Targeting B-Cell Receptor Signaling in Leukemia and Lymphoma: How and Why?

Allen, John C.; Talab, Fatima; Slupsky, Joseph R.

doi:10.2217/ijh-2016-0003

Cited by 8 publications

(14 citation statements)

References 219 publications

(242 reference statements)

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“…Signal transmission upon BCR crosslinking follows a molecular scheme similar to TCR triggering where the Src family kinase Lyn phosphorylates the ITAMs within CD79a and CD79b. This results in the recruitment and activation of the Syk family kinase Syk to the BCR, an event which is necessary for the assembly of a signalosome including the adaptor molecules BLNK and Grb2, the Tec family kinase Bkt and the Rho family GEF Vav, which is essential for the activation of PLCγ2 and the activation of more downstream signaling such as Akt, NF-kB and mitogen-activated protein kinases (MAPKs) [84]. Few studies have investigated the role of Lck in BCR signaling in detail.…”

Section: Expression and Function Of Lck In Leukemic Cellsmentioning

confidence: 99%

Beyond TCR Signaling: Emerging Functions of Lck in Cancer and Immunotherapy

Bommhardt

Schraven

Simeoni

2019

IJMS

111

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In recent years, the lymphocyte-specific protein tyrosine kinase (Lck) has emerged as one of the key molecules regulating T-cell functions. Studies using Lck knock-out mice or Lck-deficient T-cell lines have shown that Lck regulates the initiation of TCR signaling, T-cell development, and T-cell homeostasis. Because of the crucial role of Lck in T-cell responses, strategies have been employed to redirect Lck activity to improve the efficacy of chimeric antigen receptors (CARs) and to potentiate T-cell responses in cancer immunotherapy. In addition to the well-studied role of Lck in T cells, evidence has been accumulated suggesting that Lck is also expressed in the brain and in tumor cells, where it actively takes part in signaling processes regulating cellular functions like proliferation, survival and memory. Therefore, Lck has emerged as a novel druggable target molecule for the treatment of cancer and neuronal diseases. In this review, we will focus on these new functions of Lck.

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Section: Expression and Function Of Lck In Leukemic Cellsmentioning

confidence: 99%

Beyond TCR Signaling: Emerging Functions of Lck in Cancer and Immunotherapy

Bommhardt

Schraven

Simeoni

2019

IJMS

111

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“…The B-cell receptor signaling pathway is a key driver of pathogenesis in human B-cell malignancies [9,10]. Constitutive signaling through B-cell receptors leads to activation of Class I phosphoinositide 3-kinase (PI3K) and other downstream signaling pathways [10,11].…”

Section: Introductionmentioning

confidence: 99%

Phase 2 study of parsaclisib (INCB050465), a highly selective, next-generation PI3Kδ inhibitor, in relapsed or refractory diffuse large B-cell lymphoma (CITADEL-202)

Coleman

Belada

Casasnovas

et al. 2020

Leukemia & Lymphoma

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Parsaclisib, a potent, highly selective, next-generation PI3Kd inhibitor, was evaluated as monotherapy in CITADEL-202 (NCT02998476), an open-label, multicenter, phase 2 study in patients with relapsed or refractory diffuse large B-cell lymphoma. Patients enrolled into 2 groups (A, Bruton tyrosine kinase [BTK] inhibitor naïve, n ¼ 55; B, BTK inhibitor experienced, n ¼ 5) received oral parsaclisib 20 mg once daily for 8 weeks, then 20 mg once weekly while deriving benefit. The futility boundary was crossed at the interim analysis of Group A, resulting in a negative study. Parsaclisib monotherapy demonstrated an objective response rate (ORR) of 25.5% (8 complete metabolic responses/6 partial metabolic responses) and a median duration of response of 6.2 months. ORR in Group B was 20.0% (1 complete metabolic response). Parsaclisib monotherapy demonstrated manageable toxicities with no new safety signals reported. Further evaluation of parsaclisib in combination with standard therapies and active investigational agents is underway.

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“…Non‐Hodgkin lymphomas are lymphoproliferative malignancies that derive mostly from B cells (85–90%) 1 . B‐cell NHL subtypes are generally characterized by signaling pathway regulation (eg, B‐cell receptor pathway activation in DLBCL, FL, MCL, and MZL) 2‐4 . B‐cell receptor stimulation activates complex molecular pathways, including PI3K, Bruton’s tyrosine kinase, and phospholipase Cγ2, which transmit downstream signals that promote B‐cell survival and proliferation 3,4 .…”

Section: Introductionmentioning

confidence: 99%

“… 1 B‐cell NHL subtypes are generally characterized by signaling pathway regulation (eg, B‐cell receptor pathway activation in DLBCL, FL, MCL, and MZL). 2 , 3 , 4 B‐cell receptor stimulation activates complex molecular pathways, including PI3K, Bruton’s tyrosine kinase, and phospholipase Cγ2, which transmit downstream signals that promote B‐cell survival and proliferation. 3 , 4 Phosphatidylinositol 3‐kinase consists of four isoforms, α, β, δ, and γ; the α and β isoforms are expressed ubiquitously, whereas δ and γ isoform expression is predominantly restricted to hematopoietic cells.…”

Section: Introductionmentioning

confidence: 99%

Parsaclisib in Japanese patients with relapsed or refractory B‐cell lymphoma (CITADEL‐111): A phase Ib study

et al. 2022

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Parsaclisib, a potent, selective, next‐generation PI3Kδ inhibitor, has shown clinical benefit in patients with relapsed or refractory B‐cell lymphoma. We undertook a phase Ib study (CITADEL‐111) evaluating safety, pharmacokinetics, and efficacy of parsaclisib in Japanese patients with relapsed or refractory B‐cell malignancies. Patients received oral parsaclisib daily for 8 weeks then once weekly (10‐mg dose, n = 3; 20‐mg dose, n = 14). Pharmacokinetic samples were collected on days 1, 8, and 15, and efficacy was monitored according to Lugano criteria. At data cut‐off (August 14, 2020), 6 patients (35.3%) remained on study treatment and 11 (64.7%) discontinued due to progressive disease (9 [52.9%]) or adverse events (2 [11.8%]). Median duration of treatment was 8.3 (range, 0.3–24.4) months. The most commonly reported nonhematologic adverse events were constipation (6 [35.3%]), nausea, and pyrexia (each 4 [23.5%]). Five patients (29.4%) experienced treatment‐emergent new or worsening decreased neutrophils to grade 3 or 4. No treatment‐emergent worsening in aminotransferase elevations to grade 3 or 4 were observed. Ten patients (58.8%) required dose interruption and 5 (29.4%) dose reduction. Body weight–normalized parsaclisib exposure was comparable between Japanese and Western patients. Objective response rate was 100% in follicular lymphoma (9 of 9 patients, including complete response in 2 patients [22.2%]) and marginal zone lymphoma (2 of 2 patients), and 16.7% in diffuse large B‐cell lymphoma (1 of 6 patients). Results observed in Japanese patients with relapsed or refractory follicular or marginal zone lymphoma support further clinical development of parsaclisib in these patient populations.

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Targeting B-Cell Receptor Signaling in Leukemia and Lymphoma: How and Why?

Cited by 8 publications

References 219 publications

Beyond TCR Signaling: Emerging Functions of Lck in Cancer and Immunotherapy

Beyond TCR Signaling: Emerging Functions of Lck in Cancer and Immunotherapy

Phase 2 study of parsaclisib (INCB050465), a highly selective, next-generation PI3Kδ inhibitor, in relapsed or refractory diffuse large B-cell lymphoma (CITADEL-202)

Parsaclisib in Japanese patients with relapsed or refractory B‐cell lymphoma (CITADEL‐111): A phase Ib study

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