Immunotherapy targeting genetic frameshift mutation in cancer cells

There is still a significant medical need for new treatments for cancer. Hubro Therapeutics develops novel vaccines targeting mutations in genes that are present in cancers associated with so called microsatellite instability (MSI). MSI is known in many different cancer indications, particularly in colorectal cancer, stomach cancer and endometrial cancer. The vaccines activate T cells of the immune system and enable them to recognise and destroy cancer cells having the mutations. The lead candidate vaccine, FMPV-1, is ready for clinical development. FMPV-1 activates T cells recognising mutation in TGFbR2 that is present in about 75% MSI associated colorectal cancer and 80% of MSI related stomach cancer. Over 90% of hereditary colorectal cancer have mutation in TGFbR2. The scope of the project is to assess and document the clinical safety and immunogenicity of FMPV-1 in healthy volunteers. The project entails production of vaccine, pre-clinical testing in animals, planning and conducting a phase I clinical trial in helathy volunteers as well as related research to document immune responses and other clinical characteristics of the treated subjects. In 2021 FMPV-1 for phase I has been produced, pre-clinical studies completed and an application for conducting the phase I study has been submitted to the competent regulatory authorities. The final preparations for the phase I study is ongoing. In 2022 the focus of the project will be to conduct the phase I study and to continue product development.

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Addressing unmet medical need for treatment of cancer the project entails development of novel vaccines targeting genetic frameshift mutations (FM) present in microsatellite instability-high (MSI-H) cancer. MSI-H is known in many different cancer indications, particularly in colorectal cancer (CRC) (15%), stomach cancer (SC) (22%) and endometrial cancer (28%). FM occurs in genes with stretches of short tandem DNA repeats (microsatellites) and is constituted by nucleotide deletion and/or insertion in the micro satellite. FM genes express proteins with completely different amino acid sequences (neo-antigens) compared to the normal proteins expressed by the unmutated genes. Neo-peptides from FM proteins are foreign to the immune system and are potentially strong antigens that can be used as vaccines for induction of anti-cancer immune responses. A selection of key FM neo-antigens has been identified and used as templates for designing novel optimised candidate neo-peptides. Based on result from in vitro screening the candidate peptide FMPV-1 has been selected for clinical development as cancer vaccine. Two patent applications covering FMPV-1 and its uses has been filed. FMPV-1 activates T cells recognising FM TGFbR2, present in 44% of all MSI-H cancers; in about 75% of MSI-H CRC, 80% of MSI-H SC and 90% of hereditary CRC. FMPV-1 is designed to activate both CD4+ T helper cells and CD8+ cytotoxic T cells. In vitro Testing has shown that FMPV-1 is immunogenic. The scope of the project is to assess and document the clinical safety and immunogenicity of FMPV-1 in healthy volunteers. The project entails production of FMPV-1, pre-clinical testing, regulatory submissions, conducting a phase I clinical study incl. immuno-monitoring and characterisation of immune responses in the vaccinated subjects. A method for confirmation of TGFbR2 FM is needed for enrolment of patients to subsequent phase II and II studies. Detection in liquid biopsies will be explored.