Advancing In Vivo Detection of T-Cell Function: Development and Preclinical Evaluation of Zr-Ivuxolimab, a Human OX40 PET Tracer.

The variable response to cancer immunotherapies highlights a critical gap in our ability to predict and monitor treatment efficacy. To address this, there is an urgent clinical need for advanced molecular imaging technologies that can noninvasively and precisely assess whole-body immune responses. The OX40 receptor (CD134), a potent costimulatory molecule on T cells, serves as a highly specific marker of T-cell activation, an early and crucial event in immunotherapy efficacy.

Time-of-day dependency of adoptive cell therapies.

Adoptive cell therapies (ACTs), such as chimeric antigen receptor (CAR)-T cell therapy, have revolutionized cancer treatment, especially for hematological cancers. However, patient responses vary considerably. Emerging research reveals a striking influence of time of day (ToD) on ACT efficacy.

IL-16 production is a mechanism of resistance to BTK inhibitors and R-CHOP in lymphomas.

Introducing Bruton's tyrosine kinase (BTK) inhibitors has significantly improved outcomes for patients with B-cell malignancies and autoimmune disorders. However, resistance, either primary or acquired, remains a major clinical challenge. To better understand the underlying resistance mechanisms to BTK inhibitors, we established an ibrutinib-resistant model from a patient-derived splenic marginal zone lymphoma (MZL) cell line (VL51) through prolonged drug exposure.

How I approach hematopoietic stem cell transplantation for CML in a TKI world.

Following the introduction of tyrosine kinase inhibitors (TKI), the number of patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic phase chronic myeloid leukemia (CP-CML) has dramatically decreased. Imatinib was the 1st TKI introduced into the clinical arena, predominantly utilized in the 1st line setting. In cases of insufficient response, resistance, or intolerance, CML patients can subsequently be treated with a 2nd, 3rdor 4th generation TKI.

Blood Virome After Allogeneic Hematopoietic Stem Cell Transplantation.

Background: Haploidentical allogeneic hematopoietic cell transplant recipients (allo-HCTr) receiving posttransplant cyclophosphamide (haplo-PTCy) are at higher risk for infectious complications, including viral infections.

Methods: We performed a retrospective, single-center, propensity-score matched-pair study including adult haplo-PTCy and allo-HCTr from human leukocyte antigen (HLA)-matched donors, undergoing transplantation in our institution between 2016 and 2022. For each patient, 4 blood samples (day [D] 0, D30, D90, and D180 posttransplantation) were extracted from the biobank and tested with metagenomic next-generation sequencing (mNGS) to describe the blood virome and identify viral RNA/DNA signatures potentially unrecognized by routinely available tests.

Current use of donor lymphocyte infusions after allogenic stem cell transplantation in Europe: a survey on behalf of the cellular therapy and immunobiology working party of the EBMT.

Unmanipulated donor lymphocyte infusions (DLI) are crucial for enhancing the graft versus tumor (GVT) effect in post-transplant settings. Practices regarding DLI use vary widely among centers, encompassing differences in indications, prerequisites, and application methods. To explore current DLI policies, we developed a comprehensive survey that garnered responses from 165 EBMT centers across 43 countries.

Anti-BCMA and GPRC5D bispecific antibodies in relapsed/refractory primary plasma cell leukemia: a case report.

Plasma cell leukemia (PCL) is an aggressive and high-risk variant of multiple myeloma (MM) with a very poor prognosis. Given its rarity and aggressiveness, there is a lack of clinical trials testing the efficacity of novel therapies in these patients. New immune approaches such as B-cell maturation antigen (BCMA) and G protein-coupled receptor, family C, group 5, member D (GPRC5D) -targeting agents, including chimeric antigen receptor (CAR) T-cells and bispecific antibodies could play a role in PCL treatment.

A novel mitochondrial pyruvate carrier inhibitor drives stem cell-like memory CAR T cell generation and enhances antitumor efficacy.

Adoptive cell transfer with chimeric antigen receptor (CAR)-expressing T cells can induce remarkable complete responses in cancer patients. Therapeutic success has been correlated with central and stem cell-like memory T cell subsets in the infusion product, which are better able to drive efficient CAR T cell expansion and long-term persistence. We previously reported that inhibition of the mitochondrial pyruvate carrier (MPC) during mouse CAR T cell culture induces a memory phenotype and enhances antitumor efficacy against melanoma.

Severe anaphylaxis after chimeric antigen receptor T-cell injection: a case report.

Anaphylactic reactions at the time of chimeric antigen receptor T (CAR-T) cell infusion are adverse events that have not been reported in pivotal clinical trials or in real-world series. We report the case of patient with severe anaphylaxis with cardiac arrest after tisagenlecleucel injection for Diffuse Large B cell Lymphoma, who recovered after resuscitation and intensive care treatment; we also conducted a Food and Drug Administration Adverse Event Reporting System database analysis and found several cases of severe anaphlyaxis after CAR-T cell injection. Although not reported in pivotal CAR-T cell studies, anaphylaxis can occur after CAR-T cell injection, highlighting the need to include anaphylaxis as a possible side effect in future studies.

Donor lymphocyte infusion after allogeneic haematopoietic cell transplantation for haematological malignancies: basic considerations and best practice recommendations from the EBMT.

Since the early description of three patients with relapsed leukaemia after allogeneic haematopoietic cell transplantation (HCT) who obtained complete remission after donor lymphocyte infusions (DLIs), the added value of this procedure to induce or maintain graft-versus-leukaemia immunity has been undisputed. For more than 30 years, DLIs have become common practice as prophylactic, pre-emptive, or therapeutic immunotherapy. However, as with many aspects of allogeneic HCT, centres have developed their own routines and practices, and many questions related to the optimal applications and toxicity, or to the immunobiology of DLI induced tumour-immunity, remain.

Selective haematological cancer eradication with preserved haematopoiesis.

Haematopoietic stem cell (HSC) transplantation (HSCT) is the only curative treatment for a broad range of haematological malignancies, but the standard of care relies on untargeted chemotherapies and limited possibilities to treat malignant cells after HSCT without affecting the transplanted healthy cells. Antigen-specific cell-depleting therapies hold the promise of much more targeted elimination of diseased cells, as witnessed in the past decade by the revolution of clinical practice for B cell malignancies. However, target selection is complex and limited to antigens expressed on subsets of haematopoietic cells, resulting in a fragmented therapy landscape with high development costs.

Targeting TGFβ-activated kinase-1 activation in microglia reduces CAR T immune effector cell-associated neurotoxicity syndrome.

Cancer immunotherapy with chimeric antigen receptor (CAR) T cells can cause immune effector cell-associated neurotoxicity syndrome (ICANS). However, the molecular mechanisms leading to ICANS are not well understood. Here we examined the role of microglia using mouse models and cohorts of individuals with ICANS.

Circadian tumor infiltration and function of CD8 T cells dictate immunotherapy efficacy.

The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8 T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day.

Remission of relapsed/refractory classical Hodgkin lymphoma induced by brentuximab vedotin and pembrolizumab combination after allogeneic hematopoietic stem cell transplantation: a case report.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with highly chemorefractory Hodgkin lymphoma (HL). The CD30-targeting antibody-drug conjugate Brentuximab-Vedotin (BV) and programmed cell death protein-1 (PD-1) blocking agents have demonstrated clinical activity with durable responses in relapsed/refractory (r/r) HL. However, patients with a history of allo-HSCT were frequently excluded from clinical trials due to concerns about the risk of graft-versus-host disease (GVHD).

Molecular Imaging of Acute Graft-Versus-Host Disease.

Noninvasive molecular imaging of acute graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation has great potential to detect GvHD at the early stages, aid in grading of the disease, monitor treatment response, and guide therapeutic decisions. Although the specificity of currently available tracers appears insufficient for clinical GvHD diagnosis, recently, several preclinical studies have identified promising new imaging agents targeting one or more biologic processes involved in GvHD pathogenesis, ranging from T-cell activation to tissue damage. In this review, we summarize the different approaches reported to date for noninvasive detection of GvHD using molecular imaging with a specific focus on the use of PET.

Granulocyte-Macrophage Colony-Stimulating Factor in Allogenic Hematopoietic Stem Cell Transplantation: From Graft-versus-Host Disease to the Graft-versus-Tumor Effect.

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a widely used treatment for a broad range of hematologic malignancies because of its graft-versus-tumor (GVT) effect. Unfortunately, allo-HSCT is still associated with morbidity and mortality related to relapse and transplantation complications, namely graft-versus-host-disease (GVHD). In an era of therapies specifically targeting molecular pathways, transcription factors, and cytokines, a better understanding of GVHD physiopathology is essential for the development of new therapeutic approaches.

How to integrate CD19 specific chimeric antigen receptor T cells with other CD19 targeting agents in diffuse large B-cell lymphoma?

About one third of patients with diffuse large B-cell lymphoma (DLBCL) have a relapsing/refractory (R/R) disease after first line chemo-immunotherapy, with particularly poor outcomes observed in patients with primary refractory disease and early relapse. CD19 specific chimeric antigen receptor (CAR) T cell therapy is a game changer that results in durable and complete response rates in almost half of the patients with R/R DLBCL. Other emerging CD19-targeting therapies include monoclonal antibodies, bispecific antibodies and targeting antibody-drug conjugates, which also show encouraging results.

Epitope-engineered human hematopoietic stem cells are shielded from CD123-targeted immunotherapy.

Targeted eradication of transformed or otherwise dysregulated cells using monoclonal antibodies (mAb), antibody-drug conjugates (ADC), T cell engagers (TCE), or chimeric antigen receptor (CAR) cells is very effective for hematologic diseases. Unlike the breakthrough progress achieved for B cell malignancies, there is a pressing need to find suitable antigens for myeloid malignancies. CD123, the interleukin-3 (IL-3) receptor alpha-chain, is highly expressed in various hematological malignancies, including acute myeloid leukemia (AML).

Single-cell transcriptomics reveal different maturation stages and sublineage commitment of human thymic invariant natural killer T cells.

Invariant natural killer T cells are a rare, heterogeneous T-cell subset with cytotoxic and immunomodulatory properties. During thymic development, murine invariant natural killer T cells go through different maturation stages differentiating into distinct sublineages, namely, invariant natural killer T1, 2, and 17 cells. Recent reports indicate that invariant natural killer T2 cells display immature properties and give rise to other subsets, whereas invariant natural killer T1 cells seem to be terminally differentiated.