Human Vaccines & Immunotherapeutics: news

CRISPR-mediated gene induction targets tumors for clearance

Multiplexed activation of endogenous genes as an immunotherapy (MAEGI) led to tumor elimination in mouse models of pancreatic and triple-negative breast cancers.¹ This technique identifies tumor neoantigens and induces their expression via inactivated CRISPR machinery tethered to transcription factors This facilitates immune recognition of the tumors, whose cells often reduce cell-surface antigen presentation.

MAEGI was shown to increase antigen presentation and promote local and systemic anti-tumor responses mediated by both CD4⁺ and CD8⁺ T cells. The authors envision that the versatility of CRISPR targeting will enable simultaneous induction of cytokines and other immunomodulatory molecules to further enhance anti-tumor responses.

Broadly protective antibodies against influenza have been isolated from a patient

Antibodies isolated from a patient hospitalized with influenza protected mice against all 12 antigenically diverse strains tested in a lethal challenge experiment.² The most potent antibody, 1G01, which protected against human, avian and swine influenza, targets the viral neuraminidase, contrasting with seasonal influenza vaccines targeting hemagglutinin.

“Typically, anti-neuraminidase antibodies can be broad within a subtype, like H1N1, but an antibody with potent activity across subtypes was unheard of,” senior author Florian Krammer of Icahn School of Medicine at Mount Sinai said. The researchers hope that the epitope recognized by 1G01 could be the basis for a new universal influenza vaccine.

Combination immunotherapy delays progression of lung and liver tumors

The combination of chemotherapy, the anti-CTLA-4 tremelimumab and anti-PD-L1 durvalumab (both AstraZeneca) extended progression-free survival compared to chemotherapy alone in a Phase 3 POSEIDON trial of untreated, metastatic non-small cell lung cancer (NSCLC). Details of the analysis have not been published. Durvalumab is approved in the US as a second-line treatment of NSCLC, which accounts for most cases of lung cancer.

Concomitant treatment with two checkpoint-blocking MAbs, the anti-PD-1 nivolumab (Opdivo) and anti-CTLA-4 ipilimumab (Yervoy, both BMS), along with chemotherapy improved overall survival compared to chemotherapy alone as a first-line therapy of advanced NSCLC in a Phase 3 CheckMate -9LA trial. The combined immunotherapeutics showed promise in hepatocellular carcinoma patients in both second-line and perioperative settings. The Phase 2 CheckMate 040 study found it had manageable toxicity profile and signs of efficacy.

Measles infection decreases antibodies against other pathogens

Measles impairs previously acquired immune memory, according to a pair of studies in ferrets, macaques and humans.^3,4 Natural measles infection eliminated 11–73% of preexisting antibody repertoire in 77 unvaccinated children and 40–60% in monkeys. No such effect was observed in subjects vaccinated against measles. In ferrets, measles impaired vaccine-acquired immunity against influenza and exacerbated the severity of infection after influenza challenge.

The authors conclude that measles vaccination is important not only for controlling measles infection itself, but also for maintaining immune protection from other diseases.

Antiviral immune pathway boosts checkpoint-blocking immunotherapy

A pair of studies suggests that inducing the RIG-I immune pathway might overcome resistance to checkpoint-targeting immunotherapy.^5,6 RIG-I is an RNA-sensing receptor involved in innate antiviral immunity. Its stimulation with RNA agonists improved the effect of CTLA-4 and PD-1 inhibitory MAbs in a mouse cancer model, triggering apoptosis and tumor-specific CD⁸⁺ T-cell expansion. In melanoma patients, durable clinical responses to CTLA-4 blockade were associated with high expression of RIG-I.

“Unfortunately, checkpoint inhibitors aren’t effective in all patients. Thanks to our recent study, we now understand why that is the case in some forms of cancer, and using experimental approaches, we have even been able to reverse the situation,” lead author of one of the studies Simon Heidegger of Technical University of Munich said.

Tuberculosis vaccine candidate provides long-term protection

50% protection against pulmonary tuberculosis disease at the 3-year mark was reported for the vaccine candidate M72/AS01_E (GSK). The randomized, placebo-controlled Phase 2b trial took place in tuberculosis-endemic regions of Africa.

The vaccine is based on a fusion protein of two Mycobacterium tuberculosis antigens (Mtb32A and Mtb39A) adjuvanted with the liposome-based AS01 system.

CAR-T approach treated lupus in a preclinical study

T cells with engineered chimeric antigen receptor (CAR) targeting the CD19 molecule on the surface of B cells effectively treated lupus in a mouse model.⁷ While all animals in the placebo group died within 10 months, most mice in the experimental group lived with reduced disease, CD19⁺ B cells depleted and CAR-T cells active for at least one year.

Other immunotherapies for lupus, such as the anti-CD20 rituximab, have been largely unsuccessful, presumably due to transient and incomplete B-cell depletion.

Tau vaccine ameliorated Alzheimer’s disease in mice

The Alzheimer’s disease (AD) vaccine candidate AV-1980R/A elicited high antibody responses, reduced the levels of insoluble tau protein, and improved both motor and cognitive functions in a mouse model of AD.⁸ The vaccine targets the N-terminal domain of the tau protein, which is exposed in misfolded version of tau typical in AD, but hidden in native conformation. AV-1980R/A, a recombinant vaccine administered with Advax^CpG adjuvant, combines the targeted peptide with several viral and bacterial antigens.

“For a vaccine to be effective, it has to induce therapeutically potent levels of antibodies which our anti-tau vaccine achieved,” lead author Armine Hovakimyan of Institute for Molecular Medicine said. “Importantly, MultiTEP platform-based vaccines do not induce potentially harmful autoreactive T helper cell responses while still generating antibodies that bind strongly to pathological forms of tau in human brain tissue from AD cases.”

Modified CAR-T targets latent HIV

A CAR-T-based approach for recognizing and killing HIV-infected cells was able to specifically eliminate infected CD⁴⁺ T cells cultured from human blood, spleen and tonsils.⁹ The convertible CAR cells are engineered to recognize a peptide, which the scientists fused to the Fc portion of HIV broadly neutralizing antibodies. When combined with a latency-reversing agent, convertible CAR eliminated more than half of HIV-expressing cells from a latent reservoir cultured from HIV-positive individuals within two days.

“This flexible technology has the potential to revolutionize the CAR-T system by allowing a one-time delivery of convertible CAR cells to the patient and giving the physician the ability to administer the antibody or cocktail of antibodies best suited to treat the patient’s disease, be it HIV/AIDS or a leukemia,” senior author Warner Greene of Gladstone Institute of Virology and Immunology said.