CRISPR/Cas9 gene editing technology used in cancer immunotherapy for the first time
A dose-escalation phase 1 trial of CRISPR/Cas9-mediated treatment of metastatic non-small cell lung cancer has started in China. Scientists at Sichuan University in Chengdu harvest patients’ T cells, knock out the PD-1 gene with this technology, expand cells in vitro, and infuse them back.
It is the first time the CRISPR/Cas9 technology is used in human subjects, and similar studies with other cancer types are planned for early 2017.
PD-1 signaling is used by some tumors to inhibit T cells and prevent an immune response. Conventional PD-1-based immunotherapy uses MAbs to target components of the pathway.
Development of Zika vaccines and antibodies
The third Zika vaccine candidate to enter clinical trials is a purified inactivated virus vaccine developed by the Walter Reed Army Institute of Research. The Phase 1 study will enroll 75 participants. Some of them will first be vaccinated against other flaviviruses (such as yellow fever and dengue), since immunity against them can boost response against the Zika vaccine.
The U.S. National Institute of Allergy and Infectious Diseases (NIAID) will also test the candidate in combination with its own DNA Zika vaccine in another Phase 1 trial.
Another synthetic DNA vaccine against Zika has been developed at the Wistar Institute. It protected 100% of animals against the infection, elicited antibody and T-cell responses and prevented the virus from spreading to the brain.
A team of NIAID researchers has also been able to isolate neutralizing antibodies from Zika-infected people. One of the antibodies, ZIKV-117, neutralized every strain that was tested, and increased the survival rate when administered to a mouse model. Furthermore, it prevented mother-to-fetus transmission in pregnant mice. The research might lead to the development of novel therapeutics.
Axalimogene filolisbac cancer vaccine tested in various combinations to treat HPV-positive cancers
The combination immunotherapy of axalimogene filolisbac (Advaxis) and durvalumab (MedImmune) was well tolerated with no toxicities in a Phase 1/2 trial in patients with metastatic cervical or squamous-cell head-and-neck cancer. One subject with cervical cancer had a complete response at 12 months.
A preclinical study of axalimogene filolisbac combined with therapeutic MAbs showed potential in the treatment of HPV-related cancers. Particularly CD137 agonist and CTLA-4 antagonist antibodies proved efficient in increasing the tumor-specific T cells and decreasing Tregs.
Axalimogene filolisbac is a live attenuated Listeria monocytogenes engineered to express HPV antigens. It is also being tested as an adjuvant to chemotherapy.
Progress towards an HIV vaccine
A new HIV vaccine regimen HVTN 100 will be tested in a large-scale Phase 2/3 trial in South Africa. 5,400 uninfected men and women will receive five injections over the course of one year. HVTN 100 consists of two vaccines developed by Sanofi Pasteur and GSK, which are adapted to the HIV subtype predominant in South Africa. Results are expected in 2020.
A therapeutic HIV vaccine Ad26/MVA combined with a TLR7 agonist decreased the viral load 50-fold compared to controls in a rhesus macaque model of SIV infection.1 Moreover, the combination was able to suppress the virus even after the treatment was stopped.
Another preclinical study tested a vaccine based on the common cold virus engineered to express HIV proteins.2 This intranasally delivered vaccine elicited mucosal immunity in mice, which might help to limit transmission via genital mucosal surfaces.
1.Borducchi EN, Cabral C, Stephenson KE, Liu J, Abbink P, Ng'ang'a D, Nkolola JP, Brinkman AL, Peter L, Lee BC, Jimenez J, Jetton D, Mondesir J, Mojta S, Chandrashekar A, Molloy K, Alter G, Gerold JM, Hill AL, Lewis MG, Pau MG, Schuitemaker H, Hesselgesser J, Geleziunas R, Kim JH, Robb ML, Michael NL, Barouch DH. Ad26/MVA Therapeutic Vaccination with TLR7 Stimulation in SIV-Infected Rhesus Monkeys. Nature 2016; doi: 10.1038/nature20583
2.Tomusange K, Wijesundara D, Gummow J, Wesselingh S, Suhrbier A, Gowans EJ, Grubor-Bauk B. Mucosal vaccination with a live recombinant rhinovirus followed by intradermal DNA administration elicits potent and protective HIV-specific immune responses. Sci Rep 2016; 6:36658
Melanoma patients with diverse gut microbiota respond better to immunotherapy
Diversity of the gut microbiota appears to be linked to the success of immunotherapy in people with advanced melanoma. Researchers at MD Anderson Cancer Center studied 100 samples from patients' gut and found that the outcome of treatment also depends on the bacterial species inhabiting the human intestine. Mouth microbiota was not found to correlate with response to immunotherapy.
These results corroborate earlier studies showing that changing the gut microbiota in mice can directly improve immunotherapy results. The hope is that antibiotics, probiotics or fecal microbiota transplantation might help improve cancer treatment in the clinic.
Pilot malaria vaccinations campaigns to start in Africa in 2018
The World Health Organization (WHO) has secured funds to start small-scale malaria immunization programs in sub-Saharan Africa in 2018. The first malaria vaccine ever to be approved, RTS,S (Mosquirix, GSK), is administered in four doses and has limited efficacy.
“These pilot projects will provide the evidence we need from real-life settings to make informed decisions on whether to deploy the vaccine on a wide scale,” director of the WHO's Global Malaria Programme Pedro Alonso told the media.
Malaria affects >200 million people annually and kills almost half a million, mainly among babies in sub-Saharan Africa.
CAR-T immunotherapy of all put on hold after two patient deaths
A Phase 2 ROCKET trial of CAR-T immunotherapy of B-cell acute lymphoblastic leukemia was stopped after two patients died from cerebral edema. The therapy, known as JCAR015 (Juno Therapeutics), targets the CD19 protein expressed on B lymphocytes. It was successful in Phase 1 and was granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA).
The current Phase 2 trial had been put on hold in July 2016 after three patients died from cerebral edema. The FDA lifted the hold after a change of protocol was adopted.
Hepatitis B vaccine application rejected by FDA
The FDA has rejected the hepatitis B vaccine Heplisav-B (Dynavax). The safety-related concerns included autoimmune disease occurrence and the number of cardiac events in clinical trials. This is the second time Heplisav-B has been rejected by the FDA.
The company said it will look for a partnership before preparing for another application.
China has approved the pneumococcal vaccine Prevenar 13
The 13-valent pneumococcal vaccine Prevenar 13 (Pfizer) has been approved in China for children aged 6 weeks to 15 months. ∼30,000 children of that age die annually in China alone.
The vaccine contains 13 strains of pneumococcal polysaccharide conjugated to diphtheria carrier protein. It was approved in the U.S. in 2010 and recommended also for adults aged >65 years.