Immunotherapy targeting genetic frameshift mutation in cancer cells

Det er fortsatt et stort medisinsk behov for nye behandlingsformer for kreft. Hubro Therapeutics utvikler nye vaksiner rettet mot mutasjoner i gener som er tilstede i kreftformer assosiert med såkalt genetisk mikro-satellitt ustabilitet (MSI). MSI er kjent i mange forskjellige kreftformer og spesielt i tykktarmskreft, magekreft og livmorhalskreft. Vaksinene aktiverer T celler i immunsystemet og setter dem i stand til å gjenkjenne og ødelegge kreftceller som har mutasjonene. Den første vaksinen, FMPV-1, er under klinisk utprøving. FMPV-1 aktiverer T celler som gjenkjenner mutasjon i TGFbR2 som er tilstede i cirka 75% av MSI-assosiert tarmkreft og 80% av MSI-assosiert magekreft. Over 90% av arvelig tarmkreft har TGFbR2 mutasjon. Hubro Therapeutics har gjennomført en klinisk fase 1 studie i friske frivillige for å dokumentere at FMPV-1 er trygg og for å undersøke den immunologiske effekten av vaksineringen. Fase 1 studien viste at vaksinen var trygg og at den ønskede immunolgiske effekten var god. Studien ga et godt grunnlag for videre klinisk utvikling i kreft pasienter.

The project has provided a solid basis for further clinical development of a safe and easy to use low cost cancer vaccine. •Potential therapy to cancer patients with an unmet medical need and increased quality of life for patients, patients’ families and friends •Relief and improved work environment for health personnel and significant savings of costs for cancer care for the society •A first in class prophylactic cancer vaccine – cutting edge technology and learning •Bio-degradable product, environmentally friendly and sustainable production •Creation of sustainable workplaces in Norway •Increased learning, competence and scientific knowledge in academia and the society •A basis for further innovation and development of life science technology in Norway •Increased national and international cooperation

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.