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AI and Autoimmunity
Published in Louis J. Catania, AI for Immunology, 2021
Chimeric antigen receptor T-cells (CAR-T-cells) are T-cells that have been genetically engineered to give them the new ability to target a specific protein. The receptors are “chimeric” because they combine both antigen-binding and T-cell activating functions into a single receptor. The premise of CAR-T immunotherapy is to modify T-cells to recognize cancer cells to more effectively target and destroy them.56 CAR-T-cell therapy (see Figure 4.1) begins by removing a patient’s T lymphocytes and transducing them with a DNA plasmid vector (a DNA molecule distinct from the cell’s DNA used as a tool to clone, transfer, and manipulate genes)57 that encodes specific tumor antigens. These modified and targeted lymphocytes are then reintroduced to the patient’s body through a single infusion to attack tumor cells. Known as autologous CAR-T-cell therapy, this treatment has been in development for more than 25 years, resulting in four generations of improving therapy that has generated responses for up to four years in some studies.58
Enzymes for Prodrug-Activation in Cancer Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Until December 2015, more than 200 protocols related to adoptive T cell therapy (ATC) in human cancers were registered by the U.S. National Library of Medicine, and about 40% of these deal with the use of CAR T cells of which 65% are studied in trials for hematological malignancies which include relapsed B-cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), and B-cell non-Hodgkin lymphoma (B-NHL) (Park et al., 2016). The most commonly targeted antigen for treating these diseases with CAR-Ts is the B-lymphocyte antigen CD19. CAR-T cell therapy for solid tumors is still in its early stages. Among the targeted biomarkers are mesothelin, a protein overexpressed in several cancers, or human epidermal growth factor receptor family members, overexpressed in several solid tumors (breast, ovarian, bladder, pancreatic, non-small-cell lung cancer, etc.). For reviews related to CAR-T cell therapy for solid tumors, see Newick et al. (2017), Yong et al. (2017) or Almåsbak et al. (2016). More general reviews have been published, e.g., by Abate-Daga and Davila (2016) and Smith et al. (2016) and by the National Cancer Institute at the National Institutes of Health (2017).
Current and Rising Concepts in Immunotherapy: Biopharmaceuti cals versus Nanomedicines
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
Cytotoxic T cells can actively kill cancer cells, but during autoimmune disease, they destroy the body’s-own cells. In the course of therapies, they can be depleted using anti-CD8 antibodies [64]. In order to use their killing capabilities to fight cancer, innovative strategies already make use of cytotoxic CD8 cells. Many fields of research have been inspired a lot by the inhibitors of programmed cell death 1 (PD1), such as pembrolizumab. In this regard, immunomodulatory therapies utilize the killing capabilities of T cells for killing tumor cells [65]. The so-called chimeric antigen receptor (CAR)-T cells represent another major innovation which has been approved in 2017 by the FDA for children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia [66]. CAR T cells are generated based on extracting a patient’s immune cells and genetically engineering and reinjecting them into the patient where they shall seek and destroy cancer cells [67].
A calibration-free method for biosensing in cell manufacturing
Published in IISE Transactions, 2021
Jialei Chen, Zhaonan Liu, Kan Wang, Chen Jiang, Chuck Zhang, Ben Wang
Cell therapy is one of the most promising treatment approaches to have emerged over the last decades, demonstrating great potential in treating cancers, including leukemia and lymphoma (Kim and de Vellis, 2009; Yin, 2017). Among those therapies, Chimeric Antigen Receptor (CAR) T-cell therapy (Bonifant et al., 2016; June et al., 2018), involving the reprogramming of a patient’s T cells to effectively target and attack tumor cells, has shown innovative therapeutic effects in clinical trials, leading to a recent approval (i.e., the treatment of CD19+ hematological malignancies, see Prasad (2018)) by the FDA as a new cancer treatment modality. As illustrated in Figure 1, a typical CAR T-cell therapy involves four steps: deriving cells from a patient, genetically modifying the cells, culturing the cells, and re-administering back to the patient. With increasingly mature gene modification technology, more and more researchers focus on the culturing step (i.e., the red box in Figure 1), where the goal is to substantially increase the cell amount from a small batch to one dose for delivery to the patient. However, a key challenge is the intrinsic patient-to-patient variability in the starting material, i.e., cells derived from different patients vary in their viabilities, acceptance rates of genetic modification, and reactions to culture media (Hinrichs and Restifo, 2013). These variabilities introduce difficulties in cell culturing scale-up (i.e., cell manufacturing), and therefore, the current CAR T-cell therapy is hindered by low scalability, labor-intensive processes, and extremely high cost (Harrison et al., 2019). To achieve high quality and acceptable vein-to-vein cost, we present in this work a statistical framework for online monitoring in cell manufacturing, which can alleviate the negative effect of the intrinsic patient-to-patient variability.