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Phase I neoadjuvant study of intravesical recombinant fowlpox-GM-CSF (rF-GM-CSF) or fowlpox-TRICOM (rF-TRICOM) in patients with bladder carcinoma

Abstract

Intravesical BCG is a highly effective treatment for high-grade nonmuscle invasive bladder cancer and carcinoma in situ (CIS); however, for patients who are either resistant or become unresponsive to BCG therapy there is a need for alternative treatment approaches. This study examined the safety and feasibility of intravesically administered recombinant fowlpox virus encoding GM-CSF (Arm A) or TRICOM (Arm B); and the local and systemic immunologic responses generated to the vector(s). Twenty bladder cancer patients scheduled for cystectomy as their standard of care received preoperatively four weekly doses of intravesical recombinant fowlpox. Treatment was well tolerated, however, three patients experienced transient elevations of liver transaminases, with one rising to the level of a DLT. Cystectomy derived tumor and normal bladder mucosa demonstrated mRNA for the virally encoded LacZ gene supporting effective infection/transfection. Detected serum antibody to the LacZ encoding β-galactosidase indicated successful expression of vector-encoding gene products and the ability to immunize via the bladder site. H&E and IHC using a panel of immune cell specific antigens demonstrated immune cell infiltration of the bladder wall. These findings demonstrate good safety profile, successful infection/transfection, ability to generate systemic immune response, and local recruitment of immune cell populations with intravesical administration of fowlpox-based constructs encoding for GM-CSF(rF-GM-CSF) or TRICOM (rF-TRICOM), and support further evaluation of this treatment modality for bladder cancer.

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Acknowledgements

Studies made use of the Rutgers Cancer Institute of New Jersey Biospecimen and Immunohistochemistry and Research Pharmacy, Shared Resources.

Funding

This trial was supported by the Cancer Therapy Evaluation Program (CTEP), a division of the National Cancer Institute (NCI/CTEP #5585, U01CA132194), R21CA121589, and a grant from the National Cancer Institute (P30CA072720). The fowlpox vaccine, rF-GM-CSF (NSC 707299) and rF-TRICOM (NSC 710658), was manufactured by Therion Biologics Corporation and supplied by the Pharmaceutical Management Branch, CTEP, DCTD, NCI.

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Correspondence to Edmund C. Lattime.

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Conflict of interest

ECL is an inventor of the patented recombinant vaccinia GM-CSF that has been licensed to Sillajen and is being studied as JX-594 (Pexa-Vec). As such, he derives royalties and licensing fees from the Thomas Jefferson University where the patent is held. EAS receives research funding from Astellas/Medivation. The remaining authors declared no potential conflicts.

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Portal, D.E., Weiss, R.E., Wojtowicz, M. et al. Phase I neoadjuvant study of intravesical recombinant fowlpox-GM-CSF (rF-GM-CSF) or fowlpox-TRICOM (rF-TRICOM) in patients with bladder carcinoma. Cancer Gene Ther 27, 438–447 (2020). https://doi.org/10.1038/s41417-019-0112-z

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