Technology platform
Hubro Therapeutics has established a proprietary neo-peptide technology platform. The vaccines are based on peptides corresponding to neo-antigens resulting from frameshift mutation characteristically present in cancers associated with genetic microsatellite instability (MSI).
Hubro Therapeutics’ vaccines induce cancer specific T cells. T cells that recognize peptide epitopes processed from neo-antigens, and that is displayed on cancer cells, can be stimulated to attack and kill cancer cells. Cancer cells attacked by T cells establish immune suppressive mechanisms to protect themselves (e.g. PDL-1 expression).
Check point Inhibitors (CPIs) reactivate already existing T cells by removing immune suppressive brakes and are only effective in so called “hot” tumours with T cell infiltration. The effect of turning cold tumours hot can potentially be achieved by targeted peptide vaccines and as such will be effective tools for immunotherapy of cancer. Vaccines and CPIs are expected to work synergistically, providing clinically effective anti-cancer immunotherapy.
Diagnosing the underlying cause of MSI
The underlying cause of MSI, a deficient MMR machinery, can be diagnosed. Therefore, in addition to treatment of cancer, these vaccines have a potential in prophylactic settings for protection against development of MSI related cancer. The vaccines are designed to entail nested epitopes for both CD4+ and CD8+ T cells.
MSI is observed across a range of cancers and is particularly prominent in colorectal cancer, stomach cancer and endometrial cancers with a frequency of 15-28% (Cortes-Ciriano I et al 2017; NATURE COMMUNICATIONS|8:15180| (2017)). The major risk factor for development of hereditary non-polyposis colorectal cancer is MSI status.
| Cancer | MSI | Annual incidence (MSI) | |
| Europe + N. America | Asia | ||
| Colorectal (CRC) | 15-20% | ≈100 000 | ≈140 000 |
| Endometrial (EC) | 28% | ≈50 000 | ≈40 000 |
| Stomach (SC) | 22% | ≈35 000 | ≈170 000 |
Frameshift mutations
Frameshift mutations, the hallmark of MSI related cancers, are caused by defects in the DNA mismatch repair (MMR) machinery. It occurs in genes with stretches of short tandem DNA repeats (microsatellites) and is constituted by nucleotide deletion and/or insertion in the micro satellite. The frameshift mutation creates a shift of codons for protein expression, resulting in a mutant protein, neoantigen, with a completely different amino acid sequence when compared to the normal protein expressed by the wild type gene.
Neo-peptide epitopes from frameshift mutant protein sequences are foreign to the immune system of the host and are therefore potentially strong antigens that can be used as vaccines for activating specific anticancer T cellular immune responses. Frameshift mutant TGFβR2 is present in 44% of MSI related cancers and particularly in more than 77% of MSI-H colorectal cancer (Maby P. et al. Cancer Res; 75(17) September 1, 2015 (3446 – 3455)) and 80% of MSI-H stomach cancer (Cortes-Ciriano I et al 2017; NATURE COMMUNICATIONS|8:15180| (2017)). Over 90% of patients with familial hereditary colorectal cancer have TGFβR2 frameshift mutation (Pinheiro M et al, British Journal of Cancer (2015) 113, 686–692).
| Cancer | Population risk | MLH1 and MSH2 | MSH6 | PMS2 | |||
| Risk | Mean age of onset | Risk | Mean age of onset | Risk | Mean age of onset | ||
| Colon | 5.5% | 55-80% | 44-61 | 10-20% | 54 | 15-20% | 61-66 |
| Endometrial | 2.7% | 25-60% | 48-62 | 16-26% | 55 | 15% | 49 |
| Stomach | <1% | 1-13% | 56 | <3% | 63 | 70-78 | |
| Ovary | 1.6% | 4-24% | 42.5 | 1-11% | 46 | 42 | |