Lenzilumab (anti-GM-CSF)

CAR-T-related Toxicity

Daniel W. Lee, Rebecca Gardner, David L. Porter, Chrystal U. Louis, Nabil Ahmed, Michael Jensen, Stephan A. Grupp, and Crystal L. Mackall. Current concepts in the diagnosis and management of cytokine. Blood 2014 124:188-195; doi:

Richard A Morgan, James C Yang, Mio Kitano, Mark E Dudley, Carolyn M Laurencot. Case Report of a Serious Adverse Event Following the Administration of T Cells Transduced With a Chimeric Antigen Receptor Recognizing ERBB2. Molecular Therapy vol. 18 no. 4, 843–851 apr. 2010

Delbrook, Crystal L. Mackall, Terry J Fry, and Nirali N Shah. Tocilizumab-Refractory Cytokine Release Syndrome (CRS) Triggered By Chimeric Antigen Receptor (CAR)-Transduced T Cells May Have Distinct Cytokine Profiles Compared to Typical CRS. Blood 2016 128:3358

David T. Teachey, Shannon L. Maude, Noelle Frey, David M. Barrett, Susan R. Rheingold, Carl H. June, David L. Porter, Stephan A. Grupp. Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T cell Therapy for Acute Lymphoblastic Leukemia. Cancer Discov. 2016 June ; 6(6): 664–679. doi:10.1158/2159-8290.CD-16-0040

Frederick L. Locke et al. Immune signatures of cytokine release syndrome and neurologic events in a multicenter registrational trial (ZUMA-1) in subjects with refractory diffuse large B cell lymphoma treated with axicabtagene ciloleucel (KTE-C19). AACR Presentation April 2017

David T Teachey, Simon F. Lacey, Pamela A Shaw, J Joseph Melenhorst, Noelle V. Frey, Shannon L Maude, David M. Barrett, Susan R. Rheingold, Carl H. June, David L. Porter, and Stephan A. Grupp. Biomarkers Accurately Predict Cytokine Release Syndrome (CRS) after Chimeric Antigen Receptor (CAR) T Cell Therapy for Acute Lymphoblastic Leukemia (ALL). Blood 2015 126:1334

Shannon L. Maude, David Barrett, David T. Teachey, MD, Stephan A. Grupp, MD. Managing Cytokine Release Syndrome Associated With Novel T Cell-Engaging Therapies. Cancer J. 2014; 20(2): 119–122. doi:10.1097/PPO.0000000000000035

Jennifer N. Brudno and James N. Kochenderfer. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016 Jun 30; 127(26): 3321–3330.

Bianca Santomasso, Jae Hong Park, Isabelle Riviere, Elena Mead, Elizabeth Halton, Claudia Diamonte. Biomarkers associated with neurotoxicity in adult patients wiith relapsed or refractory. DOI: 10.1200/JCO.2017.35.15_suppl.3019 Journal of Clinical Oncology 35, no. 15_suppl (May 2017) 3019-3019.

Michael Fanger. Dampening CAR therapy induced cytokine storm with anti-GM-CSF antibodies.

Marie-Louise Sentman, Joana M. Murad,W. James Cook,Ming-Ru Wu, Jake Reder, Susanne H. Baumeister, Glenn Dranoff, Michael W. Fanger and Charles L. Sentman. Mechanisms of Acute Toxicity in NKG2D Chimeric Antigen Receptor T Cell-Treated Mice.

Mark Wunderlich, Courtney Stockman, Mahima Devarajan, Navin Ravishankar, Christina Sexton, Ashish R. Kumar, Benjamin Mizukawa, and James C. Mulloy. A xenograft model of macrophage activation syndrome amenable to anti-CD33 and anti–IL-6R treatment.

Steven Katz et al. Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T. Cancer Immunol Immunother. 2015 July ; 64(7): 817–829. doi:10.1007/s00262-015-1692-6

David M. Barrett, Nathan Singh, Ted J. Hofmann, Zachary Gershenson, and Stephan A. Grupp. Interleukin 6 Is Not Made By Chimeric Antigen Receptor T Cells and Does Not Impact Their Function. Blood 2016 128:654;

Mark Wunderlich, Courtney Stockman, Mahima Devarajan, Navin Ravishankar, Christina Sexton, Ashish R Kumar, Benjamin Mizukawa, and James C. Mulloy. A Xenograft Model of Lymphocyte‑Independent, Effector‑Driven Macrophage Activation Syndrome Amenable to Anti‑CD33 and Anti‑IL‑6R Treatment. Blood 2016 128:3684;

Paul Spear, Amorette Barber, Agnieszka Rynda-Apple, and Charles L. Sentman. Chimeric antigen receptor (CAR) T cells shape myeloid cell function within the tumor microenvironment through IFN-γ and GM-CSF. J Immunol. 2012 June 15; 188(12): 6389–6398. doi:10.4049/jimmunol.1103019.

Siri Tähtinen, Saija Kaikkonen, Maiju Merisalo-Soikkeli, Susanna Grönberg-Vähä-Koskela, Anna Kanerva, Suvi Parviainen, Markus Vähä-Koskela, Akseli Hemminki. Favorable Alteration of Tumor Microenvironment by Immunomodulatory. PLOS ONE | DOI:10.1371/journal.pone.0131242

Marco Ruella, Saad S Kenderian, Olga Shestova, Michael Klichinsky, J. Joseph Melenhorst, Mariusz A Wasik, Simon F. Lacey, Carl H June, and Saar I Gill. Kinase Inhibitor Ibrutinib Prevents Cytokine-Release Syndrome after Anti-CD19 Chimeric Antigen Receptor T Cells (CART) for B Cell Neoplasms. Blood 2016 128:2159

Biliang Hu, Jiangtao Ren, Yanping Luo, John Scholler, Yangbing Zhao, Carl H. June. Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18.

Annemarie E. van Nieuwenhuijze,* Elise Coghill,* Daniel Gray,yz Sandro Prato,*y Donald Metcalf,yx Warren S. Alexander,yx and Ian P. Wicks. Transgenic Expression of GM-CSF in T cells Causes Disseminated Histiocytosis. The American Journal of Pathology, Vol. 184, No. 1, January 2014

Sabine Spath, Juliana Komuczki, Mario Hermann, Pawel Pelczar, Florian Mair, Bettina Schreiner, Burkhard Becher. Dysregulation of the Cytokine GM-CSF Induces Spontaneous Phagocyte Invasion and Immunopathology in the Central Nervous System.

Syed Abbas Ali, Victoria Shi, Irina Maric, Michael Wang, David F. Stoncek, Jeremy J. Rose, Jennifer N. Brudno, Maryalice Stetler-Stevenson, Steven A. Feldman, Brenna G. Hansen, Vicki S. Fellowes, Frances T. Hakim, Ronald E. Gress, and James N. Kochenderfer. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood, 29 September 2016 x Volume 128, Number 13

John M. Rossi, Marika Sherman, Allen Xue, Yueh wei-Shen, Lynn Navale, Steven A. Rosenberg, James N. Kochenderfer, Adrian Bot. Low-Dose Conditioning Chemotherapy and anti-CD19 CAR T Cells May Elicit Distinct Immune Programs Associated With Clinical Responses. EMA Workshop Nov 15-16 2016

Tessa Gargett, Susan N Christo, Timothy R Hercus, Nazim Abbas, Nimit Singhal, Angel F Lopez, Michael P Brown. GM-CSF signaling blockade and chemotherapeutic agents act in concert to inhibit the function of myeloid-derived suppressor cells. Clinical & Translational Immunology (2016) 5, e119;  doi:10.1038/cti.2016.80

Rachel A. Burga, Mitchell Thorn, Gary R. Point, Prajna Guha, Cang T. Nguyen, Lauren A. Licata, Ronald P. DeMatteo, Alfred Ayala, N. Joseph Espat, Richard P. Junghans, Steven C. Katz. Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T. Cancer Immunol Immunother. 2015 July ; 64(7): 817–829. doi:10.1007/s00262-015-1692-6.

Ting-ting Wang, Yong-liang Zhao, Liu-sheng Peng, Na Chen, Weisan Chen, Yi-pin Lv, Fang-yuan Mao, Jin-ju Zhang, Ping Chang, Yong-sheng Teng, Xiao-long Fu, Pei-wu Yu, Gang Guo, Ping Luo, Yuan Zhuang, Quan-ming Zou. Tumour-activated Neutrophils in Gastric Cancer Foster Immune Suppression and Disease Progression through GM-CSF PD-L1 Pathway. Gut 2017;66:1900-1911.  doi:10.1136/gutjnl-2016-313075



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Disclaimer: The information contained in the listed publications concerns biologics that are under pre-clinical and/or clinical investigation and which have not yet been approved for marketing by the U.S. Food and Drug Administration (FDA). They are currently limited by Federal law to investigational use, and no representations are made as to their safety or effectiveness for the purposes for which they are being investigated.