Restricting CAR T Cell Trafficking Expands Targetable Antigen Space.

Chimeric antigen receptor (CAR) T cells are an effective treatment for some blood cancers. However, the lack of tumor-specific surface antigens limits their wider use. We identified a set of surface antigens that are limited in their expression to cancer and the central nervous system (CNS).

Autologous stem cell boost improves persistent immune effector cell associated hematotoxicity following BCMA directed chimeric antigen receptor T (CAR T) cell therapy in multiple myeloma.

Persistent Immune Effector Cell Associated Hematotoxicity (ICAHT) is a significant side effect of BCMA CAR T-Cell therapy in patients with relapsed multiple myeloma (MM). The use of stem cell boosts in ICAHT has been described, however studies have been limited by small patient numbers and short follow up. Herein, we report on our multi-institutional experience of ICAHT, defined by an absolute neutrophil count (ANC) of ≤ 1000, thrombocytopenia with a platelet count ≤ 50,000 or/and anemia as hemoglobin (hgb) ≤9 g/dL, in patients who received BCMA CAR T therapy, and the effects of subsequent stem cell boost on hematopoietic reconstitution and clinical outcome.

Systematic single amino acid affinity tuning of CD229 CAR T cells retains efficacy against multiple myeloma and eliminates on-target off-tumor toxicity.

T cells expressing chimeric antigen receptors (CARs) have shown remarkable therapeutic activity against different types of cancer. However, the wider use of CAR T cells has been hindered by the potential for life-threatening toxicities due to on-target off-tumor killing of cells expressing low amounts of the target antigen. CD229, a signaling lymphocyte-activation molecule (SLAM) family member, has previously been identified as a target for CAR T cell-mediated treatment of multiple myeloma (MM) due to its high expression on the surfaces of MM cells.

CD229 CAR T cells eliminate multiple myeloma and tumor propagating cells without fratricide.

Multiple myeloma (MM) is a plasma cell malignancy and most patients eventually succumb to the disease. Chimeric antigen receptor (CAR) T cells targeting B-Cell Maturation Antigen (BCMA) on MM cells have shown high-response rates, but limited durability. CD229/LY9 is a cell surface receptor present on B and T lymphocytes that is universally and strongly expressed on MM plasma cells.

A Phase 1 Study of Intravenous Busulfan as a Conditioning Regimen for Multiple Myeloma.

The efficacy of melphalan (MEL) 140 mg/m pre-transplant conditioning versus MEL 200 mg/m for the elderly is still debated. We hypothesized that single-agent intravenous busulfan (BU) would show significant anti-myeloma efficacy and be better tolerated by elderly patients. A prospective 3+3 dose escalation study enrolled symptomatic multiple myeloma (MM) patients 65 years or older with SWOG performance 0-2 for treatment with intravenous BU pre-transplant at different administration levels.

The role of surface molecule CD229 in Multiple Myeloma.

The outcome of Multiple Myeloma (MM) patients has dramatically improved, however, most patients will still succumb to their disease. Additional therapeutic options are urgently needed and novel immunotherapies are enormously promising in the therapeutic armamentarium against MM. The first step in the development of any immunotherapy needs to be the identification of an appropriate target structure.

Novel anti-myeloma immunotherapies targeting the SLAM family of receptors.

Treatment for multiple myeloma (MM) has significantly advanced in the last decade with the introduction of proteasome inhibitors and immunomodulatory therapies. Unfortunately, MM continues to cause significant morbidity and most patients eventually succumb to the disease. As in other areas of cancer, immunotherapy in MM has also evolved and holds promise to deliver long-lasting remissions or even cure.

Elotuzumab as a novel anti-myeloma immunotherapy.

Treatment of multiple myeloma has undergone significant change in the last decade with the introduction of new immunomodulatory agents, proteasome inhibitors, and immunotherapeutic approaches. Elotuzumab is a humanized monoclonal antibody targeting CS1, which is a member of the SLAM (Signaling Lymphocyte Activation Molecule) family of proteins, expressed on the surface of myeloma plasma cells. Here we review the preclinical investigations that led to the development of elotuzumab and the clinical studies that resulted in its approval for the treatment of relapsed/refractory multiple myeloma.

Oscillating expression of interleukin-16 in multiple myeloma is associated with proliferation, clonogenic growth, and PI3K/NFKB/MAPK activation.

Multiple myeloma (MM) is an incurable hematologic malignancy emerging from a plasma cell clone located in the bone marrow and is characterized by a high rate of fatal relapses after initially effective treatment. We have previously identified Interleukin-16 (IL-16) as an important factor promoting the proliferation of MM cells. We demonstrate here an upregulated, periodic expression, and secretion of IL-16 by MM cells leading to high extracellular IL-16 levels.

Current Strategies for the Immunotherapy of Multiple Myeloma.

The introduction of cellular immunotherapies using genetically modified T cells has revolutionized the treatment of patients with B-cell lymphomas. However, despite the progress made in this field, similarly effective immunotherapeutic approaches have not yet been identified for patients with solid tumors or other hematologic malignancies such as multiple myeloma. Here we outline the most promising novel cellular immune strategies for patients with multiple myeloma.

Immunotherapies targeting CD38 in Multiple Myeloma.

Recently, the monoclonal antibody daratumumab was approved as a single agent for the treatment of patients with relapsed/refractory Multiple Myeloma (MM). Daratumumab is an antibody targeting surface molecule CD38 on myeloma cells and the agent is already widely being used based on its good tolerability and proven efficacy. We believe, however, that the efficacy of this drug and other anti-CD38 monoclonal antibodies can be further improved by combining it with other types of immunotherapies.

Chimeric Antigen Receptor (CAR) therapy for multiple myeloma.

The introduction of chimeric antigen receptor (CAR)-modified T cells has revolutionized immunotherapy and cancer treatment as a whole. However, so far, clinical efficacy has only been demonstrated for CD19-positive B cell lymphomas. For Multiple Myeloma (MM), the second most common haematological malignancy, there are currently no clinical results supporting the usefulness of the adoptive transfer of CAR-modified T cells.

A call to arms: a critical need for interventions to limit pulmonary toxicity in the stem cell transplantation patient population.

Noninfectious pulmonary toxicity after allogeneic hematopoietic stem cell transplantation (allo-HSCT) causes significant morbidity and mortality. Main presentations are idiopathic pneumonia syndrome (IPS) in the acute setting and bronchiolitis obliterans syndrome (BOS) and cryptogenic organizing pneumonia (COP) at later time point. While COP responds well to corticosteroids, IPS and BOS often are treatment refractory.

Preventive azithromycin treatment reduces noninfectious lung injury and acute graft-versus-host disease in a murine model of allogeneic hematopoietic cell transplantation.

Noninfectious lung injury and acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) are associated with significant morbidity and mortality. Azithromycin is widely used in allogeneic HCT recipients for pulmonary chronic GVHD, although current data appear controversial. We induced GVHD and noninfectious lung injury in lethally irradiated B6D2F1 mice by transplanting bone marrow and splenic T cells from allogeneic C57BL/6 mice.

Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage.

Acute graft-versus-host disease (GVHD) considerably limits wider usage of allogeneic hematopoietic cell transplantation (allo-HCT). Antigen-presenting cells and T cells are populations customarily associated with GVHD pathogenesis. Of note, neutrophils are the largest human white blood cell population.

Murine cytomegalovirus immediate-early 1 gene expression correlates with increased GVHD after allogeneic hematopoietic cell transplantation in recipients reactivating from latent infection.

The success of allogeneic (allo) hematopoietic cell transplantation (HCT) is limited by its treatment related complications, mostly graft versus host disease (GVHD) and fungal and viral infections. CMV reactivation after HCT has been associated with increased morbidity and mortality, and a causal relation between GVHD, immunosuppressive therapy and vice versa has been postulated. Using a low GVHD severity murine HCT model, we assessed the role of MCMV reactivation and GVHD development.