Papillomavirus pseudoviruses that comprise the L1/L2 capsid proteins can package a wide variety of non-viral DNA plasmids and deliver the packaged genetic material to cells. This function makes them attractive candidates as targeted gene delivery vehicles.
The successful treatment of cancer is correlated with the early detection of the cancerous cells. Conventional cancer diagnosis is largely based on qualitative morphological criteria, but more accurate quantitative tests could greatly increase early detection of malignant cells. It has been observed that the spatial arrangement of DNA in the nucleus is altered in cancer cells in comparison to normal cells. Therefore, it is possible to distinguish malignant cells by mapping the position of labeled marker genes in the nucleus.
Vascular Endothelial Growth Factor-A (VEGF-A) is an angiogenic agent that drives blood vessel formation in solid tumors and other diseases, such as macular degeneration and diabetic retinopathy. Several therapies that target the ability of VEGF to stimulate angiogenesis have been approved. These therapies regulate VEGF-A activity by binding VEGF-A, thereby blocking VEGF-A from binding to its receptor on target cells. This technology utilizes a different approach to regulating VEGF-A activity by providing a VEGF-A protein antagonist that is produced by engineering native VEGF-A protein.
T cell immunotherapy is used in the treatment of various pathologies – including cancers and infections. Current therapies employ chimeric antigen receptors (CARs) consisting of the intracellular fragment of CD3-zeta as the signaling domain with varied combinations of co-stimulatory, transmembrane, spacer/hinge, and extracellular targeting domains. While effective in treating hematological malignancies, CAR T cells need to be activated through T cell receptor (TCR) activation.
Mutation of amino acid 61of the neuroblastoma rat sarcoma viral oncogene homologue (NRAS) is a known driver of oncogenesis in melanoma. Glutamine (Q) to lysine (K) mutation at this position of NRAS is prevalent in approximately 10% of all melanoma cases and associated with aggressive tumors and low patient survival. Therefore, Q61K mutated NRAS is an important candidate for targeted therapies, including cellular immunotherapy.
Neurofibromatosis type 1 (NF1) is a genetic disorder affecting 1 per 3000 individuals on average. Patients develop a variety of developmental benign and malignant pathologies. The most common tumors associated with NF1 are peripheral sheath tumors, including neurofibromas, optical gliomas, and malignant peripheral nerve sheath tumors.
Human cancers contain genetic mutations that are unique to each patient. Some of the mutated peptides are immunogenic, can be recognized by T cells, and therefore, may serve as therapeutic targets.
Several Fibroblast Growth Factor Receptor 4 (FGFR4) specific antibodies with binding affinity at the nanomolar range have been successfully developed at the Genetics Branch. These antibodies have been made into different formats of therapeutic including Antibody Drug Conjugate (ADC), Bispecific T cell engager (BiTE) ae well as Chimeric Antigen Receptor (CAR)-T cells.
Proof of principle experiments have shown that when treated with FGFR4 positive tumor cells:
Chimeric antigen receptors (CARs) are hybrid proteins consisting of an antibody binding fragment fused to protein signaling domains that cause T-cells which express the CAR to become cytotoxic. Once activated, these cytotoxic T-cells can selectively eliminate the cells which they recognize via the antibody binding fragment of the CAR. By engineering a T-cell to express a CAR that is specific for a certain cell surface protein, it is possible to selectively target those cells for destruction. This is a promising new therapeutic approach known as adoptive cell therapy.
Primary liver tumors and secondary hepatic malignancies are among the leading causes of cancer-related deaths. Liver metastases account for 95% of all hepatic cancers, and the liver is the most common site for organ metastasis in the body. The gut microbiome serves an important role in antitumor immunity regulating the efficacy of chemo- and immunotherapies. The liver is exposed to gut bacteria through blood from the intestine, with 70% of the whole liver’s blood supply coming from intestinal blood. Changes in the commensal microbiome may affect immune cell function in the liver.