China
Africa
Explore chapters and articles related to this topic
Bacteria-Derived Alternatives to Live Mycobacterium bovis Bacillus Calmette–Guerin for Nonmuscle Invasive Bladder Cancer Treatment
Published in Ananda M. Chakrabarty, Arsénio M. Fialho, Microbial Infections and Cancer Therapy, 2019
Esther Julián, Estela Noguera-Ortega
A fusion protein combining Pseudomonas exotoxin A and transforming growth factor alpha (TP-40) was designed to specifically bind the epidermal growth factor receptor (EGFR), which is overexpressed on BC cells [96]. Although no treatment-associated toxicity was observed in a phase I clinical trial, this fusion protein only conferred advantageous outcomes in carcinoma in situ (CIS) patients and not in Ta/T1 patients [97]. Following a similar strategy, oportuzumab monatox (OM) was created as a fusion of the humanized antibody against the epithelial cell adhesion molecule (EpCAM) and the Pseudomonas exotoxin A. This fusion protein binds to the BC cell surface, is internalized, and drives apoptosis of BC cells [98]. Since EpCAM is mainly expressed in malignant cells and its expression correlates with BC cell grade, as more EpCAM is expressed in higher-grade cells [99], this therapy specifically targets BC cells. This therapy has been administered to BCG-refractory or BCG-intolerant patients in phase I and II trials. The results of the phase I trial showed that the therapy did not cause severe side effects and that it was more effective in T1 and Ta patients than in CIS patients [99]. In the phase II trial, 44% of the patients completely responded but some of them experienced recurrences [100]. In view of these promising results, in May of 2015, a phase III study started to recruit patients in whom BCG failed (NCT02449239).
Antibodies to watch in 2023
Published in mAbs, 2023
Hélène Kaplon, Silvia Crescioli, Alicia Chenoweth, Jyothsna Visweswaraiah, Janice M. Reichert
Discontinuation of an antibody therapeutic after a marketing application has been submitted to a regulatory agency is highly unusual, with fewer than a half-dozen cases occurring in the past 20 y. Oportuzumab monatox (Vysyneum™, Vicineum), an immunotoxin composed of a humanized anti-epithelial cell adhesion molecule scFv linked to ETA(252–608) Pseudomonas exotoxin, seems poised to join this select group, but its final fate is still uncertain. Sesen Bio, Inc. developed oportuzumab monatox for the treatment of BCG-unresponsive non-muscle invasive bladder cancer, and submitted a BLA and MAA to FDA and EMA, respectively, for this indication. In August 2021, however, the company received a complete response letter from the FDA that recommended additional clinical/statistical data and analyses, and then withdrew the MAA. In 2022, Sesen announced a voluntary pause on further development of the asset, underwent a company restructuring, and then entered into a definitive merger agreement with Carisma Therapeutics Inc, which develops cell and gene therapies.174 Sesen had previously licensed certain rights to oportuzumab monatox in Greater China, the Middle East and North Africa, and Turkey to Qilu Pharmaceutical Co., Hikma Pharmaceuticals Plc Ltd., and Eczacibasi Pharmaceuticals Marketing Co., respectively. We await further news of progress (or the lack of it) from these companies.
The emerging role of antibody-drug conjugates in urothelial carcinoma
Published in Expert Review of Anticancer Therapy, 2020
Michael Lattanzi, Jonathan E. Rosenberg
A phase I dose escalation study was also carried out with intravesical oportuzumab monatox in NMIBC [107]. A total of 64 patients with BCG-refractory (or BCG-ineligible) NMIBC grade 2 or 3 and stage Ta or T1 or patients with carcinoma in situ were enrolled. Treatment was well-tolerated, and the maximum tolerated dose was not reached. Encouragingly, 39% of patients achieved a complete response at twelve weeks by cystoscopy and cytology. To better characterize the efficacy of this agent, investigators carried out a two-cohort phase II study of oportuzumab monatox (OM) in BCG-refractory urothelial carcinoma in situ [108]. Cohort 1 received an induction of 6 weekly doses intravesical OM, while cohort 2 received a twelve-dose induction; all patients were eligible for up to three maintenance cycles. Toxicities were generally mild and related to direct irritation of the bladder. Of 45 evaluable patients, 20 (44%) achieved a complete response, which is noteworthy given the lack of effective cystectomy-sparing local therapies in the BCG-refractory setting and the potential for immune-mediated adverse events with systemic anti-PD-1 immunotherapy. Unfortunately, only 16% of responses were ongoing at last follow-up (18–25 months), with a median time to recurrence of 274 days and 408 days in cohorts 1 and 2, respectively. A phase I trial is underway investigating the safety of intravesical OM in combination with the systemic PD-L1 antibody durvalumab (NCT03258593).
Antibodies to watch in 2019
Published in mAbs, 2019
Hélène Kaplon, Janice M. Reichert
This immunotoxin is composed of a recombinant humanized antibody scFv targeting epithelial cell adhesion molecule (EpCAM) conjugated to Pseudomonas aeruginosa exotoxin A.85 Once bound to EpCAM expressed by cancer cells, oportuzumab monatox is internalized into the cytoplasm, where it induces apoptosis. Oportuzumab monatox was granted US and EU Orphan Drug designations in 2005, and FDA’s Fast Track designation for non-muscle invasive bladder cancer (NMIBC) that is unresponsive to treatment with bacillus Calmette-Guérin (BCG) in August 2018.86 The efficacy and tolerability of intravesical Vicinium™ is being evaluated in the open-label, multicenter Phase 3 VISTA study (NCT02449239) of NMIBC patients previously treated with BCG. Enrollment was completed in March 2018 with a total of 133 patients with high-grade NMIBC that is either carcinoma in situ (CIS) or papillary with or without CIS, who have been previously treated with BCG. The primary endpoint is the complete response rate in patients with CIS with or without papillary disease. In an analysis assessing pooled CIS patients (n = 77), Vicinium treatment resulted in a complete response rate of 42% at three months.87 Sesen Bio expects to provide a six-month update from the VISTA study in December 2018, and is on track to report 12-month VISTA study data in mid-2019.88 Positive results could allow a BLA submission by the end of 2019.