancer through molecular modelling, docking, and dynamics approach

Rimjhim Mohanty

Manoswini Manoswini

Ajit Kumar Dhal

et al.

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Cited by 3 publications

References 61 publications

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Enhancing the Treating Efficacy of Immunotherapy through the Restructure of Tumor Microenvironment

Gong,

Jia,

Zhou

et al. 2023

Advanced NanoBiomed Research

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The therapeutic modes of cancers have been profoundly renovated by immunotherapies, which have shown extraordinary treating efficacy in certain tumor entities. However, the majority of cancer patients have not profited from it because of the negative effects of tumor microenvironment (TME) on human innate and/or adaptive immunity, including hypoxia, acidification, irregular vasculature, and a plethora of immunosuppressive cells and small molecules, which contribute to tumor progression, migration, resistance to drug, and so forth. Accordingly, it is feasible to enhance the efficacy of immunotherapies and increase the patients’ survival through the restructure of TME. Herein, the mechanisms and reverberations of aforementioned immunosuppressive elements are concentrated on, and latest therapeutic achievements and combined technologies that have been demonstrated effective in boosting immunotherapies by TME modulation are enumerated.

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Enhancing the Treating Efficacy of Immunotherapy through the Restructure of Tumor Microenvironment

Gong,

Jia,

Zhou

et al. 2023

Advanced NanoBiomed Research

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Design and development of dual targeting CAR protein for the development of CAR T-cell therapy against KRAS mutated pancreatic ductal adenocarcinoma using computational approaches

Ramalingam,

Premkumar,

Sundararajan

et al. 2024

Discov Onc

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Mutant KRAS promotes the proliferation, metastasis, and aggressiveness of various cancers including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal adenocarcinoma (CRC) respectively. Mutant KRAS therapeutics are limited, while Sotorasib and Adagrasib were the only FDA-approved drugs for the treatment of KRASG12C mutated NSCLC. Chimeric antigen receptor (CAR) T-cell therapy has been emerged as an effective strategy against hematological malignancies and being extended towards solid cancers including PDAC. mesothelin (MSLN) and Carcinoembryonic Antigen (CEA) were reported to be highly overexpressed in KRAS-mutated PDAC. Meanwhile, in clinical trials, several CAR T-cell therapy studies are mainly focused towards these two cancer antigens in PDAC, however, the dual targeting of these two neoantigens is not reported. In the present study, we have designed and developed a novel dual-targeting CAR protein by employing various bioinformatics approaches such as functional analysis (antigenicity, allergenicity, antigen binding sites & signalling cascades), qualitative analysis (physicochemical, prediction, refinement & validation of 2D and 3D structures), molecular docking, and in silico cloning. Our results revealed that the designed CAR protein specifically binds with both MSLN & CEA with significant binding affinities, and was predicted to be stable & non-allergenic. Additionally, the protein–protein interaction network reveals the T-cell mediated antitumor responses of each domain in the designed CAR. Conclusively, we have designed and developed a dual targeting (MSLN & CEA) CAR protein towards KRAS-mutated PDAC using computational approaches. Alongside, we further recommend to engineer this designed CAR in T-cells and evaluating their therapeutic efficiency in in vitro and in vivo studies in the near future.

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Designing, cloning and simulation studies of cancer/testis antigens based multi-epitope vaccine candidates against cutaneous melanoma: An immunoinformatics approach

Khalid,

Guo,

Muhammad

et al. 2024

Biochemistry and Biophysics Reports

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In silico analysis of a novel protein in CAR T- cell therapy for the treatment of hematologic cancer through molecular modelling, docking, and dynamics approach

Cited by 3 publications

References 61 publications

Enhancing the Treating Efficacy of Immunotherapy through the Restructure of Tumor Microenvironment

Enhancing the Treating Efficacy of Immunotherapy through the Restructure of Tumor Microenvironment

Design and development of dual targeting CAR protein for the development of CAR T-cell therapy against KRAS mutated pancreatic ductal adenocarcinoma using computational approaches

Designing, cloning and simulation studies of cancer/testis antigens based multi-epitope vaccine candidates against cutaneous melanoma: An immunoinformatics approach

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