with Dr. Daniel deOliveira, Sr. Director, Peptide Development, Tech. Ops. & Manufacturing, Genocea Biosciences
At the virtual TIDES: Oligonucleotide and Peptide Therapeutics conference in September 2020, Dr. Daniel deOliveira from Genocea Biosciences explained how his company moved towards differentiated immunotherapies through precision antigen selection with their personalized immune response profiling platform ATLAS, which stands for AnTigen Lead Acquisition System.
This platform mainly comprises two programs: GEN-009, a neoantigen vaccine for which a Phase 1/2a clinical trial is ongoing; and GEN-011, a neoantigen-specific cell therapy using T cells derived from peripheral blood. There is also in the Genocea Biosciences discovery pipeline the GEN-010 platform, which is a follow-on neoantigen cancer vaccine, still in Pre-IND phase; and, shared antigen cancer vaccines and vaccines for cancers of viral origin (e.g., Epstein-Barr virus).
The focus of the ATLAS profiling platform is neoantigen selection, that is the identification of mutations that allow the cancer cells to propagate and invade tissues in a thoroughly biological sense. ATLAS empirically selects the relevant neoantigens of tumour-specific T cell responses in patient and tumour-relevant conditions. Tumour biopsies together with saliva samples from patient donors are sent for Next-Generation Sequencing (NGS) analysis.
From that inquiry, plasmids are then selected for every candidate neoantigen and are inserted in a e-coli vector. At the same time, from a blood sample of the patient, a selection of dendritic cells is made, together with CD4+ and CD8+ T-cells.
Afterwards, the dendritic cells sampled are treated with the neoantigen bacterial vectors, and the ones with positive immune responses to the patient CD8+ T-cells are then selected for autologous treatment. From this personalized experimental analysis, two read-outs can be made: (1) is it a true antigen or not; and, (2) is it stimulatory or inhibitory?
As such, personalized tumour mutations presented to dendritic cells are digested and offered through MHC bound peptides that are recognized by T cells. If, from this presentation, an anti-tumour CD8+ T-cell reaction based on a normalized cytokine concentration (IFN-gamma) response is made, then a new stimulatory neoantigen has been positively selected. If, on the other hand, a negative normalized cytokine concentration (IFN-gamma) response is obtained in CD4+ T-cells, then an inhibitory antigen (Inhibigens’) is confidently obtained.
What this means is that this specific inhibigen is removed from the patient vaccine neoantigen pool, because it inhibits the immune response against the cancer.
This feature of the ATLAS platform, of having the ability to select inhibitory antigens that suppress the anti-tumour T cell response, makes the ATLAS neoantigen readout complete, since only neoantigens with a positive immune-response against the cancer cells are selected for treatment, avoiding inhibigen-specific T cells that may be responsible for hyper-progression after checkpoint blockade therapies.
In the specific case of the GEN-009 vaccine, it actually consists of 4-20 stimulatory Synthetic Long Peptides (SLPs) divided into 4 pools, with each pool containing 1-5 SLPs, administered subcutaneously and presented by circulating antigen-presenting cells directly to T cells in the lymph nodes. The expanded T cells specific to GEN-009 neoantigen then go into the circulation, look for tumour cells that show that “harmful” peptide and kill it.
The Part A GEN-009 Phase 1/2a Clinical trial showcased the vaccine safety and immunogenicity in terms of the adjuvant. The preliminary results of Part B of the ongoing trial of GEN-009 in combination with a PD-1 inhibitors in advanced solid cancers, confirmed tumour reduction or stable outcomes for all patients treated; suggesting that GEN-009 vaccination could be used in conjunction with standard-of-care checkpoint inhibitor-based regimens (CPI) to augment their effects.
In the case of GEN-011, the idea is to use already expanded T cells specific to previously selected neoantigens and give those to the patients. The selection of neoantigens is done through ATLAS as before; and, the neoantigen-specific T cell expansion is done with the PLANET platform. PLANET stands for Proliferation of Lymphocytes Activated by Neoantigens Endogenous in Tumours.
This is a new category of neoantigen T cell therapy with peripheral blood-derived ATLAS neoantigens, that are specific for 89% of all intended neoantigen targets. The IND has been filled and preliminary clinical data is expected in first half of 2021.
Find out more about the 2020 TIDES: Oligonucleotide and Peptide Therapeutics virtual event in our full overview here.
