Three early studies mark progress in checkpoint cancer immunotherapy
Checkpoint inhibition helped post-stem cell (SC) transplantation patients with hematologic malignancies into remission. About 1/3 of blood cancer patients, whose tumor was eliminated by SC transplantation, relapse and face a very poor prognosis. In a Phase 1 study published in New England Journal of Medicine,Citation1 28 subjects with relapsed leukemia, lymphoma, multiple myeloma, and myelodysplastic tumors were treated with anti-CTLA-4 MAb ipilimumab. 60% of those treated with the highest dose experienced complete or partial remission.
Chemotherapy targeted against focal adhesion kinase (FAK) might render pancreatic tumors susceptible to immunotherapy, according to a preclinical study published in Nature Medicine.Citation2 Pancreatic ductal adenocarcinoma creates an immunosuppressive tumor microenvironment, and FAK inhibition led to increased responsivity to T-cell immunotherapy and PD-1 inhibition in a mouse model.
Another preclinical study showed that treating glioblastoma (GBM) with a combination of dendritic cell vaccine and a PD-1 inhibitor might be more beneficial than either treatment alone.Citation1 “We discovered that effective anti-tumor immunity to glioblastoma must have a significant infiltration of killer T cells and a blockade of the important checkpoint axes that make these killer T cells dysfunctional within the tumor,” said senior author Robert Prins of UCLA. The combination therapy led to long-term survival in mice. The estimated median survival in human GBM patients is <1.5 years.
- Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, Lukez AP, Avigan D, Chen YB, McSweeney P, LeBoeuf NR, Rooney MS, Bowden M, Zhou CW, Granter SR, Hornick JL, Rodig SJ, Hirakawa M, Severgnini M, Hodi FS, Wu CJ, Ho VT, Cutler C, Koreth J, Alyea EP, Antin JH, Armand P, Streicher H, Ball ED, Ritz J, Bashey A, Soiffer RJ; Leukemia and Lymphoma Society Blood Cancer Research Partnership. Ipilimumab for Patients with Relapse after Allogeneic Transplantation. N Engl J Med. 2016; 375(2):143-53
- Jiang H, Hegde S, Knolhoff BL, Zhu Y, Herndon JM, Meyer MA, Nywening TM, Hawkins WG, Shapiro IM, Weaver DT, Pachter JA, Wang-Gillam A, DeNardo DG. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 2016; doi: 10.1038/nm.4123
- Antonios JP, Soto H, Everson RG, Orpilla J, Moughon D, Shin N, Sedighim S, Yong WH, Li G, Cloughesy TF, Liau LM, Prins RM. PD-1 blockade enhances the vaccination-induced immune response in glioma. JCI Insight. 2016; doi:10.1172/jci.insight.87059
Seasonal influenza vaccine could reduce cardiovascular events in type 2 diabetes patients
People with type 2 diabetes might benefit from influenza vaccination in ways other than preventing the disease. In a large retrospective study, published in Canadian Medical Association Journal,Citation1 the seasonal vaccine was associated with a decreased risk of hospitalization due to stroke (by 30%), heart failure (22%), and pneumonia (15%).
The researchers examined a total of >120,000 subjects in England's electronic healthcare records and monitored patients’ hospital admissions during a 7-year period 2003–10. Confounding variables were controlled by, e.g., monitoring smoking status, medication, blood pressure, or frequency of cardiovascular events during summer.
“Most flu deaths every year occur in people with pre-existing health conditions such as type 2 diabetes. This study suggests that the vaccine may have substantial benefits for patients with long-term health conditions. Not only might it help reduce serious illness such as stroke—and possibly heart attack—in high-risk individuals, but it may also reduce the risk of death in the flu season,” said lead author Eszter Vamos of Imperial College London.
- Vamos EP, Pape UJ, Curcin V, Harris MJ, Valabhji J, Majeed A, Millett C. Effectiveness of the influenza vaccine in preventing admission to hospital and death in people with type 2 diabetes. CMAJ 2016; doi: 10.1503/cmaj.151059
Immunotherapy can ameliorate cardiovascular condition of rheumatoid arthritis patients
Low-dose anti-TNFα and anti-IFNγ combination immunotherapy can reduce cardiovascular risk in people suffering from rheumatoid arthritis (RA). In a study presented at the Frontiers in CardioVascular Biology meeting, 68 subjects with at least 5 years of RA received standard therapy plus extra low doses of the two antibodies (38) or placebo (30). In addition to decreased RA activity marker, the experimental group had a lower incidence of unstable angina, severe hypertensive crisis, and deterioration of chronic heart failure (13% compared to 37% in the control group).
“Our findings suggest that the decreased RA disease activity with the combination of anti-cytokines translates into decreased cardiovascular risk. RA promotes the development of cardiovascular disease in a number of ways. Therefore, decreasing disease activity may also reduce cardiovascular risk by slowing down or halting these processes,” lead author Aida Babaeva of Volgograd State Medical University said in a press release.
A norovirus vaccine candidate enters a Phase 2 trial
A candidate vaccine against norovirus, TAK-214 (Takeda), has started a Phase 2b placebo-controlled study. It will assess immunogenicity and efficacy in several thousand adults aged 18–49 years. As the only advanced human trial for a norovirus vaccine, this trial should be completed in December 2017.
Norovirus infection is a cause of severe gastroenteritis, causing ∼700 million cases annually especially in the developing world. TAK-214 is an aluminum-adjuvanted virus-like particle vaccine targeting two most common norovirus genotypes, GI.1 and GII.4.
Further progress in Zika vaccine development
The most advanced candidate in the effort to have a Zika vaccine is GLS-5700 (Inovio and GeneOne). This DNA vaccine is being evaluated in a first-in-human Phase 1 trial in 40 healthy North American volunteers. Previously, the candidate elicited strong antibody and T-cell responses in animal models.
Clinical trials in the first half of 2017 are planned for a measles-vectored vaccine developed by Institut Pasteur and Themis Biosciences. The technology has been tested in the development of Chikungunya vaccine, and passed safety and tolerability testing in human subjects.
Two more candidates are being developed in preclinical settings: a self-amplifying RNA vaccine (GSK and NIH), and a purified inactivated virus vaccine (Sanofi and Walter Reed Institute), which might enter clinical trials soon.
Finally, two studies reported the development of protective antibodies against Zika infection. The antibodies were either purified from patientsCitation1 or developed in mice,Citation2 and both offered protection in a mouse challenge model.
- Stettler K, Beltramello M, Espinosa DA, Graham V, Cassotta A, Bianchi S, Vanzetta F, Minola A, Jaconi S, Mele F, Foglierini M, Pedotti M, Simonelli L, Dowall S, Atkinson B, Percivalle E, Simmons CP, Varani L, Blum J, Baldanti F, Cameroni E, Hewson R, Harris E, Lanzavecchia A, Sallusto F, Corti D. Specificity, cross-reactivity and function of antibodies elicited by Zika virus infection. Science 2016; doi: 10.1126/science.aaf8505
- Zhao H, Fernandez E, Dowd KA, Speer SD, Platt DJ, Gorman MJ, Govero J, Nelson CA, Pierson TC, Diamond MS, Fremont DH. Structural Basis of Zika Virus-Specific Antibody Protection. Cell 2016; doi: 10.1016/j.cell.2016.07.020
CAR-T immunotherapy of HIV promising in vitro
Chimeric antigen receptor T-cell (CAR-T) therapy could lead to potent inhibition of HIV infection. According to a study published in Journal of Virology,Citation1 T cells, genetically modified to match eight recently discovered broadly neutralizing antibodies, proliferated in response to HIV-1 and induced killing of infected cells in tissue culture.
CAR-T immunotherapy has been used widely in cancer treatment. It was originally designed to combat HIV in the 1990s, but failed efficacy tests. With the identification of broadly neutralizing antibodies, the researchers hope the method can be successfully applied to human patients.
“What works in a test tube doesn't necessarily work in a person, so the next step is to find strategies to put these receptors into humans. But this therapy shows enough promise to move forward with further research,” senior author Otto Yang of UCLA said in a statement.
- Ali A, Kitchen SG, Chen IS, Ng HL, Zack JA, Yang OO. HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies. J Virol 2016; 90(15):6999-7006
13-valent pneumococcal vaccine approved in the U.S. for all ages
The U.S. Food and Drug Administration has expanded the indication of the 13-valent pneumococcal conjugate vaccine Prevnar 13 (Pfizer) to adults aged 18–49 years. It has thus become the first pneumococcal vaccine approved in the U.S. for use from 6 weeks of age through all of adulthood.
In addition, Prevnar 13 has received prequalification by the World Health Organization (WHO), which enables its use in developing countries. WHO endorsed the vaccine in a special formulation, which is durable, easy-to-store, and reduces the costs by 75%.
Makaria vaccine efficacy dramatically wanes over time
Long-term efficacy of the malaria vaccine RTS,S/AS01 (Mosquirix, GSK) is very low. According to a randomized study published in New England Journal of Medicine,Citation1 the number of malaria episodes was comparable among African children who received three doses of RTS,S/AS01 and those who received a control vaccine. The decline in efficacy is most rapid in areas with high malaria rates.
After encouraging short-term data, which suggested that RTS,S/AS01 could prevent >35% cases, the long-term results cast doubt on whether the vaccine should be used in routine vaccination. Nevertheless, the researchers point out that RTS,S/AS01 still might be able to prevent a substantial number of malaria cases during the 7-year period.
- Olotu A, Fegan G, Wambua J, Nyangweso G, Leach A, Lievens M, Kaslow DC, Njuguna P, Marsh K, Bejon P. Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine among Young African Children. N Engl J Med. 2016; 374(26):2519-29
Efficacy of an HIV vaccine candidate exceeded expectations in early trial
An HIV vaccine candidate developed by Janssen Pharmaceuticals was safe and immunogenic in a Phase 1/2 placebo-controlled trial HVTN 100 involving >250 healthy South African volunteers. According to interim data all recipients developed antibodies against the three vaccine antigens.
The vaccine is tailored to the virus strain widespread in South Africa. It elicited stronger antibody and T-cell responses than its predecessor tested in the RV144 ‘Thai’ trial, and exceeded predetermined efficacy criteria. “It is gratifying to see vaccines that were designed and manufactured specifically for South Africa meet and even exceed the criteria established to advance them into the large efficacy trial,” principal investigator for the HIV Vaccine Trials Network Larry Corey said in a press release.
The first human trial starts for a CMV vaccine candidate
Safety of a cytomegalovirus (CMV) vaccine HB-101 (Hookipa Biotech) will be tested on 54 healthy volunteers in a Phase 1 trial. The bivalent candidate is based on the Vaxwave vector platform, which utilizes a replication-defective lymphocytic choriomeningitis virus to induce strong humoral and cellular immune responses. The study will test three different doses against a placebo.
Although CMV infection is common in adults throughout the world, it can be a significant threat during pregnancy, and to infants and immunocompromised patients.
A universal influenza vaccine candidate enters clinical trials
An H3N2 influenza vaccine RedeeFlu (FluGen) has started a Phase 1 trial to evaluate its safety and immunogenicity. The randomized, dose-ranging study enrolls 96 healthy adults 18–49 years of age. The vaccine aims to improve the relatively low efficacy of the established live attenuated seasonal influenza vaccines.
RedeeFlu contains an M2-mutated strain, which can infect cells and express full range of influenza antigens, but cannot generate infectious virions, and thus does not cause any pathological signs of infection.
First steps towards a vaccine against chlamydia
A chlamydial antigen BD584 potently inhibited Chlamydia trachomatis infection in a preclinical study.Citation1 The intranasal vaccine reduced bacterial shedding by 95% and hydrosalpinx, the blocking of fallopian tubes, by almost 90% in a mouse model.
Chlamydia is a sexually transmitted pathogen that affects >100 million people annually. The infection is asymptomatic, but if left untreated, it can cause upper genital tract infections, pelvic inflammatory disease, and infertility. There is no approved vaccine against the disease.
- Bulir DC, Liang S, Lee A, Chong S, Simms E, Stone C, Kaushic C, Ashkar A, Mahony JB. Immunization with chlamydial type III secretion antigens reduces vaginal shedding and prevents fallopian tube pathology following live C. muridarum challenge. Vaccine. 2016; 34(34):3979-85