RTS,S/AS01 partially successful in preventing malaria in children
Malaria vaccine candidate RTS,S/AS01 (GSK) provided substantial protection in children from sub-Saharan Africa, according to a study published in The Lancet 1. The Phase 3 clinical trial followed >15,000 infants (aged 6-12 weeks at first dose) and children (5-17 months) who received 3 prior injections, and investigated an effect of a booster dose administered 18 months later. Vaccine efficacy in the first part of this Phase 3 trial was 46% against clinical malaria in children and 27% among young infants.
“An average of 1,363 cases of clinical malaria were prevented over 4 years of follow-up for every 1,000 children vaccinated, and 1,774 cases in those who also received a booster shot. Over 3 years of follow-up, an average 558 cases were averted for every 1,000 infants vaccinated, and 983 cases in those also given a booster dose,” senior author Brian Greenwood said in a press release. With ∼200 million cases annually, this efficacy translates into millions of cases of potentially prevented malaria.
There is no available vaccine against malaria, which kills ∼1,300 children every day. RTS,S/AS01 is the first vaccine to reach this stage of development. “The European Medicines Agency (EMA) will assess the quality, safety and efficacy of the vaccine based on these final data. If the EMA gives a favorable opinion, WHO could recommend the use of RTS,S/AS01 as early as October this year,” concludes Dr. Greenwood.
1. RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomized, controlled trial. Lancet 2015; doi: 10.1016/S0140-6736(15)60721-8
Malaria antibodies recruit complement to protect children from the disease
Infusion of purified malaria-specific antibodies can protect from clinical malaria and parasitemia, according to a study published in Immunity1. Researchers tested a group of 206 children from Papua New Guinea aged 5-14 years and monitored them for 6 months.
According to the study, the antibodies recruited proteins of complement to prevent the parasite from invading erythrocytes. James Beeson, a senior author and head of the Burnet Centre for Biomedical Research in Melbourne, hopes that this finding will pave a way to a vaccine. “It's a really important first step but there are a number of questions to address before we can develop a highly effective vaccine.”
Malaria kills ∼600,000 people annually and affects mainly children in Africa. Despite extensive effort, an effective vaccine is still lacking.
1. Boyle MJ, Reiling L, Feng G, Langer C, Osier FH, Aspeling-Jones H, Cheng YS, Stubbs J, Tetteh KK, Conway DJ, McCarthy JS, Muller I, Marsh K, Anders RF, Beeson JG. Human Antibodies Fix Complement to Inhibit Plasmodium falciparum Invasion of Erythrocytes and Are Associated with Protection against Malaria. Immunity 2015; 42:580-90
PD-1 Inhibitor promising in treatment of triple-negative breast cancer
Anti-PD-1 antibody (MPDL3280A, Roche) showed lasting activity in metastatic triple-negative breast cancer patients. The Phase 1 trial enrolled 54 women, who were administered MPDL3280A every 3 weeks. In 21 patients evaluable for efficacy after one year, the overall response rate was 19% and progression-free survival at 24 weeks was 27%, with 2 complete and 2 partial responses.
“This is very exciting because longer responses are not typical of what occurs when patients with metastatic triple-negative breast cancer are treated with chemotherapy,” Leisha Emens of Johns Hopkins Kimmel Cancer Center said in a statement.
MPDL3280A was relatively safe, with the most common adverse events being fatigue, nausea, fever, decreased appetite, and weakness.
Broadly-neutralizing-antibody treatment suppresses HIV viremia
A new broadly neutralizing antibody 3BN117 eliminated HIV from blood of infected individuals. In a Phase 1 dose-escalation study, a single intravenous injection of the antibody resulted in up to 300-fold decrease in virus levels. The results were published in Nature 1.
3BN117 targets the CD4-binding site on the HIV envelope. It is the first new-generation HIV antibody to have been tested in humans. “What's special about these antibodies is that they have activity against over 80 percent of HIV strains, and they are extremely potent,” co-first author of the study Marina Caskey of Rockefeller University said in a press release.
3BN117 was well tolerated and had the strongest effect after one week. Half of the individuals receiving the highest dose showed lower-than-starting levels of HIV at the end of the 8-week study period.
1. Caskey M, Klein F, Lorenzi JC, Seaman MS, West AP Jr, Buckley N, Kremer G, Nogueira L, Braunschweig M, Scheid JF, Horwitz JA, Shimeliovich I, Ben-Avraham S, Witmer-Pack M, Platten M, Lehmann C, Burke LA, Hawthorne T, Gorelick RJ, Walker BD, Keler T, Gulick RM, Fätkenheuer G, Schlesinger SJ, Nussenzweig MC. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 2015; doi: 10.1038/nature14411
CART-meso immunotherapy improved anti-tumor response in early trial
Personalized cancer therapy CART-meso induced immune cells to target tumor sites in 5 patients with advanced mesothelioma (2), ovarian (2) and pancreatic (1) cancers. The response lasted for up to 28 days. The Phase 1 trial enrolled patients who stopped responding to conventional treatments.
CAR T therapy is based on adoptive-cell-transfer approach, in which patient's own T cells are collected and genetically engineered to express a chimeric antigen receptor (CAR) that recognizes a tumor-specific surface antigen, in this case mesothelin. The cells are subsequently grown in vitro and infused back into the patient.
The subjects experienced no major adverse events, and normal tissue was not attacked. Now the patients will be closely monitored for 15 years to further assess CAR T cells’ persistence and anti-tumor activity.
Two Ebola vaccine candidates pass phase 2, three others in phase 1
Ebola vaccines rVSV-ZEBOV (Merck) and ChAd3-EBO Z (GSK) were safe in a double-blind Phase 2 trial led by the U.S. National Institute of Allergy and Infectious Diseases in Liberia. The joint effort is now recruiting ∼27,000 people at risk of Ebola infection for a Phase 3 study. Another Phase 3 trial for rVSV-EBOV is underway in Sierra Leone, where it is tested in 6,000 frontline healthcare workers.
There are at least three other candidates in Phase 1 trials: Johnson & Johnson's, Novavax’ and most recently results were announced for a vaccine developed by Beijing Institute of Biotechnology and Tianjin CanSino Biotechnology. In a double-blind, placebo-controlled trial conducted in China, the candidate proved safe and immunogenic in 120 healthy individuals.
The Ebola epidemic in West Africa is estimated to have killed almost 11,000 people with >26,000 infections according to the World Health Organization.
Combination immunotherapy mitigated metastatic melanoma in early trial
The anti-CTLA-4 inhibitor tremelimumab together with CD40-specific antibody showed promise in fighting metastatic melanoma. 24 patients were enrolled in a Phase 1 trial led by University of Pennsylvania School of Medicine researchers, and received tremelimumab every 12 weeks and anti-CD40 every 3 weeks.
After a median follow-up of 22 months, the immunotherapy was safe and elicited complete responses in 2 subjects and partial response in 4 others. “There was clear, clinical evidence of response to this combination, even in some patients with highly morbid, visceral disease,” David Bajor of Penn Medicine said in a statement.
Both drugs are monoclonal antibodies. Tremelimumab targets and inhibits T-cell surface protein CTLA-4, which suppresses the immune system. CD40 antibody is a CD40 receptor agonist. Both help to boost the immune system in fighting cancer tissue.
Tetanus toxoid helps dendritic cell vaccines fight glioblastoma
Tetanus toxoid can boost the immune system for increased efficacy of a dendritic cell (DC) vaccine against glioblastoma. In an early clinical trial published in Nature 1, 13 patients with newly diagnosed glioblastoma received a DC vaccine either alone or following prior injection of tetanus toxoid. The latter group showed increased DC migration into lymph nodes and survival of >36 months compared with 19 months in DC-alone group.
In DC immunotherapy, patient's own DCs are genetically engineered to express a tumor-specific protein, after which they are injected back into the body to elicit a T-cell response. In this case, DCs expressed a cytomegalovirus (CMV)-specific antigen, as CMV infection is a common marker of glioblastoma, contributing to tumor formation and/or progression.
In a mouse model, the researchers found that the tetanus booster caused a CCL3 chemokine-mediated inflammatory response that helped the DCs migrate to lymph nodes.
1. Mitchell DA, Batich KA, Gunn MD, Huang MN, Sanchez-Perez L, Nair SK, Congdon KL, Reap EA, Archer GE, Desjardins A, Friedman AH, Friedman HS, Herndon JE 2nd, Coan A, McLendon RE, Reardon DA, Vredenburgh JJ, Bigner DD, Sampson JH. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 2015; 519:366-9
37. million doses of pentavalent Shan5 ready for the developing world
Sanofi's Shantha Biotechnics is ready to supply 37 million doses of its low-cost Shan5 vaccine. The first 400,000 doses have been delivered to children in Indian regions of Gwalior and Jabalpur.
Shan5 protects against diphtheria, tetanus, pertussis, Hib and hepatitis B. It received a World Health Organization's prequalification last year, based on auditors’ inspections of Shantha's facilities. 5 years ago, 24 million doses of Shan5 had to be withdrawn from 7 countries due to manufacturing problems.
Personalized immunotherapy tested in skin and ovarian cancers
Personalized DC-based immunotherapy was safe and immunogenic in advanced melanoma patients. Researchers from Washington University in St. Louis identified mutated tumor-specific surface proteins by sequencing healthy and cancer tissue from three subjects, computationally predicted those that are most likely immunogenic, and expressed these neoantigens in patients’ DCs, which were subsequently implanted back into the patients.
According to the results published in Science 1, the neoantigens were presented and elicited strong T-cell response. “The tumor antigens we inserted into the vaccines provoked a broad response among the immune system's killer T cells responsible for destroying tumors. Our results are preliminary, but we think the vaccines have therapeutic potential based on the breadth and remarkable diversity of the T-cell response,” senior author Gerald Linette said in a press release.
In another application of personalized immunotherapy, researchers at Texas Oncology delayed recurrence in stage 3 and 4 ovarian cancer patients. The Phase 2 trial enrolled 31 women after surgery, of which 20 received treatment. While in the control group the tumor returned after a median of 14.5 months, the median was not reach in the immunotherapy-treated group at the time of the report. In addition, the treatment was well tolerated.
“This was a preliminary study with promising results that may give women with advanced ovarian cancer an option for a maintenance regimen,” Jonathan Oh of Texas Oncology said in a statement.
1. Carreno BM, Magrini V, Becker-Hapak M, Kaabinejadian S, Hundal J, Petti AA, Ly A, Lie WR, Hildebrand WH, Mardis ER, Linette GP. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 2015; doi: 10.1126/science.aaa3828
Vaccinating boys against HPV can by cost-effective prevention of oropharyngeal cancer
Vaccinating 12-year-old boys against HPV is cost-effective in preventing oropharyngeal cancer, according to a study published in Cancer 1. A statistical model applied to a cohort of >190,000 Canadian boys born in 2000 revealed that vaccination at age 12 could save $8-28M with respect to prevention of oropharyngeal cancer.
“We believe this study is important because HPV-related oropharyngeal cancer has increased significantly in incidence, especially in developed countries,” Donna Graham of the Princess Margaret Cancer Centre in Toronto said in a press release. “It is projected that by 2020, HPV-related oropharyngeal cancer will become the most common HPV-related cancer in the US, surpassing cervical cancer.”
1. Graham DM, Isaranuwatchai W, Habbous S, de Oliveira C, Liu G, Siu LL, Hoch JS. A cost-effectiveness analysis of human papillomavirus vaccination of boys for the prevention of oropharyngeal cancer. Cancer 2015; doi: 10.1002/cncr.29111