The anti-CD33 antibody drug conjugate gemtuzumab ozogamicin depletes and functionally resets CD33+ myeloid-derived suppressor cells in patients with metastatic cancer: a phase II single arm, open label trial
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ID: 317942
2026
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Abstract
We previously demonstrated that the anti-CD33 antibody drug conjugate, gemtuzumab ozogamicin (GO) binds CD33-expressing monocytic myeloid-derived suppressor cells (M-MDSCs), is internalised, and decreases their viability. Treatment of MDSCs with GO restores T-cell proliferation in co-culture, overcomes M-MDSC suppression of CAR-T-cell proliferation, and enhances target-cell killing. GOTHAM is a phase II single arm trial. Patients with a diagnosis of solid cancer with radiological or clinical evidence of disease progression, or primary or secondary hemophagocytic lymphohistiocytosis, or macrophage activation syndrome disease relapsing/refractory to treatment at enrolment were eligible. An initial regimen of 3 mg/m2 GO on days 1, 8, and 15 was tested, adjusted to 21-day intervals, days 1, 22, and 43. The primary outcome was the impact of GO therapy on peripheral CD33+ myeloid cells. Trial registration: ISRCTN 89158144. Using two schedules of GO, we could not convincingly demonstrate safe feasibility in patient with solid cancer because of neutropenia. However, GO reproducibly and significantly reduces circulating MDSCs. Importantly, there is consistent preliminary evidence that upon rebound the monocyte population of CD33+ cells is replaced with non-suppressive monocytes. These data support the phase Ib dose-escalation testing of GO up to 2 mg/m2 in combination with immune checkpoint blockade and other immunotherapies in patients with solid cancer to find a dose that depletes and repolarises MDSCs without causing undue neutropenia, paving the way to using GO as an immune potentiator in this patient population.
| Reference Key |
openalex_W7165193385
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| Authors | Carmela De Santo, Aimee Jackson, Francis Mussai, Saly Al‐Taei, N. Lal, Thomas Starkey, Livingstone Fultang, Nicola McJannett, V Kunene, Lucinda Billingham, Anna Lawson, Su Lee, Joseph Rogers, Gary Middleton |
| Journal | journal of leukocyte biology |
| Year | 2026 |
| DOI |
10.1093/jleuko/qiag083
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| URL | |
| Keywords | Keywords not found |
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