Innovation shapes the future

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 (Leoni et al, 2020).

NOUS-209 in combination with pembrolizumab has been demonstrated to be safe, highly immunogenic and with promising signs of clinical efficacy in dMMR/MSI-H patients with unresectable and metastatic gastric, colorectal and gastro-esophageal junction tumors enrolled in the phase-I study (NCT04041310).1,2 The trial is now enrolling patients in an open label Phase 2 multicenter study to assess the clinical efficacy of NOUS-209 in combination with pembrolizumab. The Phase 2 study includes two dMMR/MSI-H unresectable and metastatic colorectal cancer (CRC) cohorts: the first cohort is enrolling patients who are eligible for anti-PD-1 first line treatment (randomized 2:1 in favor of NOUS-209 plus pembrolizumab vs pembrolizumab), and the second cohort is enrolling patients who stopped responding to anti-PD1 and other approved therapies.

Moreover, NOUS-209 is also being evaluated in a Phase 1b NCI sponsored Trial in Lynch Syndrome (LS) carriers as monotherapy (NCT05078866). The study aims to show safety and immunogenicity of the approach in a population at high risk for cancer in which the vaccine could intercept disease and reduce its occurrence.

References

1. ASCO Presentation: First clinical and immunogenicity results including all subjects enrolled in a phase I study of NOUS-209, an off-the-shelf immunotherapy, with pembrolizumab, for the treatment of tumors with a deficiency in mismatch repair/microsatellite instability (dMMR), Professor Marwan G. Fakih, M.D.
2. A.M. D’Alise et al. Adenoviral Based-Vaccine Promotes Neoantigen Specific CD8+ T Cell Stemness And Tumor Rejection, Science Translational Medicine. Online publication:www.science.org/doi/10.1126/scitranslmed.abo7604

NOUS-PEV is a personalised cancer 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).

Nouscom has developed a robust and rapid manufacturing process from patient biopsy to vaccine release. This process allows for the assembly of strings of up to 60 unique patient mutanome-specific neoantigens within a single vector and the production of small patient-specific quantities of personalized vaccine.

In March 2021, Nouscom received regulatory approval to initiate a multicenter Phase 1b trial of NOUS-PEV and will be enrolling patients in Spain and other European countries. The trial will evaluate, feasibility and preliminary efficacy per RESIST 1.1 criteria of NOUS-PEV in combination with the anti-PD-1 checkpoint inhibitor in 28 patients with either locally advanced 1L melanoma or 1L NSCLC expressing more than 50% PD-L1.