Pexa-Vec (pexastimogene devacirepvec)

AI-powered spatial analysis suggests that combination therapy with Pexa-vec and cemiplimab enhances the immune response, evidenced by increased TIL densities in the tumor microenvironment.Table 1: Changes in TIL Densities from Pre- to Post-TreatmentMeasureCohortPre-Treatment (mm²)(Median, IQR)Post-Treatment (mm²)(Median, IQR)p-value isTILOverall (n = 18)87.53 (179.37-114.65)214.02 (257.50-389.74)0.0040 Arm A (n = 9)41.30 (257.13-81.61)190.17 (830.30-389.34)0.0078 Arm B (n = 9)165.43 (180.52-147.69)390.17 (340.11-387.14)0.1641iTILOverall (n = 18)88.89 (129.08-116.99)161.11 (376.62-321.79)0.0237 Arm A (n = 9)56.42 (125.56-101.70)157.44 (421.03-469.55)0.0273 Arm B (n = 9)96.27 (57.33-132.29)154.92 (194.87-184.03)0.3716sTILOverall (n = 18)100.91 (291.38-193.61)219.37 (370.85-466.27)0.0599 Arm A (n = 9)35.59 (257.13-67.38)140.55 (286.46-157.15)0.0391 Arm B (n = 9)303.37 (171.24-319.84)353.58 (189.15-735.39)0.4961

Analysis of sequential tissue biopsies and plasma samples revealed an increase in CD8 density and upregulation of immune-related protein biomarkers, including CXCL10.Intra-tumoral administration of JX-594 in combination with cyclophosphamide and avelumab is safe and capable of modulating the TME in cold STS. However, the limited efficacy observed warrants further research to define the therapeutic potential of oncolytic viruses, particularly in relation to specific histological subtypes of STS.

P1/2, N=34, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed

We reviewed seven virus types that have been investigated in past or ongoing pediatric tumor clinical trials: adenovirus (AdV-tk, Celyvir, DNX-2401, VCN-01, Ad-TD-nsIL-12), herpes simplex virus (G207, HSV-1716), vaccinia (JX-594), reovirus (pelareorep), poliovirus (PVSRIPO), measles virus (MV-NIS), and Senecavirus A (SVV-001). However, the antitumor effects of OVT remain variable depending on tumor type and viral agent used. Although the widespread adoption of OVT faces many challenges, we are optimistic that OVT will play an important role alongside standard chemotherapy and radiotherapy for the treatment of malignant pediatric solid tumors in the future.

The most common treatment-related adverse event was pyrexia, with a Grade ≥ 3 of 13.3% in Arm A, 0% in Arm B,0% in Arm C, and 3.6% in Arm D. No Grade 5 events occurred in any of the study arms. Table: 1885P Summary of efficacy results Conclusions The combination immunotherapy of IV PV and cemiplimab demonstrated an acceptable safety profile and encouraging efficacy of ORR and survival with durable responses in patients with metastatic or unresectable RCC, regardless of previous ICI treatment.

Vaccinia virus potently induces in vitro oncolysis in RCC cell lines, while also increasing expression of adenosine rate limiting enzymes in vitro and in vivo, which could explain tumor escape to oncolytic VV. MJX-594 combination with A2AR and A2BR inhibition safely and significantly improves renal cancer oncolysis and tumor control in vivo. Our studies uncover a novel, translationally relevant strategy to improve OV efficacy in vivo, in RCC and other cancers.

PexaVec in combination with durvalumab and tremelimumab is safe and tolerable. No unexpected toxicities were observed. The combination of PexaVec/durvalumab/tremelimumab demonstrated potential clinical activity in patients with pMMR mCRC, but further studies are needed to identify the predictive biomarkers.

High throughput analysis of sequential plasma samples revealed an upregulation of protein biomarkers reflecting immune induction such as IFN gamma. Whether the combination of JX-594 with an immune checkpoint inhibitor is associated with meaningful clinical activity is therefore worth to investigate.

Systemic treatment with JX-594 is safe in patients with advanced STS. Further investigations are needed to improve immune response to oncolytic viruses and define their therapeutic potential in patients with STS.

Pexa-Vec (Pexastimogene Devacirepvec; JX-594, TG6006) is a principally immunotherapeutic oncolytic virus that has reached late-phase clinical trials...In the two patients with significant and complete tumor necrosis, a reduction in the peripheral T-cell receptor diversity was observed at the time of surgery. These results support the development of pre-surgical oncolytic vaccinia virus-based therapies to stimulate anti-cancer immunity and increase the chances to cure patients with cancer.

In particular, the proteins related to cell cycle (Wee1, Cdc25c, CHK1/2, and Cyclin B1) and Akt signaling (PI3K, mTOR, Rictor and FOXO), MAPK signaling (JAK2, PAK1, FAK and MEK1) were down regulated, while proteins involved in apoptosis and necrosis were upregulated. In summary, our studies show that human and murine renal cancer cells are permissive to infection and replication by JX-594 and mJX-594, which induce potent oncolytic effects in clear and non-clear cell RCC, effects associated with significant modulation of RCC pathways associated with cell cycle, proliferation, and survival and stress responses.

P1/2, N=34, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2021 --> Jun 2023

This study determined the influence of intravenous (i.v.) oncolytic vaccinia virus mpJX-594 (mpJX) on antitumor activity of anti-programmed death receptor-1 antibody (aPD1) in functional and metastatic pancreatic neuroendocrine tumors (PanNETs)...Reduction of tumor insulin secretion from functional PanNETs prolonged survival, and anti-metastatic actions on aggressive PanNETs reduced the metastatic burden to less than before treatment. The findings support the efficacy of the vaccinia virus with aPD1 for functional and metastatic PanNETs.

Systemic JX-594 monotherapy demonstrated significantly better therapeutic outcomes compared with sunitinib monotherapy in both early- and advanced-stage mRCCs by converting cold tumors into hot tumors. Sunitinib monotherapy effectively suppressed primary tumor growth and lung metastasis in early-stage mRCC.

P2, N=30, Not yet recruiting, Royal Melbourne Hospital

P1/2, N=34, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Dec 2020 --> Sep 2020

P1/2, N=34, Active, not recruiting, National Cancer Institute (NCI) | N=23 --> 34

Intraperitoneal immunotherapy with JX restores peritoneal anticancer immunity and potentiates immune checkpoint blockade to suppress PC and malignant ascites in colon cancer.

P1/2, N=197, Recruiting, Institut Bergonié | N=118 --> 197 | Trial completion date: Sep 2020 --> Nov 2024 | Trial primary completion date: Sep 2018 --> May 2023

P1/2, N=23, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=35 --> 23

4-E03 shows improved Treg-depleting activity compared with ipilimumab. BT-001 also encodes GM-CSF, the cytokine expressed in clinically advanced products like T-Vec (Imlygic) or Pexa-Vec...A clinical batch of BT-001 has been produced and toxicological evaluation is ongoing. Transgene and BioInvent are preparing CTA and IND filings for a multicentre clinical trial targeting injectable superficial tumors.

Our results show that intratumoral JX treatment induces dramatic remodeling of TME and more potently suppresses cancer progression with immune checkpoint blockades by overcoming resistance to immunotherapy.

In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV-10 and toll-like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa-Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types...This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T-VEC, the only U.S. FDA-approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T-VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.

In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV-10 and toll-like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa-Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types...This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T-VEC, the only U.S. FDA-approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T-VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.