Combination of Vaccine and Immunotherapy Decreases Recurrence in HER2+ Breast Cancer Patients
In a recent Phase 2 trial, the new breast cancer vaccine candidate GP2 was shown to be safe and effective for breast cancer patients, reducing recurrence rates by 57%. Women with the highest overexpression of HER2 (known as HER2 +3) had no cancer recurrences when they received GP2 after completing trastuzumab (Herceptin), a monoclonal antibody (MAb) immunotherapy. The study results were presented at the recent 2014 Breast Cancer Symposium of the American Society of Clinical Oncology in San Francisco.
“This is an important and different avenue in immunotherapy research, in that we are investigating ways to prevent cancer recurrence by stimulating the immune system to treat cancer,” said principal investigator Dr Elizabeth Mittendorf, associate professor of Surgical Oncology at the University of Texas MD Anderson Cancer Center. “The ultimate goal is to develop a preventative tool that will minimize the risk of recurrence in women who have already had breast cancer and for whom standard therapies have failed.”
The randomized Phase 2 study included 180 breast cancer patients with varying levels of HER2, an oncoprotein that promoted tumor growth and is expressed to some extent in 75–80% of breast cancers. Participants were randomized to receive GP2 vaccine with the immune stimulant granulocyte/macrophage colony stimulating factor (GM-CSF) (89 women) or GM-CSF alone (91 women). Eight patients did not complete the trial due to early recurrence or development of a second malignancy. All others received monthly subcutaneous inoculations for six months, followed by four cycles of booster shots administered every six months thereafter. The patients were monitored for nearly three years.
The study results for all 180 patients showed disease-free survival (DSF) rates of 88% among those who received GP2 and 81% in the control group, representing a 37% reduction in recurrence. When excluding the patients who did not complete the vaccine series, the results were higher with 94% DFS rate in the GP2 group versus 85% in the control group, a 57% risk reduction. Women with HER2 +3 who had received trastuzumab as part of the standard of care prior to receiving the GP2 vaccine experienced no cases of cancer recurrence.
Trastuzumab stimulates CD4+ T cells to release substances that fight cancer cells and initiates an antibody response. The new vaccine candidate GP2 is designed to stimulate the CD8+ cells, commonly known as killer T cells. According to Dr Mittendorf, trastuzumab may act like a primer for the GP2 vaccine. MD Anderson is now testing this combination of immunotherapies in other clinical trials.
“We believe many more patients will benefit in some way from immunotherapy”, said Dr Mittendorf. “The challenge will be identifying the right immunotherapeutic approach for each individual patient. When doctors are able to do that, cancer therapy, and immunotherapy specifically, will follow a more personalized approach.”
Human Trials for Ebola Vaccines Begin
The death toll from the current Ebola outbreak in West Africa continues to rise, and the World Health Organization (WHO) estimates that as many as 20,000 poeple may become infected with the deadly viral disease. Thanks to combined efforts from the public and private sector, the first Ebola vaccine, developed by GlaxoSmithKline (GSK) and the US National Istitutes of Health (NIH) has recently entered clinical trials. Two other Ebola vaccines, developed by NewLink Genetics and Johnson & Johnson, are also lining up to be tested soon in humans, with two more from Inovio Pharmaceuticals and Vaxart in the preclinical phase.
In September, GSK together with the NIH started a Phase 1 trial of its Ebola vaccine candidate. GSK acquired the experimental vaccine in the 2013 purchase of Okairos. The vaccine uses a chimpanzee-derived replication-defective adenovirus vector (ChAd) containing two Ebolavirus gene segments. The vaccine works by entering a cell, delivering DNA, and expressing Ebola protein for eliciting an immune response. Promising results from animal studies were recently published in the journal Nature Medicine (http://www.ncbi.nlm.nih.gov/pubmed/25194571). The ChAd vaccine rapidly induced uniform protection in macaques against acute lethal Ebolavirus challenge. Because protection waned over several months, the researchers boosted ChAd3 with modified vaccinia Ankara (MVA) and generated, for the first time, durable protection against lethal challenge.
The clinical trial in Oxford, including 60 healthy volunteers, aims to establish whether the vaccine can produce a strong serum immune response within two to four weeks with acceptable side-effects. Further testing of the vaccine is planned for the coming months in Africa as well as in the United Statesw with a different vaccine formulation.
Professor Dr Adrian Hill, director of the Jenner Institute in Oxford, who is leading the trial, said: “This is a remarkable example of how quickly a new vaccine can be progressed into the clinic, using international co-operation.”
The FDA recently also agreed that the US-based company NewLink Genetics proceed with a Phase 1 clinical trial of its Ebola vaccine candidate, originally developed by the Public Health Agency of Canada. This vaccine targets an Ebolavirus surface protein and has been shown to induce neutralizing antibodies in animals. The trial will enroll 40 healthy volunteers and aims to test safety as well as measure whether vaccinees develop the same levels of antibodies shown to be protective in preclinical monkey challenge studies. NewLink also plans to launch trial sites in Europe and Africa and has recently signed agreement with manufacturers to ramp up vaccine production.
The FDA also agreed to fast-track the development of an investigational combination vaccine developed by Crucell, the vaccine arm of Johnson & Johnson, alongside partner Bavarian Nordic. J&J hopes to test the vaccine in clinical trials in early 2015. The vaccine regimen combines elements of two different technologies from each company: the MVA-BN platform from Danish Bavarian Nordic and AdVac from Crucell, based in the Netherlands. They plan to follow a prime-boost vaccine strategy that uses one vector to prime and another to boost immune response. The experimental monovalent vaccine is part of a bigger, ongoing effort at Crucell and Bavarian Nordic to eventually develop a multivalent vaccine against all deadly filoviruses that affect humans, including Ebola and Marburg viruses.
Australia`s HPV Vaccine Program Achieves 61% Reduction of Genital Warts
According to a new study in the journal PLOS ONE (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0105967), general pratitioners in Australia are managing 61% fewer cases of genital warts among young women since the introduction of the national human papillomavirus (HPV) vaccination program.
In 2007, Australia was one of the first countries to provide free HPV vaccine to young women through the national program. The vaccine protects against the two major viral causes of genital warts (HPV 6 and 11) and the two major viral causes of cervical cancer (HPV 16 and 18). It was previously reported that the management rate of genital warts in sexual health clinics and private hospitals had decreased since the introduction of Australia's HPV vaccination program.
Most gential warts are managed in general practice (GP), and this prompted researchers from University of Sydney to investigate whether a similar decrease occurred in Australian GP after the introduction of the program. They analyzed a nationally representative database of Australian GP activity (∼1,176,000 patient encounters with 11.780 GPs), looking at genital wart management rates in the periods before (July 2002–June 2006) and after (July 2008–June 2012) HPV vaccine program introduction. Control conditions included genital herpes and gardnerella / bacterial vaginosis in females and genital herpes and urethritis in males. Trends in management rates by year, pre-vaccine and post-vaccine were also calculated.
The study results showed that management of genital warts among women potentially covered by the program (aged 15–27 years) had decreased by 61% from 4.33 per 1000 encounters in the pre-vaccine period to 1.66 in the post-vaccine period. For other age groups who had not been covered by the program, no significant change in the management rate of genital warts was observed. There was also no significant decrease in other sexually transmitted infections in the study period, which means that the decrease in genital warts was most likely due to the vaccination program, not a change in the women's behaviour.
“This is an excellent result as not only do genital warts cause distress in affected patients, but treatment is at a substantial cost to the health system. The [HPV] program has proved to be a great success and of huge benefit to the sexual health of Australia, and has clearly proven to be very worthwhile,” said study lead author Dr Christopher Harrison of the University of Sydney.
Sanofi's Dengue Vaccine Successful in Final Landmark Phase 3 Trial
Sanofi Pasteur, the vaccines division of Sanofi, recently announced positive data from the final landmark Phase 3 efficacy study of its dengue vaccine candidate. Results of the Latin America study showed an overall significant reduction of 60.8% of dengue disease cases in children and adolescents 9–16 years old after a three-dose vaccination schedule. Importantly, efficacy was observed against each of the four dengue serotypes. In addition, the risk of hospitalization due to dengue was reduced by 80.3%.
Dengue, which is transmitted by mosquitoes, is caused by four different virus serotypes. Nearly half the world's population is at risk to contracting the disease, making it a pressing public health priority in over 100 countries in the Americas and in Asia, where epidemics occur regularly. A dengue vaccine would represent a major advance for the control of the disease and would be an important tool for reaching the World Health Organization's (WHO) goal of reducing dengue mortality by at least 50% and morbidity by at least 25% by 2020.
“For the first time ever, after 20 years of research and industrial commitment, dengue is set to become a vaccine-preventable disease,” said Dr Olivier Charmeil, President and Chief Executive Officer, Sanofi Pasteur. “The data generated from our comprehensive research and clinical program involving 40,000 children, adolescents and adults from 15 countries, will be submitted to the health authorities in countries where dengue is a public-health priority.”
The randomized, observer-blind, placebo-controlled Phase 3 study in Latin America and the Caribbean included more than 20,800 children aged 9–16 years from dengue-endemic areas of Brazil, Colombia, Mexico, Honduras and Puerto Rico. They were randomized in a 2:1 ratio to either receive three injections of the dengue vaccine or a placebo at 0, 6, and 12 months.
The safety data were consistent with the favorable safety profile documented in all previous clinical studies (Phase 1, 2 and 3). Overall vaccine efficacy was 60.8%, with good efficacy against each of the four dengue serotypes (50.3% against ST1, 42.3% against ST2, 74% against ST3, and 77.7% against ST4). Especially for ST2, this result is an improvement compared to the relatively weak 35% protection rate against this serotype seen in the second large-scale Phase 3 trial in Asia earlier this year. The risk of hospitalization due to dengue was found to be reduced by 80.3%, confirming the potential public health impact of the vaccine. The results also showed in the study population a level of efficacy against dengue haemorrhagic fever, the severe form of dengue, which is consistent with the results released from Sanofi's Phase 3 dengue study in Asia. Lastly, the results suggest better protection in case of prior exposure to dengue.
Meningococcal Vaccines Reduce Carriage by Almost 40%
Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. A new study in the The Lancet (http://www.ncbi.nlm.nih.gov/pubmed/25145775) has looked at the effects of two licensed meningococcal vaccines on meningococcal carriage rates in 18–24 year-olds. Both vaccines reduced meningococcal carriage up to one year after vaccination and therefore might affect transmission when widely implemented.
Meningitis is an infection of the meninges, the membrane that surrounds the brain and spinal cord. About one in ten people carry meningococcal bacteria in the nose or throat without getting sick, which can be passed on through close contact. While anyone can get meningococccal meningitis, babies and young adults are most vulnerable.
The Phase 3, observer-blind, randomized controlled trial included over 2950 university students aged 18–24 years at 10 centers across the UK. Participants were assigned to receive two doses one month apart of Japanese Encephalitis (JE) vaccine (controls), 4CmenB (serogroup B protein vaccine), or one dose of MenACWY-CRM (serogroup A-C-W135-Y conjugate vaccine) then placebo. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over the course of one year. Primary outcomes were cross-sectional carriage one month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination.
The researchers found that by one month, there was no significant difference in carriage between controls and 4CMenB or MenACWY-CRM groups. However, 3 months after the second dose, recipients of the 4CMenB vaccine showed carriage reductions of any meningococcal strain and serogroups BCWY of 18.2% and 26.6%, respectively, when compared to controls. Significantly lower carriage rates also were noted in the MenACWY-CRM group compared with controls: 36.2% carriage reduction for serogroups CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group.
The study results show that the two new meningococcal vaccines can prevent transmission of meningococcal bacteria, by the mechanism of reducing carriage of meningococcal bacteria in the nose and throats of the population. Even when specific antibodies are no longer detectable, carriage in the throat is still prevented, and thus is onward transmission of the infection to others. If vaccine uptake rates are high enough, this mechanism could provide a degree of herd protection against meningitis.
Dr. Robert Read, Professor of Infectious Diseases at the University of Southampton, who led the study, said: "The standard practice is to vaccinate with the aim of inducing high levels of antibodies in the blood to protect against the disease, but we know that these antibodies can disappear over the course of a few months. This study is telling us that the vaccines also have an effect on carriage in the throat and explains why they can be so effective across the population."
How Vaccine Message Framing Influences Parents' Vaccine Intentions
Emphasizing societal benefits of vaccines has been linked to increased vaccination intentions in adults. A recent study in the journal Pediatrics (http://pediatrics.aappublications.org/content/early/2014/08/12/peds.2013–4077) found that this is not true for parents deciding whether to vaccinate their children. Parents were more likely to immunize their child against measles, mumps and rubella (MMR) if the informational material highlighted the benefit of the vaccine for their own child, compared to the benefit for society.
Researchers from Indiana University (IU) performed a national online survey, in which about 800 parents of infants (<12 months) were randomly assigned to receive one of four MMR vaccine messages: (1) Centers for Disease Control and Prevention Vaccine Information Statement (VIS), (2) VIS and information emphasizing the MMR vaccine's benefits to the child, (3) VIS and information emphasizing societal benefits, or (4) VIS and information emphasizing benefits both to the child and society. Parents reported their likelihood of vaccinating their infants for MMR on a response scale of 0 (extremely unlikely) to 100 (extremely likely).The first MMR vaccine is recommended at 12 months.
The investigators found that parents who viewed informational material highlighting direct benefits to their own child were the most likely to subsequently indicate that they would have their baby vaccinated for MMR. In particular, 86.3% in the VIS-only group reported intentions for immunizing their child, similar to 86.4% in the group that received information emphasizing societal benefits only. Parents receiving informational material highlightig either the direct benefits for their own child, or the combined benefits for their child and society, reported intentions to vaccinate their offspring of 91.6% and 90.8%, respectively.
The study results show that mentioning societal benefits without of also highlighting benefits directly to the child did not increase parents’ MMR vaccine intentions for their infants. Mentioning societal benefits seemed to neither add value to, nor interfere with, information highlighting benefits directly to the child.
“For parents in our study, mentioning the direct positive impact for their own child trumped mention of societal benefits,” said study lead author Dr. Kristin Hendrix, social psychologist and pediatric health services researcher at IU. “To me, this indicates that health care providers and public health officials should be explicit in mentioning the benefits of MMR vaccination directly to the child to help counter parents' over-inflation of risk of vaccination and related anxiety. However, we know community immunity is a critical societal benefit of vaccination, and perhaps there is a way to more compellingly communicate this to parents.”
Study senior author Dr Stephen Downs, Professor of Pediatrics and director of the Children's Health Services Research at IU School of Medicine said: “We were surprised to find that pointing out that vaccinating their children could benefit others had no influence on parents' intention to vaccinate. In studies of people considering vaccines for themselves, talking about benefit to society increased their intention to receive the vaccines. This didn't happen among parents.”
Old HIV Pediatric Vaccines Revisited: Were they Protective After All?
According to a new study in the Journal of Infectious Diseases (http://jid.oxfordjournals.org/content/early/2014/08/26/infdis.jiu444), human immunodeficiency virus type 1 (HIV-1) infant vaccination can induce robust, durable Envelope-specific IgG including anti-V1V2 IgG responses. In this retrospective study, researchers re-analyzed the findings of two historic pediatric HIV trials conducted in the 1990s. They showed that the vaccines in fact had triggered an antibody response that is now known to be associated with protection in adults, but was previously unrecognized in the infants studied.
The induction of broadly neutralizing antibodies has long been considered necessary for developing a successful HIV vaccine, and thus vaccine research has mainly focused on designing such a vaccine. However, researchers from Duke University now has found that antibodies that attached to a specific region of the HIV outer envelope, and not neutralizing antibodies, were responsible for reducing the number of HIV infections by ∼30% in the adult HIV vaccine trial RV144 (http://www.ncbi.nlm.nih.gov/pubmed/22475592). The immune correlate analysis of RV144 revealed an association between high levels of IgG against the envelope (Env) V1V2 loops and reduced HIV-1 acquisition risk.
In order to test whether infant vaccination can induce similar immune responses, another team of researchers from Duke University tested serum samples from two earlier pediatric HIV trials (PACTG 230 and PACTG 326) conducted in the 1990s. At that time, the more specific antibody response was unknown and therefore not measured, and since neither of the investigational vaccines had elicited the broadly neutralizing antibodies considered the hallmark of success, development was not continued.
The PACTG 230 trial was initiated in 1993 enrolling infants born to mothers with HIV. The infants were randomly assigned to three groups that received four doses of either VaxGen‘s rgp120 vaccine with aluminium hydroxide, Chiron‘s rgp120 vaccine with MF59, or placebo.
The PACTG 326 trial began in 1998, again testing a vaccine candidate among infants born to HIV-infected mothers. The babies were randomly assigned to receive either four doses of an ALVAC-HIV vaccine alone, or with a booster.
Reanalysing the infants blood samples, the Duke researchers found that by 52 weeks of age, the majority of maternally-acquired antibodies had waned and vaccine Env-specific IgG responses were higher in vaccinees than placebo recipients. The Chiron vaccine induced higher and more durable IgG responses than the other two tested vaccines. At one year of age, 59% of the infants receiving VaxGen and 79% of those receiving the Chiron vaccine still showed this Env-specific antibody response. At two years of age, 28% of VaxGen and 56% of Chiron vaccinees continued to have detectable responses. Remarkably, at peak immunogenicity, the concentration of anti-V1V2 IgG, a response associated with reduced risk of HIV acquisition in the RV144 adult vaccine trial, was 22 fold higher in Chiron than in RV144 vaccinees.
“It's encouraging to find that the vaccines had induced an antibody response that lasted so long,” said study lead author Dr Genevieve G. Fouda, assistant professor of pediatrics at Duke. “In this population of infants, where the main goal is to prevent HIV transmission from mother-to-child during the period of breast feeding, inducing a two-year immunity would be long enough to be beneficial.”
With an estimated 260,000 babies worldwide contracting HIV-1 from their mothers annually, many from breastfeeding, developing a vaccine for use in infants remain and important pursuit. Dr Fouda said additional studies should help determine whether the immune response identified in the early vaccine candidates actually provided protection against HIV infection, or whether it was simply a marker of protection.
Amgen's Oncolytic Melanoma Immunotherapy Submitted to FDA and EMA
Amgen recently announced the submission of a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for their immunotherapeutic oncolytic product talimogene laherparepvec (T-Vec) for the treatment of adults with melanoma that is regionally or distantly metastatic. If approved, T-Vec will represent the first in a class of novel agents known as oncolytic immunotherapies.
Melanoma is a skin cancer characterized by the uncontrolled growth of melanocytes, which are the cells responsible for providing the pigment to skin. Melanoma is the most aggressive and serious form of skin cancer. In patients with advanced melanoma, the cancer has metastasized from the origin site to deeper parts of the skin, lymph nodes, lungs or other parts of the body. Every year, 132,000 melanoma cases occur globally, and this nuber is expected to rise considerably in the years to come.
T-Vec is designed to selectively replicate in tumors but not normal tissue, and to initiate an immune response to target cancer cells that have metastasized. T-Vec works in two important and complementary ways: (1) it is injected directly into tumors where it replicates inside the tumor cells, causing the cell to lyse and die, and (2) the lysis of the tumor cells can release tumor-derived antigens along with GM-CSF, which can stimulate a system-wide immune response where T cells can seek out and target cancer that have spread throughout the body.
Earlier this year, T-Vec had been submitted to the US FDA) Now, Amgen has also submitted its melanoma vaccine candidate to EMA. “The submission of the Marketing Authorization Application in Europe for talimogene laherparepvec brings us a step closer to helping address an unmet medical need for patients with metastatic melanoma,” said Dr Sean E Harper, executive vice president of Research and Development at Amgen. “This regulatory milestone, on the heels of our Biologics License Application submission to the U.S. FDA, represents an important step for our pipeline and we look forward to working with the European Medicines Agency as it conducts its review of talimogene laherparepvec.”
The MAA for T-Vec contains data from >400 patients and is based on a global, randomized, open-label Phase 3 trial evaluating the safety and efficacy of the vaccine in patients with advanced melanoma. The Phase 3 data showed a 16% durable response rate and an increased median overall survival (OS) rate of 4.4 months.