Preclinical evaluation of VAX-IP, a novel bacterial minicell-based biopharmaceutical for nonmuscle invasive bladder cancer

Tsuji, S.; Chen, Xuguang; Hancock, Bryan; Hernández, Vicent; Visentin, Barbara; Reil, Katherine; Sabbadini, Roger A.; Giacalone, Matthew J.; Godbey, W.T.

doi:10.1038/mto.2016.4

Cited by 19 publications

(18 citation statements)

References 49 publications

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“…As described herein and elsewhere, VAX014 selectively kills tumor cells expressing unligated α3β1/α5β1 integrins (15). Both the α3β1 and α5β1 integrin family members may be of particular relevance in the context of re-seeding of tumor cells post-TURBT in NMIBC.…”

Section: Discussionmentioning

confidence: 58%

“…VAX014 (invasin-positive, pfopositive), VAX-P (invasin-negative, pfo-positive) and VAX-I (invasinpositive, pfo-negative) minicells were generated from recombinant minicell-producing E. coli strains as previously described (15).…”

Section: Methodsmentioning

confidence: 99%

“…The anti-implantation variation of the MB49 model serves as a surrogate for the immediate postoperative treatment of NMIBC and can be useful in the pharmacological assessment of agents being investigated for this purpose (11,14). Characterized in an earlier report under the research name VAX-IP, VAX014 recombinant Escherichia coli bacterial minicells (VAX014 hereafter) have been engineered to express invasin from Yersinia pseudotuberculosis to selectively target and deliver a novel bacterial protein toxin, perfringolysin O (PFO), to human and murine urothelial carcinoma cells (UCCs) expressing α3β1 or α5β1 (15). The mechanism of action of VAX014 is rapid permeabilization of target cell plasma membranes and simultaneous induction of apoptosis.…”

Section: Been Previously Characterized As An Integrin-specific Oncolymentioning

confidence: 99%

“…The establishment of syngeneic orthotopic tumors in the MB49 murine bladder cancer model was performed as previously described using four mice per group for anti-implantation experiments and 8-10 mice per group for survival experiments (15,16). After creation of urothelial burn injuries in all animals, 10 5 MB49 cells (in 50 μl of DMEM with 10% FBS) were instilled via transurethral catheterization into the bladders of anesthetized mice and catheters kept in place for 60 min to prevent voiding.…”

Section: Anti-implantation and Survival Experimentsmentioning

confidence: 99%

“…Bladders were removed and drained, and bladder weights were recorded as a surrogate measure of tumor burden ( Figure 2A). Dosages of 1×10 8 minicells were used based on our previous findings using multiple administrations in mice with well-established MB49 bladder tumors (15). This experiment demonstrated show that a single dose of 1×10 8 VAX014 significantly reduced tumor growth and development, compared to saline-treated controls: the VAX014-treated group had a median bladder weight of 27 mg (range of 24-129 mg) versus the saline-treated group which had a median bladder weight of 217 mg (range of 164-257 mg) (p=0.029).…”

Section: Vax014 Is Capable Of Rapidly Killing a Panel Of Dissociatementioning

confidence: 99%

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A Single Intravesical Instillation of VAX014 Inhibits Orthotopic Superficial Bladder Tumor Implantation to Increase Survival

Hancock

McGuire

Tsuji

et al. 2016

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Abstract. Background/Aim: VAX014 minicells (VAX014) Bladder cancer ranks second amongst newly diagnosed urothelial carcinomas worldwide, is the sixth leading cause of cancer death and the fourth most common malignancy of men in developed countries (1). Current estimates suggest that as many as 75-80% of patients with bladder cancer present for the first time with localized non-muscle invasive bladder cancer (NMIBC). It is further estimated that of those newly diagnosed NMIBC cases, 70% present with what the European Association of Urologists classifies as low-risk disease (2).Current recommended clinical practice for the treatment of low-risk NMIBC is cystoscopic transurethral resection of bladder tumor (TURBT) followed by an immediate postoperative intravesical instillation of a chemotherapeutic agent. Without adjuvant treatment, as many as 35.8% of patients treated for low-risk NMIBC will suffer recurrence within 2 years (3). There have been several studies and meta-analyses published indicating that the immediate postoperative instillation of adjuvant therapy may lead to a decrease in the overall risk of recurrence of up to 39%, with absolute reduction in recurrence rates as high as 17% (4). While clearly effective in reducing recurrence, several recently conducted surveys have revealed that immediate single-dose post-operative adjuvant therapy is not consistently administered (5, 6). A prominently cited reason among those clinicians who do not administer immediate post-operative chemotherapy is that the potential for systemic exposure and agent-associated toxicity outweighs the clinical benefit, especially in cases where bladder perforation is suspected. The perceived clinical benefit-torisk ratio argument seems justified given that while patients with low-and intermediate-risk NMIBC have a high rate of recurrence, the initial risk of progression is low (0.8% and 6% at 5 years, respectively) (2). However, the risk of progression increases with the number and interval of recurrences, so any initial prevention or delay of recurrence would be of clear benefit (2). Moreover, because of the high rate of recurrence, frequent monitoring and treatment are required, making NMIBC one of the most expensive cancer types to treat over the course of the disease (7). Therefore, an effective agent for use in the immediate post-operative setting would impart considerable pharmacoeconomic benefit. Recent failures in mid-and late-stage clinical trials highlight the unmet clinical need for the development of new agents that can be safely administered in the immediate post-operative setting (8).

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Section: Discussionmentioning

confidence: 58%

Section: Methodsmentioning

confidence: 99%