Combination Therapy for BRAF-Mutant Thyroid Cancer: Preclinical Model
Posted: Thursday, September 3, 2020
Researchers from the United Kingdom and the United States are exploring a novel combination therapy in the hope of improving the heretofore poor outcomes for patients with aggressive, poorly differentiated, and anaplastic thyroid cancers. With BRAF mutations found in 30% to 60% of these tumors, combining BRAF inhibition and oncolytic herpes simplex virus (HSV) has piqued the interest of Malin Pedersen, PhD, of The Institute of Cancer Research, London, and her team. In the Journal for Immunotherapy of Cancer, the investigators shared their preclinical experience with this combination therapy, which improved outcomes by enhancing immune-mediated antitumor effects.
“Combining the cytotoxic and/or immunogenic effects of BRAF inhibitors and oncolytic HSV to generate a favorable immune response in the context of drug-mediated tumor cell kill, which can be further boosted by immune checkpoint blockade, is worthy of further testing in the clinic,” wrote the investigators.
Using a BRAF V600E–driven mouse model of anaplastic thyroid carcinoma, Dr. Pedersen’s team detected only modest immune changes with BRAF inhibitors alone; thus, they opted to add oncolytic virotherapy to BRAF inhibition in the hopes of “creating a more favorable tumor immune microenvironment, boosting the inflammatory status of tumors, and improving BRAF inhibitor therapy.” And, they observed that the combination therapeutic strategy did in fact boost such changes.
Of note, gene and protein expression data demonstrated an increase in T-cell and natural killer (NK) activation in the tumor in the samples treated with the combination therapy. “The benefit of combination oncolytic HSV and BRAF inhibitor therapy was abrogated when T cells or NK cells were depleted in vivo,” the investigators explained. In addition, upregulation of PD-L1 and CTLA-4 were noted after the combination therapy, and triplet combination therapies consisting of BRAF inhibition, oncolytic HSV, and either PD-1 or CTLA-4 blockade appeared to further improve therapy.
Disclosure: For full disclosures of the study authors, visit jitc.bmj.com.
