Alfredo Nicosia

Our group develops genetic vaccines for major infectious diseases, using the highly innovative chimpanzee-derived adenovirus (ChAd) platform. Unlike the human adenoviruses which are rapidly inactivated by our immune system – we have all been exposed to adenoviral infection –, those of chimpanzees are not recognised by our immune system and trigger a strong response, both from the T- and the B-lymphocytes. We therefore used chimpanzees’ adenoviruses as a ‘Trojan horses’ in which we inserted pathogen-specific proteins. We proved the efficacy of our T-cell based vaccines including ChAd as a primer and Modified Vaccinia Ankara as a booster in relevant animal models. These vaccines have now been evaluated in thousands of subjects in a wide age range and were shown to be safe and highly immunogenic.
We are also expanding our research to the field of cancer vaccines encoding tumor-specific neo-antigens. We have combined the use of viral vectors that have been engineered and optimized to express artificial genes encoding high-dimensional strings of human neoantigens, with state-of-the art bioinformatics for cancer neoantigen prediction. The unprecedented neoantigen-encoding capacity of our platform and its ability to efficiently

and consistently express large numbers of neoantigens, provides significant advantages over other strategies, offering a unique approch to the potentiation of human anti-tumor immune responses.
Tumors associated with Mismatch Repair Deficiency (dMMR) and Microsatellite instability (MSI) accumulate insertion/deletion mutations (indels) that are predictable as they principally arise at mononucleotide repeats. These indel mutations in coding regions result in a translational shift that generate frame shift peptides (FSPs). FSPs are highly immunogenic and may be safely utilized in vaccines as they bear no resemblance to natural protein sequences found in the human proteome. As such, they are ideal tumor- specific neoantigens.

As these mutations are targeted to a limited number of genes across the genome, several of them are shared across different patients. MSI-associated tumors consequently offer a unique opportunity for an ‘off-the-shelf’ vaccine.
NOUS-209 encodes 209 unique FSP cancer neoantigens found in different MSI tumor types. It has the potential to be the first ‘off-the-shelf’ cancer genetic vaccine to be tested in humans.

The first-in-human NOUS-209 Phase I clinical study is scheduled to commence in early 2019.
NOUS-100-PV is a personalised cancer genetic vaccine based on patient-specific neoantigens sourced from individual patient tumor mutanomes. The technology may be applied to any cancer indication where a tumor biopsy is available that is suitable for next- generation sequencing (NGS). Our initial studies will in the first instance target tumors with high frequencies of somatic mutations, such as advanced non-small cell lung cancer (NSCLC).

We have developed a robust and rapid 5 week needle-to-needle vaccine manufacturing process from the time of patient biopsy to vaccine production. This process allows for the assembly of strings of over 60 unique patient mutanome-specific neoantigens within a single genetic vaccine vector and the production of small patient-specific quantities of personalized vaccine.

NOUS-100-PV is anticipated to enter the clinic in 2019.