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Wistar Science Highlights: New Synthetic DNA Vaccine for an Emerging Infectious Disease, Combination Treatment for Therapy-resistant Melanoma Patients and New Link Between Cellular Senescence and Cancer

February 15, 2019

A novel, synthetic DNA vaccine developed by the lab of Kar Muthumani, Ph.D., director of the Laboratory of Emerging Infectious Diseases and assistant professor in Wistar’s Vaccine & Immunotherapy Center at Wistar, induces protective immunity against Mayaro virus (MAYV), a mosquito-borne infection endemic to South America, that has the potential to become a global emerging viral threat. Study results were published in PLOS Neglected Tropical Diseases.

MAYV infection causes fever, rash, headache, nausea, and vomiting for prolonged periods in many people and can lead to persistent and debilitating muscle and joint pain in some patients. There are no approved treatments or preventative medicines for Mayaro fever.

Immunization with the new vaccine scMAYV-E induced potent protective and MAYV-specific immune responses in mice and provided complete protection from death and clinical signs of infection in a MAYV-challenge mouse model.

“The robust immunogenicity of the scMAYV-E vaccine demonstrated here supports the need for further testing of this vaccine as a viable means to halt the spread of this virus and protect individuals at risk from MAYV disease,” said Muthumani. READ MORE

Collaborative research by the lab of Dmitry I. Gabrilovich, M.D., Ph.D., Christopher M. Davis Professor and program leader of the Immunology, Microenvironment and Metastasis Program at Wistar, and Moffitt Cancer Center has demonstrated that BRAF-targeted therapies render resistant melanoma more sensitive to the attack of killer T cells. This result, published online in Clinical Cancer Research, suggests that adoptive T cell therapy may benefit patients that have become resistant to BRAF inhibitors.

Study showed that BRAF inhibitors (BRAFi) targeting the BRAF protein, which is mutated in approximately 50% of melanoma patients, induce upregulation of a protein called mannose-6-phosphate receptor (M6PR) on cancer cells. This receptor mediates intake of the toxic substances released by killer T cells to destroy their target cells. As a consequence, increased expression of M6PR correlated with increased sensitivity of melanoma cells to the toxic activity of tumor infiltrating lymphocytes. Importantly, this effect was also seen in BRAFi-resistant cells.

The translational relevance of these observations was evaluated in a pilot clinical trial in which 16 patients with metastatic melanoma were treated with the BRAFi vemurafenib followed by adoptive T cell therapy, or infusion of tumor infiltrating lymphocytes isolated from the same patient and expanded ex vivo. The combination treatment was well tolerated and BRAFi caused a marked increase in M6PR in the patients’ tumors.

This study thus suggests that adoptive T cell therapy may be therapeutically useful for patients who experienced tumor progression on BRAFi. READ MORE

In a study published online in Nature Cell Biology, the lab of Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center, professor and co-program leader of the Gene Expression and Regulation Program, described a novel mechanism by which senescent cells release tumor-promoting molecules.

During cellular senescence, which represents a potent tumor suppressive mechanism, cells irreversibly stop dividing. At the same time, they produce a variety of inflammatory soluble molecules that can promote tumor growth, known by the name of senescence-associated secretory phenotype (SASP).

The lab investigated the role of a family of proteins called HMGAs in these processes and unveiled the dual role they play in cancer.

Researchers found that higher levels of the HMGA1 protein, as frequently found in many cancer types, result in increased production of nicotinamide adenine dinucleotide (NAD+), a cellular factor critical for metabolism and enzyme function. Higher NAD+ metabolism promotes a higher SASP and enhances the inflammatory environment around the tumor, which translated into a stimulatory effect on cancer growth and development in mouse models of pancreatic and ovarian cancers.

“It is well documented that cellular NAD+ concentrations decrease during aging and the use of NAD+ supplementation is being studied as a new preventive opportunity for aging and age-associated disorders,” said Zhang. “Our results may have far-reaching implications on this field of investigation.” READ MORE