Trial in progress: phase I study of non-viral gene-modified CAR-T cell therapy for malignant solid tumors expressing EPHB4 receptor (CARTiEr).

Background: Ephrin type-B receptor 4 (EPHB4) is overexpressed on the surface of various tumor cells, including cells from malignant bone and soft-tissue tumors. AP8901 CAR-T cell therapy can specifically recognize and kill EPHB4 receptor-expressing malignant tumor cells by modifying the natural EPHB4 receptor ligand, ephrin B2. AP8901 is being developed via genetic manipulation involving the "piggyBac transposon" and "genetically modified feeder cell" methods, which enables the stable expression of CAR proteins in T cells and prevents T cell exhaustion.

Subcutaneous blinatumomab in adults with relapsed or refractory B-cell acute lymphoblastic leukaemia: post-hoc safety and activity analysis from a multicentre, single-arm, phase 1/2 trial.

Background: Two doses of subcutaneous blinatumomab in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia were identified as preliminary recommended phase 2 doses, based on the dose-escalation phase of this multicentre single-arm, phase 1/2 trial. Here, we aim to further study the safety, activity, and pharmacokinetics of these doses in all participants who have received them, including those treated in the completed phase 1b expansion part of the study.

Methods: We did a post-hoc analysis of data from patients enrolled in the dose-escalation and dose-expansion phases and in the pharmacokinetic evaluation cohort of this multicentre, single-arm, phase 1/2 study.

Efficacy and safety of epcoritamab in Japanese patients with relapsed or refractory diffuse large B-cell lymphoma: 3-year follow-up from the EPCORE NHL-3 trial.

Background: Primary results from the EPCORE NHL-3 trial (NCT04542824) showed deep, durable responses in Japanese patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) treated with single-agent epcoritamab, a subcutaneous CD3xCD20 bispecific antibody. Here, we report 3-year follow-up of safety and efficacy.

Methods: Japanese patients with R/R CD20 DLBCL and  ≥ 2 prior systemic therapies received epcoritamab (0.

[Campylobacter lari bacteremia during treatment of pure red cell aplasia following major ABO-mismatched hematopoietic stem cell transplantation].

Campylobacter lari is a rare cause of bacteremia in Campylobacter spp. Clinical course and symptoms vary by report, and no standard approaches to antimicrobial selection and duration of treatment have been established. A 68-year-old man who underwent haploidentical hematopoietic stem cell transplantation (HSCT) from a major ABO-incompatible donor with post-transplant cyclophosphamide for myelodysplastic syndromes developed pure red cell anemia and post-transfusion iron overload.

Phase 1 study of talquetamab, a humanized GPRC5D x CD3 bispecific antibody, in Japanese patients with relapsed/refractory MM.

The bispecific antibody talquetamab demonstrated substantial responses in heavily pretreated relapsed or refractory multiple myeloma (RRMM) in the global phase 1/2 MonumenTAL-1 study. This study, evaluated the safety and efficacy of talquetamab in Japanese patients with RRMM pretreated with a proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody. The primary endpoints were frequency and type of treatment-emergent adverse events (TEAEs) and serious AEs including dose-limiting toxicity (DLT).

Treatment selection and influencing factors for chronic lymphocytic leukemia: a physician survey in Japan.

Background: Chronic lymphocytic leukemia (CLL) is a rare form of lymphoma in Japan. This study aimed to explore hematologists' motivations and considerations in making treatment decisions for CLL.

Methods: Responses from hematologists treating CLL, obtained through an online survey, were descriptively analyzed.

[Development and prospects of bispecific antibodies for multiple myeloma].

Patients with triple-class refractory multiple myeloma once had a poor prognosis, but recently developed bispecific antibodies (bsAbs) targeting B-cell maturation antigen (BCMA), G protein-coupled receptor 5D (GPRC5D), and Fc receptor-homolog 5 (FcRH5) have shown significant clinical activity in these patients. However, responses to bsAbs are not universal, and resistance often develops during therapy. Mechanisms that mediate resistance may be tumor-intrinsic or immune-dependent.

Current status of BAFF targeting immunotherapy in B-cell neoplasm.

B-cell activating factor belonging to the TNF family (BAFF), also known as B-lymphocyte stimulator (BLyS), plays a crucial role in B-cell development. It has multiple receptors, including BCMA, TACI, and BAFF-R, with diverse roles in different cell types. BAFF induces B-cell proliferation and immunoglobulin secretion, and acts as a survival factor for immature, naive, and activated B cells.

First-in-human clinical trial results with ABBV-184, a first-in-class T-cell receptor/anti-CD3 bispecific protein, in adults with previously treated AML or NSCLC.

Background: ABBV-184, a novel survivin peptide-targeting T-cell receptor (TCR)/anti-CD3 bispecific protein, demonstrated preclinical T-cell activation and cytotoxicity toward HLA-A2:01-positive tumor lines. This first-in-human trial evaluated ABBV-184 monotherapy in patients with acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC).

Research Design And Methods: This phase 1 multicenter, open-label, dose escalation trial (NCT04272203) enrolled adult patients with relapsed/refractory AML or NSCLC with an HLA-A2:01 restricted genotype.

Bridging horizons beyond CIRCULATE-Japan: a new paradigm in molecular residual disease detection via whole genome sequencing-based circulating tumor DNA assay.

Circulating tumor DNA (ctDNA) is the fraction of cell-free DNA in patient blood that originates from a tumor. Advances in DNA sequencing technologies and our understanding of the molecular biology of tumors have increased interest in exploiting ctDNA to facilitate detection of molecular residual disease (MRD). Analysis of ctDNA as a promising MRD biomarker of solid malignancies has a central role in precision medicine initiatives exemplified by our CIRCULATE-Japan project involving patients with resectable colorectal cancer.

Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients.

Background: MCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902).

Methods: Binding of ABBV-467 to human MCL-1 was assessed in multiple cell lines.

Activity of eftozanermin alfa plus venetoclax in preclinical models and patients with acute myeloid leukemia.

Activation of apoptosis in malignant cells is an established strategy for controlling cancer and is potentially curative. To assess the impact of concurrently inducing the extrinsic and intrinsic apoptosis-signaling pathways in acute myeloid leukemia (AML), we evaluated activity of the TRAIL receptor agonistic fusion protein eftozanermin alfa (eftoza; ABBV-621) in combination with the B-cell lymphoma protein-2 selective inhibitor venetoclax in preclinical models and human patients. Simultaneously stimulating intrinsic and extrinsic apoptosis-signaling pathways with venetoclax and eftoza, respectively, enhanced their activities in AML cell lines and patient-derived ex vivo/in vivo models.

BATF epigenetically and transcriptionally controls the activation program of regulatory T cells in human tumors.

Regulatory T (T) cells suppress effective antitumor immunity in tumor-bearing hosts, thereby becoming promising targets in cancer immunotherapy. Despite the importance of T cells in tumor immunity, little is known about their differentiation process and epigenetic profiles in the tumor microenvironment (TME). Here, we showed that T cells in the TME of human lung cancers harbored a completely different open chromatin profile compared with CD8 T cells, conventional CD4 T cells in the TME, and peripheral T cells.

Asciminib vs bosutinib in CML patients pretreated with ≥2 tyrosine kinase inhibitors: Results from the Japanese subgroup analysis of ASCEMBL study.

Asciminib, a first-in-class, allosteric inhibitor of BCR-ABL1 that acts by STAMP (Specifically Targeting the ABL Myristoyl Pocket), is a novel therapeutic option for patients with chronic myeloid leukemia (CML). In the global, phase 3, open-label ASCEMBL study in patients with CML in chronic phase (CML-CP) pretreated with ≥2 tyrosine kinase inhibitors (TKIs) (NCT03106779), asciminib (40 mg twice-daily) demonstrated significant superiority over the ATP-competitive TKI bosutinib (500 mg once daily) for the primary endpoint of major molecular response (MMR; BCR::ABL1 transcript levels on the international scale [BCR::ABL1 ] ≤0.1%) at week 24.

[Tyrosine kinase inhibitors induce production of BCR-ABL splicing variants via inhibition of RNA polymerase II on genomic BCR-ABL and cause unachieved deep molecular response and fluctuating minimal residual disease].

Deep sequence analysis for BCR-ABL revealed that native BCR-ABL decreased slowly after an exponential decrease within three months of tyrosine kinase inhibitor (TKI) treatment. BCR-ABL was present at diagnosis and increased to account for 15-30% of total BCR-ABL when IS BCR-ABL was reduced to 1%. Native BCR-ABL and BCR-ABL correspond to early relapse and fluctuating minimal residue disease, respectively, in the STOP-TKI trial.

Molecular Classification and Overcoming Therapy Resistance for Acute Myeloid Leukemia with Adverse Genetic Factors.

The European LeukemiaNet (ELN) criteria define the adverse genetic factors of acute myeloid leukemia (AML). AML with adverse genetic factors uniformly shows resistance to standard chemotherapy and is associated with poor prognosis. Here, we focus on the biological background and real-world etiology of these adverse genetic factors and then describe a strategy to overcome the clinical disadvantages in terms of targeting pivotal molecular mechanisms.

Incidence of refractory cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation.

Post-transplant cytomegalovirus (CMV) disease can be almost completely avoided by current infection control procedures. However, CMV reactivation occurs in more than half of patients, and some patients can develop clinically resistant CMV infections. Whether resistance is due to the host's immune status or a viral resistance mutation is challenging to confirm.

Brentuximab vedotin maintenance after autologous stem cell transplantation for refractory gray zone lymphoma with long-term remission.

Gray zone lymphoma (GZL) is a rare type of B-cell lymphoma characterized by features of both diffuse large B-cell lymphoma and classical Hodgkin lymphoma (cHL). The prognosis of GZL is poorer than that of cHL and mediastinal large B-cell lymphoma. However, an optimal treatment strategy for relapsed/refractory (R/R) GZL has not been established in the clinical setting.