flotetuzumab (MGD006)

In acute myeloid leukemia relapse, downregulation of HLA class II on leukemic cells allows immune evasion, but this suppression can be reversed by IFN-γ or flotetuzumab, a CD123×CD3 bispecific antibody, restoring immunogenicity and potentially enhancing the graft versus leukemia (GVL) effect. Collectively, HLA class II molecules function not only in conventional antigen presentation to CD4+ T cells but also in neo-self antigen recognition, immune evasion, and tissue-specific disease expression. A deeper understanding of HLA class II biology may pave the way toward therapeutic strategies that separate GVHD from the GVL effect.

The differential prognosis of the mutation in various chromosomal and VAF settings will be explored. Lastly, we will outline therapeutic options, promising treatments on the horizon, and whether allogeneic stem cell transplant is curative.

P1, N=16, Active, not recruiting, Children's Oncology Group | Trial completion date: Sep 2024 --> Sep 2025

P1, N=3, Completed, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Recruiting --> Completed | N=16 --> 3 | Trial completion date: Dec 2027 --> Jun 2024 | Trial primary completion date: Dec 2025 --> Jun 2024

P2, N=11, Terminated, Washington University School of Medicine | Trial completion date: Mar 2026 --> Jul 2024 | Active, not recruiting --> Terminated; The sponsor is no longer supporting the drug

P2, N=11, Active, not recruiting, Washington University School of Medicine | Recruiting --> Active, not recruiting | N=25 --> 11 | Trial completion date: Jun 2029 --> Mar 2026 | Trial primary completion date: Jul 2028 --> Mar 2024

P2, N=25, Recruiting, Washington University School of Medicine | Trial completion date: Dec 2027 --> Jun 2029 | Trial primary completion date: Jan 2026 --> Jul 2028

Responses only occurred in Cohort B, with a partial response in one patient with Hodgkin's lymphoma and morphological complete remission in the bone marrow in one patient with blastic plasmacytoid dendritic cell neoplasm. In conclusion, flotetuzumab had a manageable safety profile in advanced CD123-positive hematological malignancies.

P1, N=13, Active, not recruiting, City of Hope Medical Center | Trial completion date: Nov 2023 --> May 2026 | Trial primary completion date: Nov 2023 --> May 2026

P1, N=16, Active, not recruiting, Children's Oncology Group | N=47 --> 16 | Trial completion date: Oct 2023 --> Sep 2024

Moreover, we acquired an additional dataset of pre-treatment immune-related gene expression profiling obtained from the BM of 30 flotetuzumab-treated (CD3 x CD123 bispecific antibody) refractory/relapsed (R/R) adult AML patients (NCT02152956; Vadakekolathu et al., 2020) for TIDE-based immune deconvolution (Jiang et al., 2018)...Lastly, for the first time, we identified TLS-like aggregates in the BM of AML patients, which have been associated with immunotherapy response in many cancers (Schumacher & Thommen, 2022). Additional studies to further characterize the function and relevance of these lymphoid aggregates are ongoing.

We have previously shown that TP53 abnormalities are associated with a pro-inflammatory and immunosuppressive tumor microenvironment (TME), including high CD274 and FoxP3 expression, with dysfunctional natural killer (NK)/CD8+ T-cell states and with response to flotetuzumab, a CD123 × CD3 bispecific T-cell engager...Conclusions Spatial gene programs of leukemia stemness, T-cell dysfunction and immune suppression are enriched in TP53-m AML. It remains to be determined whether TP53-m AML with a pre-existing but ineffective T-cell response may be amenable to T cell-targeting immunotherapies.