Ginsenoside Rb1 prevents deoxynivalenol-induced immune injury via alleviating oxidative stress and apoptosis in mice.

Deoxynivalenol (DON) is considered to be a grave threat to humans and animals. Ginsenoside Rb1 (Rb1) has been reported for its antioxidant potential and medicinal properties. However, the shielding effects of Rb1 and the precise molecular mechanisms against DON-induced immunotoxicity in mice have not been reported yet. In the present research, 4-weeks old healthy C57BL/6 mice were randomly assigned into four experimental groups (n = 12), viz., CON, DON 3 mg/kg BW, Rb1 50 mg/kg BW and DON 3 mg/kg + Rb1 50 mg/kg BW (DON + Rb1). Feed intake and body weight gain were monitored during the entire experiment (15 d). Our results demonstrated that Rb1 markedly increased the ADG (30%) and ADFI (25.10%) of mice compared with DON group. Furthermore, Rb1 alleviated the DON-induced immune injury by relieving the splenic histopathological alteration, enhancing the T-lymphocytes subsets (CD4+, CD8+), the levels of cytokines (IL-2, IL-6, IFN-γ, and TNF-α), as well as production of immunoglobulins (IgA, IgM, and IgG). Moreover, Rb1 ameliorated DON-inflicted oxidative stress by reducing the ROS, MDA and H2O2 contents and boosting the antioxidant defense system (T-AOC, T-SOD, CAT, and GSH-Px). Additionally, Rb1 significantly reversed the DON-induced excessive splenic apoptosis via modulating the mitochondria-mediated apoptosis pathway in mice, depicting the decreased percentage of splenocyte apoptotic cells by 26.65%, down-regulated the mRNA abundance of Bax, caspase-3, caspase-9, and protein expression of Bax, cleaved caspase-3, and Cyt-c. Simultaneously, Rb1 markedly rescued both Bcl-2 mRNA and protein expression levels. Taken together, Rb1 mitigates DON-induced immune injury by suppressing the oxidative damage and regulating the mitochondria-mediated apoptosis pathway in mice. Conclusively, our current research provides an insight into the preventive mechanism of Rb1 against DON-induced immune injury in mice and thus, presents a scientific baseline for the therapeutic application of Rb1.

Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma.

The prognosis for patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) remains poor, with a need for alternatives to current salvage therapies. Loncastuximab tesirine (ADCT-402) is an antibody-drug conjugate comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin. Presented here are final results of a phase 1 dose-escalation and dose-expansion study in patients with R/R B-NHL. Objectives were to determine the maximum tolerated dose (MTD) and recommended dose(s) for expansion and evaluate safety, clinical activity, pharmacokinetics, and immunogenicity of loncastuximab tesirine. Overall, 183 patients received loncastuximab tesirine, with 3 + 3 dose escalation at 15 to 200 µg/kg and dose expansion at 120 and 150 µg/kg. Dose-limiting toxicities (all hematologic) were reported in 4 patients. The MTD was not reached, although cumulative toxicity was higher at 200 µg/kg. Hematologic treatment-emergent adverse events were most common, followed by fatigue, nausea, edema, and liver enzyme abnormalities. Overall response rate (ORR) in evaluable patients was 45.6%, including 26.7% complete responses (CRs). ORRs in patients with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and follicular lymphoma were 42.3%, 46.7%, and 78.6%, respectively. Median duration of response in all patients was 5.4 months and not reached in patients with DLBCL (doses ≥120 µg/kg) who achieved a CR. Loncastuximab tesirine had good stability in serum, notable antitumor activity, and an acceptable safety profile, warranting continued study in B-NHL. The recommended dose for phase 2 was determined as 150 µg/kg every 3 weeks for 2 doses followed by 75 µg/kg every 3 weeks. This trial was registered at www.clinicaltrials.gov as #NCT02669017.

A novel, safe, fast and efficient treatment for Her2-positive and negative bladder cancer utilizing an EGF-anthrax toxin chimera.

Bladder cancer is the sixth most common cancer in the United States, and it exhibits an alarming 70% recurrence rate. Thus, the development of more efficient antibladder cancer approaches is a high priority. Accordingly, this work provides the basis for a transformative anticancer strategy that takes advantage of the unique characteristics of the bladder. Unlike mucin-shielded normal bladder cells, cancer cells are exposed to the bladder lumen and overexpress EGFR. Therefore, we used an EGF-conjugated anthrax toxin that after targeting EGFR was internalized and triggered apoptosis in exposed bladder cancer cells. This unique agent presented advantages over other EGF-based technologies and other toxin-derivatives. In contrast to known agents, this EGF-toxin conjugate promoted its own uptake via receptor microclustering even in the presence of Her2 and induced cell death with a LC50 < 1 nM. Furthermore, our data showed that exposures as short as ≈3 min were enough to commit human (T24), mouse (MB49) and canine (primary) bladder cancer cells to apoptosis. Exposure of tumor-free mice and dogs with the agent resulted in no toxicity. In addition, the EGF-toxin was able to eliminate cells from human patient tumor samples. Importantly, the administration of EGF-toxin to dogs with spontaneous bladder cancer, who had failed or were not eligible for other therapies, resulted in ~30% average tumor reduction after one treatment cycle. Because of its in vitro and in vivo high efficiency, fast action (reducing treatment time from hours to minutes) and safety, we propose that this EGF-anthrax toxin conjugate provides the basis for new, transformative approaches against bladder cancer.

PSMA ADC monotherapy in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide: Efficacy and safety in open-label single-arm phase 2 study.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy. METHODS: A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed. RESULTS: PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis. CONCLUSIONS: PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.

Neuroendocrine and immunotoxicity of polyaromatic hydrocarbon, chrysene in crustacean post larvae.

Polyaromatic hydrocarbons are a group of chemical pollutants which cause a significant threat to the living organisms in estuaries and marine ecosystems. We report the effect of chrysene, a major PAH pollutant found in Cochin Estuary along the southwest coast of India, on the neuroendocrine and immune gene expression of the post larvae (PL-25) of Penaeus monodon. The PL- 25 of P. monodon were administered with feed coated with increasing concentrations of chrysene (1, 2 and 3 µg/g) for 10 days and the gene expression was studied on 7th, 11th and 15th day. The PL exposed to chrysene showed moulting stress and changes in the levels of moult-inhibiting hormone I (MIH I) indicated by irregular moulting in the experimental tanks. At the molecular level, the higher concentration of chrysene induced two-fold upregulation of neuroendocrine (MIH I) and downregulation of immune (ProPO and crustin) gene on the 7th day of exposure. The expression of MIH I gene reduced on withdrawing the experimental feed (on 11th day), while continued downregulation of ProPO and crustin were observed on the 11th day. The results of the present study indicate that the microgram levels of PAH can impinge the neuroendocrine and immune system of the P. monodon, which may induce morbidity and mortality to the larvae in polluted coastal ecosystems. Therefore, more attention may be given to avoid PAH pollution in the estuaries to maintain a healthy ecosystem and to protect the animals from extinction.

Walnut Polyphenol Extract Protects against Fenitrothion-Induced Immunotoxicity in Murine Splenic Lymphocytes.

Fenitrothion (FNT), an organophosphate pesticide, exerts an immunotoxic effect on splenocytes. Dietary polyphenol compounds exert antioxidant, anticancer and antihypertensive effects. In this study, we investigated the effect of walnut polyphenol extract (WPE) on FNT-induced immunotoxicity in splenic lymphocytes in vitro. Treatment with WPE significantly increased the proliferation of FNT-exposed splenocytes, as evidenced by increases in the proportions of splenic T lymphocytes (CD3⁺ T cells) and T-cell subsets (CD8⁺ T cells), as well as the secretion of the T-cell-related cytokines interleukin (IL)-2, interferon-γ, IL-4 and granzyme B. These effects were associated with a reduction in oxidative stress, as evidenced by changes in the levels of hydroxyl radical, superoxide dismutase, glutathione peroxidase and malondialdehyde. Moreover, WPE decreased the FNT-induced overexpression of NADPH oxidase 2 and dual oxidase 1 by regulating Toll-like receptor 4 signaling in splenic T-cells. Taken together, these findings suggest that WPE protects against FNT-mediated immunotoxicity and improves immune function by inhibiting oxidative stress.

Probable Mechanisms Involved in Immunotoxin Mediated Capillary Leak Syndrome (CLS) and Recently Developed Countering Strategies.

Antibody-toxin fused agents or immunotoxins, are a newly engineered class of cytotoxic agents consisting of a bacterial or plant toxin moiety hooked up either to a monoclonal antibody or a specific growth factor. Nevertheless, acquiring a full potency in clinic is mostly restricted due to the Capillary leak syndrome (CLS), a serious immune provoked, life-threatening side effect, subsequent to the endothelial damage, resulting in fluid escape from the bloodstream into tissues including lungs, muscle and brain, developing organ failure and eventually death. Proposed underlying mechanisms include direct damage to endothelial cells, acute inflammation, Lymphokine-activated killer (LAK) cells engagement, alteration in cell-cell/cell-matrix connectivities and cytoskeletal dysfunction. Very poor biodistribution and heterogeneous extravasation pattern in tumor site result in accumulation of ITs close to the extravasation site, gradual toxin release and initiation of nearby endothelial cells lysis, secretion of pro-inflammatory cytokines, development of acute inflammation and engagement of Lymphokine-activated killer (LAK) cells. Intrinsic immunogenicity of applied toxin moiety is another important determinant of CLS incidence. Toxins with more intrinsic immunogenicity possess more probability for CLS development. Recently, development of new generations of antibodies and mutated toxins with conserved cytotoxicity has partly tapered risk of CLS development. Here, we describe probable mechanisms involved in CLS and introduce some of the recently applied strategies for lessening incidence of CLS as much as possible.

Moxetumomab Pasudotox: First Global Approval.

Moxetumomab pasudotox-tdfk (LUMOXITI™), an anti CD22 recombinant immunotoxin, has been developed by MedImmune and its parent company AstraZeneca for the treatment of hairy cell leukaemia. The product, discovered at the National Cancer Institute, is an optimised version of immunotoxin CAT-3888. Moxetumomab pasudotox is composed of the Fv fragment of an anti-CD22 monoclonal antibody fused to a 38 kDa fragment of Pseudomonas exotoxin A, PE38. The Fv portion of moxetumomab pasudotox binds to CD22, a cell surface receptor expressed on a variety of malignant B-cells, thereby delivering the toxin moiety PE38 directly to tumour cells. Once internalised, PE38 catalyses the ADP ribosylation of the diphthamide residue in elongation factor-2 (EF-2), resulting in the rapid fall in levels of the anti-apoptotic protein myeloid cell leukaemia 1 (Mcl-1), leading to apoptotic cell death. This article summarizes the milestones in the development of moxetumomab pasudotox leading to this first approval for the treatment of adults with relapsed or refractory hairy cell leukaemia who received at least two prior systemic therapies, including treatment with a purine nucleoside analogue. Development of moxetumomab pasudotox for non-Hodgkin's lymphoma, chronic lymphocytic leukaemia and precursor cell lymphoblastic leukaemia/lymphoma was discontinued.

Phase 1 study of the anti-CD22 immunotoxin moxetumomab pasudotox for childhood acute lymphoblastic leukemia.

Novel therapies are needed to overcome chemotherapy resistance for children with relapsed/refractory acute lymphoblastic leukemia (ALL). Moxetumomab pasudotox is a recombinant anti-CD22 immunotoxin. A multicenter phase 1 study was conducted to determine the maximum-tolerated cumulative dose (MTCD) and evaluate safety, activity, pharmacokinetics, and immunogenicity of moxetumomab pasudotox in children, adolescents, and young adults with ALL (N = 55). Moxetumomab pasudotox was administered as a 30-minute IV infusion at doses of 5 to 50 µg/kg every other day for 6 (cohorts A and B) or 10 (cohort C) doses in 21-day cycles. Cohorts B and C received dexamethasone prophylaxis against capillary leak syndrome (CLS). The most common treatment-related adverse events were reversible weight gain, hepatic transaminase elevation, and hypoalbuminemia. Dose-limiting CLS occurred in 2 of 4 patients receiving 30 µg/kg of moxetumomab pasudotox every other day for 6 doses. Incorporation of dexamethasone prevented further dose-limiting CLS. Six of 14 patients receiving 50 µg/kg of moxetumomab pasudotox for 10 doses developed hemolytic uremic syndrome (HUS), thrombotic microangiopathy (TMA), or HUS-like events, exceeding the MTCD. Treatment expansion at 40 µg/kg for 10 doses (n = 11) exceeded the MTCD because of 2 HUS/TMA/HUS-like events. Dose level 6B (ie, 50 µg/kg × 6 doses) was the MTCD, selected as the recommended phase 2 dose. Among 47 evaluable patients, an objective response rate of 32% was observed, including 11 (23%) composite complete responses, 5 of which were minimal residual disease negative by flow cytometry. Moxetumomab pasudotox showed a manageable safety profile and evidence of activity in relapsed or refractory childhood ALL. This trial was registered at www.clinicaltrials.gov as #NCT00659425.

[Adverse effects of immune checkpoint inhibitors used to treat melanoma and other cancer]. / Effets secondaires des inhibiteurs de checkpoint utilisés dans le traitement des mélanomes et d'autres cancers.

Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers and metastatic renal cancer. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events that may be life threatening if not anticipated and managed appropriately. This new family of dysimmune toxicities remains largely unknown to the broad oncology community. We propose here some practical guidelines for the oncologist to help in the clinical care of patients under immune checkpoint molecules.

Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells.

Immunotoxins as antiviral therapeutics are largely unexplored but have promising prospective due to their high selectivity potential and their unparalleled efficiency. One recent example targeted the virus-encoded G protein-coupled receptor US28 as a strategy for specific and efficient treatment of human cytomegalovirus (HCMV) infections. US28 is expressed on virus-infected cells and scavenge chemokines by rapid internalization. The chemokine-based fusion-toxin protein (FTP) consisted of a variant (F49A) of CX3CL1 specifically targeting US28 linked to the catalytic domain of Pseudomonas exotoxin A (PE). Here, we systematically seek to improve F49A-FTP by modifications in its three structural domains; we generated variants with (1) altered chemokine sequence (K14A, F49L, and F49E), (2) shortened and elongated linker region, and (3) modified toxin domain. Only F49L-FTP displayed higher selectivity in its binding to US28 versus CX3CR1, the endogenous receptor for CX3CL1, but this was not matched by a more selective killing of US28-expressing cells. A longer linker and different toxin variants decreased US28 affinity and selective killing. Thereby, F49A-FTP represents the best candidate for HCMV treatment. Many viruses encode internalizing receptors suggesting that not only HCMV but also, for instance, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus may be targeted by FTPs.

Ribosome-Inactivating Proteins from Plants: A Historical Overview.

This review provides a historical overview of the research on plant ribosome-inactivating proteins (RIPs), starting from the first studies at the end of eighteenth century involving the purification of abrin and ricin, as well as the immunological experiments of Paul Erlich. Interest in these plant toxins was revived in 1970 by the observation of their anticancer activity, which has given rise to a large amount of research contributing to the development of various scientific fields. Biochemistry analyses succeeded in identifying the enzymatic activity of RIPs and allowed for a better understanding of the ribosomal machinery. Studies on RIP/cell interactions were able to detail the endocytosis and intracellular routing of ricin, thus increasing our knowledge of how cells handle exogenous proteins. The identification of new RIPs and the finding that most RIPs are single-chain polypeptides, together with their genetic sequencing, has aided in the development of new phylogenetic theories. Overall, the biological properties of these proteins, including their abortifacient, anticancer, antiviral and neurotoxic activities, suggest that RIPs could be utilized in agriculture and in many biomedical fields, including clinical drug development.

Immunogenicity of therapeutic recombinant immunotoxins.

Recombinant immunotoxins (RITs) are chimeric proteins designed to treat cancer. They are made up of an Fv or Fab that targets an antigen on a cancer cell fused to a 38-kDa portion of Pseudomonas exotoxin A (PE38). Because PE38 is a bacterial protein, it is highly immunogenic in patients with solid tumors that have normal immune systems, but much less immunogenic in patients with hematologic malignancies where the immune system is suppressed. RITs have shown efficacy in refractory hairy cell leukemia and in some children with acute lymphoblastic leukemia, but have been much less effective in solid tumors, because neutralizing antibodies develop and prevent additional treatment cycles. In this paper we will (i) review data from clinical trials describing the immunogenicity of PE38 in different patient populations; (ii) review results from clinical trials using different immunosuppressive drugs; and (iii) describe our efforts to make new less-immunogenic RITs by identifying and removing T- and B-cell epitopes to hide the RIT from the immune system.

A Phase II Study of Coltuximab Ravtansine (SAR3419) Monotherapy in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia.

BACKGROUND: Long-term disease-free survival in adult patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory, and the treatment options are limited for those patients with relapse or a failure to respond after initial therapy. We conducted a dose-escalation/expansion phase II, multicenter, single-arm study to determine the optimal dose of coltuximab ravtansine (SAR3419), an anti-CD19 antibody-drug conjugate, in this setting. PATIENTS AND METHODS: The dose-escalation part of the study determined the selected dose of coltuximab ravtansine for the evaluation of efficacy and safety in the dose-expansion phase. Patients received coltuximab ravtansine induction therapy (≤ 8 weekly doses). The responding patients were eligible for maintenance therapy (biweekly administration for ≤ 24 weeks). Three dose levels of coltuximab ravtansine were examined: 55, 70, and 90 mg/m(2). The primary endpoint was the objective response rate (ORR). The secondary endpoints included the duration of response (DOR) and safety. RESULTS: A total of 36 patients were treated: 19 during dose escalation and 17 during dose expansion. One dose-limiting toxicity was observed at 90 mg/m(2) (grade 3 peripheral motor neuropathy); therefore, 70 mg/m(2) was selected for the dose-expansion phase. Five patients discontinued therapy because of adverse events (AEs). The most common AEs were pyrexia, diarrhea, and nausea. Of the 17 evaluable patients treated at the selected dose, 4 had a disease response (estimated ORR using the Bayesian method: 25.5% (80% confidence interval, 14.2%-39.6%). The DOR was 1.9 months (range, 1-5.6 months). Because of these results, the study was prematurely discontinued. CONCLUSION: Coltuximab ravtansine was well tolerated but was associated with a low clinical response rate in patients with relapsed or refractory ALL.

Removal of B-cell epitopes for decreasing immunogenicity in recombinant immunotoxin against B-cell malignancies.

Recombinant immunotoxin HA22, composed of an anti- CD22 Fv fragment fused to PE38, a truncated portion of Pseudomonas Exotoxin A (PE), has been developed for targeted treatment of various B-cell malignancies. As a foreign, internalized macromolecule, PE38 often induces lysosomal degradation and neutralizing antibodies to limit the efficacy of treating B-cell malignancies. The region of PE38 containing lysosomal protease cleavage sites deleted, leaving only furin processing site. The resulting immunotoxin HA22-LR (lysosome resistant) retains excellent biologic activity and removes immunogenic epitopes as an additional benefit. Another approach for avoiding immunogenicity is to identify B-cell epitopes and remove them by mutagenesis. Previously, to determine B-cell epitopes on PE38, murine Ab as a model, 7 major mouse-specific B-cell epitope groups with 13 subgroups were identified and located through a series of point mutations. Two new mutants, HA22-8X and HA22-LR-8X, were prepared, containing 8 epitope-silencing mutations which greatly reduced immunogenicity in mice. Later, by phage-display assay, human Fvs against PE toxin were isolated and human-specific B-cell epitopes were located by alanine scanning mutagenesis. HA22-LR as a scaffold, HA22-LR-LO10 with 7 point mutations was constructed, has low reactivity with human antisera, yet has high cytotoxic and antitumor activity. In this review, theoretical aspects and experimental evidence for the removal of B-cell epitope is discussed.

Immunotoxicological impact of occupational and environmental nanoparticles exposure: The influence of physical, chemical, and combined characteristics of the particles.

While nanotechnology is growing exponentially, the knowledge of the impact of nanoparticles (NPs) on public health and the environment is limited so far. Current nanomaterial research is focused on the applications of nanotechnology, whereas there is little information on exposure assessment and risk characterization associated with NPs. Therefore, it is essential that the factors influencing NPs associated hazards be studied. This review seeks to survey and evaluate the current literature in order to better understand the impact of both airborne and engineered NPs exposure, the mechanisms at the cellular level, and the factors influencing their immunotoxicity. In fact, NPs do have immunotoxicological significance, as immune cells in the bloodstream and tissues do act to eliminate or interact with NPs.Proper characterization of the NPs as well as understanding the processes occurring on the NPs surface when in contact with biological systems is crucial to predict or exclude toxicological effects.

Resimmune, an anti-CD3ε recombinant immunotoxin, induces durable remissions in patients with cutaneous T-cell lymphoma.

Resimmune is a second-generation recombinant immunotoxin composed of the catalytic and translocation domains of diphtheria toxin fused to two single chain antibody fragments reactive with the extracellular domain of CD3ε. We gave intravenous infusions of Resimmune 2.5 - 11.25 µg/kg over 15 minutes to 30 patients (25 with cutaneous T-cell lymphoma, 3 with peripheral T-cell lymphoma, 1 with T-cell large granular lymphocytic leukemia and 1 with T-cell prolymphocytic leukemia) in an inter-patient dose escalation trial. The most common adverse events were fever, chills, hypotension, edema, hypoalbuminemia, hypophosphatemia, and transaminasemia. Among the 25 patients with cutaneous T-cell lymphoma, there were nine responses for a response rate of 36% (95% CI, 18%-57%) including four complete remissions (16%, 95% CI, 5%-36%). The durations of the complete remissions were 72+, 72+, 60+ and 38+ months. There were five partial remissions lasting 3, 3, 3+, 6+ and 14 months. Of 17 patients with a modified skin weighted assessment tool score <50, 17 patients with stage IB/IIB, and 11 patients with both a score <50 and stage IB/IIB, nine (53%), eight (47%), and eight (73%) had responses, respectively. Further studies of Resimmune in patients with low tumor burden, stage IB-IIB cutaneous T-cell lymphoma are warranted. This trial is registered at clinicaltrials.gov as #NCT00611208.

Genotoxic and immunotoxic effects of cellulose nanocrystals in vitro.

Nanocellulosics are among the most promising innovations for a wide-variety of applications in materials science. Although nanocellulose is presently produced only on a small scale, its possible toxic effects should be investigated at this early stage. The aim of the present study was to examine the potential genotoxicity and immunotoxicity of two celluloses in vitro - cellulose nanocrystals (CNC; mean fibril length 135 nm, mean width 7.3 nm) and a commercially available microcrystalline (non-nanoscale) cellulose (MCC; particle size ∼50 µm). Both celluloses showed 55% cytotoxicity at approximately 100 µg/ml after 4-h, 24-h, and 48-h treatment of human bronchial epithelial BEAS 2B cells, as determined by luminometric detection of ATP and cell count (dead cells identified by propidium iodide). Neither of the materials was able to induce micronuclei (MN) in binucleate or mononucleate BEAS 2B cells after a 48-h treatment (2.5-100 µg/ml). In human monocyte-derived macrophages, MCC induced a release (measured by enzyme-linked immunosorbent assay; ELISA) of the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and (after lipopolysaccharide-priming) interleukin 1ß (IL-1ß) after a 6-h exposure to a dose of 300 µg/ml, but CNC (30-300 µg/ml) did not. In conclusion, our results show that nanosized CNC is neither genotoxic nor immunotoxic under the conditions tested, whereas non-nanosized MCC is able to induce an inflammatory response. More studies are needed, especially in vivo, to further assess if CNC and other nanocelluloses induce secondary genotoxic effects mediated by inflammation.