flotetuzumab (MGD006)

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.

P1, N=13, Active, not recruiting, City of Hope Medical Center | Recruiting --> Active, not recruiting | N=40 --> 13

The in vitro killing assay shows that T-cells from the spleens of immune competent C57/Bl6 hCD123eHOM mice bind to both FLZ and hCD123 on transduced murine leukemia cells. Co- culture with T-cells + target cells + FLZ showed killing at 24 hours compared to controls. T-cell activation and proliferation were noted based on cell surface markers.

Some of these agents have shown promising results at the clinical level, including tagraxofusp (CD123 conjugated with diphtheria toxin) for the treatment of BPDCN and IMGN632 (anti-CD123 drug-conjugate), and flotetuzumab (bispecific anti-CD123 and anti-CD3 monoclonal antibody) for the treatment of AML. However, the therapeutic efficacy of CD123-targeting treatments is still unsatisfactory and must be improved through new therapeutic strategies and combined treatments with other antileukemic drugs.

Finally, we report that FLZ-induced MHC-II upregulation is mediated by IFN-γ. In conclusion, we provide evidence that T-cell immunotherapies targeting relapsed AML can kill AML via both MHC-independent mechanisms and by an MHC-dependent mechanism through local release of IFN-γ and subsequent upregulation of MHC-II expression.

Of note, the CD123-directed therapy tagraxofusp has now become the standard of care (SoC) for blastic plasmacytoid dendritic cell neoplasm (BPDCN) (Pemmaraju NEJM 2019)...This new construct permits intermittent intravenous (IV) dosing due to a longer half-life (Alderson ASH 2021) compared with the first-generation DART molecule flotetuzumab, a continuous-infusion molecule that showed preliminary single-agent activity in refractory acute myeloid leukemia (AML) (Uy Blood 2021)...Secondary objectives include pharmacokinetics, immunogenicity, preliminary assessment of MGD024 clinical activity, and preliminary evaluation of safety/efficacy of tocilizumab in the management of MGD024-induced CRS...Response evaluation is determined using modified European LeukemiaNet (ELN) 2017 criteria for ALM and ALL; International Working Group (IWG) 2006 criteria for MDS; Lugano 2014 criteria for cHL; ELN 2020 criteria for CML; 2017 consensus criteria for HCL; IWG-Myeloproliferative Neoplasms Research and Treatment (MRT) & European Competence Network on Mastocytosis (ECNM) 2013 criteria for ASM; and modified criteria from Pemmaraju NEJM 2019 for BPDCN. Patients benefitting from MGD024 may continue to receive MGD024 after completion of the study treatment period, at physician discretion.

The in vitro killing assay shows that T-cells from the spleens of immune competent C57Bl/6 hCD123eHOM mice recognize FLZ and hCD123 on transduced murine leukemia cells. Co-culture with T-cells + target cells + FLZ showed killing at 24 hours compared to controls. T-cell activation and proliferation were noted based on cell surface markers.

We report the safety, RP2D, and preliminary activity of the CD123xCD3 bispecific antibody flotetuzumab in children with r/r AML. Despite the frequent occurrence of mild CRS and CLS, flotetuzumab was determined to be safe and tolerable at the RP2D of 500 ng/kg/day (DL1) with an overall response rate (CR + PR) of 20% in children and AYAs with r/r AML. This study supports the potential of CD123-targeting immunotherapies in pediatric patients with AML and provides rationale for future phase 2/3 investigation.

P1/2, N=246, Terminated, MacroGenics | Trial completion date: Dec 2023 --> Jul 2022 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2023 --> Jul 2022; Business decision

P1/2, N=330, Active, not recruiting, MacroGenics | Recruiting --> Active, not recruiting | Trial completion date: Jan 2022 --> Dec 2023 | Trial primary completion date: Jan 2022 --> Jul 2023

MGD006 enhanced T-cell proliferation and decreased the burden of AML blasts in the peripheral blood with or without cytarabine treatment. These data demonstrate the efficacy of MGD006 in prolonging survival in pediatric AML PDX models in the presence of effector T cells and show that the inclusion of cytarabine in the treatment regimen does not interfere with MGD006 activity.

P2, N=0, Withdrawn, Stichting Hemato-Oncologie voor Volwassenen Nederland | N=25 --> 0 | Not yet recruiting --> Withdrawn

Introduction: Notwithstanding recent progress, acute myeloid leukemia (AML) remains an incurable disease, particularly in patients (pts) with relapsing/refractory disorder or ineligible for intensive induction therapy (unfit pts). Consistent with its decreased affinity for CD3, MGD024 demonstrated reduced in vitro potency in killing CD123-positive target cells compared to flotetuzumab or RES234M1.1, but proportionally greater reduction in cytokine release. MGD024, however, achieved maximal cytolytic activity as flotetuzumab or RES234M1.1, albeit at increased concentrations. Similarly, MGD024 showed reduced potency in vivo against CD123-positive tumors compared to RES234M1.1; nevertheless, tumor growth reduction of the same magnitude as that observed with RES234M1.1 was attained at higher doses of MGD024 (0.5-1 mg/kg IV 2QW MGD024 vs.

P1, N=40, Recruiting, City of Hope Medical Center | Trial completion date: Nov 2022 --> Nov 2023 | Trial primary completion date: Nov 2022 --> Nov 2023

Dr. Rutella will also review the cellular constituents and signaling pathways found to impact response to bispecific antibody immunotherapy, flotetuzumab...Dr. Gill will review this work and outline its implications for other immunotherapy targets and diseases.

P2, N=25, Not yet recruiting, Stichting Hemato-Oncologie voor Volwassenen Nederland

Gemtuzumab ozogamicin, a CD33 directed antibody-drug conjugate, has provided the proof of concept for the potential efficacy of monoclonal antibody-based therapies in AML...The first-in-class anti-CD47 antibody magrolimab and anti-CD70 antibody cusatuzumab in combination with hypomethylating agent (HMA) azacitidine, in newly diagnosed AML, and flotetuzumab, a bispecific DART® (dual-affinity retargeting) antibody to CD3ε and CD123 as salvage option in relapsed/refractory AML appear promising...Ongoing research will define the choice of an appropriate complementary therapeutic agent in antibody-based combination therapy, and whether one or more than one antigen should be simultaneously targeted. Further studies will likely refine the role of antibody-based therapy in post hematopoietic cell transplant setting.

P1, N=40, Recruiting, City of Hope Medical Center

P2, N=0, Withdrawn, City of Hope Medical Center | N=52 --> 0 | Trial completion date: Dec 2021 --> Oct 2020 | Not yet recruiting --> Withdrawn | Trial primary completion date: Dec 2021 --> Oct 2020

T-cell immunotherapies represent a promising treatment approach for AML patients relapsing after allo-HCT and may lead to enhanced immune recognition in the 30-50% of patients who relapse after allo-HCT. Based on these results, a clinical trial treating patients relapsing after allo-HCT with FLZ is planned.

Patients with TP53 abnormalities who achieved a complete response experienced prolonged survival (median, 10.3 months; range, 3.3-21.3 months). These results encourage further study of flotetuzumab immunotherapy in patients with TP53-mutated AML.

P1/2, N=330, Recruiting, MacroGenics | N=179 --> 330 | Trial completion date: Apr 2021 --> Jan 2022 | Trial primary completion date: Dec 2020 --> Jan 2022

We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART® antibody-based molecule to CD3ε and CD123...Stepwise dosing during week 1, pre-treatment dexamethasone, prompt use of tocilizumab and temporary dose reductions/interruptions successfully prevented severe IRR/CRS, resulting in acceptable tolerability...Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER AML patients. Trial registration number: NCT02152956.

There are currently 31 ongoing clinical trials examining the utility of CD123-based targeted therapies. Here we focus our review on current efforts to target CD123 in acute leukemia through various therapeutic constructs.

P1/2, N=179, Recruiting, MacroGenics | Trial completion date: Apr 2020 --> Apr 2021 | Trial primary completion date: Jan 2020 --> Dec 2020

This study provides evidence for a correlation between IFN-γ-dominant immune subtypes of AML and TP53 abnormalities. The ORR seen in this patient subgroup encourages further study of this immunotherapeutic approach.