{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T23:29:09Z","timestamp":1789082949009,"version":"build-2803163510"},"reference-count":171,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T00:00:00Z","timestamp":1691366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The Philadelphia chromosome-negative (Ph\u2212) myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are enduring and well-known conditions. These disorders are characterized by the abnormal growth of one or more hematopoietic cell lineages in the body\u2019s stem cells, leading to the enlargement of organs and the manifestation of constitutional symptoms. Numerous studies have provided evidence indicating that the pathogenesis of these diseases involves the dysregulation of the immune system and the presence of chronic inflammation, both of which are significant factors. Lately, the treatment of cancer including hematological malignancy has progressed on the agents aiming for the immune system, cytokine environment, immunotherapy agents, and targeted immune therapy. Immune checkpoints are the molecules that regulate T cell function in the tumor microenvironment (TME). The first line of primary immune checkpoints are programmed cell death-1 (PD-1)\/programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4). Immune checkpoint inhibitor therapy (ICIT) exerts its anti-tumor actions by blocking the inhibitory pathways in T cells and has reformed cancer treatment. Despite the impressive clinical success of ICIT, tumor internal resistance poses a challenge for oncologists leading to a low response rate in solid tumors and hematological malignancies. A Phase II trial on nivolumab for patients with post-essential thrombocythemia myelofibrosis, primary myelofibrosis, or post-polycythemia myelofibrosis was performed (Identifier: NCT02421354). This trial tested the efficacy of a PD-1 blockade agent, namely nivolumab, but was terminated prematurely due to adverse events and lack of efficacy. A multicenter, Phase II, single-arm open-label study was conducted including pembrolizumab in patients with primary thrombocythemia, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with ruxolitinib. This study showed that pembrolizumab treatment did not have many adverse events, but there were no pertinent clinical responses hence it was terminated after the first stage was completed. To avail the benefits from immunotherapy, the paradigm has shifted to new immune checkpoints in the TME such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain immunoglobulin-containing suppressor of T cell activation (VISTA), and human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) forming the basis of next-generation ICIT. The primary aim of this article is to underscore and elucidate the significance of next-generation ICIT in the context of MPN. Specifically, we aim to explore the potential of monoclonal antibodies as targeted immunotherapy and the development of vaccines targeting specific MPN epitopes, with the intent of augmenting tumor-related immune responses. It is anticipated that these therapeutic modalities rooted in immunotherapy will not only expand but also enhance the existing treatment regimens for patients afflicted with MPN. Preliminary studies from our laboratory showed over-expressed MDSC and over-expressed VISTA in MDSC, and in progenitor and immune cells directing the need for more clinical trials using next-generation ICI in the treatment of MPN.<\/jats:p>","DOI":"10.3390\/ijms241512502","type":"journal-article","created":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T06:37:31Z","timestamp":1691390251000},"page":"12502","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Role of Next Generation Immune Checkpoint Inhibitor (ICI) Therapy in Philadelphia Negative Classic Myeloproliferative Neoplasm (MPN): Review of the Literature"],"prefix":"10.3390","volume":"24","author":[{"given":"Ruchi","family":"Yadav","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Brookdale University Hospital Medical Center, Brooklyn, NY 11212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narek","family":"Hakobyan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Brookdale University Hospital Medical Center, Brooklyn, NY 11212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9623-6645","authenticated-orcid":false,"given":"Jen-Chin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology, Brookdale University Hospital Medical Center, Brooklyn, NY 11212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1097\/MOH.0000000000000218","article-title":"New molecular genetics in the diagnosis and treatment of myeloproliferative neoplasms","volume":"23","author":"Passamonti","year":"2016","journal-title":"Curr. 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