Mutated BRAF Emerges as a Major Effector of Recurrence in a Murine Melanoma Model After Treatment With Immunomodulatory Agents.

Abstract

We used a VSV-cDNA library to treat recurrent melanoma, identifying immunogenic antigens, allowing us to target recurrences with immunotherapy or chemotherapy. Primary B16 melanoma tumors were induced to regress by frontline therapy. Mice with recurrent tumors were treated with VSV-cDNA immunotherapy. A Th17 recall response was used to screen the VSV-cDNA library for individual viruses encoding rejection antigens, subsequently targeted using immunotherapy or chemotherapy. Recurrent tumors were effectively treated with a VSV-cDNA library using cDNA from recurrent B16 tumors. Recurrence-associated rejection antigens identified included Topoisomerase-IIα, YB-1, cdc7 kinase, and BRAF. Fourteen out of 16 recurrent tumors carried BRAF mutations (595-605 region) following frontline therapy, even though the parental B16 tumors were BRAF wild type. The emergence of mutated BRAF-containing recurrences served as an excellent target for BRAF-specific immune-(VSV-BRAF), or chemo-(PLX-4720) therapies. Successful PLX-4720 therapy of recurrent tumors was associated with the development of a broad spectrum of T-cell responses. VSV-cDNA technology can be used to identify recurrence specific antigens. Emergence of mutated BRAF may be a major effector of melanoma recurrence which could serve as a target for chemo or immune therapy. This study suggests a rationale for offering patients with initially wild-type BRAF melanomas an additional biopsy to screen for mutant BRAF upon recurrence.

• Authors: Shane Zaidi, Miran Blanchard, Kevin Shim, Elizabeth Ilett, Karishma Rajani, Christopher Parrish, Nicolas Boisgerault, Tim Kottke, Jill Thompson, Esteban Celis, Jose Pulido, Peter Selby, Hardev Pandha, Alan Melcher, Kevin Harrington, Richard Vile
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 23 Issue 5 Pg. 845-856 (May 2015) ISSN: 1525-0024 [Electronic] United States
• PMID: 25544599 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Antineoplastic Agents
• Cancer Vaccines
• Immunologic Factors
• Thymidine Kinase
• Proto-Oncogene Proteins B-raf
• Ganciclovir

Topics

• Amino Acid Sequence
• Amino Acid Substitution
• Animals
• Antigens, Neoplasm (immunology)
• Antineoplastic Agents (administration & dosage, pharmacology)
• Base Sequence
• Cancer Vaccines (genetics, immunology)
• Cell Line, Tumor
• Disease Models, Animal
• Drug Resistance, Neoplasm
• Ganciclovir (pharmacology)
• Gene Expression
• Humans
• Immunologic Factors (administration & dosage, pharmacology)
• Male
• Melanoma (drug therapy, genetics, immunology, pathology)
• Melanoma, Experimental
• Mice
• Molecular Sequence Data
• Mutation
• Neoplasm Recurrence, Local
• Proto-Oncogene Proteins B-raf (chemistry, genetics)
• Thymidine Kinase (genetics)