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Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients.

ABSTRACT: Persistent inflammation driven by cytokines such as type-one interferon (IFN-I) can cause immunosuppression. We show that administration of the Janus kinase 1 (JAK1) inhibitor itacitinib after anti-PD-1 (programmed cell death protein 1) immunotherapy improves immune function and antitumor responses in mice and results in high response rates (67%) in a phase 2 clinical trial for metastatic non-small cell lung cancer. Patients who failed to respond to initial anti-PD-1 immunotherapy but responded after addition of itacitinib had multiple features of poor immune function to anti-PD-1 alone that improved after JAK inhibition. Itacitinib promoted CD8 T cell plasticity and therapeutic responses of exhausted and effector memory-like T cell clonotypes. Patients with persistent inflammation refractory to itacitinib showed progressive CD8 T cell terminal differentiation and progressive disease. Thus, JAK inhibition may improve the efficacy of anti-PD-1 immunotherapy by pivoting T cell differentiation dynamics.

SUBMITTER: Mathew D

PROVIDER: S-EPMC11327955 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

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Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients.

Mathew Divij D Marmarelis Melina E ME Foley Caitlin C Bauml Joshua M JM Ye Darwin D Ghinnagow Reem R Ngiow Shin Foong SF Klapholz Max M Jun Soyeong S Zhang Zhaojun Z Zorc Robert R Davis Christiana W CW Diehn Maximillian M Giles Josephine R JR Huang Alexander C AC Hwang Wei-Ting WT Zhang Nancy R NR Schoenfeld Adam J AJ Carpenter Erica L EL Langer Corey J CJ Wherry E John EJ Minn Andy J AJ

Science (New York, N.Y.) 20240621 6702

Persistent inflammation driven by cytokines such as type-one interferon (IFN-I) can cause immunosuppression. We show that administration of the Janus kinase 1 (JAK1) inhibitor itacitinib after anti-PD-1 (programmed cell death protein 1) immunotherapy improves immune function and antitumor responses in mice and results in high response rates (67%) in a phase 2 clinical trial for metastatic non-small cell lung cancer. Patients who failed to respond to initial anti-PD-1 immunotherapy but responded ...[more]

PMID: 38900877

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Project description:IntroductionImmune checkpoint inhibitor (ICI) monotherapy has limited efficacy in patients with non-small cell lung cancer (NSCLC) and brain metastases (BMs). With the wide use of ICI-based combinations, the efficacy of different ICI combination strategies in patients with NSCLC and BMs needs to be further elucidated.MethodsWe retrospectively reviewed 526 patients with non-small cell lung cancer (NSCLC) treated with ICIs from January 2016 to December 2019 in the Shanghai Pulmonary Hospital. Patients with BMs treated with ICIs were further divided into two groups: those with BM prior to the ICI treatment (pBM group), and those with BM after the treatment (aBM group). We assessed intracranial progression-free survival (IPFS), systemic progression-free survival (SPFS), overall survival (OS), intracranial objective response rate (IORR), and intracranial disease control rate (IDCR).ResultsWe found 77 patients out of 526 with BMs; 69 presented the BMs prior to the ICI treatments and 8 showed BMs after the ICI treatments. In the pBM group, the median IPFS and SPFS were 7.39 months and 5.39 months, respectively. Combination therapy significantly improved both the IPFS (p=0.007) and the SPFS (p=0.007) when compared with monotherapy. Further analysis demonstrated that ICIs combined with chemotherapy significantly improved both the IPFS (p=0.009) and the SPFS (p=0.006) when compared with monotherapy. While ICIs combined with anti-angiogenic therapy improved the SPFS (p=0.005) but not the IPFS (p=0.139). The median OS was 27.43 months for patients in the pBM group. Further analyses suggested that combination treatment also improved the OS when compared with monotherapy (p=0.003). Subgroup analysis results showed that ICIs combined with chemotherapy led to better OS than ICIs monotherapy (p=0.006). Radiotherapy had no significant impact on survival (IPFS p=0.272, OS p=0.142) in the patients of the pBM group.ConclusionICIs combined with chemotherapy demonstrated survival benefits over ICI monotherapy in patients with NSCLCs and BMs.

Dataset Information

Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients.

Publications

Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients.

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