GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts

Abstract

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. Although 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 cell 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 patient acute lymphoblastic leukemia xenograft model of CRS and neuroinflammation (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-CSFk/o CAR-T cells maintained normal functions and had enhanced antitumor activity in vivo, as well as improved overall survival, compared with CART19 cells. 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 2 studies with lenzilumab in combination with CART19 cell therapy are planned.

Glial injury in neurotoxicity after pediatric CD19‐directed chimeric antigen receptor T cell therapy

“…10,[30][31][32] These cytokines have also been implicated in a number of other CNS diseases 33 and are known to activate the endothelial cells at the BBB, 9,34,35 supporting the theory that ICANS is initiated by a systemic cytokine surge. Key inflammatory cytokines showed similar elevations in the CSF and serum, suggesting that local cytokine production in the CNS is not a prominent feature of neurotoxicity.…”

CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma

“…Our group has previously described monocyte/macrophage derived cytokine enrichment in blood and cerebrospinal fluid, including G-CSF and GM-CSF, with neurologic toxicity in ALL patients treated with 19-28z CAR-T. 45 A recent report from the Mayo Clinic demonstrated that, in a xenograft model, neutralization with an anti-GM-CSF can abrogate neuroinflammation. 46 We sought to immunophenotype the end of production 19-28z CAR T cells to establish correlations with outcomes. Somewhat surprisingly, higher percentages of naïve-like CD45RA+CCR7+ T cells within both CD4 and CD8 subsets of the CAR T products correlated with greater likelihood of progression events.…”

The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19

“…These data are further supported by the evidence that human pulmonary microvascular endothelial cells (HPMEC) are able to secrete GM-CSF following an inflammatory stimulus such as LPS, suggesting a potential important role in the pathogenesis of ARDS, in which increased levels of GM-CSF are present in BAL fluid [301]. Additionally, animal models have demonstrated that GM-CSF neutralization is effective in reducing the severity of neuroinflammation induced by CAR-T therapy, with no negative effect on its efficacy [302].…”