Entry for the $200 STEM Contest

10d ago in Entries

Let me walk you through my idea for this contest! It's probably something you haven't heard of before but it's definitely a field which requires more admiration and support!

It's called Oncolytic Virotherapy! It is genetically modifying a virus and creating such a virus that can only attack cancer cells while sparing healthy cells. This type of virotherapy utilizes cellular vehicles called liposomes to deliver the viral particle effectively. This virus mainly focuses on lysis of Lung and Pancreatic Cancer using the Monoclonal antibodies and BiTEs that specifically bind to Epidermal Growth Factor Receptors (EGFRs) that are excessively expressed in Lung and Pancreatic Cancer cells. The stable genes can be incorporated with lower chances of immune suppression than other oncolytic viruses and low pathogenicity for normal cells. Selected genes may be deleted or inserted to gain therapeutic effects and evade the immune system till they successfully reach the tumour cells. After this, the virus uses the tumour’s cellular machinery to replicate. This replication culminates with the cell bursting (lysis). The death of the tumour cells and release of antigens stimulate an immune response. This results in the recruitment of immune cells (T, NK and Dendritic cells) then successfully enter the Tumour Micro-Environment (TME) and attack the remaining tumour cells. Present Oncolytic Virotherapy faces several challenges: lowering toxicity to normal cells, tumour heterogeneity, proper delivery etc. Combating these challenges through a blend of unique approaches like using monoclonal antibodies (mAbs) and Bispecific T-cell Engager (BiTE) to create a synergistic treatment for Cancer proved to be successful through this study. By far, Lung and Pancreatic Cancer cells are the most challenging types of Cancer to kill mainly because of their immunosuppressive Tumour Micro-Environment (TME), high resistance to chemotherapy and their surgical operations are quite complex due to their anatomical location and positioning near vital blood vessels. Only a small percentage of patients (around 15-20%) are eligible for surgery at diagnosis due to the extent of the disease. The standard procedure, the Whipple operation, is complex and has significant risks. Oncolytic Virotherapy and can cure cancer even where Chemotherapy is not sufficient and is compatible with synergistic treatment, has broad tropism, efficient replication rate and is long-lasting. With the help of UP_210--the Oncolytic Virus (strain of Adenovirus type5) I plan to modify, the challenges faced by immunotherapies like tumour heterogeneity, effective delivery, pathogenicity, toxicity, to normal tissues, immunosuppressive TME, high cost, chances of cancer returning etc. will be significantly minimised.The UP_210 virus incorporated a strong promoter Survivin which drives selective replication in tumour cells and can survive through the harsh acidic and hypoxic conditions of the TME. The E1 gene has been deleted. By deleting E1, the virus can only replicate in cells that have specific defects in the Rb and p53 tumour suppressor pathways, which are commonly altered in cancer cells. The inserted GM-CSF Factor stimulates the proliferation and activation of immune cells, particularly dendritic cells, which are crucial for initiating immune responses. Incorporating shared introns, allows for alternative splicing of mRNA, enabling the expression of different protein isoforms from a single gene. TRAIL (TNF-Related Apoptosis-Inducing Ligand) induces apoptosis (programmed cell death) in tumour cells by binding to death receptors on their surface. By incorporating 2A Peptides, the gene lengths are shortened further. TNF (Tumor Necrosis Factor) promotes inflammation and can induce apoptosis in certain cancer cells. The shared silencers modulate gene expression by repressing transcription in non-target cells. IFN-α (Interferon Alpha) enhances the immune response and has antiviral properties. CCL2 (C-C Motif Chemokine Ligand 2) recruits immune cells, particularly monocytes, to the tumor site. CCL5 (C-C Motif Chemokine Ligand 5) attracts T cells and other immune cells to the tumor microenvironment. FLT3L (Fms-Like Tyrosine Kinase 3 Ligand) promotes the development and activation of dendritic cells. CXCL11 (C-X-C Motif Chemokine Ligand 11) attracts T cells to the tumor site. Anti-PD-1 (Immune Checkpoint Blockade) blocks PD-1 receptor enhancing T cell responses. The BiTE using MUC1 and CD3 and Monoclonal antibodies (mAbs) receptors bind to EGFR receptors overly expressed in lung and pancreatic cancers. The BiTE attaches one receptor on the tumour and other to a T cell promoting lysis. The 4-1BBL activates T cells and promotes their survival and proliferation while the OX40L produces long-lasting resistance to tumour recurrence. All these genes are expresses once the virus replicates inside the host cell. Upon virus internalization through receptor-mediated endocytosis, the viral particles are disassembled and exposed capsids that enter the cytoplasm by lysis of endosomal membrane and are subsequently transported along microtubules to the nuclear envelope, where viral genomes import into the host nucleus. Adenoviruses are one of the most widely studied viruses because they provide several advantages, such as the feasibility of manufacturing high viral titers, ease of genome manipulation, and inherently potent lytic activity. Like cytokines, BiTE and TriTE molecules have drawbacks such as short biological half-life, rapid excretion, poor residence time in TME. Luckily, the problems could be solved when they become a team with OVs.

Encapsulation of oncolytic adenovirus (Ad[I/PPT-E1A]) into liposomes coupled to chemokine CC motif ligand 2 (CCL2), which upon intravenous delivery binds to circulating monocytes expressing chemokine CC motif receptor 2 (CCR2), takes advantage of the aggregation of monocytes to hypoxic tumor vessels to deliver encapsulated OVs targeting tumor sites.This system can avoid recognition and delivery to the tumor site by the immune system after intravenous delivery, reducing the number of TAMs located near the blood vessels.

I have also attached a file that contains python simulations for the testing of the same and additional info!

Therefore, I would kindly like to request you to vote for me and support me through my scientific endeavors.

Best of Luck to everyone!

Have a great rest of the day!

Sincerely,

Udita.

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