Immunotherapy in pancreatic cancer Essay Assignment
Immunotherapy in pancreatic cancer Essay Assignment
Immunotherapy in pancreatic cancer
Introduction:
Pancreatic cancer (PC) is one of the most aggressive tumour types and a major challenge in the clinic. Pancreatic cancer is considered as the fourth most common cause of cancer death in the Western world [1, 2] and it is predicted to be the second most common cause of cancer-related deaths by 2030 [3]. The overall five-year survival rate is less than 5% [4]Immunotherapy in pancreatic cancer Essay Assignment.
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Various therapeutic approaches may be taken, including surgery, radiotherapy and chemotherapy [5]. Among these approaches surgical resection of a part or whole pancreas can lead to long-term survival in 11% of resected patients [6]. However, most pancreatic cancer patients are not suitable candidates for this technically difficult surgery, as most of these patients present to the clinic with advanced or metastasized disease [7] hence other forms of therapy have to be used. In the case of chemotherapy, patients can get single or combined chemotherapeutic drugs (e.g gemcitabine, 5-fluorouracil , or capecitabine) [8]. Immunotherapy in pancreatic cancer Essay Assignment . However, these chemotherapeutic medications have only generated modest improvements in survival [9, 10]. Clearly, alternative forms of therapy are desperately needed.
Adoptive cells transfer:
Cancer immunotherapy is an alternative cancer treatment aimed at modulating a patient’s immune system in order to enable it to eliminate malignant cells [11]. Such approaches include the use of cancer vaccines, monoclonal antibodies, immune checkpoint inhibitors and adoptive cell transfer (ACT). Among these different approaches, ACT is a promising cancer treatment for different cancer types. For example, ACT has led to complete response in lymphoma and leukaemia patients [12-14]. Also, ACT can be an effective treatment for patients with metastatic melanoma with objective cancer regression in up to 70% of patients [15]Immunotherapy in pancreatic cancer Essay Assignment.
Recent preclinical and clinical evidence has suggested that therapies targeting pancreatic cancer antigen could potentially be effective against this devastating disease and generate significant clinical benefits. Balachandran, V.P., et al [16] showed that the longest survival in patients with pancreatic cancers was associated with the presence of both the highest neoantigen burden and greater CD8+ T cell infiltration of tumours.
In this review, we focus on ACT using chimeric antigen receptor (CAR)-T cells as a therapeutic treatment for pancreatic cancer. Also, we review different antigen specific CAR-T cells used in immunotherapy for PDAC in preclinical and clinical studies. In addition, we will discuss CAR-T technology: its advantages, disadvantages and the precautions that should be taken when this method is applied in the treatment of pancreatic cancer. Immunotherapy in pancreatic cancer Essay Assignment.
Then I talked about CAR T cells in details describing it then I started to write about it in pancreatic cancer ,,,,,
The use of CARs against pancreatic cancer:
During CAR-based immunotherapy in the treatment of pancreatic cancer, different cell antigens have been used as targets. Here, we present discussion of studies targeting these individual antigens. Some of these targets include mesothelin (MSLN), mucin-1 (MUC-1), carcinoembryonic antigen (CEA) and fibroblast activation protein (FAP), Her2, EGFR and CD47 [36-38].
1. Mesothelin
Mesothelin is a form of glycoprotein present in normal mesothelial cells and a tumour differentiation antigen which overexpressed in a variety of malignancies including malignant pleural mesothelioma, pancreatic, ovarian, and lung cancer [39]. This TAA has been detected in 57%-100% of pancreatic cancer tumours [40, 41], which made it a prospective target for CAR T-cell based immunotherapy. However, off-tumour toxicities are possible as it presents on normal peritoneal, pericardial and pleural surfaces[42]Immunotherapy in pancreatic cancer Essay Assignment.
In 2018, investigations were carried out in mice to check if meso-CAR T-cells have anti-tumour effects against distance metastases that were formed as a result of intravenous injection of pancreatic tumour cells. In vitro, the human meso-CART cells show cytolytic effects and also secreted cytokines in response to mesothelin-positive tumour cells. In vivo, the transferred meso CAR T-cells slowed the growth of the subcutaneous tumour and ultimately suppressed lung metastases moderately in the tumour-bearing mice. An analysis of these results indicated that meso-CAR T-cells might provide a treatment option for metastatic mesothelin-positive tumours in pancreatic cancer patients [43]. Immunotherapy in pancreatic cancer Essay Assignment.
Beatty et al [36] used mRNA-based method to generate CAR T cells, referred to as CAR T-meso, expressing CARs transiently to limit the duration of any on target/off-tumour toxicity. When these cells were infused into a patient with metastatic pancreatic cancer the CAR T-meso cells exerted an anti-tumour effect in a peritoneal lesion and ascetic fluid without any off tumour toxicities. One patient had stable disease after receiving CARTmeso T cell infusions; however, this patient developed a confirmed partial response by the modified RECIST criteria after receiving one infusion of CARTmeso cells on the second Schedule. Immunotherapy in pancreatic cancer Essay Assignment. After 6 months the disease progressed in this patient. The second patient had stable disease by response evaluation criteria in solid tumours (RECIST) criteria after three weeks of intravenous CARTmeso cell administration and reduction of the maximum standardized uptake value (SUVmax) was seen by [18F]2-fluoro-2-deoxy-D-glucose (FDG) avidity on positron emission tomography/computed tomography (PET/CT) imaging in all sites of disease.
1. Mucin-1
Mucin-1 (MUC-1), is an epithelial cell surface glycoprotein that has extensive O-linked glycosylation in its extracellular domain [3]. Mucins are found in the lining of the epithelial surface of the lungs, stomach and intestines, among other major body organs. The primary function of mucins is thought to be protection of the body from infections by binding to oligosaccharides located in the extracellular domain thus preventing pathogens from getting to the cell surface [44]. Overexpression of alternatively glycosylated forms of this protein is associated with metastatic cancers of the colon, breast, ovary, lungs and the pancreas. MUC-1 is aberrantly expressed in 60% of pancreatic cancer and is mostly characterized by poor prognosis, enhanced metastasis, and chemoresistance [45, 46]. Immunotherapy in pancreatic cancer Essay Assignment.
To study the use of CAR immunotherapy in the therapeutic treatment of pancreatic cancer focusing on MUC-1 as the target antigen, the double transgenic mouse model (MET) can be used [47]. In this model, large amounts of human MUC-1 are expressed as a self-molecule and spontaneous pancreatic tumours develop. MET mice can produce low affinity MUC1-specific cytotoxic lymphocytes (CTLs) which do not eradicate the spontaneously occurring pancreatic tumours. However, these CTLs are effective in eradicating injectable Muc-1 positive tumours when they are adoptively transferred, leading to long-term immunity. This MET mouse provide researchers a highly relevant model to study immunotherapeutic approaches against MUC-1 antigen as it shows endogenous immune responses that develop during tumour progression.
In addition to this model, Posey et al. [48] generated a CAR that recognized the neoantigen Tn glycoform of MUC-1 (Anti-Tn-MUC1 CAR T cells). Researchers demonstrated inhibition of tumour growth and increased survival in xenograft models of pancreatic cancer and T cell leukaemia.
2. Prostate stem cell antigen.
Immunotherapy in pancreatic cancer Essay Assignment