University of Pittsburgh researchers have identified novel mutations to herpes simplex virus (HSV) and utilized these to deliver gene therapy to cancer cells. The resultant triggering of NK and T cell immune response to a cancer cell results in cytolysis. This novel approach holds the potential to change the landscape of gene therapy for cancer treatment.

Description

Methylation-related epigenetic repression, particularly repression of natural killer (NK) cell ligands, is associated with cancer development. Repression of these ligands makes cancer cells less susceptible to NK-cell medicated cytolysis. This novel approach uses HSV-based vectors to express human NK ligands, enhancing NK and T cell recognition of cancer cells allowing for destruction of tumors. This new approach using vector-medicated gene therapy to increase susceptibility of cancer cells to NK and T cell mediated demise could lead to new strategies in cancer treatment.

Applications

1. Cancer treatment
2. Gene therapy

Advantages

Viral vectors or genetically engineered viruses are increasing being developed to target many human diseases. Ideally a viral vector should specifically target diseased cells only. HSV can target a wide variety of cells. Previous strategies have involved infection of cancer cells with HSV and replication of the virus leading to cell death (oncolytic viruses). However, poor replication efficiency of oncolytic viruses, along with “off-target” infection and associated side effects limits the use of this strategy.

Using novel mutations to glycoproteins on HSV it is possible to specifically target cancer cells through targeted receptors reducing the risk of “off-target” infection. The mutations can be tailored to the target cell to improve selectivity. These mutated HSV vectors can be designed to deliver therapeutic agents directly to cancer cells, including ligands to promote recognition by NK cells and induce cytolysis.

Invention Readiness

In vivo work has demonstrated how mutated HSV vectors can infect cancer cells and induce NK and T cell mediated cytotoxicity. HSV vectors have been developed through mutation of glycoproteins and specifically target cancer cells, including HSV-resistant cells. Analysis of IDH mutant gliomas showed ligands for the NK group 2 member D (NKG2D) receptor, ULBP1 and ULBP3, were expressed at significantly lower levels making these cells resistant to NK-mediated cytotoxicity. Infection with HSV-based vectors expressing ULBP1 and ULBP3 have been shown to induce NK and T cell mediated cancer cell death.

IP Status

https://patents.google.com/patent/US11427625B2

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