Combination immunotherapy holds promise for treatment of advanced solid cancers
Manageable toxicity and anti-tumor stimulatory effects were reported from a Phase 1b trial of pegylated IL-10 (pegilodecakin) in combination with the PD-1 inhibitors pembrolizumab or nivolumab in patients with renal cell carcinoma (RCC) or non-small cell lung cancer (NSCLC).Citation1 While the checkpoint blocking MAbs prevent the tumor from inhibiting immune responses, pegilodecakin is designed to stimulate the activity of cytotoxic T cells. It consists of recombinant IL-10 conjugated to polyethylene glycol to increase its half-life in the blood.
“Our study showed this combination demonstrated favorable response in NSCLC and kidney cancer patients who previously had been treated when compared to those treated with anti-PD-1 monoclonal antibodies alone,” lead author Aung Naing of MD Anderson Cancer Center said.
The trial enrolled 111 RCC, NSCLC and melanoma patients. Objective responses were observed in ~40% of the former two groups, but only 10% in the melanoma cohort.
PCV-20 proved immunogenic in a mid-stage trial
The 20-valent pneumococcal conjugate vaccine PF-06482077 (Pfizer) is safe and immunogenic, according to preliminary results of a randomized, double-blind Phase 2 study involving 460 healthy infants. The vaccine, which targets the same serotypes as its 13-valent counterpart, Prevnar 13, plus seven additional pneumococcal strains, induced serological immunity against all 20 serotypes.
The study subjects received 3 doses of either PF-06482077 or Prevnar 13 in the first 6 months of life. They are still to receive the 4th dose at age 1. Phase 3 trials are underway that investigate protection from invasive pneumococcal disease in adults.
Combination of checkpoint blocking MABs improves outcomes in NSCLC and melanoma
Targeting both the PD-1 and the CTLA-4 immune checkpoint pathways simultaneously with antagonistic MAbs nivolumab and ipilimumab improved survival in two indications. Newly diagnosed NSCLC patients treated with the combination immunotherapy lived a median of 17 months compared to 15 months in subjects who received standard-of-care chemotherapy. The two-year survival rate was 40% in the experimental cohort irrespective of PD-L1 levels and 33% and 23% in the control subjects with high and low PD-L1 levels, respectively.
In melanoma, >50% of patients were alive at the 5-year mark in a follow-up to the Phase 3 Checkmate-067 study. The treatment also worked in patients who had discontinued the therapy due to adverse reactions.
US men benefit from herd protection following HPV vaccine introduction
Oral HPV infection rates decreased by 37% in unvaccinated US men, according to a study of 14,000 adults between 2009 and 2016.Citation2 This is likely a secondary effect of vaccinating girls, which has been recommended since 2006. HPV vaccination rates reached almost 6% for boys and 15% for girls during this period.
HPV is one of the leading causes of cervical cancer in women and genital and oropharyngeal cancers in both sexes. The study failed to find evidence for herd protection in unvaccinated women.
Pembrolizumab had mixed results in triple-negative breast cancer
The PD-1 inhibitor pembrolizumab combined with standard-of-care chemotherapy increased the complete response rate at 15 months to 65%, compared to 50% for chemotherapy alone, in patients with early-stage triple-negative breast cancer (TNBC). Blood levels of the PD-L1 biomarker did not make a difference for the results of the Phase 3 KEYNOTE-522 trial.
In another Phase 3 study, pembrolizumab monotherapy failed to halt disease progression in patients with metastatic, previously treated TNBC. Survival was longer the higher the subjects’ PD-L1 levels, but not significantly better than chemotherapy.
New vaccine against smallpox and monkeypox was approved in the U.S
The U.S. Food and Drug Administration (FDA) has approved the smallpox vaccine Jynneos (Bavarian Nordic) for use in adults at risk of contracting the infection. The vaccine, which is already marketed in Europe as Imvanex and in Canada as Imvamune, is the first to be used in immunocompromised people. Although eradicated, smallpox is considered a potential bioterrorism agent, and the U.S. has stockpiled 28 million doses of the vaccine.
Jynneos has also been approved against monkeypox, a related zoonotic disease, which has been reported from a few countries, most notably in equatorial Africa. The vaccine should thus be used in travelers going to high-risk regions.
FDA expert panel endorsed immunotherapy for food allergy for the first time
The FDA advisory committee has recommended the approval of AR101 (Aimmune), oral immunotherapy for peanut allergy, for children and adolescents. The AR101 tablet contains peanut flour with consistent amounts of allergenic protein. The doses are increased in the course of immunotherapy, which sensitizes the patient’s immune system to tolerate accidental exposure.
There is no alternative treatment for peanut allergy, other than avoiding peanut products and epinephrine injections in case of accidental exposure.
In a Phase 3 trial, administering AR101 for a year translated into 84% of subjects tolerating two peanuts with mild symptoms. However, participants also reported increased adverse reactions and use of epinephrine injections.
Despite vaccination, immunity against mumps is insufficient in some people
No mumps-specific memory B cells were detected in 10% of young adults tested in a small study. In addition, the average blood levels of these memory B cells were 5–10 -fold lower than those specific for measles or rubella, and the anti-mumps antibodies were less capable of neutralizing the virus.Citation3
Almost all of the 70 enrolled college students had received two doses of the MMR vaccine, most of them >10 years previously. Waning immunity is one of the factors behind recent recurrence of mumps outbreaks.
“What we’re seeing now with these mumps outbreaks is a combination of two things – a few people were not making a strong immune response to begin with, and the circulating strain has drifted away from the strain that is in the vaccine,” senior author of the study Sri Edupuganti of Emory University said.
Antibiotics decrease efficacy of immunotherapy and influenza vaccination
Checkpoint-blocking immunotherapy is hampered by administration of antibiotics prior to treatment. According to a study of almost 100 patients with various cancer types, subjects who received broad-spectrum antibiotics up to 30 days before immunotherapy had a median overall survival of two months, compared to 26 months in patients who received the two treatments together, and their cancer was twice as likely to progress.Citation4 The effect was reported for multiple types of antibiotics.
In another study, antibiotics reduced antibody responses to seasonal influenza vaccination in people with low preexisting immunity.Citation5 In one cohort, 22 subjects with high preexisting antibody titers against the 2014–5 vaccine strains were not affected in their responses to immunization. In the second cohort, however, broad-spectrum antibiotics given to 11 subjects with low titers against the 2015–6 influenza strains impaired immunogenicity and virus neutralization titers.
Both studies implicated gut microbiota dysbiosis as the likely mediator of the effect.
Second experimental Ebola vaccine is deployed in Congo
The Democratic Republic of the Congo has approved the use of the Ebola vaccine Ad26.ZEBOV/MVA-BN (J&J) in the ongoing outbreak. The vaccine, which is administered in two doses 56 days apart, will be provided in areas without reported Ebola transmission.
Another vaccine, rVSV-ZEBOV-GP (Merck), has been given to >200,000 people with infected acquaintances. It is >97% effective having saved thousands of lives according to the World Health Organization. Nonetheless, the aid organization Médecins Sans Frontiéres says the vaccine reaches only a small part of the eligible population. For example, local health workers are supposedly under-immunized.
The ongoing outbreak has infected >3,000 people and killed around 2,100.
Herpes vaccine proved efficacious in a preclinical trial
A genital herpes vaccine candidate prevented infection in almost 100% mouse and guinea pig models in a challenge study.Citation6 The lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine targets the HSV-2 glycoprotein D, which mediates cell entry, and two immune evasion glycoproteins C and E.
Genital herpes affects ~11% of adolescents and adults worldwide. It can lead to painful sores and increase the risk of contracting HIV.
References
- Naing A, Wong DJ, Infante JR, Korn WM, Aljumaily R, Papadopoulos KP, Autio KA, Pant S, Bauer TM, Drakaki A, et al. Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial. Lancet Oncol. 2019. doi:10.1016/S1470-2045(19)30514-5.
- Chaturvedi AK, Graubard BI, Broutian T, Xiao W, Pickard RKL, Kahle L, Gillison ML. Prevalence of Oral HPV infection in unvaccinated men and women in the United States, 2009-2016. JAMA. 2019;322(10):977–79. doi:10.1001/jama.2019.10508.
- Rasheed MAU, Hickman CJ, McGrew M, Sowers SB, Mercader S, Hopkins A, Grimes V, Yu T, Wrammert J, Mulligan MJ, et al. Decreased humoral immunity to mumps in young adults immunized with MMR vaccine in childhood. Proc Natl Acad Sci U S A. 2019;116(38):19071–76. doi:10.1073/pnas.1905570116.
- Pinato DJ, Howlett S, Ottaviani D, Urus H, Patel A, Mineo T, Brock C, Power D, Hatcher O, Falconer A, et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol. 2019. doi:10.1001/jamaoncol.2019.2785.
- Hagan T, Cortese M, Rouphael N, Boudreau C, Linde C, Maddur MS, Das J, Wang H, Guthmiller J, Zheng NY, et al. Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans. Cell. 2019;178(6):1313–1328.e13. doi:10.1016/j.cell.2019.08.010.
- Awasthi S, Hook LM, Pardi N, Wang F, Myles A, Cancro MP, Cohen GH, Weissman D, Friedman HM. Nucleoside-modified mRNA encoding HSV-2 glycoproteins C, D, and E prevents clinical and subclinical genital herpes. Sci Immunol. 2019;4(39):eaaw7083. doi:10.1126/sciimmunol.aaw7083.