Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a curative treatment option for multiple myeloma (MM), but few patients are eligible due to its high risk of treatment-related toxicity and relapse. Here, we report the feasibility and efficacy of allo-SCT after myeloablative conditioning with 8 Gy of total body irradiation (TBI) for reducing relapse of MM. We retrospectively analyzed data from 30 consecutive patients who received allo-SCT for MM after 8 Gy of TBI at Japanese Red Cross Medical Center between 2012 and 2021. Median age at allo-SCT was 47 (range 31-61) years. Stem-cell sources were peripheral blood from an HLA-matched related donor (MRD, n=5), bone marrow from an HLA-matched unrelated donor (MUD, n=5), bone marrow from an HLA-mismatched unrelated donor (MMUD, n=13), and cord blood (n=7). All patients received conditioning with 8 Gy of TBI combined with Flu/Mel (n=28) or others (n=2). Five-year PFS and 5-year OS were 36.7% and 46.2%, respectively. Sixteen patients died during the observation period (12 of primary disease and 4 of treatment-related toxicity). Patients with VGPR or better before allo-SCT had significantly better PFS (p=0.009) and OS (p=0.01) than others. Patients who received MMUD cells tended to have better PFS than those with other cell sources. Our report showed that allo-SCT for MM after 8 Gy of TBI is feasible, and the better PFS of MMUD suggests graft-versus-myeloma effects.

Relapsed and/or refractory (R/R) primary central nervous system lymphoma (PCNSL) has a poor prognosis. A 57-year-old man diagnosed with PCNSL achieved a complete response by high-dose methotrexate-based chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT). The disease was not cured, so he was treated with the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel after the third relapse. However, the disease relapsed again 28 days after CAR T-cell therapy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was attempted as curative therapy after bridging with second ASCT and tirabrutinib monotherapy. Although a temporary response was achieved, the disease relapsed 98 days after allo-HSCT. While receiving tirabrutinib for relapse after allo-HSCT, the patient developed acute respiratory failure due to transplant-related toxicity and post-transplant thrombotic microangiopathy. He died 175 days after allo-HSCT. Although various treatments for PCNSL have been investigated in recent years, the treatment strategy for R/R PCNSL has not been established. Further studies are warranted to improve the outcomes of patients with R/R PCNSL.

A 62-year-old woman with adult T-cell leukemia/lymphoma (ATL) received umbilical cord blood transplantation (CBT) in first complete remission. However, relapse of ATL was detected on day 74 post-transplantation, as evidenced by the rapid growth of lymphoma cells in peripheral blood and an increase in soluble interleukin-2 receptor (sIL2R) levels. Discontinuation of immunosuppressant therapy alone did not improve ATL findings, but treatment with lenalidomide caused lymphoma cells to disappear from the peripheral blood and sIL2R levels to return to normal. Pancytopenia was observed as a lenalidomide-associated adverse effect, but lymphocyte counts were not reduced. The patient was judged to be in complete remission based on results of Southern blot analysis and human T-cell leukemia virus 1 (HTLV-1)-infected cell analysis using flow cytometry (HAS-Flow). Flow cytometric analysis of peripheral blood and FISH analysis of X and Y chromosomes revealed that the therapeutic effect of lenalidomide was associated with an increase in the number of donor-derived peripheral natural killer cells. ATL relapse was not observed at 13 months into lenalidomide treatment. Our results suggest that lenalidomide is an effective option for the treatment of post-transplant relapsed ATL.

Chimeric antigen receptor (CAR)-T cell therapy is among the most promising immunotherapies for hematological malignancies and can be used to treat myeloid malignancies in practice. However, developing CAR-T therapies for such diseases is particularly challenging due to the heterogeneity of target antigen expression across leukemic cells and patients, the difficulty in excluding on-target/off-target tumor effects, and the immunosuppressive tumor microenvironment. To date, various targets, including CD33, NKG2D, CD123, CLL-1, and CD7, have been actively studied for CAR-T cells, especially for acute myeloid leukemia (AML). Although no CAR-T cell products have been approved, several clinical trials have shown promising results, particularly for those targeting CLL-1 and CD123. Furthermore, new ideal targets and use of allogeneic or off-the-shelf CAR-T cell products are under investigation. Meanwhile, it remains unknown whether CAR-T therapy would be effective for other myeloid malignancies, including myelodysplastic syndromes and myeloproliferative diseases. This review discusses challenges in the development of CAR-T therapy for myeloid malignancies, especially for AML, from the perspectives of target antigen characteristics and disease-specific on-target/off-tumor toxicity. Moreover, it discusses the clinical development and prospects of CAR-T cells for these diseases.

T cell malignancies pose several unique issues for CAR-T cell therapy that were not significant concerns with CAR-T cells for B-cell malignancies. A general problem to consider in the production of CAR-T cells is “on target-off tumor toxicity.” This occurs when the antigen targeted by the CAR-T cells is also expressed on normal cells, not just tumor cells, which causes CAR-T cells to damage these normal cells. In CAR-T cell therapy for T cell tumors, antigens expressed on T cells (such as CD5, CD7, etc.) are the targets, which leads to a problem known as “fratricide,” where CAR-T cells kill each other. Other issues include T cell aplasia and contamination of CAR-T cell products with tumor cells. However, several recent clinical trials have shown excellent outcomes for CAR-T cell therapy when genome editing technology is used to overcome these issues by knocking out target antigens or T cell receptors. This review article outlines these challenges and their solutions and discusses the results of recent clinical trials.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for refractory/relapsed (R/R) hematologic malignancies, with six products approved for B-cell tumors and multiple myeloma as of the end of 2023. However, adoptive cell therapy (ACT) for solid tumors is hindered by critical challenges in multiple areas, including (1) lack of appropriate tumor-specific antigens, (2) inefficient T-cell trafficking and infiltration into the tumor microenvironment, and (3) immunosuppressive signals within the tumor milieu that induce T-cell dysfunction. This review examines the existing clinical trial data on ACT for solid tumors to elucidate the current landscape of ACT development for solid tumors. It also outlines the trajectory of ACT for solid tumors and integrative approaches to overcoming the complex tumor microenvironment.

Chimeric antigen receptor T-cell therapy (CAR-T-cell therapy) has revolutionized the treatment of relapsed and refractory hematological malignancies. Targeting of the CD19 antigen on B cells has yielded high rates of remission induction and sustained remission in patients with acute lymphoblastic leukemia and B-cell lymphomas. Despite these remarkable responses, many escape mechanisms from CAR-T cell therapy have been identified, with the most common being target antigen deficiency. This paper focuses on CD19 CAR-T cell therapies, which are currently the most clinically used, and describes new strategies to overcome resistance using multi-targeted CAR-T cells, such as CD19-CD20 CAR-T cells and CD19-CD22 CAR-T cells, which are being developed in preclinical and clinical trials.

Chimeric antigen receptor-transduced autologous T (CAR-T) cell therapy targeting CD19 has revolutionized the treatment of CD19-positive hematological tumors, including acute lymphoblastic leukemia and large B-cell lymphoma. However, despite the high response rate, many problems such as exceedingly high cost, complex logistics, insufficient speed, and manufacturing failures have become apparent. One solution for these problems is to use an allogeneic cell as an effector cell for genetic modification with CAR. Allogeneic, or “off-the-shelf”, CAR-expressing immune-effector cells include 1) genome-edited, T-cell receptor (TCR) gene-deleted CAR-T cells generated using healthy adult donor T cells, 2) induced pluripotent stem cell-derived CAR-T cells, and 3) CAR NK cells. NK cells are notorious for their poor ex-vivo expansion and low susceptibility to genetic modification. In this article, I will review the current state and future prospects of allogeneic CAR cell therapies, with special reference to CAR NK cells.

Researchers in the field of acute myeloid leukemia have long sought to establish a prognostic stratification system for clinical use that combines multiple genetic mutations. In 2022, the European LeukemiaNet (ELN) proposed a new prognostic model incorporating new genetic mutations. However, Japanese National Health insurance only recently began covering clinical genetic analysis for AML. We established the Multi-center Collaborative Program for Gene Sequencing of Japanese AML (GS-JAML) to contribute to clinical practice by providing rapid genetic analysis results. Retrospective analysis of this research program revealed (1) the clinical significance of CEBPA-bZIP mutations, and (2) the clinical significance of DNMT3A mutations in NPM1 mutated AML.

FLT3 mutation is one of the most frequent genetic mutations in AML, identified in approximately 30% of patients, and FLT3-ITD mutation is considered a poor prognostic factor. Based on these molecular and clinical backgrounds, FLT3 mutations are considered promising therapeutic targets in AML, and intensive development of targeted therapeutics has been ongoing for more than two decades. Recently, combination of FLT3 inhibitors with intensive chemotherapy for untreated AML patients with FLT3 mutations and FLT3 inhibitor monotherapy for relapsed/refractory patients have been approved. In Japan, the combination of quizartinib and intensive chemotherapy for untreated FLT3-ITD-positive AML was approved in 2023. Clinical use of FLT3 inhibitors shows strong promise for improving the clinical outcomes of these AML patients with an extremely poor prognosis. Meanwhile, various resistance mechanisms to FLT3 inhibitors have been identified, including the emergence of resistance-associated mutations, and attenuated inhibitory effects of FLT3 inhibitors involving the bone marrow microenvironment surrounding AML cells. Thus, future efforts should aim to optimize combination therapy based on the characteristics of each FLT3 inhibitor, develop biomarkers that could inform treatment selection, and to better understand these resistance mechanisms and develop methods for overcoming them.

My colleagues and I previously found a subset of neutrophil-like Ly6C^hi monocytes, named “regulatory monocytes”, that expand in the bone marrow during the late phase of inflammation. Regulatory monocytes migrate to injured tissue where they promote tissue repair. Unlike classical Ly6C^hi monocytes, regulatory monocytes arise from GMP through proNeu1, which was previously thought to be committed to becoming neutrophils. G-CSF not only stimulates neutrophil differentiation but also drives the expansion of regulatory monocytes in the absence of inflammatory stimuli. The human parallel to mouse regulatory monocytes was found in the peripheral blood CD14^hiCD16^lo monocyte fraction. These monocytes can be distinguished from classical CD14^hiCD16^lo monocytes by neutrophil marker CXCR1 expression. Like mouse regulatory monocytes, human CXCR1⁺ monocytes arise from neutrophil progenitors in response to G-CSF. CXCR1⁺CD14^hiCD16^lo monocytes suppressed the proliferation of syngeneic T cells in vitro, which suggests an immunosuppressive phenotype. Overall, these findings indicate that the process of differentiation of regulatory monocytes from progenitors of neutrophil lineage is maintained across humans and mice, and may aid in resolution of excess inflammation.

Myelodysplastic syndrome (MDS) is a refractory cancer that arises from hematopoietic stem cells and predominantly affects elderly adults. In addition to driver gene mutations, which are also found in clonal hematopoiesis in healthy elderly people, systemic inflammation caused by infection or collagen disease has long been known as an extracellular factor in the pathogenesis of MDS. Wild-type HSCs have an “innate immune memory” that functions in response to infection and inflammatory stress, and my colleagues and I used an infection stress model to demonstrate that the innate immune response by the TLR-TRIF-PLK-ELF1 pathway is similarly critical in impairment of hematopoiesis and dysregulation of chromatin in MDS stem cells. This revealed that not only are MDS stem cells expanded by the TRAF6-NF-kB pathway, the innate immune response is also involved in generating MDS stem cells. In this review, I will present research findings related to “innate immune memory,” one of the pathogenic mechanisms of blood cancer, and discuss future directions for basic pathological research and potential therapeutic development.