Note: The role of neoantigen peptides in personalized medicine

The basic concept of neoantigen in cancer

Note from: https://www.youtube.com/watch?v=9WT5iDPG0K0&t=102s

New antigen of cancer cells but not expressed in wild-type tissue (normal tissue)..

Most forms are indel, but some can be frameshift mutations.

From the observations, the neoantigens are hydrophobic in nature, thus, they tend to aggregate.

Many good reasons for using immunotherapy

• Neoantigen is not highly expressed and it is not self-antigen. Thus, it is very immunogenic.

• Once neoantigen is formed -- low chances to be remutated, thus less antigenic escape -- this is due to its mutated state facilitating the tumor growth.

• Neoantigen therapeutics tend to target multiple neoantigens  simultaneously. Avoiding possibility of immune escape

• Each neoantigen can be matched to specific TCR’s -- thus, the immune response could be analyzed  in vitro before being used in a possible therapeutic.

Personalized cancer vaccine (PCV)

• Specific to the patient

○ Taking tumor biopsy from patients

○ NGS -- RNA sequencing

○ Immunopeptidome identification

○ Comparing the peptide sequence between wt-cancer vs mutated cancer to identify the neoantigens

○ Mutanome -- to predict the neoantigen

○ List the peptides and test in vitro before production in the lab

○ Neoantigens could be mRNA/DNA or peptides -- delivery to the body and using host APC to introduce the antigen

Personalized T-cell therapy (PTT)

• Same principle as PCV

• Producing genetic engineered PTT to target the neoantigens in tumor cells

• Using T-cell from patients -- > genetic engineer to target the neoantigens -- . infuse to patients

Bottleneck of neoantigen based therapy -- the ability to produce the peptide in timely manner

Ways to peptide synthesis (each has good and bad advantage)

• Synthetic production

○ Solid-phase synthesis

○ Liquid -phase synthesis

○ Native chemical ligation

• Microbial recombinant production

○ E. coli

○ S. cerevisiae

○ P pastoris

• Semi-synthetic production

○ Synthetic fragments + Recombination fragment

Neoantigen peptides are hard to synthesis -- 

• I guess from the observation it is very hydrophobic

Summary

• Neoantigens are produced very low amounts but it is a new immunogenic -- good target to launch the immune system to kill cancer cells

• Thus, the therapeutic approach can be introducing neoantigens (cancer vaccine) or genetic engineered T-cell to target the cancer harboring the neoantigen on the surface