Pre-treatment CD38-positive regulatory T cells affect the durable response to daratumumab in relapsed/refractory multiple myeloma patients

Kitadate, Akihiro; Kobayashi, Hiroki; Abe, Yoshiaki; Narita, Kentaro; Miura, Daisuke; Takeuchi, Masami; Matsue, Kosei

doi:10.3324/haematol.2019.219683

Cited by 34 publications

(37 citation statements)

References 14 publications

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“…3,4 Daratumumab directly kills myeloma cells shortly after its infusion through a variety of mechanisms, including complement-mediated cytotoxicity, antibody-dependent cytotoxicity and antibodydependent phagocytosis. 5,8 Our observations support the use of daratumumab as a first-line treatment for patients with CN.…”

supporting

confidence: 64%

Safety and efficacy of daratumumab in patients with multiple myeloma and severe renal failure

et al. 2021

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supporting

confidence: 64%

Safety and efficacy of daratumumab in patients with multiple myeloma and severe renal failure

et al. 2021

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“…Interleukin 10 (IL-10) and Tregs mitigate effector T-cell activation, function, and proliferation, thus affecting immunosuppression in MM 4,8,57,59,60 ; Tregs also promote MM tumor progression in vivo. 59 AMG 701 increased the percentage of IL-10 1 T cells in patient samples (n 5 3) in a dose-and time-dependent manner.…”

Section: Cd62lmentioning

confidence: 99%

“…1,2 Specifically, monoclonal antibodies targeting CD38 (daratumumab, isatuximab) or SLAMF7 (elotuzumab) induce significant immune effector cell-mediated killing of MM cells, and can partially restore function of immune effector cells including T and natural killer (NK) cells. [2][3][4][5][6][7][8] However, relapse of disease is common and patients with relapsed or refractory MM (RRMM) have a poor prognosis. 9 An increased number of prior lines of anti-MM treatments is associated with increased evolution, survival, and proliferation of drug-resistant clones, ultimately leading to drugresistant minimal residual disease (MRD), clinical relapse, and treatment failure.…”

Section: Introductionmentioning

confidence: 99%

The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models

et al. 2020

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We investigated here the novel immunomodulation and anti–multiple myeloma (MM) function of T cells engaged by the bispecific T-cell engager molecule AMG 701, and further examined the impact of AMG 701 in combination with immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide). AMG 701 potently induced T-cell–dependent cellular cytotoxicity (TDCC) against MM cells expressing B-cell maturation antigen, including autologous cells from patients with relapsed and refractory MM (RRMM) (half maximal effective concentration, <46.6 pM). Besides inducing T-cell proliferation and cytolytic activity, AMG 701 also promoted differentiation of patient T cells to central memory, effector memory, and stem cell–like memory (scm) phenotypes, more so in CD8 vs CD4 T subsets, resulting in increased CD8/CD4 ratios in 7-day ex vivo cocultures. IMiDs and AMG 701 synergistically induced TDCC against MM cell lines and autologous RRMM patient cells, even in the presence of immunosuppressive bone marrow stromal cells or osteoclasts. IMiDs further upregulated AMG 701–induced patient T-cell differentiation toward memory phenotypes, associated with increased CD8/CD4 ratios, increased Tscm, and decreased interleukin 10–positive T and T regulatory cells (CD25highFOXP3high), which may downregulate T effector cells. Importantly, the combination of AMG 701 with lenalidomide induced sustained inhibition of MM cell growth in SCID mice reconstituted with human T cells; tumor regrowth was eventually observed in cohorts treated with either agent alone (P < .001). These results strongly support AMG 701 clinical studies as monotherapy in patients with RRMM (NCT03287908) and the combination with IMiDs to improve patient outcomes in MM.

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“…Furthermore, the percentage of responders who had long-term deep responses with sustained ≥12-month MRD negativity (10 -5 ) was 13% in those who received DARA combined with Rd, but the percentage was smaller in those receiving other regimens, i.e., only 0.4% with Rd, 3% with DARA plus bortezomib/dexamethasone (Vd), and 0% with Vd [30]. That evidence of the immune effects of DARA was supported by a report by Kitadate et al, which showed that the absolute number of Tregs in peripheral blood was significantly higher in responders to DARA-based treatment compared with non-responders [31]. The antibody elotuzumab, a humanized IgG1 kappa immunostimulatory monoclonal antibody targeting SLAMF7 (also referred to as CS1 or CD319), in combination with lenalidomide or pomalidomide is used for the treatment of RRMM patients in clinical practice [32].…”

Section: Imid-intensified Antibody Treatmentmentioning

confidence: 87%

Immunotherapy for Multiple Myeloma

Tamura

Ishibashi

Sunakawa

et al. 2019

Cancers

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Despite therapeutic advances over the past decades, multiple myeloma (MM) remains a largely incurable disease with poor prognosis in high-risk patients, and thus new treatment strategies are needed to achieve treatment breakthroughs. MM represents various forms of impaired immune surveillance characterized by not only disrupted antibody production but also immune dysfunction of T, natural killer cells, and dendritic cells, although immunotherapeutic interventions such as allogeneic stem-cell transplantation and dendritic cell-based tumor vaccines were reported to prolong survival in limited populations of MM patients. Recently, epoch-making immunotherapies, i.e., immunomodulatory drug-intensified monoclonal antibodies, such as daratumumab combined with lenalidomide and chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen, have been developed, and was shown to improve prognosis even in advanced-stage MM patients. Clinical trials using other antibody-based treatments, such as antibody drug-conjugate and bispecific antigen-directed CD3 T-cell engager targeting, are ongoing. The manipulation of anergic T-cells by checkpoint inhibitors, including an anti-T-cell immunoglobulin and ITIM domains (TIGIT) antibody, also has the potential to prolong survival times. Those new treatments or their combination will improve prognosis and possibly point toward a cure for MM.

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Pre-treatment CD38-positive regulatory T cells affect the durable response to daratumumab in relapsed/refractory multiple myeloma patients

Cited by 34 publications

References 14 publications

Safety and efficacy of daratumumab in patients with multiple myeloma and severe renal failure

Safety and efficacy of daratumumab in patients with multiple myeloma and severe renal failure

The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models

Immunotherapy for Multiple Myeloma

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