An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non–muscle-invasive bladder cancer: Interim results

Packiam, Vignesh T.; Lamm, Donald L.; Barocas, Daniel A.; Trainer, Andrew; Fand, Benjamin; Davis, Ronald L.; Clark, William R.; Kroeger, Michael; Dumbadze, Igor; Chamie, Karim; Kader, A. Karim; Curran, D.; Gutheil, John; Kuan, Arthur; Yeung, Alex; Steinberg, Gary D.

doi:10.1016/j.urolonc.2017.07.005

Cited by 162 publications

(103 citation statements)

References 24 publications

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“…The overall response rate to CG0070 was 48.6% (17 of 35), which improved to 63.6% (14 of 22) in the multidose group. Interim results from an ongoing phase 2 multicenter trial (NCT02365818) of intravesical instillation of CG0070 in 45 NMIBC patients who failed BCG therapy and had refused radical cystectomy showed an overall complete response of 47% (21/45) (45). Unfortunately, neither of the CG0070 clinical trials reported any immunohistochemical analysis of the tumor microenvironment to fully elucidate both the mechanism of action of CG0070 and potential immune activation.…”

Section: The Urinary Microbiome: a Potential Emerging Factor In The Imentioning

confidence: 99%

“…Unfortunately, neither of the CG0070 clinical trials reported any immunohistochemical analysis of the tumor microenvironment to fully elucidate both the mechanism of action of CG0070 and potential immune activation. However, it is presumed that CG0070 works through direct tumor lysis by selective replication in Rb pathway-defective tumor cells and through immune-mediated killing resulting from immunogenic cell death and immune activation induced by the local GM-CSF production (45). Importantly, intravesical oncolytic virus therapy was extremely well-tolerated in all of the above clinical trials and thus may offer an alternative to the 40-year-old standard of care, BCG therapy, but without its limiting toxicities.…”

Section: The Urinary Microbiome: a Potential Emerging Factor In The Imentioning

confidence: 99%

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Modifying the Non-muscle Invasive Bladder Cancer Immune Microenvironment for Optimal Therapeutic Response

2020

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It is now well-recognized that the tumor microenvironment (TME) is not only a key regulator of cancer progression but also plays a crucial role in cancer treatment responses. Recently, several high-profile publications have demonstrated the importance of particular immune parameters and cell types that dictate responsiveness to immunotherapies. With this increased understanding of TME-mediated therapy, approaches that increase therapeutic efficacy by remodeling the TME are actively being pursued. A classic example of this, in practice by urologists for over 40 years, is the manipulation of the bladder microenvironment for the treatment of non-muscle invasive bladder cancer (NMIBC) by instillation of intravesical bacillus Calmette-Guerin (BCG). The success of BCG treatment is thought to be due to its ability to induce a massive influx of Th1-polarized inflammatory cells, production of Th1 inflammatory cytokines and the generation of tumor-targeted Th1-mediated cytotoxic responses. Whilst BCG immunotherapy is currently the best treatment for NMIBC, ∼30% of patients show no response to this treatment. Here we present a review highlighting a variety of promising alternative immunotherapies being developed that remodel the bladder tumor microenvironment. These include (1) the use of oncolytic viruses which selectively replicate within cancer cells whilst also modifying the immunological components of the TME, (2) manipulation of the bladder microbiome to augment the response to BCG or other immunotherapies (3) utilizing Toll-like Receptor agonists as anti-tumor agents due to their potent stimulation of innate and adaptive immunity and (4) the growing recognition that immunotherapeutic strategies that will have the largest impact on patients may require multiple therapeutic approaches combined together. The accumulating knowledge on TME remodeling holds promise for providing an alternative therapy for patients with BCG-unresponsive NMIBC.

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Section: The Urinary Microbiome: a Potential Emerging Factor In The Imentioning

confidence: 99%

Section: The Urinary Microbiome: a Potential Emerging Factor In The Imentioning

confidence: 99%

Modifying the Non-muscle Invasive Bladder Cancer Immune Microenvironment for Optimal Therapeutic Response

2020

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“…CG0070 is a GM‐CSF expressing replication‐competent oncolytic adenovirus that targets bladder tumor cells through their defective retinoblastoma pathway, thereby allowing for selective viral replication in tumor cells and the local production of GM‐CSF . In a phase II trial, the 6‐month CR rate was 47% in all patients with residual high‐grade Ta/T1 or CIS with or without Ta/T1 BCG‐unresponsive NMIBC (NCT02365818) . BC‐819 (inodiftagene vixteplasmid) is a recombinant DNA plasmid that directs the expression of an encoded lethal toxin (diphtheria toxin A) specifically in malignant cells, but not in normal tissue.…”

Section: Current Clinical Trials On Bcg‐unresponsive Nmibc Except Fomentioning

confidence: 99%

“…77 In a phase II trial, the 6-month CR rate was 47% in all patients with residual high-grade Ta/T1 or CIS with or without Ta/T1 BCG-unresponsive NMIBC (NCT02365818). 78 BC-819 (inodiftagene vixteplasmid) is a recombinant DNA plasmid that directs the expression of an encoded lethal toxin (diphtheria toxin A) specifically in malignant cells, but not in normal tissue. It has been designed to exploit the established biology of the H19 gene, which is only expressed at high levels in a number of malignancies and upregulated in malignant cell processes.…”

Section: Gene Therapymentioning

confidence: 99%

Bacillus Calmette–Guérin‐unresponsive non‐muscle‐invasive bladder cancer: Its definition and future therapeutic strategies

et al. 2019

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Bacillus Calmette–Guérin induction with or without maintenance is the gold standard therapy for intermediate‐/high‐risk non‐muscle‐invasive bladder cancer; however, one‐third of patients treated with adequate bacillus Calmette–Guérin therapy do not achieve sufficient responses, and this is referred to as “bacillus Calmette–Guérin failure.” The term, bacillus Calmette–Guérin failure, is ambiguous and includes a very heterogeneous population of patients. By strictly focusing on patients who are unlikely to benefit from additional bacillus Calmette–Guérin therapy and who need to be treated with radical cystectomy, the new concept of “bacillus Calmette–Guérin unresponsive” was recently proposed, and might accelerate the development of novel therapeutic options for bacillus Calmette–Guérin‐unresponsive disease. A promising therapeutic strategy for bacillus Calmette–Guérin‐unresponsive disease is the blockade of the programmed cell death‐1/programmed cell death‐ligand 1 pathway, which is considered to be activated by bacillus Calmette–Guérin therapy. Several large clinical trials have been carried out to assess the potential of programmed cell death‐1/programmed cell death‐ligand 1 blockade in bacillus Calmette–Guérin‐naïve high‐risk non‐muscle‐invasive bladder cancer and bacillus Calmette–Guérin‐unresponsive disease. Furthermore, clinical trials that are targeting bacillus Calmette–Guérin‐unresponsive disease with other strategies, such as vaccines, gene therapy, and targeted and cytotoxic therapies, are ongoing. The findings of these trials are awaited in order to establish appropriate bladder‐sparing approaches for patients with bacillus Calmette–Guérin‐unresponsive disease.

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“…Some OVs can cross the blood-brain barrier (BBB) to kill brain tumor cells, such as reovirus [7] and parvovirus H-1 (H-1PV) [8], and OVs can turn "cold" tumors into "hot" tumors, thereby increasing the cellular sensitivity to other immunotherapies [9,10]. To date, many OVs, including DNA viruses, such as adenovirus (AdV) [11,12], vaccinia virus (VACV) [13,14], herpesvirus [15,16], and parvovirus [17] and RNA viruses, such as reovirus [18,19], Newcastle disease virus (NDV) [20], and measles virus (MV) [21] (Table 1) have been evaluated for cancer treatment (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Development of oncolytic virotherapy: from genetic modification to combination therapy

et al. 2020

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Oncolytic virotherapy (OVT) is a novel form of immunotherapy using natural or genetically modified viruses to selectively replicate in and kill malignant cells. Many genetically modified oncolytic viruses (OVs) with enhanced tumor targeting, antitumor efficacy, and safety have been generated, and some of which have been assessed in clinical trials. Combining OVT with other immunotherapies can remarkably enhance the antitumor efficacy. In this work, we review the use of wild-type viruses in OVT and the strategies for OV genetic modification. We also review and discuss the combinations of OVT with other immunotherapies.

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An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non–muscle-invasive bladder cancer: Interim results

Cited by 162 publications

References 24 publications

Modifying the Non-muscle Invasive Bladder Cancer Immune Microenvironment for Optimal Therapeutic Response

Modifying the Non-muscle Invasive Bladder Cancer Immune Microenvironment for Optimal Therapeutic Response

Bacillus Calmette–Guérin‐unresponsive non‐muscle‐invasive bladder cancer: Its definition and future therapeutic strategies

Development of oncolytic virotherapy: from genetic modification to combination therapy

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