A Multi-Center International Survey Related to the Nutritional Support after Hematopoietic Stem Cell Transplantation Endorsed by the ASIA Pacific Blood and Marrow Transplantation (APBMT)

Background: The nutritional support after hematopoietic stem cell transplantation (HSCT) has not been well established due to the scarcity of clinical trials. To conduct international clinical trials in Asia, we performed the questionnaire survey to investigate the current standard of nutritional support after HSCT. Method: We sent the questionnaire to the physicians nominated by the Asia Pacific Blood and Marrow Transplantation (APBMT) members of each country/ region. Result: We received 15 responses from 7 different countries/regions. The target calorie amount is 1.0 - 1.3 × basal energy expenditure (BEE) in 11 institutes when partial parenteral nutrition is used. When total parenteral nutrition (TPN) is used, the target calorie amount is 1.0 - 1.3 × BEE in 9 institutes and 1.3 - 1.5 × BEE in 4 institutes. Lipid emulsion is routinely used in 12 institutes. Multivitamins and trace elements are routinely added to TPN used in most institutes. It is still uncommon to use the immunonutrition. Blood glucose levels are routinely monitored in all institutes, but the target range varies (<110 in 2 institutes, <150 in 4 institutes, and <200 in 8 institutes). Conclusions: Basic nutritional support is similar in participating institutes. However, the target glucose level varies and the use of immunonutrition is rather rare. These points can be the theme of future clinical trials.

Optimal culture conditions for the generation of natural killer cell-induced dendritic cells for cancer immunotherapy

Dendritic cell(DC)-based vaccines continue to be considered an attractive tool for cancer immunotherapy.DCs require an additional signal from the environment or other immune cells to polarize the development of immune responses toward T helper 1(Th1)or Th2 responses.DCs play a role in natural killer(NK)cell activation,and NK cells are also able to activate and induce the maturation of DCs.We investigated the types of NK cells that can induce the maturation and enhanced function of DCs and the conditions under which these interactions occur.DCs that were activated by resting NK cells in the presence of inflammatory cytokines exhibited increased expression of several costimulatory molecules and an enhanced ability to produce IL-12p70.NK cell-stimulated DCs potently induced Th1 polarization and exhibited the ability to generate tumor antigen-specific cytotoxic T lymphocyte responses.Our data demonstrate that functional DCs can be generated by coculturing immature DCs with freshly isolated resting NK cells in the presence of Toll-like receptor agonists and proinflammatory cytokines and that the resulting DCs effectively present antigens to induce tumor-specific T-cell responses,which suggests that these cells may be useful for cancer immunotherapy.

Phase Ⅱ study of R-CVP followed by rituximab maintenance therapy for patients with advanced marginal zone lymphoma:consortium for improving survival of lymphoma(CISL)study

Background:The response rate and survival improvement for rituximab,a CD20-targeting monoclonal antibody,have been demonstrated in marginal zone lymphoma(MZL)as monotherapy and in combination with chemotherapeutic regimens,yet relapses still occur despite treatment completion.Thus,extending the period of remission in MZL patients remains an essential goal.This multicenter,single-arm,open-label phase II study evaluated the survival efficacy of 2 years of rituximab-maintenance therapy in patients with stage III-IV CD20-positive MZL who had responded to first-line R-CVP(rituximab,cyclophosphamide,vincristine,and prednisolone).The objective of this study was to determine whether rituximab maintenance following R-CVP warrants further investigation.Methods:Prior to rituximab-maintenance therapy,patients received 6-8 cycles of first-line R-CVP therapy for stage III-IV MZL.Rituximab(375 mg/m^(2)),cyclophosphamide(750 mg/m^(2)),and vincristine(1.4 mg/m^(2);maximum 2 mg)were administered via an intravenous infusion on day 1 of each 3-week cycle,while oral prednisolone(100 mg)was given on days 1-5 of each 3-week cycle.The patients who achieved complete response(CR),partial response(PR),or stable disease(SD)to R-CVP treatment,were prescribed rituximab-maintenance therapy which was administered intravenously at a dose of 375 mg/m^(2) every 8 weeks for up to 12 cycles.The primary endpoint was progression-free survival(PFS).Secondary endpoints were overall survival(OS)and treatment safety.Results:47 patients were enrolled,of whom,45(96%)received rituximab-maintenance treatment.Fifteen(33%)patients had nodal MZL.Following R-CVP first-line therapy,20(44%),22(49%),and 3(7%)patients achieved CR,PR,and SD,respectively.After a median follow-up of 38.2 months,their observed 3-year PFS rate was 81%.During the rituximab-maintenance,6 PR and 1 SD patients achieved CR following the administration of R-CVP.Elevated LDH and the presence of B symptoms were found to be significant prognostic factors for PFS(P=0.003)and demonstrated a 3-year OS rate of 90%.Rituximab-maintenance therapy was well tolerated,and the common treatment-emergent adverse events were sensory neuropathy(18%),myalgia(13%),fatigue(9%),and neutropenia(9%).Conclusion: Rituximab-maintenance therapy following first-line R-CVP demonstrated good PFS in patients with stage III-IV MZL, in addition to a favorable toxicity profile.

A combination of immunoadjuvant nanocomplexes and dendritic cell vaccines in the presence of immune checkpoint blockade for effective cancer immunotherapy

Nanovaccines are used as delivery platforms for antigens and adjuvants, which activate antigen-presenting cells (APCs) and enhance anticancer immune responses.1,2 Researchers have recently developed a self-assembled nanocomplex using a polysorbitol-co-PEI (PSPEI) polymer complexed with poly(I:C) (PIC). By binding to different surface proteins, this nanocomplex enhances the intracellular delivery of cargos and induces potent anticancer immune responses against melanoma cells.3 We have previously demonstrated that PD-1/PD-L1 blockade enhanced the efficacy of DC-based cancer immunotherapy.4,5 Moreover, the combination of nanomedicines and PD-L1 blockade has been reported to enhance CD8+ T cell activation and inhibit immunosuppressive cells within the tumor microenvironment.6 In the present study, we investigated the therapeutic efficacy of a combinatorial treatment comprising the immunoadjuvant nanocomplex PSPEI-PIC, a DC vaccine, and PD-L1 blockade in a murine colon cancer model.

Type I and II interferons enhance dendritic cell maturation and migration capacity by regulating CD38 and CD74 that have synergistic effects with TLR agonists

The major limitation for the maturation of dendritic cells(DCs)using Toll-like receptor(TLR)agonists is their decreased ability to migrate into lymph nodes compared with conventional DCs.CD38 can be used as a multifunctional marker to modulate migration,survival and Th1 responses of DCs.CD74 has been shown to negatively regulate DC migration.The goal of this study was to investigate the combinations of TLR agonists and interferons(IFNs)that most effectively regulate CD38 and CD74 expression on DCs.Synergistic TLR agonist stimulation in combination with IFN-a and IFN-c was the best method for regulating CD38 and CD74 expression and inducing the highest secretion of IL-12p70.An in vitro migration assay showed that DCs treated with this combination had significantly enhanced migratory ability,similar to that observed in cells expressing CD38,CD74 and CCR7.The results of this study suggest that an alternative maturation protocol in which two TLR ligands are combined with type I and II IFNs generates potent DCs that have both a high migratory capacity and high IL-12p70 production.

Expanded natural killer cells augment the antimyeloma effect of daratumumab, bortezomib, and dexamethasone in a mouse model

The use of natural killer(NK)cells is a promising and safe immunotherapeutic approach in the field of cancer immunotherapy.However,combination treatments are required to enhance the effector functions and therapeutic efficacy of NK cells.In this study,we investigated the potential of daratumumab(Dara),bortezomib,and dexamethasone(Dvd)to augment the antitumor effects of NK cells in a multiple myeloma(MM)xenograft mouse model.NK cells were expanded and activated using the K562-OX40 ligand and membrane-bound IL-18 and IL-21 in the presence of IL-2 and IL-15 from peripheral blood mononuclear cells from MM patients.A human MM xenograft model was established using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγnull(NSG)mice.Tumor-bearing mice were divided into six treatment groups:no treatment,expanded NK cells(eNKs),Dara,Dara+eNKs,Dvd,and Dvd+eNKs.Dvd treatment strongly enhanced the cytotoxicity of eNKs by upregulating expression of NK cell activation ligands,downregulating expression of NK cell inhibitory ligands,and promoting antibody-dependent cellular cytotoxicity.The combination of eNKs with Dvd significantly prolonged mouse survival and reduced the tumor burden and serum M-protein level.Furthermore,Dvd pretreatment significantly increased eNK persistence and homing to MM sites.Our findings suggest that Dvd treatment potentiates the antimyeloma effects of NK cells expanded and activated ex vivo by modulating immune responses in MM-bearing mice.