Checkpoint inhibitor development marks multiple successes
In an expedited review, the U.S. Food and Drug Administration (FDA) has approved nivolumab (Opdivo, BMS) in advanced renal cell carcinoma (RCC) patients who failed prior anti-angiogenic therapy. The approval is based on the Phase 3 Checkmate-025 trial, in which nivolumab outperformed standard-of-care (SOC) therapy in overall survival and tumor shrinkage. After melanoma and non-small cell lung cancer, RCC is the third cancer type for which nivolumab has been approved.
A PD-1 inhibitor atezolizumab (MPDL3280A, Roche) was successful against skin cancer in a 17-patient Phase 1b study, shrinking tumors in 76% of the subjects with two complete remissions. Adverse events were manageable and reversible. The trial combined atezolizumab with the SOC drug Zelboraf to treat unresectable or metastatic melanoma.
The success of checkpoint-inhibition immunotherapy depends on the microbiome profile in the patient's gut, as two articles published in Science suggest. The first study assessed invasiveness of melanoma in mice which differed in their gut microbes and found that subjects with Bifidobacterium spp. in their gut had less severe cancer and were more prone to anti-PD-L1 immunotherapy. Moreover, these beneficial effects were transmissible with fecal transplant or Bifidobacterium implant.1 According to the second study, the CTLA-4-targeting immunotherapy of sarcoma, melanoma or colorectal cancer mouse models was successful only if the gut microbiota contained Bacteroides spp. Here, not only fecal transplant but also adding murine Bacteroides-specific memory T cells was enough to restore the effect after antibiotic treatment, suggesting that anti-tumor activity is stimulated by the immune reaction to commensal microbes.2
Checkpoint inhibition therapy of HER-2-positive breast cancer might be improved with an antibody-drug conjugate trastuzumab emtansine (T-DM1), according to a study published in Science Translational Medicine.3 T-DM1 targets the HER-2 receptor upregulated in some breast tumors, and the combination with both PD-1 and CTLA-4 immunotherapy induced innate as well as adaptive immunity and T-cell infiltration in mouse models.
1. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, Chang EB, Gajewski TF. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015; 350(6264):1084-9
2. Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Yamazaki T, Jacquelot N, Enot DP, Bérard M, Nigou J, Opolon P, Eggermont A, Woerther PL, Chachaty E, Chaput N, Robert C, Mateus C, Kroemer G, Raoult D, Boneca IG, Carbonnel F, Chamaillard M, Zitvogel L. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015; 350(6264):1079-84
3. Müller P, Kreuzaler M, Khan T, Thommen DS, Martin K, Glatz K, Savic S, Harbeck N, Nitz U, Gluz O, von Bergwelt-Baildon M, Kreipe H, Reddy S, Christgen M, Zippelius A. Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci Transl Med 2015; 7(315):315ra188
One-third of U.S. children do not receive all recommended vaccinations by age 2
Immunization completion rates among 2-year-olds has reached only 70%, according to a study published in Vaccine.1 There are 19 vaccine doses protecting against 11 diseases recommended for U.S. children within the first two years. Scientists analyzed data from almost 12,000 children from the 2012 National Immunization Survey and found that as many as 77% did not receive their vaccinations at recommended times.
Completion rates were highest in Southern states and lowest in Western states; the least compliant state was Alaska with 55% and most compliant Mississippi with 77%. “The regional patterns we observed point to a need for continued localized, evidence-based interventions that address barriers to vaccination at the family, provider, institutional and policy levels,” lead author Samantha Kurosky of RTI Health Solutions said in a statement. “By understanding each community's specific needs, we have a better chance of providing the right tools that can lead to improved vaccination rates across the nation.”
1. Kurosky SK, Davis KL, Krishnarajah G. Completion and compliance of childhood vaccinations in the United States. Vaccine 2015; doi: 10.1016/j.vaccine.2015.11.011
Rindopepimut improved survival in glioblastoma patients
In a Phase 2 trial involving 73 glioblastoma patients with EGFRvIII mutation, rindopepimut (Rintega, Celldex) administered with Avastin marked 25% survival at two years compared to 0% in the Avastin-alone group. The combined treatment also improved other indicators, such as overall survival, progression-free survival and objective response rate.
EGFRvIII-positive glioblastoma leaves patients with poor prognosis. Rintega is a therapeutic vaccine that targets this mutation, which is absent in non-cancerous tissues. The vaccine is being investigated in the Phase 3 ACT IV study.
Update on three RSV vaccines in development
The most advanced RSV vaccine candidate in the field is from Novavax, which has entered a randomized, placebo-controlled Phase 3 trial aiming to recruit almost 12,000 older adults in the U.S. The primary objective is to prevent lower respiratory tract infections by RSV. The vaccine received a Fast Track Designation by the FDA in 2014.
Another candidate is a live attenuated vaccine genetically modified to produce a less virulent form of RSV. It was tested in adults, older children previously infected with RSV, and disease-naïve infants. According to the results of this early trial published in Science Translational Medicine,1 intranasal immunization elicited virus-neutralizing antibodies and restricted viral shedding.
The third RSV vaccine in development should begin clinical trials in 2016 after encouraging preclinical data. Vaxart's tablet vaccine provided substantial protection against infection in a cotton rat model.
There is no licensed vaccine against RSV, which is the leading cause of hospitalizations in U.S. infants under the age of one, and a significant cause of respiratory illness in the elderly.
1. Karron RA, Luongo C, Thumar B, Loehr KM, Englund JA, Collins PL, Buchholz UJ. A gene deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with improved antibody responses in children. Sci Transl Med 2015; 7(312):312ra175
Phase 1 success for ‘Treg immunotherapy’ of type 1 diabetes
A novel immunotherapeutic approach to type 1 diabetes (T1D) treatment was safe and well tolerated in a Phase 1 trial. The method is based on regulatory T cells (Tregs) isolated from the patient's blood, expanded ex vivo and infused back into the body. These cells should protect the remaining insulin-producing β cells, which ordinarily are destroyed by the immune system in T1D. The results of the study, in which 14 subjects each were given up to 2.6 billion Tregs, were published in Science Translational Medicine.1
“For type 1 diabetes, we've traditionally given immunosuppressive drugs, but this trial gives us a new way forward. By using Tregs to ‘re-educate’ the immune system, we may be able to really change the course of this disease,” lead author Jeffrey Bluestone of UCSF said in a press release. The scientists hope that adoptive Treg therapy can also be used for other autoimmune diseases, such as rheumatoid arthritis and lupus.
1. Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, Herold KC, Lares A, Lee MR, Li K, Liu W, Long SA, Masiello LM, Nguyen V, Putnam AL, Rieck M, Sayre PH, Tang Q. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med 2015; 7(315):315ra189
Measles vaccination has saved 17 million lives in the past 15 years, but coverage stagnates
The measles vaccine has saved more than 17 million lives since 2000 according to the World Health Organization (WHO). The first-dose coverage has increased from 72% to 85% in the same period, but has been stagnant since 2010. 221 million children around the world were immunized in 2014.
“We cannot afford to drop our guard,” Jean-Mari Okwo-Bele, head of WHO's immunization and vaccines division, said in the statement. “If children miss routine vaccination and are not reached by national immunisation campaigns, we will not close the immunization gap.”
Measles causes rash and fever, but in some cases can lead to brain damage and death. It is a highly contagious disease and is still relatively common in the developing world.
Chordoma vaccine passes Phase 1 trial
A cancer vaccine candidate MVA-BN Brachyury (Bavarian Nordic) elicited tumor-specific immunity in a Phase 1 dose-escalation trial. The study involved 13 subjects with chordoma, a rare slow-growing cancer affecting the spine which expresses the antigen brachyury, and 25 patients with another solid tumor.
The treatment was well tolerated, and the percentage of patients with induced brachyury-specific T-cells increased with escalating doses.
BioThrax license expanded to adults with suspected exposure to anthrax
The FDA has expanded the indication of anthrax vaccine BioThrax (Emergent BioSolutions) to adults aged 18–65 suspected to have come into contact with Bacillus anthracis. The previous license included only people at high risk of exposure.
Approved in 1970, BioThrax is the only licensed anthrax vaccine. In addition, the company is developing an improved vaccine, NuThrax, which is in a Phase 3 clinical trial.
Therapeutic HPV vaccine GTL001 initiated U.S.-based clinical trials
The investigational therapeutic HPV vaccine GTL001 (Genticel) entered a Phase 1 trial in the U.S. The study will assess safety and tolerability in 20 women aged 25–65. The vaccine targets HPV strains 16 and 18, which account for 70% of cervical cancer cases. It has been subjected to Phase 1/2 testing in Europe with encouraging results.
The company is simultaneously developing GTL002 vaccine, which targets the six most oncogenic HPV strains.
New cholesterol vaccine effective in animal models
A vaccine candidate against hypercholesterolemia reduced levels of LDL cholesterol and triglycerides in a preclinical study published in Vaccine.1 The VLP-based vaccine targets PCSK9 protein that controls cholesterol homeostasis. It reduced LDL cholesterol in mice and had a dramatic effect in macaques when co-administered with statins.
>70 million adults in the U.S. alone have high LDL cholesterol. The most common treatment with statins can have serious side effects. MAb-based therapies, recently approved by the FDA, are much more expensive.
1. Crossey E, Amar MJ, Sampson M, Peabody J, Schiller JT, Chackerian B, Remaley AT. A cholesterol-lowering VLP vaccine that targets PCSK9. Vaccine 2015; 33(43):5747–55