Prophylactic IFN-γ blockade drives axi-cel expansion without preventing refractory toxicities: caution against pre-emptive use
Abstract Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) affect most patients receiving axicabtagene ciloleucel (axi-cel) for relapsed or refractory large B-cell lymphoma (LBCL). Based on pre-clinical data, we hypothesized that prophylactic IFN-γ blockade could prevent toxicity without impairing efficacy. We initiated an open-label phase 2 trial (NCT06550141) evaluating single-dose emapalumab one day before axi-cel. Here, we report the first two patients to caution against the pre-emptive emapalumab use prior axi-cel: Both developed treatment-refractory toxicities including high-grade ICANS and overlapping CRS-IEC-HS requiring multiple immunomodulatory agents. CAR T-cell expansion exceeded levels reported in ZUMA-1 and a standard-of-care axi-cel cohort at our institution. Despite therapeutic emapalumab and suppressed free IFN-γ, IL-2 and sIL-2R were markedly elevated, suggesting CRS was driven independent of IFN-γ. Both patients achieved complete responses, suggesting preserved efficacy. Given the unanticipated severity and refractoriness of toxicities, recruitment with this design was discontinued and the protocol was amended.
Authors
- Jeremy S. Abramson (ORCID: https://orcid.org/0000-0001-8467-9257)
- Benjamin R. Puliafito (ORCID: https://orcid.org/0000-0003-3972-6362)
- Kathleen Gallagher (ORCID: https://orcid.org/0009-0004-4818-2082)
- Mark B. Leick (ORCID: https://orcid.org/0000-0003-3111-0221)
- Deshea L Harris (ORCID: https://orcid.org/0000-0002-8194-1827)
- Alexandra M. Haugh (ORCID: https://orcid.org/0009-0005-5796-5836)
- Marcela Valderrama Maus (ORCID: https://orcid.org/0000-0002-7578-0393)
- Yi‐Bin Chen (ORCID: https://orcid.org/0000-0002-9554-1058)
- J. Erika Haydu (ORCID: https://orcid.org/0000-0003-2463-0560)
- Elliot C. Woods (ORCID: https://orcid.org/0000-0003-2920-8334)
- Matthew J. Frigault (ORCID: https://orcid.org/0000-0002-6774-5694)
- Viktoria Blumenberg (ORCID: https://orcid.org/0000-0003-1379-0876)
- David J. Bozym
- Patrick Connor Johnson (ORCID: https://orcid.org/0000-0002-3943-6608)
- Jacob Drobnyk Soumerai (ORCID: https://orcid.org/0000-0002-3062-6819)
- Jing Li (ORCID: https://orcid.org/0000-0002-0272-7073)
- Keshav Sridharan
- Marisa G. Ogier (ORCID: https://orcid.org/0009-0008-8247-7203)
- Maxx King (ORCID: https://orcid.org/0009-0002-3533-4193)
Institutions
- Harvard University (US)
- Massachusetts General Hospital (US)
- Center for Cancer Research (US)
Publication Details
- Journal
- Blood Cancer Discovery
- Published
- 2026-10-19
- DOI
- https://doi.org/10.1158/2643-3230.bcd-26-0249
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 0.00