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Using cusatuzumab to target CD70 has shown to eliminate acute myeloid leukemia stem cells in humans

Jan 20, 2020

Acute myeloid leukemia (AML) is a heterogenous malignancy originating from transformed leukemic stem cells (LSCs). LSCs play a vital role in initiating and sustaining AML as a result of their self-renewal ability, persistence, and resistance to chemotherapy. In addition, LSCs are believed to be the cause of relapsed AML, and their presence after treatment is seen as a negative prognostic factor for patient overall outcome.

Treatment with hypomethylating agents (HMAs) is insufficient at eliminating the disease-initiating LSCs. These cells have been previously demonstrated to express the surface markers CD70 and CD27, which represent a tumor necrosis factor ligand–receptor pair inducing cell-autonomous signaling in LSCs to propagate growth. Therefore, Adrian Ochsenbein, Bern University Hospital, University of Bern, CH, sought to evaluate if treatment with HMAs can be improved by the addition of the anti-CD70 monoclonal antibody, cusatuzumab, in an open-label, non-randomized phase I/II study. Data were presented during the 61 stAmerican Society of Hematology Annual  Meeting & Exposition. 1

Pre-clinical data

  • High levels of CD27 in patients with AML significantly correlate with a poor prognosis (p < 0.001), independent of other risk factors
  • Data from mouse models demonstrate that cusatuzumab has a dual mode of action, in vivo, by i) blocking CD70–CD27 signaling and blocking the release of soluble CD27 ii) killing cells via Fc-dependent, complement-dependent cytotoxicity and enhancing antibody-dependent cellular cytotoxicity (ADCC)
  • In vitrodata has shown αCD70 (a Fc-diminished blocking version of cusatuzumab without ADCC potential) in combination with HMA treatment can eliminate patient derived LSCs, whilst leaving healthy non-hematopoietic stem cells
  • Xenograft models show cusatuzumab is more effective in eliminating AML LSCs than blockade of CD70/CD27 signaling alone, particularly when natural killer cells are added
  • In vitrodata confirms that when exposed to HMAs, LSCs can upregulate CD70, and the combination of HMA and cusatuzumab can act synergistically to reduce the number of LSCs

Method

Dosing schedule:

Twelve patients have been enrolled and received one infusion with cusatuzumab, ranging from 1–20 mg/kg, followed after 14 days with two 28-day cycles of subcutaneous azacitidine (75 mg/m 2) from Day 1–7 and biweekly cusatuzumab, starting at Day three of each cycle.

Inclusion criteria:

  • Newly diagnosed AML
  • Not eligible for intensive chemotherapy
  • No prior chemotherapy

Endpoints:

  • Primary endpoint was safety and tolerability
  • Main secondary endpoints were efficacy, pharmacokinetics, and effect on LSCs

Phase II dose expansion using 10 mg/kg of cusatuzumab is currently ongoing.

For further details on dosing and patient characteristics see Table 1.

Table 1.Baseline characteristics and dosing schedule
*As per ELN 2017
Escalation phase – cusatuzumab dose
    1 mg/kg
(N= 3)
3 mg/kg
(N= 3)
10 mg/kg
(N= 3)
20 mg/kg
(N= 3)
Total
(N= 12)
Expansion phase 10 mg/kg
(N= 26)
Age (years) Median (range) 7775–81 7171–84 7464–75 7672–77 7564–84 75.559–90
Gender Male/female 2/1 1/2 2/1 2/1 7/5 12/14
Risk categories*

Favorable

Intermediate

Adverse

0

2

1

1

1

1

0

2

1

1

0

2

2

5

5

2

4

20

Results

Safety

For further details on patient safety see Table 2.

Table 2.Most frequent grade 3 or higher treatment-emergent adverse events
GI, gastrointestinal
Escalation phase – cusatuzumab dose

1 mg/kg

(N= 3)

3 mg/kg
(N= 3)

10 mg/kg

(N= 3)

20 mg/kg
(N= 3)
Total
(N= 12)
Anemia 1 3 1 0 5
Febrile neutropenia 2 0 1 2 5
Leukopenia 0 0 1 0 1
Neutropenia 0 0 1 2 3
Thrombocytopenia 0 0 1 0 1
Cardiac disorders 1 0 0 1 2
GI disorders 0 1 0 1 2
Infections and infestations 1 2 0 3 6
Laboratory abnormalities 3 3 0 1 7
  • One patient receiving a 3 mg/kg dose experienced an adverse event that led to discontinuation
  • No dose-limiting toxicities were observed in the phase I portion of the study

Efficacy

  • The overall response was promising as 100% of patients achieved a response, with 67% (8/12) of patients achieving complete response (CR), 17% (2/12) achieving CR with incomplete hematological recovery (CRi), and 17% (2/12) achieving a partial response (PR)
  • The average blast reduction of cusatuzumab monotherapy was 30% and at the time of best response, the blast reduction was 95% on average. Three patients responded to cusatuzumab treatment after one infusion with a significant blast reduction in the bone marrow
  • The median time to response was 3.3 months
  • One patient on dose level one (1 mg/kg) achieved CR and received subsequent allogeneic transplantation. Six patients were still receiving cusatuzumab treatment at the time of data cut-off in February 2019
  • Measurable residual disease (MRD) assessment was performed by flow cytometry in nine patients (threshold of <10 -3):
    • 44% of patients reached MRD negativity
    • 56% of patients were MRD-positive
  • The frequency of LSCs were analyzed in seven of the 12 patients enrolled in the phase I portion of the study, demonstrating a 75% reduction in LSC frequency in patients that received cusatuzumab treatment  
  • Single-cell RNA sequencing was performed in two patients and revealed that cusatuzumab monotherapy is capable of altering pathways that are related to apoptosis of LSCs and myeloid differentiation

Conclusion

The authors demonstrated promising safety and efficacy data using cusatuzumab in combination with azacitidine in patients with newly diagnosed AML. Cusatuzumab monotherapy was able to reduce AML blasts and LSC frequency after one infusion. Currently, the phase II trial, AML2001 CULMINATE, is actively recruiting ( NCT04023526) and the phase Ib study ( NCT04150887) aims to continue with preclinical and translational data generation to inform novel and rational cusatuzumab combinations for future studies.

  1. Ochsenbein A et al.,Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in humans. 2019 Dec 7. Oral Abstract #234. 61st ASH Annual Meeting & Exposition, Orlando, US