Nobel Prize awarded for cancer immunotherapy
The immunotherapy pioneers James Allison and Tasaku Honjo have received the Nobel Prize in Physiology or Medicine. Their groundbreaking discoveries of the functions of the negative T-cell regulators CTLA-4 and PD-1, respectively, have led to the application of selective inhibitory MAbs in cancer immunotherapy.
The so-called checkpoint blockade immunotherapy, which suppresses the CTLA-4 and PD-1 inhibitory pathways in T-cells, enables the immune system to attack and clear tumors. Clinical responses are usually seen in only a subset of patients, although some such cases have resulted in virtual cure from the tumor. Checkpoint blockade MAbs have been approved for treatment of melanoma, lymphoma, lung, bladder, kidney and head-and-neck cancers, and are being investigted continually in a wide range of additional tumor types.
Clinical progress in new influenza vaccine development
>1,300 healthy older adults are taking part in a randomized Phase 2 trial of the quadrivalent nanoparticle seasonal influenza vaccine NanoFlu (Novavax). The study will investigate the optimal dose of the vaccine with or without the Matrix-M adjuvant. NanoFlu is a recombinant hemagglutinin-targeting protein vaccine produced in insect cells.
Safety and immunogenicity have been demonstrated in a Phase 2a trial of the H1-targeting, nasal influenza vaccine NasoVAX (Altimmune) in 60 healthy adults. Specific mucosal antibodies were elicited by all doses and persisted through the tested period of 6 months, unlike in the control cohort that received another nasal vaccine (Fluzone, Sanofi Pasteur).
A double-blind, placebo-controlled Phase 1 study has started in 50 healthy 9- to 17-year-old children investigating another nasal-spray influenza vaccine (FluGen) targeting the H3N2 strains. The single-replication vaccine will be administered three months prior to the licensed quadrivalent vaccine to see whether the combination broadens protection.
Clinical progress in new influenza vaccine development
HER2 vaccine benefits patients with multiple cancer types
A HER2-expressing dendritic cell (DC) vaccine elicited responses in 6 out of 11 evaluable patients who received higher than the smallest dose in a dose-escalation Phase 1 trial. One subject had a complete response for at least 90 weeks.
“We are using a vaccine approach to generate an immune response to HER2, which is found at high levels on and drives the growth of several types of cancer, including breast, ovarian, lung, colorectal, and gastroesophageal cancers,” investigator Jay Berzofsky of National Cancer Institute said.
In the study, patients’ DCs were collected and engineered with an adenovirus expressing a HER2-derived peptide, then the expanded cells were infused back into the participants five times in three different dosage levels.
Promising Phase 2 results for a candidate tuberculosis vaccine
An investigational vaccine M72 (GSK) showed a 54% overall efficacy in preventing pulmonary tuberculosis in a placebo-controlled Phase 2b study involving 3,500 HIV-negative African adults. 10 subjects progressed to disease in the experimental group compared to 22 subjects in the placebo group.
BCG, which is the only approved tuberculosis vaccine, was developed almost 100 years ago. It is administered in infancy, and with waning immunity does not provide consistent protection in adults.
Autologous T-cell therapy was safe in HIV patients in a small trial
Ex-vivo expanded HIV-specific T cell infusions were well tolerated in six HIV-positive patients on antiretroviral therapy (ART). Two of the subjects had a detectable increase in antiviral T-cell activity.
The HIV reservoir is kept latent in patients on ART. The ultimate goal is to combine the treatment with latency-reversal drugs and cure the disease by inducing the virus and eliminating it with the infused T cells.
1. Sung JA, Patel S, Clohosey ML, Roesch L, Tripic T, Kuruc JD, Archin N, Hanley PJ, Cruz CR, Goonetilleke N, Eron JJ, Rooney CM, Gay CL, Bollard CM, Margolis DM. HIV-Specific, Ex Vivo Expanded T Cell Therapy: Feasibility, Safety, and Efficacy in ART-Suppressed HIV-Infected Individuals. Mol Ther 2018; doi: 10.1016/j.ymthe.2018.08.015
Experimental Zika vaccine enters human trials
Safety and immunogenicity of the live attenuated Zika vaccine rZIKV/D4Δ30-713 will be assessed in a Phase 1 study which enrolls 28 healthy adults up to 50 years of age. The vaccine consists of a chimeric virus with a dengue genetic backbone and Zika surface proteins.
“Zika virus infection remains a significant threat to pregnant women and their developing fetuses, and we can expect to see periodic outbreaks and cases in areas where Aedes aegypti mosquitoes thrive,” said Anthony Fauci, director of National Institute of Allergy and Infectious Diseases, which developed the vaccine and conducts the trial.
The Zika outbreak, which started in 2015, has seen a rapid decrease of the number of clinical cases, which makes it difficult to test candidate vaccines in large-scale studies. Some scientists therefore are considering human challenge trials.
Novel adjuvant boosts cancer vaccine potency
Adding a new TLR1/2 agonist, Diprovocim, to a combination therapy of PD-1 blockade and cancer vaccination resulted in 100% survival after two months in a mouse model of melanoma. Mice that received the conventional aluminum adjuvant showed 25% survival rate in a small study with 8 animals in each cohort.1
Diprovocim-adjuvanted vaccination induced antigen-specific humoral and T-cell responses, and established a long-term antitumor memory, which prevented later engraftment of melanoma.
1. Wang Y, Su L, Morin MD, Jones BT, Mifune Y, Shi H, Wang KW, Zhan X, Liu A, Wang J, Li X, Tang M, Ludwig S, Hildebrand S, Zhou K, Siegwart DJ, Moresco EMY, Zhang H, Boger DL, Beutler B. Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti-PD-L1 to eliminate melanoma in mice. Proc Natl Acad Sci U S A 2018; 115(37):E8698-E8706
20-valent pneumococcal vaccine receives breakthrough designation by FDA
The US Food and Drug Administration has granted its breakthrough therapy designation to the 20-valent pneumococcal conjugate vaccine PF-06482077 (Pfizer). The decision was based on data from a Phase 2 trial, which have not been published, demonstrating safety and immunogenicity in older adults.
The designation is designed to expedite the development and review of vaccines against serious conditions. In this case it applies to invasive pneumococcal disease in adults caused by vaccine strains of Streptococcus pneumoniae.
Therapeutic hepatitis C vaccine started a Phase 1 trial
24 patients with hepatitis C and 8 healthy controls are enrolled in an early trial of the therapeutic hepatitis C vaccine GLS-6150 (Inovio & GeneOne). The electroporation-delivered DNA vaccine, which expresses three viral epitopes and the cytokine IL-28b, will be administered in two different doses in a three-dose prime and a boost six months later.
Novel H3N2 influenza vaccine provides complete protection in a preclinical model
100% mice vaccinated with a DNA influenza vaccine (Inovio) survived a lethal challenge with two pandemic strains of H3N2. The vaccine, which encodes a mixture of H3 hemagglutinin antigens, elicited robust CD4 and CD8 T-cell responses.
H3N2 is one of the deadliest strains of influenza. In the 2017/8 season the efficacy of conventional influenza vaccines against this strain was particularly low due to mismatch with the circulating types.
Key drugs accelerated for approval in China
The shingles vaccine Shingrix (GSK) and the PD-1 inhibitor pembrolizumab (Merck) are among “urgently needed new drugs” identified by the Chinese State Drug Administration. The list aims at encouraging companies to apply for approval in China with the possibility to use foreign data as the basis for priority review.