Blood Cancer Discovery最新文献

BCMA-targeted bispecific antibodies (BiAb) are efficacious in relapsed/refractory multiple myeloma; however, serious infections have emerged as important toxicities. In this retrospective study, we characterized all infections and their risk factors, and evaluated the impact of infection prophylaxis in patients treated with BCMA-targeted BiAbs. Among 37 patients, 15 (41%) experienced a grade 3-5 infection, with two infection-related deaths during deep remissions. Most (84%) infections occurred during disease remissions. The cumulative probability of grade 3-5 infection increased over time with no plateau. Among responders (n = 26), profound hypogammaglobulinemia occurred in 100% and continued throughout the entire duration of treatment. During periods when patients were receiving intravenous immunoglobulin (IVIg), the rate of grade 3-5 infections was 90% lower than during observation (incidence rate ratio, 0.10; 95% confidence interval, 0.01-0.80; P = 0.0307). No other risk factors for infection were identified. This study demonstrates that profound hypogammaglobulinemia is universal with BCMA-targeted BiAbs, with intravenous immunoglobulin potentially abrogating most of the infection risk.

Significance: To the best of our knowledge, this is the first study to comprehensively analyze risk factors and mitigation strategies to prevent infections in myeloma patients receiving anti-BCMA bispecific antibodies. Profound and prolonged hypogammaglobulinemia was universal among responders, while immunoglobulin replacement was associated with 90% lower rates of grade 3-5 infections. See related commentary by Garfall and Stadtmauer, p. 427 . This article is featured in Selected Articles from This Issue, p. 419.

Therapy-resistant leukemia stem and progenitor cells (LSC) are a main cause of acute myeloid leukemia (AML) relapse. LSC-targeting therapies may thus improve outcome of patients with AML. Here we demonstrate that LSCs present HLA-restricted antigens that induce T-cell responses allowing for immune surveillance of AML. Using a mass spectrometry-based immunopeptidomics approach, we characterized the antigenic landscape of patient LSCs and identified AML- and AML/LSC-associated HLA-presented antigens absent from normal tissues comprising nonmutated peptides, cryptic neoepitopes, and neoepitopes of common AML driver mutations of NPM1 and IDH2. Functional relevance of shared AML/LSC antigens is illustrated by presence of their cognizant memory T cells in patients. Antigen-specific T-cell recognition and HLA class II immunopeptidome diversity correlated with clinical outcome. Together, these antigens shared among AML and LSCs represent prime targets for T cell-based therapies with potential of eliminating residual LSCs in patients with AML.

Significance: The elimination of therapy-resistant leukemia stem and progenitor cells (LSC) remains a major challenge in the treatment of AML. This study identifies and functionally validates LSC-associated HLA class I and HLA class II-presented antigens, paving the way to the development of LSC-directed T cell-based immunotherapeutic approaches for patients with AML. See related commentary by Ritz, p. 430 . This article is featured in Selected Articles from This Issue, p. 419.

The BCL2 inhibitor venetoclax combined with the hypomethylating agent azacytidine shows significant clinical benefit in a subset of patients with acute myeloid leukemia (AML); however, resistance limits response and durability. We prospectively profiled the ex vivo activity of 25 venetoclax-inclusive combinations on primary AML patient samples to identify those with improved potency and synergy compared with venetoclax + azacytidine (Ven + azacytidine). Combination sensitivities correlated with tumor cell state to discern three patterns: primitive selectivity resembling Ven + azacytidine, monocytic selectivity, and broad efficacy independent of cell state. Incorporation of immunophenotype, mutation, and cytogenetic features further stratified combination sensitivity for distinct patient subtypes. We dissect the biology underlying the broad, cell state-independent efficacy for the combination of venetoclax plus the JAK1/2 inhibitor ruxolitinib. Together, these findings support opportunities for expanding the impact of venetoclax-based drug combinations in AML by leveraging clinical and molecular biomarkers associated with ex vivo responses.

Significance: By mapping drug sensitivity data to clinical features and tumor cell state, we identify novel venetoclax combinations targeting patient subtypes who lack sensitivity to Ven + azacytidine. This provides a framework for a taxonomy of AML informed by readily available sets of clinical and genetic features obtained as part of standard care. See related commentary by Becker, p. 437 . This article is featured in Selected Articles from This Issue, p. 419.

Summary: In this issue of Blood Cancer Discovery, Nelde and colleagues used a sensitive mass spectrometry-based immunopeptidomics approach to characterize the antigenic landscape of acute myeloid leukemia (AML) and were able to identify immunogenic peptides presented by both leukemia stem cells (LSC) and bulk primary AML blasts. These immunogenic peptides elicit primarily CD4 T-cell responses and the diversity of the HLA class II immunopeptidome and presence of CD4 memory T-cell responses were both associated with improved clinical outcome. See related article by Nelde et al., p. 468 (1) .

Summary: Basic and clinical cancer research discoveries stemming from the nation's cancer centers have markedly improved outcomes for many cancer patients. Despite this forward momentum in our progress against this complex disease, cancer in all its forms remains a major public health challenge that touches the lives of nearly every American, either directly or indirectly. The newly formed AACR Cancer Centers Alliance will accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources, developing national demonstration projects, and driving innovation that impacts cancer science, cancer care delivery, and science and health policy.

The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics during the first year after idecabtagene vicleucel (ide-cel) infusion in 125 relapsed/refractory multiple myeloma patients enrolled in KarMMa. At month 1 after ide-cel, there were no differences in progression-free survival (PFS) between patients in less than complete response (CR) versus those in CR; only MRD status was predictive of significantly different PFS at this landmark. In patients with undetectable MRD at 3 months and beyond, PFS was longer in those achieving CR versus

Significance: This is one of the first studies evaluating the impact of CR and MRD dynamics after CAR T therapy in relapsed/refractory multiple myeloma. These data help interpret the prognostic significance of serological and MRD responses at early and late time points after CAR T-cell infusion. See related commentary by Landgren and Kazandjian, p. 346 . This article is featured in Selected Articles from This Issue, p. 337.

Selective inhibitors of Janus kinase (JAK) 2 have been in demand since the discovery of the JAK2 V617F mutation present in patients with myeloproliferative neoplasms (MPN); however, the structural basis of V617F oncogenicity has only recently been elucidated. New structural studies reveal a role for other JAK2 domains, beyond the kinase domain, that contribute to pathogenic signaling. Here we evaluate the structure-based approaches that led to recently-approved type I JAK2 inhibitors (fedratinib and pacritinib), as well as type II (BBT594 and CHZ868) and pseudokinase inhibitors under development (JNJ7706621). With full-length JAK homodimeric structures now available, superior selective and mutation-specific JAK2 inhibitors are foreseeable.

Significance: The JAK inhibitors currently used for the treatment of MPNs are effective for symptom management but not for disease eradication, primarily because they are not strongly selective for the mutant clone. The rise of computational and structure-based drug discovery approaches together with the knowledge of full-length JAK dimer complexes provides a unique opportunity to develop better targeted therapies for a range of conditions driven by pathologic JAK2 signaling.

Summary: In this issue, Paiva and colleagues characterize the dynamics of minimal residual disease (MRD) and clinical responses during chimeric antigen receptor (CAR) T-cell therapy of relapsed/refractory multiple myeloma. Although both correlate with prolonged progression-free survival, MRD is reached faster in the bone marrow than complete response in peripheral blood; consequently, the study addresses the need for future guidelines to explore new MRD-negative definitions that are independent of the monoclonal (M) protein to overcome this limitation, particularly in clinical trials using early depth of response as an endpoint. See related article by Paiva et al., p. 365 (1).

The 17th International Conference on Malignant Lymphoma (ICML) took place in Lugano, Switzerland, from June 13-17 this year. The conference has been held every 2 to 3 years since its inception in 1981 and has become a significant and influential gathering for lymphoma researchers from around the world, this year hosting 4,761 registered attendees. Here, we provide some highlights of what we felt were the most noteworthy findings, both clinical and pre-clinical, across various lymphoma entities, presented at the 17th ICML.