Oncolytic Viruses for the Treatment of Bladder Cancer

The phase 3 BOND-003 study (NCT04452591) evaluating cretostimogene grenadenorepvec  (formerly, CG0070) had completed enrollment of patients with high-risk non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG). Subsequently, the result of the phase 3 BOND-003 study was announced during Society of Urologic Oncology Annual Meeting (SUOA) in December 2023.  The result of the phase 3 showed very good efficacy with little side effects which led to receiving  FDA Fast Track Designation for the treatment of patients with BCG-unresponsive CIS with or without Ta/T1 papillary disease.  

Cretostimogene grenadenorepvec (CG007) belongs to oncolytic virus technology as bellasmith posted.    Oncolytic virus uses virus such as common cold virus but edit virus DNA or RNA and remove the gene which causes sickness, then edit DNA or RNA to so the virus achieves intended behavior.   In case of CG007,  the DNA of the virus was modified so the virus enters into every cell but it only replicate itself in the cell that has an Rb deficiency or defect which is often found in bladder cancer cell.  This will ensure only bladder cancer cells will be be affected by CG0070 but not normal cells. In addition, CG0070 encodes the cDNA for human granulocyte macrophage-colony stimulating factor (GM-CSF), a cytokine known to be a potent inducer of specific, long-lasting antitumor immunity in animal model.

In short, CG0070 kills bladder cancer cells in two ways.  One is by CG0070 (the virus) replicating in bladder cancer cell and bursting the cancer cell.   The other is by the DNA of CG0070 enabling producing human granulocyte macrophage-colony stimulating factor (GM-CSF), which invokes dendritic cell, which then delivers antigen ( information) of bladder cancer to near by lymph nodes, which then produces the tumor specific T-cells which will kill bladder cancer cell.  Because CG0070 invokes immune response and those immune cells kill bladder cancer cell, CG0070 is also called oncolytic immunotherapy.  CG0070 is considered to give durability response because it invokes T-cells.  The efficacy of CG0070 exceeded the efficacy of pembrolizumab (Keytruda) immunotherapy alone for BCG Unresponsive.

Also CG0070 and Pembrolizumab (Keytruda) combination has shown better efficacy than CG0070 alone CORE-1 phase 2 clinical trial.  

The summary of efficacy of CG0070 and CG0070 + Pembrolizumab(Keytruda) immunotherapy

BOND-003 CG0070 alone Phase 3
CR at 6 months  44%   and at 12 months 28%  CG0070 alone

CORE-001  CG0070  + Pembrolizumab (Keytruda) combination  Phase 2
Complete Repose Rate   82% at 6 months, 81% at 9 months and 68% 12 months.  


Mechanism of Action of CG0070
https://lh7-us.googleusercontent.com/BaoICW3cXlRS1iWsO-xcq-WGKX10mRY-uPt1JqauBdYEFJfIcm78HPB5VXQxKkrUOIz1-2LtWdWi-Xw6WZT_iDTmzM-N0bgHPODQiT3Zl3hdwjizGrX83nFHPtKej3PbyYmb6Io81IZUTJ3Zn5u_gks


www.cancernetwork.com/view/cretostimogene-grenadenorepvec-yields-durable-responses-in-nmibc

As a clinical setting in which local live biological therapy is already well established, bladder cancer presents intriguing opportunities for oncolytic virotherapy. Bladder cancer is an ideal target for the evaluation of local oncolytic viral therapy for several reasons, including easy intravesical instillation allowing the tumor to be exposed to large titers of vector, limited systemic exposure and papillary configuration increasing surface area for topical application.

CG0070  As a selectively replicating adenovirus, CG0070 has a human E2F-1 promoter driving expression of the E1A viral gene. Besides, CG0070 also encodes the human granulocyte macrophage-colony stimulating factor (GM-CSF), which stimulates the maturation and recruitment of macrophages and dendritic cells, and GM-CSF is known to be a potent inducer of local antitumor immunity. In bladder TCC cells compared to normal human fibroblast cells, the tumor selectivity of CG0070 was indicated by the 100-fold higher replication and 1000-fold greater cytotoxicity. In normal lung fibroblast cells, expression of GM-CSF was up to 45-fold lower than in the TCC cell lines. CG0070 has shown tumor killing in orthotopic and subcutaneous human xenograft bladder tumor models. The promising preclinical data of CG0070 have led to a phase I/II clinical trial that focused on NMIBC in patients with recurrent bladder cancer after BCG treatment. The encouraging results of phase I/II clinical trial have promoted the phase II/III trials that are set to evaluate CG0070 in patients with NMIBC who have failed BCG therapy.

G207 and NV1020  G207 is a modified genetically modified herpes simplex virus (HSV) type-1 by deletions of both copies of Υ-34.5 and interruption of the UL39 gene, while NV1020 has a deletion in the TK region of the genome and a 15 kb deletion across the junction of the long and short segments of the HSV-1 genome. In animals, the treatment effect of G207 and NV1020 was compared to BCG and proved very successful. The encouraging results in bladder cancer suggest that clinical trials are needed to be performed for the further evaluation of intravesical oncolytic HSV therapies for bladder cancer.

OncoVEXGALV/CD  Another oncolytic HSV-1, OncoVEXGALV/CD expresses a potent prodrug activating gene Fcy::Fur that combines the activity of the yeast cytosine deaminase (CD) and uracil phosphoribosyltransferase (UPRT) to make cells sensitive to 5-fluorocytosine (5-FC). It also contains the fusogenic gibbon ape leukemia virus envelope (GALV) glycoprotein that can cause an anti-tumor immune response. The deletion of viral ICP34.5 gene results in tumor-selective viral replication. In the rat AY27 orthotopic bladder tumor model, an 84.5% decrease in tumor size in the presence of both OncoVEXGALV/CD and 5-FC when compared with control was observed. Multiple oncolytic mutants have shown promise in both preclinical studies in bladder cancer models and clinical studies in patients with bladder cancer. Thus, there is a huge untapped potential for oncolytic HSV to be used in the treatment of bladder cancer patients.

Reovirus  Reovirus is a naturally occurring double-stranded RNA virus that exploits altered signaling pathways (including Ras) in a myriad of cancers. Researches have demonstrated the oncolytic activity of reovirus in an orthotopic bladder tumor model. Female rats were treated with low, medium, and high doses of intravesical reovirus or BCG as control. In 90% at 100 days after tumor implantation in medium- and high-dose reovirus-instilled animals, complete tumor response was observed while the highest survival in the control groups was 50%. Oncolytic virotherapy using reovirus is a promising new anti-bladder cancer treatment with the potential for use in humans.

Vaccinia virus (VAC)  VAC, the prototype for the family Poxviridae, is a large double-stranded DNA virus that encodes numerous enzymes and factors needed for RNA and DNA synthesis, enabling it to replicate in the cytoplasm of infected cells. A phase I study of wild-type VAC was performed in patients with muscle-invasive-bladder carcinoma, for whom radical cystectomy was planned as a final treatment. This study has demonstrated that even wild-type VAC can be administered safely into the bladder and cause the recruitment of lymphocytes and induction of local inflammatory response. Besides mild local toxicity, no serious treatment-related side effects were reported. The excellent effect of intravesical VAC supports the potential use of VAC as an oncolytic agent for intravesical bladder cancer therapy.