Novel Prophylactic Vaccine Using a Prime-Boost Method and Hemagglutinating Virus of Japan-Envelope against Tuberculosis

Objective. Mycobacterium tuberculosis infection is a major global threat to human health. The only tuberculosis (TB) vaccine currently available is bacillus Calmette-Guérin (BCG), although it has no efficacy in adults. Therefore, the development of a novel vaccine against TB for adults is desired. Method. A novel TB vaccine expressing mycobacterial heat shock protein 65 (HSP65) and interleukin-12 (IL-12) delivered by the hemagglutinating virus of Japan- (HVJ)- envelope was evaluated against TB infection in mice. Bacterial load reductions and histopathological assessments were used to determine efficacy. Results. Vaccination by BCG prime with IgHSP65+murine IL-12/HVJ-envelope boost resulted in significant protective efficacy (>10, 000-fold versus BCG alone) against TB infection in the lungs of mice. In addition to bacterial loads, significant protective efficacy was demonstrated by histopathological analysis of the lungs. Furthermore, the vaccine increased the number of T cells secreting IFN-γ. Conclusion. This vaccine showed extremely significant protection against TB in a mouse model, consistent with results from a similar paper on cynomolgus monkeys. The results suggest that further development of the vaccine for eventual testing in clinical trials may be warranted

Preclinical study and clinical trial of a novel therapeutic vaccine against multi-drug resistant tuberculosis

[Purpose] Multi-drug resistant (MDR), Mycobacterium tuberculosis (TB) is a big problem in the world. We have developed novel TB therapeutic vaccine (HVJ-E/HSP65 DNA +IL-12 DNA). [Methods and Results] DNA vaccine expressing TB heat shock protein 65 and IL-12 was delivered by the hemagglutinating virus of Japan (HVJ)-envelope. This vaccine provided remarkable protective efficacy and strong therapeutic efficacy against MDR-TB and XDR-TB in murine models. Furthermore, this vaccine provided therapeutic efficacy of prolongation of survival time of TB infected monkeys and augmented the immune responses. Therefore, the preclinical tests were studied for clinical trial. The injection of 100 μg of the vaccine /mouse i.m. three times in two weeks induced significantly strong production of IFN-γ and IL-2. 100 μg and 200 μg DNA vaccine/mouse i.m. augmented the production of these cytokines compared with 25 μg DNA vaccine/mouse i.m.. The ratio of 100 μg pDNA to 1AU HVJ-E enhanced the production of IFN-γ and IL-2. The decrease in the number of M. tuberculosis in liver of mice was observed by the vaccination of 100μg pDNA. By using these conditions, safety pharmacology study and toxicology test is being studied in monkeys administered by GMP level DNA vaccines. By the toxicology test using monkeys, high dose GMP level vaccine/ monkey is administrated. Safety pharmacological study of repeated administration is also being investigated in GLP level. Furthermore, we have planned to do clinical phase I trial. Targets are human patients with MDR-TB. The safety and tolerability of the vaccine will be evaluated. [Conclusion and recommendations] These data indicate that our novel vaccine might be useful against tuberculosis including XDR-TB and MDR-TB for human therapeutic clinical applications

Good response to leucovorin and fluorouracil plus oxaliplatin and cetuximab therapy in a patient with metastatic ascending colon cancer harboring a KRAS p.G13D mutation

The effectiveness of cetuximab (Cmab) against KRAS p.G13D mutant-type tumors has been reported. In this study, we report a case of metastatic ascending colon cancer harboring a KRAS p.G13D mutation in a 65-year-old female. Considering the absence of symptoms and the post-operative risk of respiratory system complications due to multiple lung metastases, particularly at the entrance to the left main bronchus, anticancer drug therapy was selected as first-line therapy. With informed consent, FOLFOX4 [folinic acid (FOL), fluorouracil (F) plus oxaliplatin (OX)] + Cmab therapy was administered as preoperative chemotherapy. A good preoperative response was obtained to the chemotherapy, with a metastatic lesion disappearing from the entrance to the left main bronchus. Subsequent resection was performed successfully with no post-operative complications. Although a histopathological examination of the resected tissue specimen revealed residual cancer cells, it also showed the marked efficacy of the chemotherapy regimen used. In this study, we describe a case of metastatic ascending colon cancer harboring a KRAS p.G13D mutation in which the patient responded well to first-line therapy with FOLFOX4 + Cmab