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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Gemtuzumab ozogamicin works by targeting and binding to the CD33 antigen, a sialic acid-dependent adhesion protein. This is an attractive target for antibody therapy as it appears on the surface of immature normal cells of myelomonocytic lineage and the surface of leukemic myeloblasts. Although it is expressed by normal hematopoietic cells, the intensity diminishes with the maturation of stem cells, thus providing a therapeutic window. Thus, CD33 is expressed on normal and leukemic myeloid colony-forming cells, including leukemic clonogenic precursors. For example, more than 80% of patients with AML express CD33 on their leukemic blasts. When gemtuzumab binds to the CD33 antigen, the complex formed is subsequently internalized, which is followed by release of calicheamicin inside the lysosomes of the cells. After reaching the nucleus, calicheamicin binds in the minor groove of DNA causing DNA double-strand breaks that lead to cell death (see Chapter 5 for more details).
Radioimmunotherapy of Hematological Malignancies
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
CD33 is a 67-kDa type 1 transmembrane protein whose expression is restricted to early multilineage hematopoietic progenitors, myelomonocytic precursors, and more mature myeloid cells. CD33 is absent on normal pluripotent hematopoietic stem cells, though 85% to 90% of adult and pediatric cases of AML express CD33 (14). Therefore, CD33 has gained clinical importance as a suitable tumor-associated antigen and target for mAb-based AML therapies.
Precision medicine in acute myeloid leukemia
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Immunotherapies, which have shown promise in the treatment of hematologic malignancies, have the potential to target AML through pathways that are distinct and complementary to current approaches (Lichtenegger et al., 2015). A second-generation CD33-specific chimeric antigen receptor capable of redirecting cytolytic effector T cells against leukemic cells was prepared. CD33 is expressed in approximately 90% of AML cases and has demonstrated utility as a target of therapeutic antibodies. Chimeric antigen receptor (CAR)-modified T cells efficiently killed leukemia cell lines and primary tumor cells in vitro. The antileukemia effect was CD33-specific, mediated through T-cell effector functions, and displayed tumor lysis at effector:target ratios as low as 1:20. Furthermore, the CD33-redirected T cells were effective in vivo, preventing the development of leukemia after prophylactic administration and delaying the progression of established disease in mice. These data provide preclinical validation of the effectiveness of a second-generation anti-CD33 chimeric antigen receptor therapy for AML, and support its continued development as a clinical therapeutic (O'Hear et al., 2015; Minagawa et al., 2016). An alternative antibody-based immunotherapeutic strategy is a novel class of bispecific T-cell-engaging antibodies (BiTEs) targeting CD33 antigen on AML cells and the CD3e component of the T-cell receptor complex (AMG 330) (Lichtenegger et al., 2015).
Antibody-drug conjugates (ADCs) delivering pyrrolobenzodiazepine (PBD) dimers for cancer therapy
Published in Expert Opinion on Biological Therapy, 2021
Despite impressive pre-clinical and early-phase clinical data with vadustuximab talirine in AML, the phase 3 CASCADE trial was terminated early due to toxicity. This highlights the difficulties inherent in translating promising phase 1 results to much larger studies, in this case of an older population of HMA-eligible patients with AML who are more susceptible to toxicity and where many develop potentially fatal cytopenias. The toxicity profile was markedly different to the non-target hepatotoxicity and veno-occlusive disease caused by the instability of Mylotarg. Expression of CD33 on normal hemopoietic precursor cells likely contributed to target-related myelosuppression. Further efforts to identify a dose regimen and cycle interval that maintains remission while minimising myelosuppression were warranted. The chequered history of gemtuzumab ozogamicin (Mylotarg), targeting the same CD33 antigen on AML, is a good example where changes to dose and schedule can revive a failed agent resulting ultimately in clinical and commercial success [67].
Association of TRF2 expression and myeloid-derived suppressor cells infiltration with clinical outcome of patients with cutaneous melanoma
Published in OncoImmunology, 2021
Marius Ilié, Elisabeth Lantéri, Emmanuel Chamorey, Brice Thamphya, Marame Hamila, Henri Montaudié, Alexandra Picard-Gauci, Sophie Gardrat, Thierry Passeron, Sandra Lassalle, Elodie Long-Mira, Julien Cherfils-Vicini, Eric Gilson, Véronique Hofman, Paul Hofman
In our study, the high density of CD33+ cells was significantly correlated with worse OS. Only one other recent study evaluated the relationship between the expression of CD33+ MDSCs and the outcome of patients with cutaneous melanoma, showing that high expression of CD33 was associated with poor clinicopathological variables and was an independent prognostic factor.43 Moreover, CD33+ MDSCs are increased in the peripheral blood of advanced melanoma patients, being an indicator of worse survival at baseline and following treatment with ipilimumab.28,44 MDSCs have been shown to exert immunosuppressive function on T cells, thereby possibly counteracting the beneficial effect of ICIs.45 However, CD33 is found in maturing granulocytes, monocytes, and multipotent myeloid precursors and is also expressed in subsets of activated T cells, natural killer cells, and B cells.25,26 Instead neutrophils (or G-MDSCs) besides expressing CD33, are found to be CD14 low and CD15 high, whereas monocytes (or Mo-MDSCs) are CD14 high and CD15 low.
Identifying effective drug combinations for patients with acute myeloid leukemia
Published in Expert Review of Anticancer Therapy, 2020
Musa Yilmaz, Tapan Kadia, Farhad Ravandi
The CD33 surface antigen is expressed on the majority of AML cells and represents an important target for AML therapy [65]. Gemtuzumab ozogamicin, an anti-CD33 monoclonal antibody conjugated to calicheamicin, was approved by the FDA in 2000 for older AML patients who are ineligible for intensive chemotherapy. However, in 2010, it was removed from the market when the confirmatory trial performed by the Southwest Oncology Group (SWOG) demonstrated no OS benefit and increased incidence of induction death [66]. However, when evaluated at lower and/or fractionated dosages, adding gemtuzumab to chemotherapy has shown superior survival in multiple other randomized studies [67–71]. Hills and colleagues performed a meta-analysis of data from five randomized clinical studies and showed that using gemtuzumab in combination with standard intensive chemotherapy reduces the relapse risk and improves OS; however, this benefit is limited to the patients without adverse risk cytogenetics. In 2017, FDA reapproved gemtuzumab based on ALFA-0701 clinical study, which showed an improvement in event-free survival (EFS) and OS (Table 3). Persistent cytopenias were more common in gemtuzumab arm, but lower gemtuzumab dose was not associated with increased induction death.