Hepatitis B vaccine candidate successful in late trial with diabetic patients
Hepatitis B vaccine Heplisav-B (Dynavax) outperformed standard EngerixB (GSK) in a Phase 3 trial, which enrolled >8,000 adults aged 18–70 with type 2 diabetes. Heplisav-B conferred a seroprotection rate of 90% compared to 65% by Engerix-B. 2/3 of the subjects received two doses of Heplisav-B one month apart, and 1/3 received three doses of Engerix-B on a 0-1-6-month basis.
The License Application for Heplisav-B was rejected by the U.S. FDA in 2013, because there were concerns that autoimmune diseases were induced in the participants. In the current trial, autoimmune events were noted, but the frequency was not higher in the Heplisav-B group.
Atezolizumab promising for bladder cancer patients
The checkpoint inhibitor atezolizumab (MPDL3280A, Roche) posted encouraging results in a Phase 2 trial involving 310 subjects with locally advanced or metastatic urothelial carcinoma who failed prior chemotherapy. Treatment resulted in a 15% overall response rate and 5% complete response rate. The numbers were 26% and 11%, respectively, in patients with high levels of atezolizumab's target PD-L1.
Atezolizumab is a monoclonal antibody (MAb) designed to inhibit the PD-1 pathway responsible for downregulating the immune system's response to the presence of tumors. It was granted breakthrough therapy designation in urothelial carcinoma by the U.S. FDA. Urothelial cancer is the 9th most common cancer accounting for almost 150,000 deaths each year.
A prime-boost combination vaccine regimen against H7N9 successfully tested
A combination vaccine against H7N9 avian influenza was safe and immunogenic in a small trial led by the U.S. National Institute of Allergy and Infectious Diseases.1 A group of 65 volunteers aged 18-70 received one or two initial doses of live attenuated vaccine from MedImmune followed by a booster dose of inactivated vaccine from Sanofi 12 weeks later.
The H7N9 influenza strain is not easily transmissible from person to person, but it causes a severe illness with a high mortality rate. The virus, which was first described in China in 2013, has infected ~680 people and killed at least 275.
Sobhanie M, Matsuoka Y, Jegaskanda S, Fitzgerald T, Mallory R, Chen Z, Luke C, Treanor J, Subbarao K. Evaluation of the Safety and Immunogenicity of a Candidate Pandemic Live Attenuated Influenza Vaccine (pLAIV) Against Influenza A(H7N9). J Infect Dis 2015; doi: 10.1093/infdis/jiv526
Peanut allergy therapeutic vaccine candidate has entered Phase 3 trial
Peanut allergy patients have enrolled for a double-blind, placebo-controlled Phase 3 PALISADE trial of a therapeutic vaccine candidate AR101 (Aimmune). The trial will involve ~500 volunteers aged 4-55 in the U.S., Canada and the EU. The subjects will be given escalating doses for 22 weeks and continue to receive the maximum dose of 300 mg AR101 per day for the next 6 months. At the end of the trial, efficacy as a desensitization therapy will be tested in an exit food challenge, in which up to 1 g of the peanut protein will be administered.
China has approved two EV71 vaccines
The China FDA has approved two Enterovirus 71 (EV71) vaccines in close succession. The first one, which was developed at the Chinese Academy of Medical Sciences, showed >97% efficacy in clinical trials. The second vaccine, manufactured by Sinovac, is administered in a two-dose regimen to children aged 0.5-3 years.
EV71 causes the hand, foot and mouth disease, which is a major concern in China. It has become the most common of any diseases affecting especially children <5 years old. There were 2.7 million cases in 2014 in China with almost 400 deaths.
FDA expands approval of anti-PD1 immunotherapy of melanoma
The U.S. FDA has expanded the indication of the combination of checkpoint inhibitor MAbs nivolumab (Opdivo) and ipilimumab (Yervoy, both BMS) to unresectable or metastatic melanoma regardless of BRAF mutational status. The decision was based on the Phase 3 CheckMate-067 study, in which patients with both wild-type and BRAF-mutant tumors benefited from the combination therapy compared to ipilimumab mono-therapy.1
The FDA has also granted accelerated approval of nivolumab as monotherapy for previously untreated BRAF mutation-positive advanced melanoma.
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015; 373(1):23-34
HIV vaccine promising in a combination therapy
HIV vaccine Vacc-4x (Bionor) in combination with romidepsin (Istodax, Celgene) decreased the viral load in the Phase 1/2 REDUC trial. Out of 17 tested patients, 11 (65%) had undetectable HIV in the blood, and 4 (24%) had measurable but low levels. The treatment was safe and well tolerated.
The combination therapy employs the so-called kick-and-kill approach, in which the latent virus is activated by romidepsin, and Vacc4x induces a T-cell response against the virus-producing cells.
Combination immunotherapy of Hodgkin's lymphoma enters clinical trials
Pembrolizumab (Keytruda, Merck) will be tested in combination with AFM13 (Affimed) to treat Hodgkin's lymphoma patients, whose cancer has relapsed after previous treatment. The Phase 1b trial is designed to test safety and efficacy, as well as establish an optimal dosing regimen.
Pembrolizumab is a PD-1 pathway inhibitor MAb. AFM13 is a bispecific antibody targeting CD30 expressed by some tumors and CD16A on the surface of natural killer cells, thus bringing them in close proximity. AFM13 has shown antitumor activity as a monotherapy in clinical trials, and it was highly efficacous in combination with pembrolizumab in preclinical studies.
Progress in Ebola vaccine and immunotherapy development
A vesicular stomatitis virus-vectored Ebola vaccine candidate (Profectus BioSciences) has entered clinical trials. The dose-escalating Phase 1 study will assess safety and immunogenicity in 39 volunteers. The vaccine successfuly protected non-human primates in a previous study.
Another Ebola vaccine candidate from GSK has passed two Phase 1 trials held in Mali and the U.S. It was safe and immunogenic in a sample of >100 adults aged 18–65 years.Citation1
In addition, scientists at the Albert Einstein College of Medicine and the USAMRIID developed MAbs that were able to neutralize two deadliest Ebola strains, Zaire and Sudan, and prevent hemorrhagic fever in mouse challenge models.Citation2 The cocktail, dubbed ZMapp, contains bispecific antibodies that cross-react with surface glycoproteins of the two strains.
- Tapia MD, Sow SO, Lyke KE, Haidara FC, Diallo F, Doumbia M, Traore A, Coulibaly F, Kodio M, Onwuchekwa U, Sztein MB, Wahid R, Campbell JD, Kieny MP, Moorthy V, Imoukhuede EB, Rampling T, Roman F, De Ryck I, Bellamy AR, Dally L, Mbaya OT, Ploquin A, Zhou Y, Stanley DA, Bailer R, Koup RA, Roederer M, Ledgerwood J, Hill AV, Ballou WR, Sullivan N, Graham B, Levine MM. Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial. Lancet Infect Dis 2016; 16(1):31-42
- Frei JC, Nyakatura EK, Zak SE, Bakken RR, Chandran K, Dye JM, Lai JR. Bispecific Antibody Affords Complete Post-Exposure Protection of Mice from Both Ebola (Zaire) and Sudan Viruses. Sci Rep 2016; 6:19193