Immunotherapy in adult acute leukemia

Blum, Sabine; Martins, Filipe; Lübbert, Michael

doi:10.1016/j.leukres.2017.06.011

Cited by 15 publications

(8 citation statements)

References 107 publications

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“…A number of targeted immunotherapies have been developed to meet this urgent medical need for novel treatments for adults with R/R ALL, including bispecific T‐cell engager (BiTE) molecules, antibody‐drug conjugates and chimeric antigen receptor T cells (CART) . Blinatumomab is a BiTE immuno‐oncology therapy with dual specificity for CD19 and CD3 .…”

Section: Introductionmentioning

confidence: 99%

Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia

Kiyoi

Morris

et al. 2020

Cancer Science

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Adult patients with relapsed/refractory (R/R) B-precursor acute lymphoblastic leukemia (ALL) have a poor prognosis. Blinatumomab is a bispecific T-cell engager (BiTE) immuno-oncology therapy with dual specificity for CD19 and CD3 that redirects patients' CD3-positive cytotoxic T cells to lyse malignant and normal B cells. We conducted an open-label, phase 1b/2 study to determine the safety, pharmacokinetics, efficacy and recommended dose of blinatumomab in Japanese adults with R/R B-precursor ALL. Patients received 9 μg/day blinatumomab during week 1 and 28 μg/ day during weeks 2-4, with a 2-week treatment-free interval (6-week cycle); patients received 28 μg/day blinatumomab in subsequent cycles. Primary endpoints were the incidence of dose-limiting toxicities (DLT) in phase 1b and complete remission (CR)/ CR with partial hematologic recovery (CRh) within the first two cycles in phase 2. A total of 26 patients enrolled and 25 (96%) reported grade ≥3 adverse events (mostly cytopenias). There were no DLT. CR/CRh within two cycles was achieved by 4 of 5 patients (80%) in phase 1b and 8 of 21 patients (38%) in phase 2. Among patients with evaluable minimal residual disease, 4 (100%) in phase 1b and 3 (38%) in phase 2 had a complete MRD response. Median RFS for 8 patients who achieved CR/CRh in phase 2 was 5 (95% CI: 3.5-6.4) months; median OS was not estimable. There were no significant associations between maximum cytokine levels or percentage of specific cell types during cycle 1 and response. Consistent with global studies, blinatumomab appeared to be safe and efficacious in Japanese adults with R/R ALL. K E Y W O R D S acute lymphoblastic leukemia, blinatumomab, clinical study, Japan, phase 1b, refractory, relapsed | 1315 KIYOI et al.

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Section: Introductionmentioning

confidence: 99%

Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia

Kiyoi

Morris

et al. 2020

Cancer Science

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“…Checkpoint inhibitors and chimeric antigen receptor T cell therapies show promising results for melanomas, lung cancers and acute leukemias but not for breast cancer 3,9,21,69 . Oncogenic mechanisms such as CCR2 may prevent effectiveness of immunotherapies in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

CCR2 signaling in breast carcinoma cells promotes tumor growth and invasion by promoting CCL2 and suppressing CD154 effects on the angiogenic and immune microenvironments

et al. 2019

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Breast cancer is the second leading cause of cancer related deaths for women, due mainly to metastatic disease. Invasive tumors exhibit aberrations in recruitment and activity of immune cells, including decreased cytotoxic T cells. Restoring the levels and activity of cytotoxic T cells is a promising anti-cancer strategy; but its success is tumor type-dependent. The mechanisms that coordinate recruitment and activity of immune cells and other stromal cells in breast cancer remain poorly understood. Using the MMTV-PyVmT/FVB mammary tumor model, we demonstrate a novel role for CCL2/CCR2 chemokine signaling in tumor progression by altering the microenvironment. Selective targeting of CCR2 in the PyVmT mammary epithelium inhibited tumor growth and invasion, elevated CD8+ T cells, decreased M2 macrophages and decreased angiogenesis. Co-culture models demonstrated these stromal cell responses were mediated by tumor derived CCL2 and CCR2-mediated suppression of the T cell activating cytokine, CD154. Co-culture analysis indicated that CCR2-induced stromal reactivity was important for tumor cell proliferation and invasion. In breast tumor tissues, CD154 expression inversely correlated with CCR2 expression and correlated with relapse free survival. Targeting the CCL2/CCR2 signaling pathway may reprogram the immune angiogenic and microenvironments and enhance effectiveness of targeted and immuno-therapies.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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“…Immune checkpoint blockade (ICB) is reshaping the treatment paradigm of solid tumors (1) and hematologic cancers, such as Hodgkin lymphoma (2). Furthermore, CD19-directed chimeric antigen receptor (CAR)-T cells and the bispecific T cell engager (BiTE R ) blinatumomab have produced spectacular remissions in acute lymphoblastic leukemia and diffuse large B cell lymphoma (3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

B7-Positive and B7-Negative Acute Myeloid Leukemias Display Distinct T Cell Maturation Profiles, Immune Checkpoint Receptor Expression, and European Leukemia Net Risk Profiles

et al. 2020

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Immunotherapy in adult acute leukemia

Cited by 15 publications

References 107 publications

Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia

Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia

CCR2 signaling in breast carcinoma cells promotes tumor growth and invasion by promoting CCL2 and suppressing CD154 effects on the angiogenic and immune microenvironments

B7-Positive and B7-Negative Acute Myeloid Leukemias Display Distinct T Cell Maturation Profiles, Immune Checkpoint Receptor Expression, and European Leukemia Net Risk Profiles

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