Results of the phase I open label clinical trial SAKK 06/14 assessing safety of intravesical instillation of VPM1002BC, a recombinant mycobacterium Bacillus Calmette Guérin (BCG), in patients with non-muscle invasive bladder cancer and previous failure of conventional BCG therapy.

Background: VPM1002BC is a modified mycobacterium Bacillus Calmette Guérin (BCG) for the treatment of non-muscle invasive bladder cancer (NMIBC). The genetic modifications are expected to result in better immunogenicity and less side effects. We report on patient safety and immunology of the first intravesical application of VPM1002BC in human. Methods: Six patients with BCG failure received a treatment of 6 weekly instillations with VPM1002BC. Patients were monitored for adverse events (AE), excretion of VPM1002BC and cytokines, respectively. Results: No DLT (dose limiting toxicity) occurred during the DLT-period. No grade ≥3 AEs occurred. Excretion of VPM1002BC in the urine was limited to less than 24 hours. Plasma levels of TNFα significantly increased after treatment and blood-derived CD4+ T cells stimulated with PPD demonstrated significantly increased intracellular GM-CSF and IFN expression. Conclusion: The intravesical application of VPM1002BC is safe and well tolerated by patients and results in a potential Th1 weighted immune response.

The Recombinant Bacille Calmette-Guérin Vaccine VPM1002: Ready for Clinical Efficacy Testing.

The only licensed vaccine against tuberculosis (TB), bacille Calmette-Guérin (BCG), protects against severe extrapulmonary forms of TB but is virtually ineffective against the most prevalent form of the disease, pulmonary TB. BCG was genetically modified at the Max Planck Institute for Infection Biology to improve its immunogenicity by replacing the urease C encoding gene with the listeriolysin encoding gene from Listeria monocytogenes. Listeriolysin perturbates the phagosomal membrane at acidic pH. Urease C is involved in neutralization of the phagosome harboring BCG. Its depletion allows for rapid phagosome acidification and promotes phagolysosome fusion. As a result, BCGΔureC::hly (VPM1002) promotes apoptosis and autophagy and facilitates release of mycobacterial antigens into the cytosol. In preclinical studies, VPM1002 has been far more efficacious and safer than BCG. The vaccine was licensed to Vakzine Projekt Management and later sublicensed to the Serum Institute of India Pvt. Ltd., the largest vaccine producer in the world. The vaccine has passed phase I clinical trials in Germany and South Africa, demonstrating its safety and immunogenicity in young adults. It was also successfully tested in a phase IIa randomized clinical trial in healthy South African newborns and is currently undergoing a phase IIb study in HIV exposed and unexposed newborns. A phase II/III clinical trial will commence in India in 2017 to assess efficacy against recurrence of TB. The target indications for VPM1002 are newborn immunization to prevent TB as well as post-exposure immunization in adults to prevent TB recurrence. In addition, a Phase I trial in non-muscle invasive bladder cancer patients has been completed, and phase II trials are ongoing. This review describes the development of VPM1002 from the drawing board to its clinical assessment.

Therapeutic vaccination with an interleukin-2-interferon-gamma-secreting allogeneic tumor vaccine in patients with progressive castration-resistant prostate cancer: a phase I/II trial.

Immunotherapy with whole cell cancer vaccines has been tested in various tumor types. This study investigated the safety profile and antitumor activity of an allogeneic prostate carcinoma cell line, LNCaP, expressing recombinant human interleukin-2 and human interferon-gamma. Thirty HLA-A*0201-matched patients with progressive, castration-resistant prostate cancer received four intradermal injections on days 1, 15, 29, and 92, and then every 90 days, as long as no tumor progression occurred. Three patients received a dose level of 7.5 million cells, and 27 patients received 15 million cells per injection. The primary study criteria were safety and the difference in prostate-specific antigen doubling time (PSA-DT), determined in the pretreatment phase (before the start of vaccination) and in the trial treatment phase (during vaccination). No dose-limiting or autoimmune toxicity was seen. During vaccination there was a significant prolongation of the PSA-DT compared with the prevaccination period (prolongation from 63 to 114 days; p < 0.01; intention to treat). In addition, results showed a period of PSA stabilization of at least 12 weeks, together with stable bone scans in 12 of 30 patients, and 3 patients sustained a >50% decrease in PSA versus baseline. The median overall survival time from first vaccination was 32 months (mean value, 34 months). Immune monitoring revealed T cell stimulation in the majority of patients. This vaccine strategy was found to be safe and well tolerated and was accompanied by prolongation of PSA-DT. The results of this trial warrant clinical development of this vaccine.