Durvalumab (PD-L1 Inhibitor)

Proposed Mechanism of Action

Durvalumab is an engineered human monoclonal antibody of the immunoglobulin G1 kappa subclass.1-3 In vitro studies have demonstrated that durvalumab inhibits binding of programmed death-ligand 1 (PD-L1) to programmed death-1 (PD-1) and CD80.3 Expression of PD-L1 is one mechanism through which tumor cells can evade the immune system response.4 PD-L1 activates its receptor, PD-1, which inhibits activity of T cells.4 Preclinical studies have shown that blocking the PD-1/PD-L1 pathway increases immune activation, anti-tumor immune functions, and may help restore T cell function.5-7

Durvalumab is under clinical development as an investigational product for the treatment of hematological malignancies.

Durvalumab Hypothesized Mechanism of Action

PD-1, programmed death-1; PD-L1, programmed death-ligand 1; IFNγ, interferon gamma; TNFα, tumor necrosis factor alpha; IL-2, interleukin-2; TCR-MHC, tumor cell receptor- major histocompatibility complex. IMiD® is a registered trademark of Celgene Corporation.

Rationale for Clinical Development: Durvalumab + an IMiD® Agent

NK cell, natural killer cell; PD-1, programmed death-1; PD-L1, programmed death-ligand 1. IMiD® is a registered trademark of Celgene Corporation.

Rationale for Clinical Development: Durvalumab + a Hypomethylating Agent

PD-1, programmed death-1; PD-L1, programmed death-ligand 1.

Durvalumab by Disease State

Durvalumab in Acute Myeloid Leukemia

  • Phase 2 Acute Myeloid Leukemia

Rationale for Clinical Development

Compared with healthy volunteers, patients with acute myeloid leukemia (AML) have higher expression of PD-L1.8 Experiments using mouse models of AML have shown that mice lacking PD-1 demonstrated a lower frequency of leukemia cells compared with controls.9 PD-L1 blockade also resulted in the mitigation of decreased CD8+ T-cell proliferation and interferon gamma production observed in a mouse model of the graft-vs-leukemia effect.10 In addition, higher levels of regulatory T cells (Tregs) have been associated with poorer prognosis in patients with AML,11 and blockade of PD-L1 has demonstrated the potential to decrease transforming growth factor beta (TGF-β)–induced Treg generation in vitro.12

Durvalumab in Chronic Lymphocytic Leukemia

  • Phase 1 Chronic Lymphocytic Leukemia
  • View Trials Investigating Durvalumab in Chronic Lymphocytic Leukemia.

    Durvalumab in CLL

Rationale for Clinical Development

Both PD-1 and PD-L1 are upregulated in immune cells of patients with CLL.13-15 Flow cytometry experiments have shown that the expression of PD-L1 on B cells13,14 and PD-1 on CD4+ and CD8+ T cells15 is increased relative to controls. Additionally, stimulated T cells from patients with CLL exhibit greater PD-1 expression than stimulated T cells from healthy controls.15

Durvalumab in Lymphoma

  • Phase 1 Lymphoma Non-Hodgkin lymphoma (NHL)

Rationale for Clinical Development

PD-1 and/or PD-L1 are upregulated in non–Hodgkin lymphomas (NHL), including anaplastic large-cell lymphomas (ALCL), diffuse large B-cell lymphomas (DLBCL), and follicular lymphomas (FL).16-18 Anti–PDL1 increases proliferation of T cells cultured with ALCL cells,12 supporting the utility of PD-1–PD-L1 blockade in stimulating the immune system in NHL. Tissue microarray immunostainings showed greater expression of PD-1 in FL and DLBCL biopsies as compared with control samples. In the same experiment, expression of PD-L1 was significantly greater in DLBCL biopsies compared with control samples.18 Furthermore, anti–PD-L1 has been shown to increase proliferation of T cells cultured with ALCL cells and to increase cytotoxic T-cell responses (degranulation) and decrease tumor cell growth in a T cell–ALCL cell coculture.12

Durvalumab in Multiple Myeloma

  • Phase 1 Multiple Myeloma Relapsed/refractory, Newly diagnosed

Rationale for Clinical Development

PD-1 and/or PD-L1 are upregulated in malignant cells and T cells in patients with multiple myeloma (MM).19,20 More specifically, PD-1 expression on MM cells has been shown to be significantly higher than on bone marrow plasma cells, and PD-L1 expression on patient T cells is significantly higher than on normal donor cells.19 Additionally, stimulated T cells from patients with myeloma express higher levels of PD-1 than T cells from healthy controls.20 Patients with MM also have demonstrated elevated serum soluble PD-L1 (sPD-L1), which is predictive of shorter progression-free survival.21 In vitro experiments have demonstrated that anti–PD-L1 led to a decrease in viable MM cells in the presence of CD8+ T cells or natural killer cells isolated from patients.19

Durvalumab in Myelodysplastic Syndromes

  • Phase 2 Myelodysplastic Syndromes Post HMA failure
  • View Trials Investigating Durvalumab in Myelodysplastic Syndromes.

    Durvalumab in MDS

Rationale for Clinical Development

When compared with healthy volunteers, patients with myelodysplastic syndromes (MDS) have higher expression of PD-L1.8 In vitro experiments have demonstrated that PD-1–PD-L1 blockade may decrease apoptosis and increases proliferation of T cells in the presence of MDS cells.22 In addition, increased numbers of Tregs in patients with MDS are associated with less effective anti-tumor T-cell responses and are a poor prognostic indicator; however, in vitro experiments suggest that blockade of PD-L1 may decrease TFG-beta induced Treg generation.23

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.

Durvalumab is owned by Medimmune Inc., a member of the AstraZeneca Group. Celgene entered into a partnering agreement with Medimmune to lead the development of this compound in hematological malignancies while Medimmune is leading the development of durvalumab in solid tumor indications.

References

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  21. Wang L, et al. Oncotarget. 2015;6:41228-41236.
  22. Kondo A, et al. Blood. 2010;116:1124-1131.
  23. Kordasti SY, et al. Blood. 2007;110:847-850.