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T cell receptors (TCRs) are proteins that recognize antigens in the context of infected or transformed cells and activate T cells to mediate an immune response and destroy abnormal cells. TCRs consist of two domains, one variable domain that recognizes the antigen and one constant region that helps the TCR anchor to the membrane and transmit recognition signals by interacting with other proteins. When a TCR is stimulated by an antigen, such as a tumor antigen, some signaling pathways activated in the cell lead to the production of cytokines, which mediate the immune response.

The tumor-suppressor p53 protein plays a major role in tumor development. Most human cancers fail to normally activate wild-type p53, which is at least partly responsible for the unregulated growth of cancer cells and their failure to undergo apoptosis. While many chemotherapeutics enhance p53 levels, their non-specific DNA damage (genotoxicity) causes unfavorable side effects.
 

Hematopoietic progenitor cells (HPC) are multi-potent hematopoietic lineage cells that can differentiate into any type of blood cell, including but not limited to erythrocytes, T cells, B cells, and natural killer cells. As such, they have high therapeutic potential in the fields of regenerative medicine and cancer immunotherapy, especially when generated from patient-derived induced pluripotent stem cells (iPSC). Currently, the most efficient protocol to produce HPCs is co-culturing human iPSCs (hiPSC) with mouse stromal cells as a two-dimensional (2D) monolayer.

Adoptive T cell therapy (ACT) with tumor infiltrating lymphocytes (TIL), T cell receptor (TCR) and Chimeric Antigen Receptor (CAR) engineered T cells, or hematopoietic stem cell transplantation, is a promising new approach to cancer treatment. ACT harnesses an individual's adaptive immune system to fight against cancer, with fewer side-effects and more specific anti-tumor activity. Despite their promise of ACT as curative, these therapies are often limited by the persistence and robustness of the responses of the T cells to the cancer cells.

In the United States alone, one of four cancer deaths occur from lung cancer and there are over 8 million individuals considered to be at high-risk due to cigarette smoking and other behaviors. It's well known that early detection of cancer significantly improves survival of this disease, however a lack of lung cancer screenings and analysis precludes fast results at a low cost.

Pancreatic ductal adenocarcinoma (PDA) accounts for more than 90% of pancreatic cancer cases, and it is one of the most aggressive malignancies with a 5-year survival rate of 6%. The high mortality rate caused by PDA is primarily from the lack of early diagnosis – it is often asymptomatic in early stages – and a poor response to conventional chemotherapy and radiotherapy. One of the major immune cell types present in the PDA microenvironment is a subset of macrophages commonly termed tumor-associated macrophages (TAM).

Chemotherapy resistance in a wide array of cancers is often associated with enhanced glucose uptake and dysregulation of the insulin signaling pathway.  Therapeutics capable of inhibiting insulin signaling would be valuable as a stand-alone treatment and for sensitizing resistant tumors to standard chemotherapy regiments.  Researchers at NCI’s Genitourinary Malignancies Branch have synthesized and developed a series of Englerin-A ana

Steroid hormones have been implicated to play a fundamental role in the pathogenesis of prostate cancer. Polymorphisms in the genes that code for enzymes, or hormones involved in androgen regulatory pathway, reportedly influence risk for developing prostate cancer. Since many membrane transporters are modulators of steroid hormones absorption and tissue distribution, genetic polymorphisms in genes encoding these transporters may account for the risk of prostate cancer and the predicting of survival.

Despite several partially effective prophylactic vaccines for SARS-CoV-2 exist, patients worldwide still succumb to COVID-19. New therapeutics to treat this disease are still needed.  Upon host invasion, a critical step in the pathogenesis of COVID-19 is intracellular replication of SARS-CoV-2 before viral particles invade nearby healthy cells. This triggers an extreme inflammatory response that may lead to acute respiratory distress syndrome (ARDS) or transmission to another host.

This technology describes additional methods of using the griffithsin anti-viral polypeptides described in related NCI invention (reference number E-106-2003).  Specifically, this invention describes the use of GRFT to inhibit viral infection of hepatitis C viral infection, a severe acute respiratory syndrome (SARS) viral infection, an H5N1 viral infection, or an Ebola viral infection.