Durable Response and Improved CD8 T Cell Plasticity in Lung Cancer Patients After PD1 Blockade and JAK Inhibition

Persistent inflammation including type-one interferon (IFN-I) can cause immunosuppression. We show that delayed administration of the JAK1 inhibitor itacitinib after anti-PD1 improves immune function and anti-tumor response in mice, and results in high response rates (67%) in a phase-2 clinical trial for metastatic non-small cell lung cancer with tumor PDL1≥50%. In contrast to patients with low inflammation who responded to anti-PD1, patients with elevated inflammation had poor immune and tumor responses to anti-PD1 that improved after adding itacitinib. Itacitinib promoted features of CD8 T cell plasticity and therapeutic responses of exhausted and effector-memory clonotypes. Patients with persistent IFN-I signaling refractory to itacitinib showed progressive CD8 T cell terminal differentiation and progressive disease. Thus, JAK inhibition may improve anti-PD1 efficacy by pivoting T cell differentiation dynamics. ### Competing Interest Statement A.J.M. has received research funding from Merck. He has also received honoraria from Merck, AstraZeneca, Pfizer, and Takeda. A.J.M. is an inventor on patents filed or issued on the IFN pathway and modified CAR T cells. He is a scientific founder for Dispatch Biotherapeutics and advisor for Related Sciences, Diagonal Therapeutics, and Xilio. E.J.W. has consulting agreements with and/or is on the scientific advisory board for Merck, Roche, Pieris, Elstar, and Surface Oncology. E.J.W. is a founder of Surface Oncology and Arsenal Biosciences. E.J.W. has a patent licensing agreement on the PD-1 pathway with Roche/Genentech. E.J.W. is an inventor on a patent (U.S. patent number10,370,446) submitted by Emory University that covers the use of PD-1 blockade to treat infections and cancer. M.E.M. has received research funding from Eli Lilly (Inst), Trizell (Inst), AstraZeneca (Inst), Merck (Inst), and Genentech (Inst). M.E.M. has a consulting role for Astra Zeneca, Novocure, Boehringer Ingelheim, Janssen, Takeda, Blueprint Pharmaceuticals, Bristol Myers Squibb, and Ikena. M.E.M. also has stock in Gilead Sciences, Portola Pharmaceuticals, Merck, Bluebird Bio, Johnson & Johnson, and Pfizer. J.M.B. has a consulting or advisory role for Bristol-Myers Squibb, Merck, AstraZeneca, Genentech, Celgene, Boehringer Ingelheim, Guardant Health, Takeda, Novartis, Janssen, Ayala Pharmaceuticals, Regeneron, Inivata, and Foundation Medicine. J.M.B. has received research funding from Merck, Carevive Systems, Novartis, Incyte, Bayer, Janssen, AstraZeneca, Takeda, Amgen, Pfizer, and Mirati Therapeutics. J.M.B. was affiliated with University of Pennsylvania for the duration of this study but is now currently employed by Janssen Research & Development. C.J.L. has received honoraria from Bristol-Myers Squibb, Genentech/Roche, Lilly/ImClone, AstraZeneca, Takeda Science Foundation, and Merck. C.J.L. has a consulting or advisory role for Genentech/Roche, Lilly/ImClone, Merck, Abbott Biotherapeutics, Bayer/Onyx, Clarient, Clovis Oncology, Celgene, Cancer Support Community, Bristol-Myers Squibb, ARIAD, Takeda, AstraZeneca, Pfizer, Novocure, and Gilead Sciences. C.J.L. has received research funding from Merck, Advantagene, Clovis Oncology, Celgene, Inovio Pharmaceuticals, Ariad, GlaxoSmithKline, Genentech/Roche, Stem CentRx, Lilly, and Trizell. C.J.L. has other relationships with Lilly, Amgen, Peregrine Pharmaceuticals, and Synta. ### Clinical Trial NCT03425006 ### Funding Statement This study was supported by the Mark Foundation for Cancer Research, the Parker Institute for Cancer Immunotherapy, the LUNGevity Foundation, and Incyte. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The clinical trial (ClinicalTrials.gov identifier: [NCT03425006][1]) was approved by the institutional review board at the University of Pennsylvania and was completed in accordance with international standards of good clinical practice. All patients provided written informed consent at the time of enrollment. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study will be made available upon publication of the manuscript in a peer-reviewed journal. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03425006&atom=%2Fmedrxiv%2Fearly%2F2022%2F11%2F07%2F2022.11.05.22281973.atom