147 JAK1- altered checkpoint inhibitor-resistant melanoma treated with intratumoral oncolytic viral therapy: a 2-patient case series
Year: 2026
Type: conference-abstract
Abstract: Background Immune checkpoint inhibitors (ICIs) have improved outcomes in advanced melanoma, yet resistance is common. JAK1 or JAK2 loss-of-function impairs IFN-gamma-JAK-STAT signaling, abolishing PD-L1 expression and antigen presentation, mediating primary and acquired ICI resistance. 1 2 Mucosal melanoma has lower ICI response rates, half those in cutaneous disease.3 JAK1/2-altered tumors may be susceptible to oncolytic viral replication due to impaired antiviral IFN-gamma signaling.4 Talimogene laherparepvec (T-VEC), an oncolytic herpes simplex virus type 1 (HSV-1) therapy expressing GM-CSF, improved durable response rates in melanoma in the OPTiM trial.5Methods We reviewed two patients with JAK1 loss-of-function-mutated melanoma and limited ICI sensitivity. NGS and clinical records were reviewed.Results Patient 1 is a 73-year-old man with stage III in-transit recurrent cutaneous melanoma (cT2b cN1c cM0). NGS identified TMB 131.6 mut/Mb, BRAF wild-type, and a loss-of-function JAK1 mutation. He received neoadjuvant ipilimumab 1 mg/kg plus nivolumab 3 mg/kg for 3 cycles; pathologic response was poor (~90% viable tumor). After adjuvant nivolumab, he developed biopsy-proven unresectable in-transit recurrence. Nivolumab + relatlimab + T-VEC resulted in a complete clinical response after 5 doses, ongoing at 9 months.Patient 2 is an 88-year-old woman with recurrent localized anal mucosal melanoma refractory to nivolumab + relatlimab.6 NGS showed elevated TMB (12.6 mut/Mb) and loss-of-function JAK1 mutation. Surgery and radiation were not feasible; prior ICI toxicities and advanced age precluded ipilimumab + nivolumab. T-VEC was injected into a 4-cm protruding anorectal mass with surgical assistance, concurrent with nivolumab/relatlimab. After 9 doses, PET/CT showed marked metabolic response (SUV 9 to 3); T-VEC was discontinued when lesion was too small to inject.Conclusions We report two patients with JAK1 loss-of-function-mutated melanoma and limited ICI benefit who achieved meaningful clinical responses when T-VEC was added to ICI ( table 1). Notably, the phase III MASTERKEY-265 trial showed that T-VEC plus pembrolizumab did not improve progression-free or overall survival over pembrolizumab alone in an unselected melanoma population.7 Our cases suggest JAK1 LOF alterations may define a biomarker-selected population in which T-VEC offers a mechanistic strategy to circumvent JAK-mediated ICI resistance: T-VEC is directly oncolytic and recruits antigen-presenting cells (APCs) via GM-CSF, enabling T-cell priming through professional APC presentation rather than tumor-intrinsic MHC class I machinery impaired by JAK1 LOF. To the authors’ knowledge, these cases constitute the first clinical evidence of oncolytic viral therapy overcoming JAK-mediated ICI resistance. These data support a prospective biomarker-selected study combining T-VEC with ICI in melanoma harboring LOF JAK mutations.References Shin DS, et al. Cancer Discov. 2017;7(2):188–201.Zaretsky JM, et al. N Engl J Med. 2016;375(9):819–829.D’Angelo SP, et al. J Clin Oncol. 2017;35(2):226–235.Nguyen TT, et al. Clin Cancer Res. 2021;27(12):3432–3442.Andtbacka RHI, et al. J Clin Oncol. 2015;33:2780–2788.Tawbi HA, et al. N Engl J Med. 2022;386:24–34.Chesney JA, et al. J Clin Oncol. 2023;41(3):528–540. doi:10.1200/JCO.22.00343.Abstract 147 Table 1Patient summary. Clinicopathologic characteristics and outcomes for two patients with JAK1 loss-of-function-mutated melanoma treated with T-VECLOF, loss-of-function; TMB, tumor mutational burden; WT, wild-type; ICI, immune checkpoint inhibitor; T-VEC, talimogene laherparepvec; ipi, ipilimumab; nivo, nivolumab; rela, relatlimab; adj, adjuvant; SUV, standardized uptake value
Authors: Khola Khan, Daniel H Johnson
Institutions: Ochsner Health System, Ochsner Medical Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225153750