NK cells have therapeutic potential for a wide variety of human malignancies. However, because NK cells expand poorly in vitro, have limited life spans in vivo, and represent a small fraction of peripheral white blood cells, obtaining sufficient cell numbers is the major obstacle for NK-cell immunotherapy. Genetically-engineered artificial antigen-presenting cells (aAPCs) expressing membrane-bound IL-15 (mbIL15) have been used to propagate clinical-grade NK cells for human trials of adoptive immunotherapy, but ex vivo proliferation has been limited by telomere shortening. We developed K562-based aAPCs with membrane-bound IL-21 (mbIL21) and assessed their ability to support human NK-cell proliferation. In contrast to mbIL15, mbIL21-expressing aAPCs promoted log-phase NK cell expansion without evidence of senescence for up to 6 weeks of culture. By day 21, parallel expansion of NK cells from 22 donors demonstrated a mean 47,967-fold expansion (median 31,747) when co-cultured with aAPCs expressing mbIL21 compared to 825-fold expansion (median 325) with mbIL15. Despite the significant increase in proliferation, mbIL21-expanded NK cells also showed a significant increase in telomere length compared to freshly obtained NK cells, suggesting a possible mechanism for their sustained proliferation. NK cells expanded with mbIL21 were similar in phenotype and cytotoxicity to those expanded with mbIL15, with retained donor KIR repertoires and high expression of NCRs, CD16, and NKG2D, but had superior cytokine secretion. The mbIL21-expanded NK cells showed increased transcription of the activating receptor CD160, but otherwise had remarkably similar mRNA expression profiles of the 96 genes assessed. mbIL21-expanded NK cells had significant cytotoxicity against all tumor cell lines tested, retained responsiveness to inhibitory KIR ligands, and demonstrated enhanced killing via antibody-dependent cell cytotoxicity. Thus, aAPCs expressing mbIL21 promote improved proliferation of human NK cells with longer telomeres and less senescence, supporting their clinical use in propagating NK cells for adoptive immunotherapy.

Childhood, adolescent, and young adult cancer survivors demonstrate increased cardio-metabolic risk factors, which are amenable to lifestyle changes. The use of technology to impact lifestyle change expands previously limited intervention access, yet little is known about its use. We summarized lifestyle interventions for survivors delivered using technology, finding six studies, primarily targeting physical activity. Study samples were small and durations ranged from 5 to 16 weeks and outcomes modest. Participants were older, white, survivors of leukemia or brain tumors, and the majority received Web-based interventions. Study quality was moderate. Few technology-based interventions have been developed, suggesting an area of opportunity for survivors.

BMAB may not be required for initial staging of pediatric and young adult EWS patients deemed non-metastatic by imaging. In patients with metastatic disease, there is a high correlation of BM involvement with multiple bone metastases.

Background : New investigational agents and chemotherapy regimens including cyclophosphamide + topotecan, temozolomide + irinotecan, and anti-IGF-1R antibodies in Ewing's sarcoma (ES) and liposomal muramyltripeptide phosphatidylethanolamine (L-MTP-PE), aerosol therapy, and bone-specific agents in osteosarcoma (OS) may improve survival and/or quality of life on 'continuation' therapy. Objective : Review of investigational approaches and control paradigms for recurrent or metastatic primary bone tumors. Methods : Analyze temozolomide + irinotecan data and review in the context of other newer approaches including antiangiogenesis, anti-IGF-1R antibodies and bisphosphonates for ES. Review some current stateof-the-art approaches for OS including L-MTP-PE, anti-IGF-1R inhibition, aerosol therapies and bone specific agents. Results/conclusion : L-MTP-PE with chemotherapy in OS has been shown to improve survival; compassionate access is available for recurrence and/or metastases. Aerosol therapy (granulocyte-macrophage colony stimulating factor, cisplatin, gemcitabine) for lung metastases is a promising approach to reduce systemic toxicity. The bone-specific agents including denosumab (anti-receptor activator of NF-κ B ligand antibody) and bisphosphonates may have benefit against giant cell tumor, ES and OS. Anti-IGF-1R antibody SCH717454 has preclinical activity in OS but best effectiveness will most likely be in combination with chemotherapy earlier in therapy. Both temozolomide + irinotecan and cyclophosphamide + topotecan combinations are very active in ES and are likely to be tested with anti-IGF-1R antibodies against ES.