Personalized cancer vaccines pass early tests in melanoma
Two Phase 1 trials showed the potential of personalized neoantigen cancer vaccines. In the first one, neo-epitopes from five melanoma patients were identified and utilized in an RNA vaccine that matched each patient's tumor.Citation1 All subjects developed T-cell responses against multiple tumor targets, and one patient had a complete response to the vaccine in combination with a checkpoint inhibitor.
In the second study, a synthetic peptide-based personalized vaccine elicited T cells that recognized the majority of ∼100 neo-epitopes across six melanoma patients. Four of the subjects had no disease recurrence after 2 years, and the remaining two reported a complete response after subsequent anti-PD-1 treatment.
- Sahin U, Derhovanessian E, Miller M, Kloke BP, Simon P, Löwer M, Bukur V, Tadmor AD, Luxemburger U, Schrörs B, Omokoko T, Vormehr M, Albrecht C, Paruzynski A, Kuhn AN, Buck J, Heesch S, Schreeb KH, Müller F, Ortseifer I, Vogler I, Godehardt E, Attig S, Rae R, Breitkreuz A, Tolliver C, Suchan M, Martic G, Hohberger A, Sorn P, Diekmann J, Ciesla J, Waksmann O, Brück AK, Witt M, Zillgen M, Rothermel A, Kasemann B, Langer D, Bolte S, Diken M, Kreiter S, Nemecek R, Gebhardt C, Grabbe S, Höller C, Utikal J, Huber C, Loquai C, Türeci Ö. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 2017;547(7662):222-226.
- Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, Zhang W, Luoma A, Giobbie-Hurder A, Peter L, Chen C, Olive O, Carter TA, Li S, Lieb DJ, Eisenhaure T, Gjini E, Stevens J, Lane WJ, Javeri I, Nellaiappan K, Salazar AM, Daley H, Seaman M, Buchbinder EI, Yoon CH, Harden M, Lennon N, Gabriel S, Rodig SJ, Barouch DH, Aster JC, Getz G, Wucherpfennig K, Neuberg D, Ritz J, Lander ES, Fritsch EF, Hacohen N, Wu CJ. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 2017;547(7662):217-221.
HIV vaccine was safe and immunogenic in early trial
An HIV vaccine candidate (J&J) was well tolerated and induced specific antibodies in all 400 participants of a Phase 1/2a trial in the US, Thailand and several African countries. The “mosaic” vaccine contains pieces of different viral strains and thus might elicit immune responses against diverse HIV-1 subtypes from around the world.
Pertussis vaccine ameliorates the course of disease
Children who suffered pertussis despite being vaccinated were 60% less likely to develop a severe form of the disease than unvaccinated subjects.Citation1 A US study, which analyzed Enhanced Pertussis Surveillance data from 2010–2, also found that vaccination was associated with a 30% lower rate of severe vomiting in most age groups.
“These findings are very important because they show that even though pertussis vaccines do not prevent all cases of pertussis, breakthrough cases that occur in vaccinated people are less likely to be severe. That means fewer hospitalizations and serious complications for patients,” lead author Lucy McNamara of Centers for Disease Control and Prevention told Reuters.
- McNamara LA, Skoff T, Faulkner A, Miller L, Kudish K, Kenyon C, Bargsten M, Zansky S, Sullivan AD, Martin S, Briere E. Reduced Severity of Pertussis in Persons With Age-Appropriate Pertussis Vaccination—United States, 2010–2012. Clin Infect Dis. 2017;doi:10.1093/cid/cix421
Promising Phase 2 data for a universal influenza vaccine
A 9-valent influenza vaccine candidate M-001 (BiondVax) induced higher antibody responses than a placebo when used as a primer to H5N1 pandemic vaccine. The trial enrolled >200 participants and tested two dosage levels of M-001. By using nine stable epitopes, the vaccine is designed to provide priming for protection across seasons and against both seasonal and pandemic strains. A Phase 3 trial will evaluate the efficacy of M-001 alone.
RSV vaccine candidate immunogenic in older people
The RSV F vaccine (Novavax) showed some promise in a Phase 2 trial involving 300 subjects aged ≥60 years, who were divided into 12 groups to receive one or two of two different dosage levels or placebo, with or without aluminum or Matrix-M adjuvants. The two-dose regimens with an adjuvant markedly increased immune responses.
The candidate had failed a large-scale Phase 3 trial last year, but the company said that a subsequent analysis showed a reduction of chronic obstructive pulmonary disease-related hospitalizations.
FDA advisory committee recommends CAR-T therapy of ALL
The US Food and Drug Administration (FDA) advisory committee has recommended approval of chimeric antigen T-cell (CAR-T) therapy (Novartis) for children and young adults with acute lymphoblastic leukemia (ALL) who failed chemotherapy. The unanimous decision was based on a trial in which 80% of ALL patients were alive one year after CAR-T treatment.
80–90% of ALL tumors in children can be treated with chemotherapy or bone marrow transplant, but the rest only have <30% chance of survival. Annually, around 6,000 people are diagnosed with ALL in US alone, or which 60% are children.
Peanut allergy immunotherapy progressed into large-scale clinical testing
The oral immunotherapy AR101 (Aimmune) is being tested for safety and efficacy in 250,000 European children aged 4–17 who have, or are expected to develop, peanut allergy. AR101, which contains a purified peanut protein, successfully desensitized 90% of patients enrolled in Phase 2 trials, although ∼20% were not able to complete the program due to gastrointestinal adverse events.
Development of new hepatitis B vaccines
The hepatitis B vaccine Sci-B-Vac (VBI) will be tested in a two-part Phase 3 study. The first part (Protect) looks for safety and immunogenicity of a 3-dose regimen in 1,600 subjects. The second part, Constant, tests consistency of different lots on 3,200 people. In both parts, Sci-B-Vac is compared to the licensed Engerix-B (GSK). Sci-B-Vac is a VLP-based vaccine containing three HBV surface antigens. It has been licensed in 15 countries, but not in the US, Canada and EU where the trial takes place.
Another hepatitis B vaccine candidate, Heplisav-B (Dynavax), was recommended for adults by an FDA expert panel. Although the vaccine was associated with more deaths and heart problems than the licensed Engerix-B in a clinical trial, the overall rate of adverse events was low, the panel concluded.
Challenges in the development of new indications for checkpoint inhibitor antibodies
The anti-PD1 antibody pembrolizumab (Keytruda, Merck) failed to extend survival compared to standard treatment in patients with advanced head-and-neck cancer. This immunotherapeutic antibody had received accelerated approval by the US FDA for this population on the condition that a large-scale trial would show clinical benefit.
At the same time, the FDA has placed a clinical hold on three studies of pembrolizumab in multiple myeloma, saying that the risks of the treatment outweigh any potential benefit for patients.
A combination therapy of anti-PD-L1 durvalumab and anti-CTLA-4 tremelimumab (both AstraZeneca) was no more effective than chemotherapy in patients with metastatic non-small cell lung cancer with high PD-L1 levels. Nevertheless, the Mystic trial will continue to assess progression-free survival after a longer period of time.
Zika vaccines successfully protected newborn mice
Two Zika vaccines prevented infection of newborns in a preclinical challenge model.Citation1 Female mice were given a lipid nanoparticle mRNA vaccine or a live attenuated vaccine shortly before pregnancy. Compared to placebo, the vaccines protected 50% and 80% of fetuses, respectively. None of the placebo cohort completed pregnancy. The vaccines still need to be tested when administered during pregnancy.
Zika virus causes relatively mild illness, but when pregnant women are infected, the developing embryo can suffer reduction of growth and microcephaly, and infection can result in miscarriage.
- Richner JM, Jagger BW, Shan C, Fontes CR, Dowd KA, Cao B, Himansu S, Caine EA, Nunes BTD, Medeiros DBA, Muruato AE, Foreman BM, Luo H, Wang T, Barrett AD, Weaver SC, Vasconcelos PFC, Rossi SL, Ciaramella G, Mysorekar IU, Pierson TC, Shi PY, Diamond MS. Vaccine Mediated Protection Against Zika Virus-Induced Congenital Disease. Cell 2017;170(2):273-283.e12.