About Individualized Neoantigen-Specific Immunotherapy (iNeST)
An investigational individualized approach to mobilizing an immune response
Through a deeper understanding of cancer immunology and technological improvements in genomic sequencing and bioinformatics, we, in collaboration with BioNTech, are advancing the development of Individualized Neoantigen-Specific Immunotherapy (iNeST). iNeST is designed based on each patient's particular tumor mutations (neoantigens), with the goal of inducing high-affinity immune T-cell responses against cancer.1,2
How iNeST is designed to work
As malignant tumors grow, genetic mutations lead to the expression of unique tumor antigens called neoantigens, which have emerged as a promising target in oncology. In order to identify candidate neoantigens, DNA is extracted from an individual patient’s tumor cells and sequenced. By comparing the sequences of the patient’s tumor mutations with germline DNA from normal cells, tumor mutations are identified.1-4
Then, using proprietary algorithms that evaluate the immunogenic potential of the tumor mutations in the context of the patient’s HLA type, the neoantigens most likely to elicit an immune response are selected and incorporated into an iNeST. iNeST is not restricted by patients’ HLA types.1-4
Elicitation of immune response
In one approach, these neoantigens are incorporated into mRNA. Subsequently, the mRNA is complexed with lipids to make an mRNA-lipoplex that can be delivered to the individual patient. Upon administration, the mRNA-lipoplex preferentially localizes to the spleen, where it is taken up by dendritic cells. The mRNA provides two critical components of this iNeST approach. It serves as an adjuvant through stimulation of TLR7 and TLR8, licensing dendritic cells to activate T cells. The mRNA is also translated into a polypeptide that is processed into neoantigens. These neoantigens are then loaded onto MHC molecules and presented to T cells, inducing de novo generation and expansion of pre-existing T cells that in turn can recognize and kill tumor cells.3-6
iNeST may complement other strategies that target different steps of the cancer immunity cycle. As a first step, we aim to combine iNeST with checkpoint inhibitors to further increase T-cell–mediated immunity.
HLA=human leukocyte antigen; mRNA-LPX=messenger ribonucleic acid lipoplex; TLR=toll-like receptor.
- Sahin U, Derhovanessian E, Miller M, et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature. 2017;547:222-226.
- Capietto A-H, Jhunjhunwala S, Delamarre L. Characterizing neoantigens for personalized cancer immunotherapy. Curr Opin Immunol. 2017;46:58-65.
- Vormehr M, Schrörs B, Boegel S, Löwer M, Türeci Ö, Sahin U. Mutanome engineered RNA immunotherapy: towards patient-centered tumor vaccination. J Immunol Res. 2015;2015:595363.
- Rammensee H-G. Some considerations on the use of peptides and mRNA for therapeutic vaccination against cancer. Immunol Cell Biol. 2006;84:290-294.
- Kranz LM, Diken M, Haas H, et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature. 2016;534:396-401.
- Heil F, Hemmi H, Hochrein H, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004;303:1526-1529.