Target Background
CD33 or Siglec-3 (sialic acid binding immunoglobulin-like lectin 3) is a trans-membrane receptor, consisting of two extracellular immunoglobulin domains and two intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs). The expression of CD33 is restricted in the myeloid lineage. It is highly expressed on myeloid progenitor cells but much lower on differentiated cells such as tissue macrophages and peripheral granulocytes. In addition, CD33 is highly expressed on, and considered as a marker of acute myeloid leukemia (AML), which is the most common form of leukemia in human. The prognosis of AML is very poor. Several studies have utilized CD33-targeted antibody-drug conjugate (ADC) such as vadastuximab talirine (developed by Seattle Genetics) to induce the lysis of myeloid leukemia cells in vivo.
Anti-CD33 CAR-T Cell Therapy
A preclinical test of anti-CD33 CAR-T cells showed significant effector functions in vitro, and induced reduction of leukemia burden and prolonged survival of AML xenograft murine models. However, the anti-CD33 CAR-T cell treatment resulted in serious hematopoietic toxicity in animal models, suggesting the permanent infusion of anti-CD33 CAR-T cells may yield unacceptable toxicity. Therefore, the novel 4th generation CARs that contain an "off switch" may be used to avoid long-term myelosuppression. Several clinical trials on relapsed and/or chemotherapy refractory CD33+ AML with autologous or allogeneic anti-CD33 CAR-T cells are being conducted. It is reported that adverse effect including fever, pancytopenia and elevated cytokine levels in serum are observed.
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