Reference Detail

Ref Type

Journal Article

PMID

(33593882)

Authors

Nguyen TT, Ramsay L, Ahanfeshar-Adams M, Lajoie M, Schadendorf D, Alain T, Watson IR

Title

Mutations in the IFNγ-JAK-STAT Pathway Causing Resistance to Immune Checkpoint Inhibitors in Melanoma Increase Sensitivity to Oncolytic Virus Treatment.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	27	12	2021 Jun 15	3432-3442	Clin Cancer Res

URL

Abstract Text

Next-generation sequencing studies and CRISPR-Cas9 screens have established mutations in the IFNγ-JAK-STAT pathway as an immune checkpoint inhibitor (ICI) resistance mechanism in a subset of patients with melanoma. We hypothesized ICI resistance mutations in the IFNγ pathway would simultaneously render melanomas susceptible to oncolytic virus (OV) therapy.Cytotoxicity experiments were performed with a number of OVs on a matched melanoma cell line pair generated from a baseline biopsy and a progressing lesion with complete JAK2 loss from a patient that relapsed on anti-PD-1 therapy, in melanoma lines following JAK1/2 RNA interference (RNAi) and pharmacologic inhibition and in Jak2 knockout (KO) B16-F10 mouse melanomas. Furthermore, we estimated the frequency of genetic alterations in the IFNγ-JAK-STAT pathway in human melanomas.The melanoma line from an anti-PD-1 progressing lesion was 7- and 22-fold more sensitive to the modified OVs, herpes simplex virus 1 (HSV1-dICP0) and vesicular stomatitis virus (VSV-Δ51), respectively, compared with the line from the baseline biopsy. RNAi, JAK1/2 inhibitor studies, and in vivo studies of Jak2 KOs B16-F10 melanomas revealed a significant increase in VSV-Δ51 sensitivity with JAK/STAT pathway inhibition. Our analysis of The Cancer Genome Atlas data estimated that approximately 11% of ICI-naïve cutaneous melanomas have alterations in IFNγ pathway genes that may confer OV susceptibility.We provide mechanistic support for the use of OVs as a precision medicine strategy for both salvage therapy in ICI-resistant and first-line treatment in melanomas with IFNγ-JAK-STAT pathway mutations. Our study also supports JAK inhibitor-OV combination therapy for treatment-naïve melanomas without IFN signaling defects.See related commentary by Kaufman, p. 3278.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
HSV1-dICP0	HSV1-dICP0	1	0
VSV-delta51	VSV-delta51	3	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
HSV1-dICP0				HSV1-dICP0 is an oncolytic herpes simplex virus type 1 with deletion of the ICP0 gene, which may induce a cytotoxic response in tumor cells (PMID: 33593882).
VSV-delta51		VSV(M Delta 51)		VSV-delta51 is an oncolytic vesicular stomatitis virus (VSV) with a deletion of methionine 51 in the M protein, which may induce a cytotoxic response in tumor cells and an antitumor immune response (PMID: 14585354, PMID: 33593882).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
JAK2 LOH JAK2 inact mut	melanoma	predicted - sensitive	VSV-delta51	Preclinical - Patient cell culture	Actionable	In a preclinical study, a melanoma patient-derived cell line harboring an inactivating JAK2 mutation and JAK2 loss of heterozygosity resulted in sensitivity to treatment with an oncolytic virus, VSV-delta51, in culture (PMID: 33593882).	33593882
JAK2 loss	melanoma	sensitive	VSV-delta51	Preclinical - Cell line xenograft	Actionable	In a preclinical study, treatment with VSV-delta51 resulted in decreased cell viability in melanoma cell lines with a loss of JAK2 in culture, and resulted in an increased median survival in a syngeneic mouse model grafted with a CRISPR-mediated JAK2 knockout melanoma cell line (PMID: 33593882).	33593882
JAK2 dec exp	melanoma	predicted - sensitive	VSV-delta51	Preclinical - Cell culture	Actionable	In a preclinical study, siRNA knockdown of JAK2 in a melanoma cell line resulted in increased sensitivity to treatment with an oncolytic virus, VSV-delta51, in culture (PMID: 33593882).	33593882
JAK2 LOH JAK2 inact mut	melanoma	predicted - sensitive	HSV1-dICP0	Preclinical - Patient cell culture	Actionable	In a preclinical study, a melanoma patient-derived cell line harboring an inactivating JAK2 mutation and JAK2 loss of heterozygosity resulted in sensitivity to treatment with an oncolytic virus, HSV1-dICP0, in culture (PMID: 33593882).	33593882