Sterner, Sakemura, and Cox et al. showed in ALL xenograft models that neutralization of GM-CSF via a GM-CSF knockout in CAR T cells or via lenzilumab enhanced the proliferation and antitumor activity of CAR T cells. The combination of CD19 CAR T cells with lenzilumab further prevented development of cytokine release syndrome and reduced the severity of neuroinflammation in a patient-derived primary ALL xenograft model. GM-CSF inhibition led to a decrease in the levels of several myeloid and inflammatory cytokines and chemokines. A phase II clinical trial of CD19 CAR T cells in combination with lenzilumab is planned.
Chimeric antigen receptor T (CAR-T) cell therapy is a new pillar in cancer therapeutics; however, its application is limited by the associated toxicities. These include cytokine release syndrome (CRS) and neurotoxicity. While the IL-6R antagonist tocilizumab is approved for treatment of CRS, there is no approved treatment of neurotoxicity associated with CD19 targeted CAR-T (CART19) cell therapy. Recent data suggest that monocytes and macrophages contribute to the development of CRS and neurotoxicity after CAR-T cell therapy. Therefore, we investigated neutralizing granulocyte macrophage colony-stimulating factor (GM-CSF) as a potential strategy to manage CART19 cell associated toxicities. In this study, we show that GM-CSF neutralization with lenzilumab does not inhibit CART19 function in vitro or in vivo. Moreover, CART19 cell proliferation was enhanced and durable control of leukemic disease was maintained better in patient derived xenografts after GM-CSF neutralization with lenzilumab. In a primary acute lymphoblastic leukemia (ALL) xenograft model of CRS and neuro-inflammation (NI), GM-CSF neutralization resulted in a reduction of myeloid and T cell infiltration in the central nervous system and a significant reduction in NI and prevention of CRS. Finally, we generated GM-CSF deficient CART19 cells through CRISPR/Cas9 disruption of GM-CSF during CAR-T cell manufacturing. These GM-CSF(k/o) CAR-T cells maintained normal functions, had enhanced anti-tumor activity in vivo, and improved overall survival compared to CART19. Together, these studies illuminate a novel approach to abrogate NI and CRS through GM-CSF neutralization, which may potentially enhance CAR-T cell function. Phase II studies with lenzilumab in combination with CART19 therapy are planned.
Author Info: (1) Mayo Clinic Medical Scientist Training Program, Mayo Clinic College of Medicine and Science, Rochester, MN, United States. (2) Division of Hematology, Mayo Clinic, Rochester, M
Author Info: (1) Mayo Clinic Medical Scientist Training Program, Mayo Clinic College of Medicine and Science, Rochester, MN, United States. (2) Division of Hematology, Mayo Clinic, Rochester, MN, United States. (3) Division of Hematology, Mayo Clinic, Rochester, MN, United States. (4) Division of Hematology, Mayo Clinic, Rochester, MN, United States. (5) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (6) Division of Hematology, Mayo Clinic, Rochester, MN, United States. (7) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (8) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (9) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (10) Division of Hematology, Mayo Clinic, Rochester, MN, United States. (11) Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States. (12) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (13) Humanigen, Burlingame, CA, United States. (14) Humanigen, Burlingame, CA, United States. (15) Humanigen, Burlingame, CA, United States. (16) Humanigen, Burlingame, CA, United States. (17) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (18) Division of Hematology, Mayo Clinic, Rochester, MN, United States. (19) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (20) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (21) Division of Hematology, Mayo Clinic, Rochester, MN, United States. (22) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (23) Department of Immunology, Mayo Clinic, Rochester, MN, United States; kenderian.saad@mayo.edu.
