Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Nov 28;15(23):5616.
doi: 10.3390/cancers15235616.

Clonal Neoantigen: Emerging "Mechanism-based" Biomarker of Immunotherapy Response

John Nemunaitis  1 , Laura Stanbery  1 , David Willoughby  2 , Ernest Bognar  1 , Scott Brun  3 , Adam Walter  1 , Bradley J Monk  4   5 , Rodney P Rocconi  6 , Khalil Choucair  7 , Robert L Coleman  8
Affiliations

Clonal Neoantigen: Emerging "Mechanism-based" Biomarker of Immunotherapy Response

John Nemunaitis et al. Cancers (Basel). .

Abstract

Clonal mutations represent the initiating molecular defects related to cellular transition of a normal phenotype to a malignant phenotype. Molecular genomic assessment utilizing next generation and whole exome sequencing is now being increasingly applied to biomarker determination to refine the use of targeted immune therapies. Case examples followed by retrospective study assessment have convincingly demonstrated clonal neoantigens provide a relevant predictor of response to checkpoint inhibition. A meta-analysis, by Litchfield et al., of over 1000 cancer patients from 12 landmark trials demonstrated no clinical benefit to checkpoint inhibitor (CPI) therapy in correlation to high subclonal tumor mutational burden (TMB), whereas high clonal TMB was found to be significantly correlated with better overall survival (p = 0.000000029). We discuss the mechanism of clonal vs. subclonal neoantigen targeting relationship to homologous recombination proficient (HRP) profile, evidence of preclinical and clinical benefit related to clonal neoantigens, and review a novel developing therapy called Vigil®, designed to expand the clonal neoantigen targeting effector cell populations. Vigil® is an autologous cellular immunotherapy which is designed to carry the full set of personal clonal neoantigens. Phase 2b results demonstrate a durable recurrence-free survival (RFS) and overall survival (OS) advantage for Vigil® in a subset ovarian cancer population with an HRP cancer profile.

Keywords: Vigil; biomarker; cancer; clonal neoantigen; immunotherapy.

PubMed Disclaimer

Conflict of interest statement

J.N reports employment, stockholder and Board member of Gradalis, Inc. L.S. and A.W. are employees of Gradalis, Inc. D.W. is an employee of Frontage Laboratories, Inc. E.B. reports stockholder and employee of Gradalis, Inc. S.B. reports being a paid consultant for Gradalis, Inc. B.J.M. reports being a paid consultant for Acrivon, Adaptimmune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Easai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Inc., Heng Rui, ImmunoGen, Karyopharm, Iovance, Laekna Health Care, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, TESARO/GSK, US Oncology Research, VBL, Verastem, Zentalis. R.P.R. reports being paid consultant for Gradalis, Inc., ImmunoGen, Easai, and GSK. KC has no conflict of interest to declare. R.L.C. reports grants and contracts from AstraZeneca, Clovis, Genelux, Genmab, Merck, Immunogen, Roche/Genentech; paid consultant for Agenus, Alkermes, AstraZeneca, Clovis, Deciphera, Genelux, Genmab, GSK, Immunogen, OncoQuest, Onxerna, Regeneron, Roche/Genentech, Novocure, Merck, Abbvie; participation on a data safety monitoring board or advisory board for NRG Oncology and Eisai/BMS.

Figures

Figure 1
Figure 1
T cell receptor (TCR) is a complex of integrated membrane proteins that participate in activation of T cells in response to clonal neoantigens. Stimulation of TCR is triggered by major histocompatibility complex molecules on tumor cells displaying the clonal neoantigen.
Figure 2
Figure 2
(A) expansion of T cell TCR targeting clonal neoantigen via dendritic cell response; (B) improved activity of T cell activity against high clonal neoantigens (low subclonal); (C) limited T cell activity against high subclonal (low clonal neoantigens).
Figure 3
Figure 3
Schematic workflow for identification of candidate clonal neoantigens and determination of clonal tumor mutation burden (TMB).
Figure 4
Figure 4
Phase 2b demonstrated statistically significant recurrence-free survival (RFS) and overall survival (OS) results in homologous recombination proficient (HRP) patients compared to placebo; robust differences maintained with further follow up. # = number.
Figure 5
Figure 5
Vigil® improved overall survival following frontline chemotherapy in homologous recombination proficient (HRP) ovarian cancer patients as maintenance therapy. Comparison of Vigil® vs. placebo overall survival (OS) at 2 year and 3 year follow up as maintenance in newly diagnosed Stage IIIb-IV ovarian cancer.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Fang X., Guo Z., Liang J., Wen J., Liu Y., Guan X., Li H. Neoantigens and their potential applications in tumor immunotherapy. Oncol. Lett. 2022;23:88. doi: 10.3892/ol.2022.13208. - DOI - PMC - PubMed
    1. Turke A.B., Zejnullahu K., Wu Y.L., Song Y., Dias-Santagata D., Lifshits E., Toschi L., Rogers A., Mok T., Sequist L., et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 2010;17:77–88. doi: 10.1016/j.ccr.2009.11.022. - DOI - PMC - PubMed
    1. Diaz L.A., Jr., Williams R.T., Wu J., Kinde I., Hecht J.R., Berlin J., Allen B., Bozic I., Reiter J.G., Nowak M.A., et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486:537–540. doi: 10.1038/nature11219. - DOI - PMC - PubMed
    1. Wilmott J.S., Tembe V., Howle J.R., Sharma R., Thompson J.F., Rizos H., Lo R.S., Kefford R.F., Scolyer R.A., Long G.V. Intratumoral molecular heterogeneity in a BRAF-mutant, BRAF inhibitor-resistant melanoma: A case illustrating the challenges for personalized medicine. Mol. Cancer Ther. 2012;11:2704–2708. doi: 10.1158/1535-7163.MCT-12-0530. - DOI - PubMed
    1. Chen Z.Y., Zhong W.Z., Zhang X.C., Su J., Yang X.N., Chen Z.H., Yang J.J., Zhou Q., Yan H.H., An S.J., et al. EGFR mutation heterogeneity and the mixed response to EGFR tyrosine kinase inhibitors of lung adenocarcinomas. Oncologist. 2012;17:978–985. doi: 10.1634/theoncologist.2011-0385. - DOI - PMC - PubMed

LinkOut - more resources