Evaluation of a metal fuselage panel selectively reinforced with filamentary composites for space shuttle application

The use of high strength and modulus of advanced filamentary composites to reduce the structural weight of aerospace vehicles was investigated. Application of the technology to space shuttle components was the primary consideration. The mechanical properties for the boron/epoxy, graphite/epoxy, and polyimide data are presented. Structural testing of two compression panel components was conducted in a simulated space shuttle thermal environment. Results of the tests are analyzed

Tumorantigen-Specific CD40B Cells: Combining Enhanced Antigen-Presentation and Antibody-Secretion for Tumor Targeting

Efficient antigen presentation is a prerequisite for the development of a T-cell-mediated immune response in vitro and in vivo. As “nature’s adjuvant”, dendritic cells (DCs) are the most prominent professional antigen-presenting cells (APCs). However, they have several significant disadvantages concerning application as an adjuvant in cancer immunotherapy. They are rare in peripheral blood and the isolated population is not homogenous, since it also contains unwanted tolerogenic DCs. Therefore, an alternative approach to DCs was developed, in which polyclonal B cells can serve as potent APCs by treatment with the inflammatory cytokine IL-4 and the CD40 ligand. CD40-activation dramatically improves antigen presentation by normal and malignant B cells, efficiently inducing naïve and memory CD4+ and CD8+ T-cell responses. Moreover, these CD40-activated (CD40) B cells do not only home to secondary lymphoid organs, but also induce anti-tumor immunity in mice. However, antigen-processing and -presentation by antigen-specific B cells is 1000-fold more effective compared to polyclonal B cells. Therefore, tumorantigen-specific B cells were used in the present study to improve the antigen-presenting function of CD40B cells. Purified tumorantigen-specific B cells highly upregulate activation markers upon CD40-stimulation resulting in an enhanced antigen-presentation and a specific T-cell response in vitro and in vivo. The T cell response elicited by antigen-specific CD40B cells is significantly stronger than that induced by polyclonal CD40B cells and comparable to the stimulation induced by mature DCs. Alone or in combination with antibody-secreting plasma cells, preventive vaccination with these antigen-specific CD40B cells leads to an anti-tumor immune response in vivo resulting in complete inhibition of tumor growth. Moreover, antigen-specific B cells home to the tumor site, thereby offering new application perspectives as vehicle for tumor imaging and drug delivery. These results provide new insights into the role of activated antigen-specific B cells as APCs and their use for cancer immunotherapy

Reverted exhaustion phenotype of circulating lymphocytes as immune correlate of anti-PD1 first-line treatment in Hodgkin lymphoma

While classical Hodgkin lymphoma (HL) is highly susceptible to anti-programmed death protein 1 (PD1) antibodies, the exact modes of action remain controversial. To elucidate the circulating lymphocyte phenotype and systemic effects during anti-PD1 1st-line HL treatment we applied multicolor flow cytometry, FluoroSpot and NanoString to sequential samples of 81 HL patients from the NIVAHL trial (NCT03004833) compared to healthy controls. HL patients showed a decreased CD4 T-cell fraction, a higher percentage of effector-memory T cells and higher expression of activation markers at baseline. Strikingly, and in contrast to solid cancers, expression for 10 out of 16 analyzed co-inhibitory molecules on T cells (e.g., PD1, LAG3, Tim3) was higher in HL. Overall, we observed a sustained decrease of the exhausted T-cell phenotype during anti-PD1 treatment. FluoroSpot of 42.3% of patients revealed T-cell responses against ≥1 of five analyzed tumor-associated antigens. Importantly, these responses were more frequently observed in samples from patients with early excellent response to anti-PD1 therapy. In summary, an initially exhausted lymphocyte phenotype rapidly reverted during anti-PD1 1st-line treatment. The frequently observed IFN-y responses against shared tumor-associated antigens indicate T-cell-mediated cytotoxicity and could represent an important resource for immune monitoring and cellular therapy of HL

CD40-activated B cells induce anti-tumor immunity in vivo

The introduction of checkpoint inhibitors represents a major advance in cancer immunotherapy. Some studies on checkpoint inhibition demonstrate that combinatorial immunotherapies with secondary drivers of anti-tumor immunity provide beneficial effects for patients that do not show a strong endogenous immune response. CD40-activated B cells (CD40B cells) are potent antigen presenting cells by activating and expanding naïve and memory CD4 + and CD8 + and homing to the secondary lymphoid organs. In contrast to dendritic cells, the generation of highly pure CD40B cells is simple and time efficient and they can be expanded almost limitlessly from small blood samples of cancer patients. Here, we show that the vaccination with antigen-loaded CD40B cells induces a specific T-cell response in vivo comparable to that of dendritic cells. Moreover, we identify vaccination parameters, including injection route, cell dose and vaccination repetitions to optimize immunization and demonstrate that application of CD40B cells is safe in terms of toxicity in the recipient. We furthermore show that preventive immunization of tumor-bearing mice with tumor antigen-pulsed CD40B cells induces a protective anti-tumor immunity against B16.F10 melanomas and E.G7 lymphomas leading to reduced tumor growth. These results and our straightforward method of CD40B-cell generation underline the potential of CD40B cells for cancer immunotherapy

B Cell-Based Cancer Immunotherapy

B cells are not only producers of antibodies, but also contribute to immune regulation or act as potent antigen-presenting cells. The potential of B cells for cellular therapy is still largely underestimated, despite their multiple diverse effector functions. The CD40L/CD40 signaling pathway is the most potent activator of antigen presentation capacity in B lymphocytes. CD40-activated B cells are potent antigen-presenting cells that induce specific T-cell responses in vitro and in vivo. In preclinical cancer models in mice and dogs, CD40-activated B cell-based cancer immunotherapy was able to induce effective antitumor immunity. So far, there have been only few early-stage clinical studies involving B cell-based cancer vaccines. These trials indicate that B cell-based immunotherapy is generally safe and associated with little toxicity. Furthermore, these studies suggest that B-cell immunotherapy can elicit antitumor T-cell responses. Alongside the recent advances in cellular therapies in general, major obstacles for generation of good manufacturing practice-manufactured B-cell immunotherapies have been overcome. Thus, a first clinical trial involving CD40-activated B cells might be in reach. (C) 2019 S. Karger AG, Base

Results of a Phase II clinical trial with Id-protein-loaded dendritic cell vaccine in multiple myeloma: encouraging or discouraging?

Evaluation of: Zahradova L, Mollova K, Ocadlikova D et al. Efficacy and safety of Id-protein-loaded dendritic cell vaccine in patients with multiple myeloma - Phase II study results. Neoplasma 59(4), 440-449 (2012). Recently gained insight into the role of dendritic cells (DCs) as APCs has attracted the attention of many researchers who hope to use them as a tool in immunotherapy for the induction of tumor-specific immunity in cancer settings. Despite high expectations, in multiple myeloma patients the results of DC-based vaccines in terms of clinical response have been disappointing. The findings of Zahradova et al. in a Phase II clinical trial with multiple myeloma patients corroborated these results. Although no clinical responses were observed, the investigators induced immunity after vaccination with Id-protein-loaded DC vaccine in some patients. These immunological results showed a trend towards a longer duration of stable disease in those patients that received the vaccination. Moreover, this study showed that Id-protein-loaded DC vaccines are safe and nontoxic and that they are able to induce immunity in some patients. Therefore, standardization of vaccination protocols appears to be the key to achieving a better clinical outcome