The Functional Transcriptomic Landscape Informs Therapeutic Strategies in Multiple Myeloma.

Several therapeutic agents have been approved for treating multiple myeloma (MM), a cancer of bone marrow resident plasma cells. Predictive biomarkers for drug response could help guide clinical strategies to optimize outcomes. Here, we present an integrated functional genomic analysis of tumor samples from MM patients that were assessed for their ex vivo drug sensitivity to 37 drugs, clinical variables, cytogenetics, mutational profiles, and transcriptomes.

Survivin Dendritic Cell Vaccine Safely Induces Immune Responses and Is Associated with Durable Disease Control after Autologous Transplant in Patients with Myeloma.

Purpose: We investigated whether a dendritic cell (DC) vaccine transduced with an adenoviral vector encoded with full-length survivin (Ad-S), with mutations neutralizing its antiapoptotic function, could safely generate an immune response and deepen clinical responses when administered before and after autologous stem cell transplant (ASCT) for multiple myeloma.

Patients And Methods: This phase I first-in-human trial (NCT02851056) evaluated the safety of DC:Ad-S in newly diagnosed multiple myeloma not having achieved complete response with induction, given 7 to 30 days prior to stem cell collection and 20 to 34 days after ASCT. Anti-survivin antibodies and CD4+ and CD8+ specific T cells were quantified.

CYAD-01, an autologous NKG2D-based CAR T-cell therapy, in relapsed or refractory acute myeloid leukaemia and myelodysplastic syndromes or multiple myeloma (THINK): haematological cohorts of the dose escalation segment of a phase 1 trial.

Background: CYAD-01 is an autologous chimeric antigen receptor (CAR) T-cell product based on the natural killer (NK) group 2D (NKG2D) receptor, which binds eight ligands that are overexpressed in a wide range of haematological malignancies but are largely absent on non-neoplastic cells. Initial clinical evaluation of a single infusion of CYAD-01 at a low dose in patients with relapsed or refractory acute myeloid leukaemia, myelodysplastic syndromes, and multiple myeloma supported the feasibility of the approach and prompted further evaluation of CYAD-01. The aim of the present study was to determine the safety and recommended phase 2 dosing of CYAD-01 administered without preconditioning or bridging chemotherapy.

Early cytopenias and infections after standard of care idecabtagene vicleucel in relapsed or refractory multiple myeloma.

Idecabtagene vicleucel (ide-cel) was FDA-approved in March 2021 for the treatment of relapsed/refractory multiple myeloma after 4 lines of therapy. On the KarMMa trial, grade ≥ 3 cytopenias and infections were common. We sought to characterize cytopenias and infections within 100 days after ide-cel in the standard-of-care (SOC) setting.

Adding Cyclophosphamide to Bortezomib and Dexamethasone was not Associated With Improved Outcomes of Patients With Newly Diagnosed Light Chain Amyloidosis: A Retrospective Study.

Introduction: Before 2021, the combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) was one of the most used upfront therapy for systemic immunoglobulin light chain (AL) amyloidosis. Recently, daratumumab in combination with VCd resulted in improved outcomes compared to VCd. However, it's still unclear the role of cyclophosphamide in this combination.

Racial and ethnic differences in clonal hematopoiesis, tumor markers, and outcomes of patients with multiple myeloma.

Multiple myeloma (MM) incidence, mortality, and survival vary by race and ethnicity, but the causes of differences remain unclear. We investigated demographic, clinical, and molecular features of diverse MM patients to elucidate mechanisms driving clinical disparities. This study included 495 MM patients (self-reported Hispanic, n = 45; non-Hispanic Black, n = 52; non-Hispanic White, n = 398).

Plasma cell dependence on histone/protein deacetylase 11 reveals a therapeutic target in multiple myeloma.

The clinical utility of histone/protein deacetylase (HDAC) inhibitors in combinatorial regimens with proteasome inhibitors for patients with relapsed and refractory multiple myeloma (MM) is often limited by excessive toxicity due to HDAC inhibitor promiscuity with multiple HDACs. Therefore, more selective inhibition minimizing off-target toxicity may increase the clinical effectiveness of HDAC inhibitors. We demonstrated that plasma cell development and survival are dependent upon HDAC11, suggesting this enzyme is a promising therapeutic target in MM.

High-Dimensional Flow Cytometry Analysis of Regulatory Receptors on Human T Cells, NK Cells, and NKT Cells.

The field of flow cytometry has witnessed rapid technological advancements in the last few decades. While the founding principles of fluorescent detection on cells (or particles) within a uniform fluid stream remains largely unchanged, the availability more sensitive cytometers with the ability to multiplex more and more florescent signals has resulted in very complex high-order assays. This results in the co-use of fluorophores with increased levels of emission overlap and/or spillover spreading than in years past and thus requires careful and well thought out planning for flow cytometry assay development.

Lenalidomide-based response-adapted therapy for older adults without high risk myeloma.

Combined lenalidomide and dexamethasone is a standard-of-care therapy for the treatment of older adults with multiple myeloma. Lenalidomide monotherapy has not been evaluated in newly diagnosed myeloma patients. We conducted a phase II study, evaluating a response-adapted therapy for older adults newly diagnosed with multiple myeloma without high-risk features who were ineligible for high-dose therapy and stem cell transplant.

The potential of ixazomib, a second-generation proteasome inhibitor, in the treatment of multiple myeloma.

The therapeutic armamentarium for multiple myeloma has recently benefited from the addition of several new agents (including second-generation proteasome inhibitors, monoclonal antibodies and histone deacetylase inhibitors). This review will focus on ixazomib, an orally bioavailable second-generation proteasome inhibitor. Specifically, we will review the preclinical data, clinical trial experience, potential indications as well as unanswered questions pertaining to this new agent in multiple myeloma.

WT1 vaccination in AML and MDS: A pilot trial with synthetic analog peptides.

Peptide vaccines are capable of eliciting immune responses targeting tumor-associated antigens such as the Wilms' Tumor 1 (WT1) antigen, often overexpressed in myeloid malignancies. Here, we assessed the safety, tolerability, and immunogenicity of a polyvalent WT1 peptide vaccine. Individuals with WT1-positive acute myeloid leukemia (AML) in first (CR1) or second (CR2) remission or with higher-risk myelodysplastic syndrome (MDS) following at least 1 prior line of therapy were vaccinated with a mixture of peptides derived from the WT1 protein, with sargramostim injections before vaccination to amplify immunogenicity.

Regression of metastatic clear cell kidney cancer with interleukin-2 treatment following nivolumab (anti-PD-1) treatment.

Aldesleukin [interleukin-2 (IL-2)] induces durable complete responses in some kidney cancer and melanoma patients. Nivolumab is an investigational antibody drug targeting programmed death-1 (PD-1) as a treatment, demonstrating activity in multiple cancer types. An expanding complement of immunotherapeutics raises important issues regarding the best way to use them.

Developing strategies in the immunotherapy of leukemias.

Background: In the current treatment paradigms for leukemias, hematopoietic stem cell transplant (HSCT) is considered the best option with a curative potential although more often than not it simply delays disease progression. Advances are needed, both in current therapies and in the development of new strategies. Partly from studying the nuances of the curative potential of stem cell transplant, we have come to appreciate the relevance of the immune response and the potential of immunotherapy.

Enhanced CD8 T cell cross-presentation by macrophages with targeted disruption of STAT3.

CD8 T cell tolerance, once thought to be largely a result of clonal deletion, is now appreciated to be much more complex, additionally involving multiple permutations of partial loss of effector function in residual clonal populations. This is especially important in the context of tumor immunity, in which persistent tolerized cytotoxic CD8 T cells (CTL), if reactivated, could potentially mount a protective response. Previously we have shown that antigen-presenting cells (APCs) with a targeted disruption of STAT3 break tolerance in CD4 T cells.

TLR5 ligation by flagellin converts tolerogenic dendritic cells into activating antigen-presenting cells that preferentially induce T-helper 1 responses.

Dendritic cells (DCs) differentiated in the presence of IL-10 preferentially induce regulatory T-cells and tolerance. Whether the tolerogenic properties displayed by these DCs (Tol-DCs) can be overcome has not been fully explored. Here we show for the first time that Tol-DCs express higher levels of TLR5 mRNA, but not TLR4 or TLR9 mRNA relative to DCs differentiated with GM-CSF and IL-4 (BM-DCs).

In vivo disruption of tolerogenic cross-presentation mechanisms uncovers an effective T-cell activation by B-cell lymphomas leading to antitumor immunity.

Bone marrow-derived antigen-presenting cells (APCs) play a central role in the induction of tolerance to tumor antigens expressed by B-cell lymphomas. Here we show that in vivo disruption of this APC-mediated tolerogenic mechanism unveils an intrinsic ability of malignant B cells to efficiently present tumor antigens to antigen-specific CD4+ T cells, resulting in a strong antitumor effect. This intrinsic antigen-presenting ability of malignant B cells is, however, overridden by tolerogenic bone marrow-derived APCs, leading instead to T-cell unresponsiveness and lack of antitumor effect.

Expansion of myeloid suppressor cells in SHIP-deficient mice represses allogeneic T cell responses.

Previously we demonstrated that SHIP(-/-) mice accept allogeneic bone marrow transplants (BMT) without significant acute graft-vs-host disease (GvHD). In this study we show that SHIP(-/-) splenocytes and lymph node cells are poor stimulators of allogeneic T cell responses that cause GvHD. Intriguingly, SHIP(-/-) splenocytes prime naive T cell responses to peptide epitopes, but, conversely, are partially impaired for priming T cell responses to whole Ag.

Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses.

T cells infiltrating tumors have a decreased expression of signal transduction proteins, a diminished ability to proliferate, and a decreased production of cytokines. The mechanisms causing these changes have remained unclear. We demonstrated recently that peritoneal macrophages stimulated with interleukin 4 + interleukin 13 produce arginase I, which decreases the expression of the T-cell receptor CD3zeta chain and impairs T-cell responses.

Extra-lymphatic solid tumor growth is not immunologically ignored and results in early induction of antigen-specific T-cell anergy: dominant role of cross-tolerance to tumor antigens.

A better understanding of how solid malignancies arise in an immunocompetent host, avoid immune recognition, and ultimately progress to widely disseminated cancer is essential to effectively harness the immune system against solid tumors. Because of their extra-lymphatic localization, it has been proposed that solid malignancies are just ignored by the immune system, thereby allowing their uncontrolled growth and dissemination. Alternatively, as most of the solid tumors are unable to express costimulatory molecules, the "signal one without signal two" model of tolerance induction has been frequently evoked to account for the failure of the immune system to reject antigenic tumors in vivo.