Human vaccines & immunotherapeutics: news

Gut microbiota transfer might induce responses to melanoma immunotherapy

Fecal microbiota transplantation (FMT) into melanoma immunotherapy non-responders improved treatment outcomes in two Phase 1 trials. In one trial, donors were patients who had had complete responses following checkpoint blockade immunotherapy of melanoma. In a sample of 10 FMT recipients with refractory metastatic melanoma, two patients reported partial responses and one patient a complete response.¹

The other trial collected fecal samples from both partial and complete responders to checkpoint blockade immunotherapy of melanoma. Clinical benefits were observed in 6 of 15 subjects who received FMT.²

The treatment was safe and well tolerated in both trials, neither of which included a control group.

Covid-19 vaccines are effective in the field, but new strains might pose a risk

The mRNA SARS-CoV-2 vaccine BNT162b2 (Pfizer & BioNTech) reduces symptomatic disease and hospitalizations by >90% as shown in the Israel population.³ This study compared 600,000 people who received both doses with a group of unvaccinated subjects with matching medical histories. Israel, which has fully vaccinated >50% of its population, is slowly lifting pandemic measures following sharp declines of hospitalizations in the most vulnerable populations.

Another trial monitored 23,000 vaccinated healthcare workers in UK and found a protection rate of 85% against both symptomatic and asymptomatic disease.⁴ According to the two studies, the vaccine is effective against the newly emerged, hyper-transmissible strain B1.1.7 first isolated in UK.

However, other emerging virus strains raise concerns about vaccine effectiveness. Lineage B.1.351, which was first isolated in South Africa and is associated with increased transmissibility and viral loads, was two-thirds less susceptible to neutralization by sera from 15 participants of a previous Phase 3 trial with the BNT162b2 vaccine, compared to the parent strain.⁵ Another licensed vaccine mRNA-1273 (Moderna) showed a sixfold decrease in a similar assay.⁶ The impact on the protective efficacy of these vaccines remains to be determined. The US Food and Drug Administration (FDA) addressed the emergence of new strains by facilitating the approval process for new vaccine variants similar to the way annual influenza vaccines are approved.

A third widely used vaccine, ChAdOx1-S (AstraZeneca), can be administered to more people by extending the time between the two doses. A reexamination of trial data from 17,000 people suggested that efficacy increased from 55% to 81% for doses <6 weeks and >12 weeks apart, respectively.⁷ However, the vaccine offered only minimal protection against the B.1.351 strain, which prompted an adjustment to the pipeline to also incorporate new variant vaccines.

More than one billion doses of the nanoparticle protein vaccine NVX-CoV2373 (Novavax) are planned to be delivered by the COVAX consortium, which aims to provide equitable worldwide distribution. NVX-CoV2373 had a 90% efficacy in a Phase 3 trial but did not protect as well against the B.1.351 variant.

The FDA has approved, under the Emergency Use Authorization, a third vaccine and an immunotherapeutic. The single-dose non-replicating adenovirus-based vaccine Ad26.COV2.S (J&J), which showed good safety and 85% efficacy against severe Covid-19 in a trial involving >40,000 people, is already being deployed.

The immunotherapy combination etesevimab (LY-CoV016) plus bamlanivimab (LY-CoV555, both Eli Lilly) was approved for patients aged ≥12 years who are at risk of disease progression. Both MAbs, which target the SARS-CoV-2 spike protein, are administered in a single injection. The combination reduced the risk of death by 70% in a Phase 3 trial.

Among other vaccines in development is the DNA vaccine ZyCoV-D (Zydus Cadila), which is being tested in 30,000 healthy volunteers. The vaccine, which is administered by a needle-free injection system, was immunogenic and protective in a preclinical trial.⁸

The immunotherapeutic tocilizumab (Actemra, Roche) showed efficacy in alleviating serious disease in hospitalized patients. In a trial involving >4,000 subjects, the tocilizumab cohort had a 33% mortality compared to 29% in the control group.⁹ Tocilizumab, an inhibitor of the IL-6 receptor, is approved for the treatment of rheumatoid arthritis.

Ovarian cancer immunotherapy fast-tracked by FDA

The DNA-based interleukin-12 immunotherapy GEN-1 (Celsion) for treatment of advanced ovarian cancer received FDA Fast Track Designation to expedite regulatory review. In the Phase 1 “OVATION 2” trial, seven of eight patients with newly diagnosed stage III/IV ovarian cancer reported a complete response, and high doses of GEN-1 induced responses in 100% of the subjects in a dose-escalating part of the trial. An open-label randomized Phase 2 trial is underway.

GEN-1, which consists of plasmid-encoded IL-12 delivered in a nanoparticle system, is designed to locally induce T- and NK-cells with anti-tumor activity. It is administered together with standard-of-care chemotherapy following surgical resection.

Chikungunya vaccine is being tested for manufacturing consistency in a late-stage trial

The chikungunya vaccine candidate VLA1553 (Valneva) has entered a randomized Phase 3 lot consistency trial VLA1553-302 enrolling 400 volunteers aged 18–45 years, with immunogenicity being investigated in a parallel Phase 3 trial. VLA1553 is the most advanced chikungunya vaccine in clinical development.

Chikungunya, a mosquito-borne viral disease with high morbidity in tropical regions, leads to fever and debilitating joint and muscle pain. VLA1553 is a genetically attenuated, single-dose vaccine.

Pembrolizumab combination therapy extends lives of kidney cancer patients

The PD-1 inhibitor pembrolizumab (Keytruda, Merck) in combination with the chemotherapy drug lenvatinib (Eisai) reduced the risk of disease progression and death by 60% and 34%, respectively, as first-line treatment of advanced renal cell carcinoma. The Phase 3 CLEAR trial compared the combination to the then standard-of-care sunitinib (Pfizer).¹⁰

The experimental cohort reported a median progression-free survival of 2 years, compared to 9 months in the control group. The most common adverse events included hypertension and diarrhea.

Cemiplimab was approved for two cancer indications

The PD-1 inhibitor cemiplimab (Libtayo, Regeneron & Sanofi) was approved by FDA for the treatment of advanced non-small cell lung cancer (NSCLC) with high PD-L1 expression and advanced basal cell carcinoma. Eligible NSCLC patients must not be candidates for other treatment options.

Clinical trials showed that cemiplimab reduced the risk of death by 40% compared to chemotherapy in NSCLC, which comprises the vast majority of lung cancer cases. The MAb achieved a 30% objective response rate in basal cell carcinoma, which has otherwise very few treatment options.

Alzheimer’s vaccine is immunogenic in an early study

The Alzheimer’s disease (AD) vaccine candidate ACI-35.030 (AC Immune) generated potent anti-Tau antibody responses, according to interim results of a randomized, placebo-controlled Phase 1/2 involving 32 patients with early-stage disease. The pathological form of the Tau protein, which is hypothesized to induce plaques in the brains of AD patients, can be recognized years before clinical disease onset.

The liposomal ACI-35.030 was well tolerated and induced IgG and IgM antibodies specific to the pathological form of Tau.