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CAR T-cell therapy can effectively inhibit disease progression and improve the survival of patients with bile duct, pancreatic, and gastric cancers.
- Thread starter ginfreely
- Start date
Abstract
Bile duct, pancreatic, and gastric cancers are deadly digestive system tumors with high malignancy and poor patient prognosis. The efficiencies of conventional surgical treatment, radiation therapy, and chemotherapy are limited. In contrast, chimeric antigen receptor (CAR) T-cell therapy represents a landmark therapeutic approach to antitumor immunity with great efficacy in treating several hematological malignancies. CAR T-cell therapy involves genetically engineering the expression of specific antibodies based on the patient's T-cell surface and amplifying these antibodies to identify and target tumor-associated antigens. CAR T-cell therapy can effectively inhibit disease progression and improve the survival of patients with bile duct, pancreatic, and gastric cancers. The effectiveness of CAR T cells in tumor therapy can be validated using xenograft models, providing a scientific testing platform. In this study, we have reviewed the progress in CAR T-cell production and its development, focusing on the current status and optimization strategies for engineered CAR T cells in the bile duct, pancreatic, and gastric cancers.
Introduction
Tumor treatment has long been an important topic of continuous research in medical science. Conventional surgery, chemotherapy, and radiation therapy can cure only a small number of early-stage tumors with low malignancy and impair the proliferation and differentiation of both normal cells and tumor cells (1). Bile duct, pancreatic, and gastric cancers are the most common digestive system tumors with high malignancy and poor patient outcomes from conventional treatment (2–4). Bile duct cancer (CCA) is a type of hepatobiliary cancer with a high mortality rate. Early-stage bile duct cancer can be removed surgically, whereas advanced cases can only be managed by bile duct drainage surgery (5). CCA tumors contain large numbers of a cluster of differentiation (CD)8+ T cells and programmed cell death-ligand 1 (PD-L1). Current immunotherapy strategies using immune checkpoint inhibitors (ICIs) have not shown satisfactory results in CCA (6). Pancreatic cancer is a common malignant tumor of the gastrointestinal (GI) tract. It has a worse prognosis than almost all other tumor types because of its low early diagnosis rate and high surgical mortality (3). Although patients with pancreatic cancer contain high PD-L1 levels, their immunogenicity is inherently poor, and do not respond well to systemic therapy consisting of vaccines and ICIs (7). Gastric cancer is the third most common cause of cancer death worldwide and shows high molecular and phenotypical heterogeneity (4). Gastric cancer cells contain a high content of CD8+ T cells. The results of treating patients with gastric cancer using immune checkpoint blockade vary greatly depending on a tumor microenvironment (TME) (8). Patients with gastric cancer suffer from poor prognoses with strong recurrence risks (9). Therefore, developing therapies targeting malignant tumors has become a crucial yet challenging area of oncology research.
Immunotherapy is an emerging tool used in cancer treatment (1). Chimeric antigen receptor (CAR) T-cell therapies have reached milestones in preclinical research and clinical treatment and are the most promising cancer immunotherapies available today (10). CAR T-cell therapy has shown promising efficacy for treating hematologic malignancies (11). Four commercially available CAR T-cell products, Kymriah, Yescarta, Tecartus, and Breyanzi, have been authorized by the U.S. Food and Drug Administration and the European Commission for patients who suffer from recurrent or refractory B-cell precursor asthmatic lymphoblastic leukemia and intractable large B-cell lymphoma (11–18). Currently, CAR T-cell therapy does not work well in solid tumors, and many characteristics of solid tumors pose great challenges for using CAR T-cell therapy. As these cancers are largely refractory to conventional treatment, bile duct, pancreatic, and gastric cancers have been treated with CAR T-cell therapy (19). In most preclinical studies, researchers have used xenograft models to test CAR T-cell therapy in treating bile duct, pancreatic, and gastric cancers (20).
In this study, we have highlighted CAR T-cell therapy in the bile duct, pancreatic, and gastric cancers, summarized existing studies, briefly discussed the role of xenograft models in CAR T research, and discussed the future of engineered CAR T cells for treating digestive system tumors.
In this study, we have highlighted CAR T-cell therapy in the bile duct, pancreatic, and gastric cancers, summarized existing studies, briefly discussed the role of xenograft models in CAR T research, and discussed the future of engineered CAR T cells for treating digestive system tumors.
CAR T-cell therapy
CAR T-cell therapy is a perinatal T-cell therapy using a patient’s immune system for treatment, as T cells collected from a patient are designed genetically to express specific antigen-binding domains that bind with intracellular signaling domains on the surface of T cells to identify specific tumor antigens and amplify these T cells (21). Lymphatic clearance is performed to enable effective cell transplantation. CAR T-cell therapy is then reinfused into the patient so that the engineered T cells target the patient’s specific antigens (22). CAR T-cell therapy has breathed new life into the field of cancer immunotherapy.
Engineered CAR protein structures
A CAR is a synthetic receptor that activates T cells to target and recognizes tumor-associated antigens (TAAs), and a CAR binds to target antigens with no restrictions within the major histocompatibility complex (MHC) (19). A CAR works as a recombination receptor and includes one domain for extracellular antigen recognition, one transmembrane domain, and one intracellular signaling domain (Figure 1A) (23). The antigen-binding domain is typically found in the variable region of immunoglobulins (Igs) and consists of VH and VL chains linked by junctions into a single chain variability domain (scFv) (24). The “spacer domain” is usually an IgG1 hinge-CH2-CH3 Fc region with a constant structure between the scFv and spacer domain, which provides the flexibility to overcome spatial blockage (25). Most structural regions across the membrane consist of natural proteins, including CD3ζ, CD4, CD8α, and CD28 (26). The expression of CARs allows T cells to identify diverse cell surface antigens, expanding the range of tumor antigen targets (27). The structural properties of CARs increase the scope that CAR T-cell therapy can offer, providing more possibilities for tumor immunotherapy.
The evolution of CAR engineering
CAR T cells have undergone five generations of updates and optimization thus far. The first-generation CARs provided signals viaonly one intracellular signaling domain, CD3ζ or FcRγ, and could not induce a considerable expansion of T cells (28). CD28 or 41BB was added between the scFv and CD3ζ chain in the second-generation CARs to strengthen the antitumor activity of CAR T cells (29). Third-generation CARs included more co-stimulatory structural domains including CD28 and 41BB as well as OX40 and CD40, in addition to exhibiting a stronger ability to activate and induce T-cell proliferation (30–32). The fourth-generation CARs added genes encoding cytokines (interleukin [IL]-12 and IL-15) to be released by the CARs to improve CAR T-cell survival in a TME (32). The fifth-generation CARs build on the second-generation CARs by adding cytoplasmic structural domains from the IL-2 receptor beta chain and signal transducers and activators of transcription (STAT)3/5 binding pattern, triggering three signals including T-cell receptors (CD3ζ structural domain), co-stimulatory factors (CD28 structural domain), and cytokines (Janus Kinase-STAT3/5 signaling) to improve the proliferation, survival, and antitumor activity of CAR T cells markedly (33). Overall, CAR T-cell therapy is upgraded mainly by optimizing the engineering of CARs, and the improvement in CAR performance effectively improves the success rate in treating tumors using CAR T cells.
Mechanism of CAR-T therapy
T cells kill tumor cells by two mechanisms. One is the release of perforins and granzymes by cytokinesis. The other is tumor cell binding to tumor necrosis factors (TNFs) and thus undergoing apoptosis (34). When T cells are attached to an engineered CAR construct to form CAR T cells, they kill bile duct, pancreatic, and gastric cancer cells by three main mechanisms ( Figure S1 ) (35, 36). These mechanisms are as follows: 1) CAR-T cells exert signal transduction and cell activation functions with the massive release of perforins and granzymes. Perforins specifically target tumor cell membranes in MHC- and Fas-independent manners to induce the formation of pores from which granzymes subsequently enter the interior of tumor cells. Granzymes trigger an enzyme chain reaction that leads to cell death by apoptosis. CAR T cells release more perforins/granzymes and have a higher affinity than natural T cells (37). 2) The main death receptor pathways are Fas and the corresponding death ligand FasL as well as TNFR and the corresponding death ligand TNF. The death receptor binds to specific death ligands, receives extracellular death signals, activates intracellular apoptotic mechanisms, and induces apoptosis. CAR-T cells are highly expressed on the surface of Fas or TNF ligands, which do not depend on antigen–antibody binding to induce apoptosis in a heterogeneous tumor environment (38). 3) CAR-T cells secret particular cytokines, such as interferon-gamma (IFN-γ). These cytokines can promote CAR-T activity, induce the tumor stroma expression of IFN- γ receptors, modify the cancer microenvironment, and enhance CAR T-cell activity against tumors, thereby mediating the killing of target cells (33). The complex and diverse mechanisms of CAR T-cell therapy potentially expand their application scope in immunotherapy oncology. Engineered CAR T cells may mediate multiple effector mechanisms simultaneously, enhancing their potential for tumor therapy.
CAR T-cell therapy for digestive system tumors
CAR T-cell therapy is one of the most promising immunotherapeutic strategies (39). Most bile duct, pancreatic, and gastric cancer studies have applied only first-generation CAR T-cell therapies and have been limited by off-target toxicity (40). Current preclinical studies involving CAR T-cell therapies against these three GI tumors are focused on the refinement and optimization of CAR T-cell engineering.
Cancer is God's way of telling an individual that his/her time is up. It is far better to accept one's fate and rather than mourn the fact that the end is near we should celebrate the life that has been lived.
All these fancy treatments are nothing more than money spinners for the drug companies. A friend of mine transferred $200,000 from his account to some big Pharma company and all it did was buy him a year and a poor quality one at that. It would have been far better to have left it to his poor wife.
All these fancy treatments are nothing more than money spinners for the drug companies. A friend of mine transferred $200,000 from his account to some big Pharma company and all it did was buy him a year and a poor quality one at that. It would have been far better to have left it to his poor wife.
No one expects nor wants to die before time. Ask the Hongkie Cantonese dog that just made a loud knock to harass me. He should be near 60 or older but spending time doing these things means he is not expecting to die any time soon and that’s why he can afford to spend time doing these things and expects to live long enough to reap the benefits of chasing me out of my home again.
And I just saw on tv tonight one 68 year old woman asking pm why things are getting so expensive? Why doesn’t she ask when is she going to die? Because obviously she doesn’t expect to die any time soon. So of course people younger than 68 will not want to die any time soon and will spend $200k on an expensive lottery ticket. There are lucky people that strike lottery afterall as posted before.
And obviously those Cantonese dogs sons of prostitutes here smearing and harassing me non stop @Cottonmouth @Balls2U @iamnobody @musclepower etc are also nor expecting to die any time soon and that’s why they have no issue to spend so much time do evil to post evil filthy lies of me non stop.
Same reason why so many sinkies kpkb no more special account after 55 years old. Everyone thinks they going to live for LONG after 55.
Who defines when "before time" is? We have these arbitrary milestones that are supposed to be reached but everyone is different. If a 40 year old gets cancer it means their time has come and acceptance should be the default option.
Who else but statistics defines “before time”. It’s called average life expectancy or normal lifespan by country whatever. No one will accept by default that they are dying before time. Everyone hangs on to hope until the last days no choice but to accept.
Everyone expects and wants to be part of long lifespan statistics while beating or against the statistic when it comes to low 5 year cancer survival rate.
In order to achieve an average there will be those who fall below average and those who go way beyond. The quality of ones life is far more important than its duration. My neighbor has reached 101 but the quality of her life is shocking. She'd be much better off dead.
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