Modified poly-L-lysine for use as a clearing agent in pretargeted radioimmunotherapy.

Background: Pretargeted radioimmunotherapy of cancer has the potential to increase tumor specific uptake of activity when compared with conventional radioimmunotherapy. This is especially true in radioimmunotherapy with nuclides that exhibit a relatively short half-life. When administering antibody-based pretargeting molecules systemically, the antibodies often show a relatively slow clearance from the blood.

Kinetics of Nirogacestat-Mediated Increases in B-cell Maturation Antigen on Plasma Cells Inform Therapeutic Combinations in Multiple Myeloma.

GSIs can enhance multiple myeloma therapies targeting BCMA by increasing mbBCMA on plasma cells. In response to the GSI nirogacestat, mbBCMA rapidly and robustly increased in vitro and in vivo. Elucidating nirogacestat's effects on BCMA kinetics will guide potential multiple myeloma dosing strategies.

Optimizing Autologous Stem Cell Transplantation in Multiple Myeloma: The Impact of Intensive Chemomobilization.

Most transplant-eligible multiple myeloma (MM) patients undergo autologous peripheral blood stem cell collection (PBSC) using G-CSF with on-demand plerixafor (G ± P). Chemomobilization (CM) can be used as a salvage regimen after G ± P failure or for debulking residual tumor burden ahead of autologous peripheral blood stem cell transplantation (ASCT). Prior studies utilizing cyclophosphamide-based CM have not shown long-term benefits.

Long-term Remissions Following CD20-Directed Chimeric Antigen Receptor-Adoptive T-cell Therapy.

Chimeric antigen receptor (CAR) T-cell therapy produces high response rates in refractory B-cell non-Hodgkin lymphoma, but long-term data are minimal to date. In this study, we present long-term follow-up of a pilot trial testing a CD20-targeting third-generation CAR in patients with relapsed B-cell lymphomas following cyclophosphamide-only lymphodepletion. Two of the three patients in the trial, with mantle cell lymphoma and follicular lymphoma, had remissions lasting more than 7 years, though they ultimately relapsed.

TIM-3 CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies.

Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (T), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with expression and motif accessibility.

Regulatory T cells suppress myeloma-specific immunity during autologous stem cell mobilization and transplantation.

Autologous stem cell transplantation (ASCT) is the standard of care consolidation therapy for eligible patients with myeloma but most patients eventually progress, an event associated with features of immune escape. Novel approaches to enhance antimyeloma immunity after ASCT represent a major unmet need. Here, we demonstrate that patient-mobilized stem cell grafts contain high numbers of effector CD8 T cells and immunosuppressive regulatory T cells (Tregs).

CD8 chimeric antigen receptor T cells manufactured in absence of CD4 cells exhibit hypofunctional phenotype.

Background: Cell culture conditions during manufacturing can impact the clinical efficacy of chimeric antigen receptor (CAR) T cell products. Production methods have not been standardized because the optimal approach remains unknown. Separate CD4 and CD8 cultures offer a potential advantage but complicate manufacturing and may affect cell expansion and function.

Unveiling the link between genetic alterations in gamma secretase and BCMA surface density in multiple myeloma.

Cattaneo et al. report a unique case of a multiple myeloma patient with elevated B-cell maturation antigen (BCMA) surface density, potentially due to genetic alterations in the gamma-secretase protease complex-responsible for BCMA cleavage from plasma cells. No mutations in the BCMA gene were detected, but there was partial deletion of PSEN1 and amplification of PSEN2 (components of the gamma-secretase complex), which may explain the lack of response to the gamma-secretase inhibitor DAPT.

Cytomegalovirus (CMV) Reactivation and CMV-Specific Cell-Mediated Immunity After Chimeric Antigen Receptor T-Cell Therapy.

Background: The epidemiology of cytomegalovirus (CMV) after chimeric antigen receptor-modified T-cell immunotherapy (CARTx) is poorly understood owing to a lack of routine surveillance.

Methods: We prospectively enrolled 72 adult CMV-seropositive CD19-, CD20-, or BCMA-targeted CARTx recipients and tested plasma samples for CMV before and weekly up to 12 weeks after CARTx. We assessed CMV-specific cell-mediated immunity (CMV-CMI) before and 2 and 4 weeks after CARTx, using an interferon γ release assay to quantify T-cell responses to IE-1 and pp65.

Targeted Radiation Delivery before Haploidentical HCT for High-risk Leukemia or MDS Patients Yields Long-term Survivors.

Purpose: Hematopoietic cell transplantation (HCT) has curative potential for myeloid malignancies, though many patients cannot tolerate myeloablative conditioning with high-dose chemotherapy alone or with total-body irradiation (TBI). Here we report long-term outcomes from a phase I/II study using iodine-131 (131I)-anti-CD45 antibody BC8 combined with nonmyeloablative conditioning prior to HLA-haploidentical HCT in adults with high-risk relapsed/ refractory acute myeloid or lymphoid leukemia (AML or ALL), or myelodysplastic syndrome (MDS; ClinicalTrials.gov, NCT00589316).

Timing of anti-PD-L1 antibody initiation affects efficacy/toxicity of CD19 CAR T-cell therapy for large B-cell lymphoma.

More than half of the patients treated with CD19-targeted chimeric antigen receptor (CAR) T-cell immunotherapy for large B-cell lymphoma (LBCL) do not achieve durable remission, which may be partly due to PD-1/PD-L1-associated CAR T-cell dysfunction. We report data from a phase 1 clinical trial (NCT02706405), in which adults with LBCL were treated with autologous CD19 CAR T cells (JCAR014) combined with escalating doses of the anti-PD-L1 monoclonal antibody, durvalumab, starting either before or after CAR T-cell infusion. The addition of durvalumab to JCAR014 was safe and not associated with increased autoimmune or immune effector cell-associated toxicities.

Immunophenotypic correlates of sustained MRD negativity in patients with multiple myeloma.

The role of the immune microenvironment in maintaining disease remission in patients with multiple myeloma (MM) is not well understood. In this study, we comprehensively profile the immune system in patients with newly diagnosed MM receiving continuous lenalidomide maintenance therapy with the aim of discovering correlates of long-term treatment response. Leveraging single-cell RNA sequencing and T cell receptor β sequencing of the peripheral blood and CyTOF mass cytometry of the bone marrow, we longitudinally characterize the immune landscape in 23 patients before and one year after lenalidomide exposure.

Revisiting the Utility of Granulocyte Colony-Stimulating Factor Post-Autologous Hematopoietic Stem Cell Transplantation for Outpatient-Based Transplantations.

The use of granulocyte colony-stimulating factor (G-CSF) after autologous stem cell transplantation (ASCT) has been shown to reduce the time to neutrophil engraftment, as well as the duration of hospitalization post-transplantation. However, prior studies have focused on inpatient-based ASCT, where patients are routinely admitted for conditioning and frequently remain hospitalized until signs of neutrophil recovery. Given improvements in post-transplantation care, an increasing number of patients, particularly those receiving ASCT for multiple myeloma, are now undergoing transplantation in an outpatient setting.

Anakinra for Refractory Cytokine Release Syndrome or Immune Effector Cell-Associated Neurotoxicity Syndrome after Chimeric Antigen Receptor T Cell Therapy.

Chimeric antigen receptor-engineered (CAR)-T cell therapy remains limited by significant toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The optimal management of severe and/or refractory CRS/ICANS remains ill-defined. Anakinra has emerged as a promising agent based on preclinical data, but its safety and efficacy in CAR-T therapy recipients are unknown.

Anti-HLA antibodies in recipients of CD19 versus BCMA-targeted CAR T-cell therapy.

Antibodies against foreign human leukocyte antigen (HLA) molecules are barriers to successful organ transplantation. B cell-depleting treatments are used to reduce anti-HLA antibodies but have limited efficacy. We hypothesized that the primary source for anti-HLA antibodies is long-lived plasma cells, which are ineffectively targeted by B cell depletion.

Radiographic Response of Solitary Plasmacytomas After Conformal Radiotherapy May Be Delayed: Outcomes in the 3D Era.

Objective: Although recurrence rates after radiotherapy for solitary plasmacytoma (SP) are well established, little is known about how SP responds radiographically, as most historical patients were treated in the 2D era. We evaluated the response to radiotherapy among SP patients staged and treated with 3D techniques, including proton therapy, which has not yet been previously reported.

Methods And Materials: Between 2007 and 2021, 15 SP patients (4 extramedullary, 11 bone) staged with 3D imaging and bone marrow evaluation were consecutively treated with definitive radiotherapy.