Clonal Neoantigen: Emerging “Mechanism-based” Biomarker of Immunotherapy Response
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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-11-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/15/23/5616 |
| _version_ | 1797400408554995712 |
|---|---|
| author | John Nemunaitis Laura Stanbery David Willoughby Ernest Bognar Scott Brun Adam Walter Bradley J. Monk Rodney P. Rocconi Khalil Choucair Robert L. Coleman |
| author_facet | John Nemunaitis Laura Stanbery David Willoughby Ernest Bognar Scott Brun Adam Walter Bradley J. Monk Rodney P. Rocconi Khalil Choucair Robert L. Coleman |
| author_sort | John Nemunaitis |
| collection | DOAJ |
| description | 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 (<i>p</i> = 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<sup>®</sup>, designed to expand the clonal neoantigen targeting effector cell populations. Vigil<sup>®</sup> 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<sup>®</sup> in a subset ovarian cancer population with an HRP cancer profile. |
| first_indexed | 2024-03-09T01:54:12Z |
| format | Article |
| id | doaj.art-c4802249e45247c4967bc44ed3f14616 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T01:54:12Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-c4802249e45247c4967bc44ed3f146162023-12-08T15:12:42ZengMDPI AGCancers2072-66942023-11-011523561610.3390/cancers15235616Clonal Neoantigen: Emerging “Mechanism-based” Biomarker of Immunotherapy ResponseJohn Nemunaitis0Laura Stanbery1David Willoughby2Ernest Bognar3Scott Brun4Adam Walter5Bradley J. Monk6Rodney P. Rocconi7Khalil Choucair8Robert L. Coleman9Gradalis, Inc., Dallas, TX 75225, USAGradalis, Inc., Dallas, TX 75225, USAFrontage Laboratories Inc., Deerfield Beach, FL 33442, USAGradalis, Inc., Dallas, TX 75225, USAGold Mast Consulting, LLC, The Woodlands, TX 77380, USAGradalis, Inc., Dallas, TX 75225, USAHonorHealth Research Institute, College of Medicine, University of Arizona, Phoenix, AZ 85012, USAUniversity of Mississippi Medical Center, Jackson, MS 39216, USADepartment of Medical Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USAUS Oncology Research, The Woodlands, TX 77380, USAClonal 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 (<i>p</i> = 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<sup>®</sup>, designed to expand the clonal neoantigen targeting effector cell populations. Vigil<sup>®</sup> 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<sup>®</sup> in a subset ovarian cancer population with an HRP cancer profile.https://www.mdpi.com/2072-6694/15/23/5616clonal neoantigenbiomarkerimmunotherapycancerVigil |
| spellingShingle | John Nemunaitis Laura Stanbery David Willoughby Ernest Bognar Scott Brun Adam Walter Bradley J. Monk Rodney P. Rocconi Khalil Choucair Robert L. Coleman Clonal Neoantigen: Emerging “Mechanism-based” Biomarker of Immunotherapy Response Cancers clonal neoantigen biomarker immunotherapy cancer Vigil |
| title | Clonal Neoantigen: Emerging “Mechanism-based” Biomarker of Immunotherapy Response |
| title_full | Clonal Neoantigen: Emerging “Mechanism-based” Biomarker of Immunotherapy Response |
| title_fullStr | Clonal Neoantigen: Emerging “Mechanism-based” Biomarker of Immunotherapy Response |
| title_full_unstemmed | Clonal Neoantigen: Emerging “Mechanism-based” Biomarker of Immunotherapy Response |
| title_short | Clonal Neoantigen: Emerging “Mechanism-based” Biomarker of Immunotherapy Response |
| title_sort | clonal neoantigen emerging mechanism based biomarker of immunotherapy response |
| topic | clonal neoantigen biomarker immunotherapy cancer Vigil |
| url | https://www.mdpi.com/2072-6694/15/23/5616 |
| work_keys_str_mv | AT johnnemunaitis clonalneoantigenemergingmechanismbasedbiomarkerofimmunotherapyresponse AT laurastanbery clonalneoantigenemergingmechanismbasedbiomarkerofimmunotherapyresponse AT davidwilloughby clonalneoantigenemergingmechanismbasedbiomarkerofimmunotherapyresponse AT ernestbognar clonalneoantigenemergingmechanismbasedbiomarkerofimmunotherapyresponse AT scottbrun clonalneoantigenemergingmechanismbasedbiomarkerofimmunotherapyresponse AT adamwalter clonalneoantigenemergingmechanismbasedbiomarkerofimmunotherapyresponse AT bradleyjmonk clonalneoantigenemergingmechanismbasedbiomarkerofimmunotherapyresponse AT rodneyprocconi clonalneoantigenemergingmechanismbasedbiomarkerofimmunotherapyresponse AT khalilchoucair clonalneoantigenemergingmechanismbasedbiomarkerofimmunotherapyresponse AT robertlcoleman clonalneoantigenemergingmechanismbasedbiomarkerofimmunotherapyresponse |