Benefit of checkpoint immunotherapy seen in various cancer types
Combination of the PD-L1 inhibitor atezolizumab (Tecentriq, Roche) and protein-bound paclitaxel (Abraxane) improved survival of locally advanced triple-negative breast cancer (TNBC) and non-squamous non-small cell lung cancer (NSCLC) patients. Two Phase 3 trials reported progression-free survival (PFS) of 7.5 months compared to 5 months in the chemotherapy-alone cohort for TNBC subjects, and 7 and 5.5 months, respectively, in NSCLC patients.
Results from the CheckMate-142 study suggest that the combination of anti-PD-1 nivolumab (Opdivo) and low-dose anti-CTLA-4 ipilimumab (Yervoy, both BMS) might be effective as the first-line treatment of microsatellite instability-high metastatic colorectal cancer. The objective response rate among 45 enrolled patients was 60% with 7% complete responses. The one-year PFS was 77%, and toxicities were reported in 16% of subjects. The combination is approved in the US as second-line treatment.
Progress in influenza vaccine development despite declining uptake
Influenza vaccination coverage among US adults was 37% in the 2017/8 season, decreasing inter-annually by 6 percentage points, the Centers for Disease Control and Prevention (CDCP) reported.1 The season was also one of the most severe in recent decades with low vaccine effectiveness, and CDCP urges healthcare providers to offer and recommend influenza vaccine to all patients.
The low effectiveness of seasonal vaccines has been linked to the method of production in chicken eggs. The cell culture-based influenza vaccine Flucelvax (Seqirus) is approvable in Europe after the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use endorsed it. The 4-valent vaccine was approved in the US in 2016. A retrospective analysis conducted by Seqirus showed that vaccines produced in cells had a higher rate of similarity to circulating strains of H3N2 than egg-derived vaccines over 12 seasons.2
Another candidate, the recombinant protein influenza vaccine (Vaxart), showed a 39% reduction of clinical influenza cases relative to placebo in a Phase 2 challenge trial. The licensed Fluzone (Sanofi) prevented 27% of influenza cases in the same study. The investigational vaccine is administered as an oral tablet, which simplifies logistics and might lead to increased uptake.
The ultimate goal of influenza vaccine research is to develop a ‘universal’ vaccine, which would protect against most or all strains without the need of re-vaccination each year. Two candidates have shown some promise. The first one, the nasal vaccine RedeeFlu (FluGen), was safe and elicited robust cell and humoral immunity in a placebo-controlled Phase 1 trial involving almost 100 healthy adults. The second candidate vaccine (InvVax), which targets 15 invariant epitopes and is administered both subcutaneously and nasally, protected 100% of mice in a challenge with one H1N1 and two H3N2 influenza strains. All control animals died.
Centers for Disease Control and Prevention. Estimates of Influenza Vaccination Coverage among Adults – United States, 2017–18 Flu Season. https://www.cdc.gov/flu/fluvaxview/coverage-1718estimates.htm; accessed November 6, 2018
Seqirus Presents Data at IDWeek Demonstrating Cell-Derived Viruses Have a Closer Match to Circulating Influenza Viruses Compared to Egg-derived Viruses Used in the Production of Influenza Vaccines. https://www.seqirus-us.com/media-room/press-releases/seqirus_presents_data_at_idweek; accessed November 6, 2018
Prostate cancer immunotherapy is tested in a phase 2 study
The prostate cancer vaccine ProscaVax (OncBioMune) has entered a Phase 2 trial, which will enroll 120 patients with early-stage disease. ProscaVax, which consists of the prostate-specific antigen protein along with IL-2 and GM-CSF adjuvants, had a good safety profile in earlier studies.
Prostate cancer is the second most common type of cancer and the second leading cause of cancer death in men.
Pediatric vaccination continues to decline in the US
1.3% of two-year-olds received no vaccine in 2017, which represents an almost 50% increase since 2013.1 Children from rural areas and uninsured or Medicaid-insured children were less likely to be immunized than their peers. At the same time, vaccine exemptions have increased in frequency, for a third year in a row, to 2.2%.2 Only one-tenth of those were for medical reasons.
Hill HA, Elam-Evans LD, Yankey D, Singleton JA, Kang Y. Vaccination Coverage Among Children Aged 19–35 Months – United States, 2017. MMWR Morb Mortal Wkly Rep 2018; 67(40):1123–1128
Mellerson JL, Maxwell CB, Knighton CL, Kriss JL, Seither R, Black CL. Vaccination Coverage for Selected Vaccines and Exemption Rates Among Children in Kindergarten – United States, 2017–18 School Year. MMWR Morb Mortal Wkly Rep 2018; 67(40):1115–1122
A phase 2 trial has started for a celiac disease vaccine
The desensitization peptide vaccine against celiac disease, Nexvax2 (ImmusanT), entered a randomized, double-blind, placebo-controlled Phase 2 study in Australia and New Zealand to test safety and efficacy.
The subcutaneous vaccine, which contains epitopes most commonly triggering inflammatory response, is designed to reprogram auto-reactive T cells to tolerate exposure to gluten.
Gardasil 9 approved for adults up to 45 years old in US
The US Food and Drug Administration (FDA) has expanded indication of the HPV vaccine Gardasil 9 (Merck) to include adults aged 27–45. Previously the vaccine could be administered only to children and adolescents aged 9–26 years.
The decision is based on data showing that the 4-valent Gardasil, which is manufactured similarly, is almost 90% effective against cervical cancer, genital warts and vulvar, vaginal and cervical precancerous lesions.
Update on HIV vaccine development
A mosaic HIV vaccine (J&J) was safe and immunogenic in a Phase 1/2 trial. HIV-negative volunteers received four doses of the 4- or 3-valent forms of the vaccine in a 0-12-24-48 week regimen. The 4-valent vaccine demonstrated broad antibody and cellular immune responses. Mosaic vaccines are designed to target HIV strains from around the world.
In another Phase 1 trial, safety and immunogenicity of an HIV vaccine candidate, eOD-GT8 60mer (IAVI), will be assessed in 48 healthy adult volunteers. Subjects will receive two doses of the vaccine with AS01B adjuvant or placebo. eOD-GT8 60mer is designed to stimulate the production of broadly neutralizing antibodies.
Progress in the development of vaccines against emerging diseases
The Chikungunya virus vaccine candidate VLA1553 (Valneva) is being tested in a second stage of a Phase 1 trial for protection against the disease. In the first stage, 120 healthy adults were immunized with different doses of the monovalent, live attenuated vaccine. One group will be re-vaccinated to simulate infection and then will be tested for prevention of vaccine-induced viremia.
Another Phase 1 study will evaluate safety and immunogenicity of the Marburg virus vaccine VRC-MARADC087-00-VP (NIAID) in 40 healthy US adults. The candidate is a recombinant chimpanzee adenovirus type 3-vectored vaccine, and study participants will be followed for one year. Similar to Chikungunya, there is no approved vaccine for the Marburg virus.
On the Ebola vaccine front, 100% of animals were protected against lethal challenge after vaccination with INO-4212 (Inovio). The vaccine is a two-dose intradermal candidate, which is stable at room temperature. In a parallel study, it elicited strong immunity in monkey, which lasted at least one year.
Dengvaxia endorsed by authorities despite withdrawal from the philippines
EMA’s committee recommended the dengue vaccine Dengvaxia (Sanofi) for people aged 9 to 45. In addition, the FDA has accepted an application for approval with a priority review. Potential acceptance both in Europe and the US would apply only to people who have had a prior dengue infection.
Dengvaxia was used in a Philippines’ national campaign to vaccinate people regardless whether they had been infected. Later it was found that the vaccine exacerbates the course of infection in dengue-naïve subjects. The country has stopped the program in response.
New slow-release device successfully delivered immunotherapy in mouse model of breast cancer
Potent local and systemic anti-tumor immune responses were elicited by a nanofluidic immunotherapy-eluting seed in a preclinical study.1 Once in the tumor, the device continually releases immunotherapy (in this case the immune stimulators OX40 and CD40) over extended periods of time, resulting in sustained immune responses without the need of repeated injections.
“Our implant releases the drug in a constant manner until the entire amount is completely gone from the reservoir,” senior author Alessandro Grattoni of Houston Methodist Research Institute said. “Since it can deliver the immunotherapy by itself for weeks to potentially months, we would only need to place the device inside the tumor once, and then the drug would be released autonomously for that long period of time.”
Chua CYX, Jain P, Susnjar A, Rhudy J, Folci M, Ballerini A, Gilbert A, Singh S, Bruno G, Filgueira CS, Yee C, Butler EB, Grattoni A. Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer. J Control Release 2018; 285:23–34
Study finds no link between HPV vaccination and risky sexual behavior
Getting vaccinated against HPV does not increase risky sexual behavior in adolescent girls, according to a longitudinal survey conducted in Canada.1 The recommendation of the vaccine for children aged 9 years and older has sparked fears that teens and adolescents would engage in risky behavior such as unprotected sex or promiscuity.
The study looked at 300,000 heterosexual girls between 2003 and 2013 in British Columbia, which introduced an HPV vaccine program in 2008. The proportion of girls who had sex and the rate of pregnancies decreased, while the use of condoms increased. The number of partners remained the same.
Ogilvie GS, Phan F, Pedersen HN, Dobson SR, Naus M, Saewyc EM. Population-level sexual behaviours in adolescent girls before and after introduction of the human papillomavirus vaccine (2003–2013). CMAJ 2018; 190(41):E1221–E1226