In silico designed mRNA vaccines targeting CA-125 neoantigen in breast and ovarian cancer

Lingeng Lu; Wenxue Ma; Caroline H Johnson; Sajid A Khan; Melinda L Irwin; Lajos Pusztai

doi:10.1016/j.vaccine.2023.02.048

In silico designed mRNA vaccines targeting CA-125 neoantigen in breast and ovarian cancer

Vaccine. 2023 Mar 17;41(12):2073-2083. doi: 10.1016/j.vaccine.2023.02.048. Epub 2023 Feb 20.

Authors

Lingeng Lu¹, Wenxue Ma², Caroline H Johnson³, Sajid A Khan⁴, Melinda L Irwin⁵, Lajos Pusztai⁶

Affiliations

¹ Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT 06510, USA; Yale Cancer Center, Yale University, New Haven, CT 06510, USA. Electronic address: lingeng.lu@yale.edu.
² Department of Medicine, Moores Cancer Center and Sanford Stem Cell Clinical Center, University of California San Diego, La Jolla, CA 92093, USA.
³ Yale Cancer Center, Yale University, New Haven, CT 06510, USA; Department of Environmental Health Science, Yale School of Public Health, Yale University, New Haven, CT 06510, USA.
⁴ Yale Cancer Center, Yale University, New Haven, CT 06510, USA; Department of Surgery, Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
⁵ Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT 06510, USA; Yale Cancer Center, Yale University, New Haven, CT 06510, USA.
⁶ Yale Cancer Center, Yale University, New Haven, CT 06510, USA; Department of Medical Oncology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA.

Abstract

Somatic mutation-derived neoantigens are associated with patient survival in breast and ovarian cancer. These neoantigens are targets for cancer, as shown by the implementation of neoepitope peptides as cancer vaccines. The success of cost-effective multi-epitope mRNA vaccines against SARS-Cov-2 in the pandemic established a model for reverse vaccinology. In this study, we aimed to develop an in silico pipeline designing an mRNA vaccine of the CA-125 neoantigen against breast and ovarian cancer, respectively. Using immuno-bioinformatics tools, we predicted cytotoxic CD8⁺ T cell epitopes based on somatic mutation-driven neoantigens of CA-125 in breast or ovarian cancer, constructed a self-adjuvant mRNA vaccine with CD40L and MHC-I -targeting domain to enhance cross-presentation of neoepitopes by dendritic cells. With an in silico ImmSim algorithm, we estimated the immune responses post-immunization, showing IFN-γ and CD8⁺ T cell response. The strategy described in this study may be scaled up and implemented to design precision multi-epitope mRNA vaccines by targeting multiple neoantigens.

Keywords: Breast cancer; CA-125; Neoantigen; Ovarian cancer; mRNA vaccine.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Antigens, Neoplasm / genetics
CA-125 Antigen
Cancer Vaccines*
Epitopes, T-Lymphocyte / genetics
Female
Humans
Ovarian Neoplasms* / therapy
mRNA Vaccines*

Substances

Antigens, Neoplasm
Cancer Vaccines
Epitopes, T-Lymphocyte
mRNA Vaccines
CA-125 Antigen

Grants and funding

K12 CA215110/CA/NCI NIH HHS/United States