Cellular and humoral immunotherapy in children, adolescents and young adults with non-Hodgkin lymphoma.

The prognosis is dismal (2-year overall survival less than 25%) for childhood, adolescent, and young adult (CAYA) with relapsed and/or refractory (R/R) non-Hodgkin lymphoma (NHL). Novel targeted therapies are desperately needed for this poor-risk population. CD19, CD20, CD22, CD79a, CD38, CD30, LMP1 and LMP2 are attractive targets for immunotherapy in CAYA patients with R/R NHL. Novel anti-CD20 monoclonal antibodies, anti-CD38 monoclonal antibody, antibody drug conjugates and T and natural killer (NK)-cell bispecific and trispecific engagers are being investigated in the R/R setting and are changing the landscape of NHL therapy. A variety of cellular immunotherapies such as viral activated cytotoxic T-lymphocyte, chimeric antigen receptor (CAR) T-cells, NK and CAR NK-cells have been investigated and provide alternative options for CAYA patients with R/R NHL. Here, we provide an update and clinical practice guidance of utilizing these cellular and humoral immunotherapies in CAYA patients with R/R NHL.

Hematopoietic Progenitor Cell Transplantation in Children, Adolescents, and Young Adults With Relapsed Mature B-Cell NHL.

Although children, adolescents, and young adults with newly diagnosed B-cell non-Hodgkin's lymphoma enjoy excellent overall survival with current chemoimmunotherapy, those with relapsed and/or refractory disease have a dismal prognosis. Although most clinicians would agree that hematopoietic progenitor cell transplantation after reinduction therapy is frontline therapy for these patients, there is no consensus as to what type of hematopoietic progenitor cell transplantation promises the best event-free and overall survival. This review outlines the disparate types of stem cell therapy that have been used in this difficult-to-treat population as well as the role of maintenance and CAR T-cell therapy in conjunction with stem cell therapy.

Protein phosphatase 1 regulatory subunit 1A regulates cell cycle progression in Ewing sarcoma.

Ewing sarcoma (ES) is a malignant pediatric bone and soft tissue tumor. Patients with metastatic ES have a dismal outcome which has not been improved in decades. The major challenge in the treatment of metastatic ES is the lack of specific targets and rational combinatorial therapy. We recently found that protein phosphatase 1 regulatory subunit 1A (PPP1R1A) is specifically highly expressed in ES and promotes tumor growth and metastasis in ES. In the current investigation, we show that PPP1R1A regulates ES cell cycle progression in G1/S phase by down-regulating cell cycle inhibitors p21Cip1 and p27Kip1, which leads to retinoblastoma (Rb) protein hyperphosphorylation. In addition, we show that PPP1R1A promotes normal transcription of histone genes during cell cycle progression. Importantly, we demonstrate a synergistic/additive effect of the combinatorial therapy of PPP1R1A and insulin-like growth factor 1 receptor (IGF-1R) inhibition on decreasing ES cell proliferation and migration in vitro and limiting xenograft tumor growth and metastasis in vivo. Taken together, our findings suggest a role of PPP1R1A as an ES specific cell cycle modulator and that simultaneous targeting of PPP1R1A and IGF-1R pathways is a promising specific and effective strategy to treat both primary and metastatic ES.

Advances in cellular and humoral immunotherapy - implications for the treatment of poor risk childhood, adolescent, and young adult B-cell non-Hodgkin lymphoma.

Patients with relapsed, refractory or advanced stage B non-Hodgkin lymphoma (NHL) continue to have a dismal prognosis. This review summarises current and novel cellular and immunotherapy for these high-risk populations, including haematopoietic stem cell transplant, bispecific antibodies, viral-derived cytotoxic T cells, chimeric antigen receptor (CAR) T cells, and natural killer (NK) cell therapy, as discussed at the 6th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma on September 26th-29th 2018 in Rotterdam, the Netherlands, and explores the future of NK/CAR NK therapies.

A Multicenter Study of Bacterial Blood Stream Infections in Pediatric Allogeneic Hematopoietic Cell Transplantation Recipients: The Role of Acute Gastrointestinal Graft-versus-Host Disease.

Blood stream infections (BSI) caused by enteric organisms are associated with a particularly high mortality rate in allogeneic hematopoietic cell transplantation (alloHCT) recipients. We conducted a retrospective multicenter study aiming to analyze the risk factors associated with antibiotic resistance and impact of BSI on transplantation-related mortality (TRM) in children after alloHCT. During the study period from 2004 to 2014, 395 children (mean age, 9.4 years) with at least 1 BSI were included. The incidences of resistant gram-negative rods were 20.7% to piperacillin-tazobactam, 10.9% to cefepime, 21% to ceftazidime, 11.4% to levofloxacin, and 8.16% to meropenem. Thirty-eight percent of Enterococcus spp. isolates were resistant to vancomycin. More than 1 episode of BSI was associated with significant increase in the risk of resistance to piperacillin-tazobactam, cefepime, and vancomycin. On multivariate analysis of risk factors for TRM, achievement of neutrophil engraftment by day 30 was associated with lower TRM (P = .002). However, infection with an antibiotic-resistant organism was not associated with TRM. Development of enteric bacterial BSI after the onset of acute gastrointestinal graft-versus-host disease (GVHD) was the strongest predictor of TRM (hazard ratio, 4.786; 95% confidence interval, 2.833 to 8.087; P < .001). In patients with acute gastrointestinal GVHD who subsequently developed enteric bacterial BSI, the incidence of 1-year TRM was 33.4% (SE = 7%), compared with 15.3% (SE = 2%) for those without acute gastrointestinal GVHD (P = .004). Primary prevention of a first episode of BSI is arguably the most important intervention to decrease antibiotic resistance. It is also imperative that we develop strategies to maintain gastrointestinal health, especially in patients with gastrointestinal GVHD, in an effort to prevent subsequent enteric bacterial BSI and improve survival.

WW domain-containing oxidoreductase's role in myriad cancers: clinical significance and future implications.

The WW domain-containing oxidoreductase (WWOX) gene, encodes a tumor suppressor located on 16q23.1, spanning FRA16D, one of the most active common fragile sites in the human genome, that is altered in numerous types of cancer. WWOX's alteration in these myriad cancers is due to disparate mechanisms including loss of heterozygosity, homozygous deletion and epigenetic changes. In vitro, WWOX has been found to be reduced or absent in numerous cancer cell lines and WWOX restoration has been found to inhibit tumor cell growth and invasion. Wwox knockout mice developed femoral focal lesions resembling osteosarcomas within one month of their life and aging Wwox heterozygous mice have an increased incidence of spontaneous lung and mammary tumors as well as B-cell lymphomas. We herein review WWOX's role that has been unearthed thus far in different types of malignancies, its clinical significance and future implications.