Abstract CT220: The anti-CD33 antibody drug conjugate gemtuzumab ozogamicin depletes and re-programmes CD33+ myeloid-derived suppressor cells in patients with metastatic cancer

Abstract Background: Myeloid-derived suppressor cells (MDSCs) are a paradigmatic, immunosuppressive cell population found in the blood and tumors of people with cancer. Alternatively-activated tumor-associated macrophages (TAMs) are immunosuppressive cells present in high numbers in the tumour microenvironment (TME) derived from circulating monocytes which in people with cancer are monocytic (M)-MDSC which migrate into the TME and polarise towards a macrophage phenotype. MDSCs express the common myeloid marker CD33. We previously reported that the anti-CD33 antibody drug conjugate, gemtuzumab ozogamicin (GO) binds predominantly to M-MDSCs, is rapidly internalised and induces dose-dependent decrease in viability. Treatment of circulating or tumor-polarised MDSCs with GO restores T cell proliferation in co-culture. We report here clinical proof of principle that the anti-CD33 antibody drug conjugate, gemtuzumab ozogamicin (GO) significantly reduces and subsequently repolarizes circulating M-MDSCs in cancer patients. Methods and results: 7 patients with relapsed/refractory cancer were treated with GO at a dose of 3mg/m2, 6 of whom had pMMR colorectal cancer (CRC) with liver metastases (LM). 0/4 patients treated on a day 1,8,15 schedule received all 3 doses and this schedule was deemed unfeasible. However, GO delivered 3-weekly was feasible and tolerable. GO administration using both dosing schedules caused a highly reproducible, and profound short-lived fall in the absolute number of circulating CD33+ cells at one week following administration which rebounds to values > baseline 2-3 weeks following each infusion. Importantly, using the 3-weekly schedule, at the time of rebound of the CD33+ CD14+ cells, there is a marked increase in the number of cells expressing HLA-DR, which suggested potential re-programming towards a less immunosuppressive phenotype following GO therapy. In line with the phenotypic shift in CD33+ cells at rebound, there is a sustained loss of monocyte suppression of activated CD4+ T cell proliferation. Thus, GO significantly reduces immunosuppressive CD33+ monocytoid cell numbers in pMMR CRC patients with LM and on CD33+ cell rebound these cells are both phenotypically and functionally no longer immune-suppressive. This loss of immune-suppressivity is maintained throughout the entire duration of treatment. Alternatively-polarised macrophages also express CD33 and are sensitive to GO. Conclusion. These results support the combination of 3 cycles of three-weekly GO alongside the initial 3 cycles of immune checkpoint blockade (ICB), during which time the initial proliferative burst is crucial, so as to improve ICB outcomes in those with liver metastatic disease, a metastatic site resistant to ICB. Citation Format: Gary Middleton, Aimee Jackson, Saly Al-Taei, Vicki Kunene, Su Lee, Anna Jackson, Joe Rogers, Francis Mussai, Carmen de Santo. The anti-CD33 antibody drug conjugate gemtuzumab ozogamicin depletes and re-programmes CD33+ myeloid-derived suppressor cells in patients with metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT220.