JX-594 is an

oncolytic virus An oncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by lysis#Oncolysis, oncolysis, they release new infectious virus particles or virus, virions to help destroy the remaining ...

is designed to target and destroy

cancer cells Cancer cells are cells that divide continually, forming solid tumors or flooding the blood with abnormal cells. Cell division is a normal process used by the body for growth and repair. A parent cell divides to form two daughter cells, and these d ...

. It is also known as Pexa-Vec,

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

pexastimogene devacirepvecPhase 1 Study of Intratumoral Pexa-Vec (JX-594), an Oncolytic and Immunotherapeutic Vaccinia Virus, in Pediatric Cancer Patients
/ref>) and was constructed in Dr. Edmund Lattime's lab at

Thomas Jefferson University Thomas Jefferson University is a private research university in Philadelphia, Pennsylvania. Established in its earliest form in 1824, the university officially combined with Philadelphia University in 2017. To signify its heritage, the univer ...

, tested in clinical trials on melanoma patients, and licensed and further developed by SillaJen. JX-594 is a modified CopenhagenTransgene Presents Data on Improved Cytotoxic Activity of Oncolytic Viruses Expressing Intrabodies in Resistant Tumor Cell Lines. October 2016
/ref> strain (or Wyeth strain)

vaccinia ''Vaccinia virus'' (VACV or VV) is a large, complex, enveloped virus belonging to the poxvirus family. It has a linear, double-stranded DNA genome approximately 190 kbp in length, which encodes approximately 250 genes. The dimensions of the ...

poxvirus ''Poxviridae'' is a family of double-stranded DNA viruses. Vertebrates and arthropods serve as natural hosts. There are currently 83 species in this family, divided among 22 genera, which are divided into two subfamilies. Diseases associated wit ...

engineered by addition of the

GM-CSF Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that ...

gene and deletion of the

thymidine kinase Thymidine kinase is an enzyme, a phosphotransferase (a kinase): 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Cert ...

gene which limits viral replication to cells with high levels of thymidine kinase, typically seen in cancer cells with a mutated

RAS Ras or RAS may refer to: Arts and media * RAS Records Real Authentic Sound, a reggae record label * Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service * Rás 1, an Icelandic radio station * Rás 2, an Icelandic radio stati ...

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

gene. The virus also has the ''LacZ'' gene insertion under control of the p7.5 promoter. The virus kills the infected/cancer cells by

lysis Lysis ( ) is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ''lysate''. In molecular bio ...

and also expresses

which may help initiate an anti-tumour immune response. It has

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

designation from US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

and EUMA for the treatment of

hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. It occurs in t ...

(liver cancer).Jennerex Granted FDA Orphan Drug Designation for Pexa-Vec in Hepatocellular Carcinoma (HCC)
/ref> In clinical trials doses have been administered by intratumoral or intravenous injection.

Technology

Pexa-Vec (JX-594) is the most advanced product candidate from SillaJen's proprietary SOLVE™ (Selective Oncolytic Vaccinia Engineering) platform. SOLVE is used to optimize virus targeting to specific cancer types, to select transgenes to include into the viral genome, and to optimize viral infection and/or replication selectively through targeted mutations.

Oncolytic virus An oncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by lysis#Oncolysis, oncolysis, they release new infectious virus particles or virus, virions to help destroy the remaining ...

es could have 3-prolonged attack on cancer: direct cell

with replication and spread,

immune In biology, immunity is the capability of multicellular organisms to resist harmful microorganisms. Immunity involves both specific and nonspecific components. The nonspecific components act as barriers or eliminators of a wide range of pathogens ...

activation, and antivascular * Tumor selective intratumoral replication of the virus leads to

of the infected cancer cell and spread to adjacent cancer cells * Induction of tumor-specific

cytotoxic T-lymphocytes A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...

and “arming” for expression of therapeutic transgene products (e.g.

) enhance immune response to the tumor * Blood flow to tumors can be blocked following intratumoral replication and spreadJX-900 (VVDD): VVDD Platform: Next-gen enhanced

oncolytic immunotherapy An oncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumour. Oncolytic viru ...

. JX-900 (VVDD): VVDD Platform: Next-gen enhanced

. * JX-900 is a series of modified

vaccine (Western Reserve strain) with enhanced oncolytic potency * Attenuation via “Double-Deletion” :

and vaccinia growth factor gene inactivation * JX-929 (vvDD expressing CD for 5-FU pro-drug) experience in

solid tumors A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

( CRC and

melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...

) * JX-970 (vvDD expressing

granulocyte-macrophage colony-stimulating factor Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that ...

next generation of the VVDD series

Clinical trials

A phase 3 randomized, open-label, clinical trial of Pexa-Vec plus

sorafenib Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer ( hepatocellular carcinoma), FLT3-ITD positive AML and r ...

versus sorafenib is being conducted on patients with advanced hepatocellular carcinoma who have not previously received any systemic therapy. The study is being done to determine and compare overall survival for patients in the two treatment arms. The study is Sponsored by SillaJen, Inc.

Mechanism of Action of Pexa-Vec (Jx-594)

The experimental therapy, Pexa-Vec, is an attenuated

virus engineered to stimulate anti-tumor immunity and directly lyse tumor cells. Pexa-Vec has cancer selectivity through the deactivation of its thymidine kinase gene, and it has been engineered to express the

gene to stimulate a systemic anti-tumor immune response. Researchers believe that Pexa-Vec may be a systemic treatment of hepatocellular carcinoma by inducing tumor necrosis and shrinkage of both injected and non-injected tumors after direct intratumoral delivery. Final data from a randomized dose-ranging phase 2 study of Pexa-Vec in mainly sorafenib naïve patients with advanced hepatocellular carcinoma demonstrated that the risk of death for patients who received Pexa-Vec at the high dose was markedly reduced (by nearly 60 percent; hazard ratio = 0.41) when compared to patients randomized to a low dose control (one-tenth of the high dose). The median overall survival for high and low dose groups was 14.1 months versus 6.7 months, respectively (p = 0.020 for superiority of the high dose). Pexa-Vec was well tolerated, with patients experiencing transient

flu Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptom ...

-like symptoms that generally resolved within 24 hours.
these are the

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

s investigating Pexa-Ve

Study Design

Participants will be randomly assigned to one of two treatment arms, having an equal chance of receiving either Pexa-Vec followed by sorafenib, or sorafenib alone.

Arm A: Pexa-Vec followed by sorafenib

* Participants will visit the study center approximately 14 times over 18 weeks. * All Pexa-Vec treatments (3) will be given by intratumoral injections into liver tumors. * Following Pexa-Vec injection series completion, patients will receive sorafenib starting at week 6 of the study

Arm B: sorafenib

* Participants will visit the study center approximately 12 times over 18 weeks and receive sorafenib as per standard of care.

Pipeline candidates

JX-Next Generation

Novel oncolytic viruses in SillaJen pipeline are engineered through the Selective Oncolytic Vaccinia Engineering (SOLVE) platform.

JX-929

JX-929 is derived from Western Reserve strain

virus. JX-929's tumor selectivity has been optimized through deletion of

and vaccinia growth factor. JX-929 has been administered as a monotherapy to patients with Breast cancer, breast,

colorectal The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being ...

, and

pancreatic cancer Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of t ...

via intratumoral & intravenous injections in a Phase 1, dose escalation clinical trial. This Phase 1 study showed delivery to and replication within tumors both IT and IV.

JX-970

JX-970 is also derived from a Western Reserve strain

vaccinia virus ''Vaccinia virus'' (VACV or VV) is a large, complex, enveloped virus belonging to the poxvirus family. It has a linear, double-stranded DNA genome approximately 190 kbp in length, which encodes approximately 250 genes. The dimensions of the ...

and utilizes the same tumor selectivity mechanisms as JX-929. In addition, it expresses

to stimulate immune responses. In nonclinical studies, the JX-970 backbone exerted a tumor debulking effect and at the same time demonstrated a selective preference for tumor tissues. The precursor of JX-970 is JX-963 which demonstrated efficacy in pre-clinical studies.

References

{{Reflist Experimental cancer treatments Virotherapy