Switchable CAR-T cells mediate remission in metastatic pancreatic ductal adenocarcinoma

Tristan

et al. 2019

Preprint

Clinical translation of human pluripotent stem cells (hPSCs) requires advanced strategies that ensure safe and robust long-term growth and functional differentiation. Pluripotent cells are capable of extensive self-renewal, yet remain highly sensitive to environmental perturbations in vitro, posing challenges to their therapeutic use. Here, we deployed innovative high-throughput screening strategies to identify a small molecule cocktail that dramatically improves viability of hPSCs and their differentiated progeny. We discovered that the combination of Chroman 1, Emricasan, Polyamines, and Trans-ISRIB (CEPT) enhanced cell survival of genetically stable hPSCs by simultaneously blocking several stress mechanisms that otherwise compromise cell structure and function. In proof-of-principle experiments we then demonstrated the strong improvements that CEPT provided for several key applications in stem cell research, including routine cell passaging, cryopreservation of pluripotent and differentiated cells, embryoid body and organoid formation, single-cell cloning, genome editing, and new iPSC line generation. Thus, CEPT represents a unique polypharmacology strategy for comprehensive cytoprotection, 2 providing a new rationale for efficient and safe utilization of hPSCs. Conferring cell fitness by multi-target drug combinations may become a common approach in cryobiology, drug development, and regenerative medicine. 4Chroman 1 has not been investigated in the context of stem cells so far. In vitro kinase assays confirmed that Chroman 1 was more potent against ROCK1 (IC50 = 52 pM) and ROCK2 (IC50 = 1 pM) than Y-27632 (ROCK1 IC50 = 71 nM and ROCK2 IC50 = 46 nM) ( Fig. 1d,e). Next, using HotSpot kinase inhibitor profiling of 369 human kinases that cover all major human protein kinase families 30

Section: Discussionmentioning

confidence: 99%

A Versatile Polypharmacology Platform Promotes Cytoprotection and Viability of Human Pluripotent and Differentiated Cells

Tristan

et al. 2019

Preprint

“…For example, an antibody-based bifunctional switch was developed, structured with a peptide neo-epitope (PNE) connected to the tumor antigen-specific Fab region targeting TAA and it could bind to the anti-PNE scFv that is connected to CAR. This switch model allows for control of activity, tissue-homing, cytokine release, and phenotype of CAR-T cells in a dose dependent manner [73,74]. Another type of switch molecule is the FITC-folate system.…”

Section: Universal Car-t By Switch Molecules For Allogenic Applicationmentioning

confidence: 99%

Recent Advances in Allogeneic CAR-T Cells

Kim

Cho

2020

Biomolecules

In recent decades, great advances have been made in the field of tumor treatment. Especially, cell-based therapy targeting tumor associated antigen (TAA) has developed tremendously. T cells were engineered to have the ability to attack tumor cells by generating CAR constructs consisting of genes encoding scFv, a co-stimulatory domain (CD28 or TNFRSF9), and CD247 signaling domains for T cell proliferation and activation. Principally, CAR-T cells are activated by recognizing TAA by scFv on the T cell surface, and then signaling domains inside cells connected by scFv are subsequently activated to induce downstream signaling pathways involving T cell proliferation, activation, and production of cytokines. Many efforts have been made to increase the efficacy and persistence and also to decrease T cell exhaustion. Overall, allogeneic and universal CAR-T generation has attracted much attention because of their wide and prompt usage for patients. In this review, we summarized the current techniques for generation of allogeneic and universal CAR-T cells along with their disadvantages and limitations that still need to be overcome.

“…Zhang E et al [78] constructed a dual CAR-modified T-cell to eradicate AsPC-1 pancreatic cells that have high expression of carcinoembryonicantigen (CEA) and mesothelin (MSLN). A study using switchable CAR T-cells to target HER-2 on patient-derived xenograft models from patients with aggressive metastatic pancreatic cancer showed considerable potency [79]. Whilding et al hypothesized that controlling IL-8 might control tumor burden in solid tumors by accomplishing a higher therapeutic activity in pancreatic and ovarian tumor xenografts.…”

Section: Pancreatic Cancermentioning

confidence: 99%

Chimeric Antigen Receptor T-Cell Therapy for Colorectal Cancer

Sur

Havași

Căinap

et al. 2020

JCM

Chimeric antigen receptor (CAR) T-cell therapy represents a new genetically engineered method of immunotherapy for cancer. The patient’s T-cells are modified to express a specific receptor that sticks to the tumor antigen. This modified cell is then reintroduced into the patient’s body to fight the resilient cancer cells. After exhibiting positive results in hematological malignancies, this therapy is being proposed for solid tumors like colorectal cancer. The clinical data of CAR T-cell therapy in colorectal cancer is rather scarce. In this review, we summarize the current state of knowledge, challenges, and future perspectives of CAR T-cell therapy in colorectal cancer. A total of 22 articles were included in this review. Eligible studies were selected and reviewed by two researchers from 49 articles found on Pubmed, Web of Science, and clinicaltrials.gov. This therapy, at the moment, provides modest benefits in solid tumors. Not taking into consideration the high manufacturing and retail prices, there are still limitations like increased toxicities, relapses, and unfavorable tumor microenvironment for CAR T-cell therapy in colorectal cancer.