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. In this study, ICAHT was observed in 60% (n = 61/101) of patients at D + 21, and risk factors for its development included history of a prior ASCT, higher number of prior lines of therapy, a decreased platelet count prior to lymphodepletion and history of ICANS. 28% of patients with ICAHT received a stem cell boost at a median of 116 days due to profound and prolonged cytopenias often requiring ongoing transfusion support. Stem cell boost significantly improved cytopenias at 3 and 6 months follow up without any adverse effects on PFS and OS, underscoring the safety of this procedure.

The changing spectrum of infection with BCMA and GPRC5D targeting bispecific antibody (bsAb) therapy in patients with relapsed refractory multiple myeloma.

There is a paucity of granular data on infection risk with B-cell maturation antigen (BMCA) and GPRC5D bispecific antibodies (bsAb) in relapsed/refractory multiple myeloma (RRMM). The aim of our multi-institutional study was to characterize the incidence, etiologies, and risk factors of infections from the start of therapy to the last follow-up or 90 days after study exit. A total of 66 patients received BCMA bsAb monotherapy, 15 GPRC5D bsAb monotherapy, and 15 GPRC5D bsAb combination therapy with daratumumab and/or pomalidomide. While the infection rate per 100 days was 0.57 for BCMA bsAb, it was 0.62 for GPRC5D bsAb combination and 0.13 for GPRC5D bsAb monotherapy; P=0.05. The proportion of infections that were grade ≥3 was higher in the BCMA bsAb group compared to the GPRC5D groups (58% vs. 36%; P=0.04). Grade 5 events were observed in 8% (n=8) of the patients, all treated with BCMA bsAb. The 9 month cumulative incidence of any grade of infection was similar in the BCMA and GPRC5D-combination groups (57% and 62%) and significantly higher than in the GPRC5D-mono group (16%); P=0.012. The cumulative incidence of grade ≥3 infections was highest in the BCMA group reaching 54% at 18 months; P=0.06. Multivariate analysis showed that BCMA bsAb therapy or GPRC5D combination therapy, history of previous infections, baseline lymphopenia, and baseline hypogammaglobulinemia were significantly associated with a higher risk of grade ≥3 infections. Our results indicate that BCMA bsAb and GPRC5D-combination therapies in RRMM are associated with higher cumulative incidence of infection and grade ≥3 infection compared to GPRC5D bsAb mono.

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. In this review we present the current knowledge on surface molecule CD229, a member of the Signaling Lymphocyte Activation (SLAM) family of immune receptors. We believe that based on its characteristics, including (1) strong and homogenous expression on all myeloma cells, (2) expression on myeloma precursors, (3) absence from most normal tissues, (4) a central function in the biology of MM, CD229 (SLAMF3) represents a promising target for anti-MM immunotherapies. The introduction of novel anti-CD229 approaches into the clinic will hopefully lead to more durable responses, or maybe even cures, in MM.

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. Although preclinical data looked very promising, elotuzumab monotherapy did not result in objective clinical responses in patients with relapsed/refractory multiple myeloma. However, combination treatment with immunomodulators and proteasome inhibitors resulted in substantial clinical activity in relapsed/refractory MM. Currently, there are several clinical trials ongoing investigating the role of elotuzumab in newly diagnosed myeloma patients and in patients receiving maintenance therapy.

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. The signaling lymphocyte activation molecules (SLAM) family of surface proteins represents a group of potential targets for immunotherapy in MM as some of the family members are expressed consistently on plasma cells and also on myeloma propagating pre-plasma cells. Here, we review the SLAM family members in detail, describe their tissue distribution, biologic pathways, as well as relevant pre-clinical studies and clinical trials in MM. Our review demonstrates the value of SLAM family receptors as potential targets for anti-myeloma immunotherapies and outlines how immunotherapeutic approaches can be developed.

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. The level of IL-16 released from a given MM cell line correlated with its proliferative activity. Establishing an inducible knockdown system and performing gene expression arrays we observed an association between IL-16 expression and activation of PI3, NFκB and MAP kinase pathways and, specifically, genes involved in tumor cell proliferation. Functional assays showed that IL-16 knockdown reduced the proliferative activity with a significant delay in cell cycle progression to G2 phase of conventional MM cells and completely suppressed the growth of clonogenic MM cells, which are suspected to be responsible for the high relapse rates in MM. Overall, our results demonstrate that tumor-regenerating MM cells may be particularly susceptible to IL-16 neutralization, suggesting an important role of anti-IL-16 therapies in the treatment of MM, particularly in combination with existing strategies targeting the bulk of myeloma cells.

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. In addition, we highlight combinatorial approaches that, it is hoped, will further optimize cellular immunotherapies for myeloma and lead to deep and durable responses and, possibly, even cures.

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. Furthermore, surface molecule CD38 can be used as a target for immunotherapies other than just naked monoclonal antibodies. In this report, we review the expression pattern of CD38 among normal tissues and in different types of plasma cell dyscrasias including their progenitor cells, minimal residual disease, and circulating tumor cells. We summarize the physiological role of CD38 as well as its role in the pathophysiology of MM and we present the most recent clinical trials using CD38 as a target. In addition, we highlight possible combination immunotherapies incorporating anti-CD38 monoclonal antibodies and we demonstrate alternative immunotherapeutic approaches targeting the same antigen such as CD38-specific chimeric antigen receptor (CAR) 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. IPS, in most cases, is rapidly fatal, whereas BOS progresses over time, resulting in chronic respiratory failure, impaired quality of life, and eventually, death. Standard second-line treatments are currently lacking, and current approaches, such as augmented T cell-directed immunosuppression, B cell depletion, TNF blockade, extracorporeal photopheresis, and tyroskine kinase inhibitor therapy, are unsatisfactory with responses in only a subset of patients. Better understanding of underlying pathophysiology hopefully results in the identification of future targets for preventive and therapeutic strategies along with an emphasis on currently underutilized rehabilitative and supportive measures.

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. Experimental groups were treated with oral azithromycin starting on day 14 until the end of week 6 or week 14 after transplantation. Azithromycin treatment resulted in improved survival and decreased lung injury; the latter characterized by improved pulmonary function, reduced peribronchial and perivascular inflammatory cell infiltrates along with diminished collagen deposition, and a decrease in lung cytokine and chemokine expression. Azithromycin also improved intestinal GVHD but did not affect liver GVHD at week 6 early after transplantation. At week 14, azithromycin decreased liver GVHD but had no effect on intestinal GVHD. In vitro, allogeneic antigen-presenting cell (APC)- dependent T cell proliferation and cytokine production were suppressed by azithromycin and inversely correlated with relative regulatory T cell (Treg) expansion, whereas no effect was seen when T cell proliferation occurred APC independently through CD3/CD28-stimulation. Further, azithromycin reduced alloreactive T cell expansion but increased Treg expansion in vivo with corresponding downregulation of MHC II on CD11c(+) dendritic cells. These results demonstrate that preventive administration of azithromycin can reduce the severity of acute GVHD and noninfectious lung injury after allo-HCT, supporting further investigation in clinical trials.

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. BALB/c mice were infected with either murine CMV (MCMV) or mock and monitored for 25 weeks to establish latency, followed by sublethal irradiation conditioning and infusion of bone marrow plus splenocytes from either syngeneic (syn) BALB/c or allo B10.D2 donors. Engraftment of allo donor cells was confirmed by PCR for D2Mit265 gene product size. Day+100 mortality and overall GVHD severity in allo MCMV pre-infected recipients was higher than in allo mock controls. Pathologic changes of lung and liver GVHD in immediate-early gene 1 (IE1) positive recipients were significantly increased compared to mock controls, and were only slightly increased in IE1 negative. No significant gut injury was seen in any group. Aggravated lung injury in IE1 positive recipients correlated with higher BAL cell counts both for total cells and for CD4+ T cells when compared with mock controls, and also with protein expression of lung IFN-gamma and liver TNF. No evidence for CMV specific morphologic changes was seen on histopathology in any organ of IE1 positive recipients, suggesting that CMV reactivation is related to increased GVHD severity but does not require active CMV disease, strengthening the concept of a reciprocal relationship between CMV and GVHD.