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Nutrient avidity is one of the most distinctive features of tumours. However, nutrient deprivation has yielded limited clinical benefits. In Gaucher disease, an inherited metabolic disorder, cells produce cholesteryl-glucoside which accumulates in lysosomes and causes cell damage. Here we develop a nanoparticle (AbCholB) to emulate natural-lipoprotein-carried cholesterol and initiate Gaucher disease-like damage in cancer cells. AbCholB is composed of a phenylboronic-acid-modified cholesterol (CholB) and albumin. Cancer cells uptake the nanoparticles into lysosomes, where CholB reacts with glucose and generates a cholesteryl-glucoside-like structure that resists degradation and aggregates into microscale crystals, causing Gaucher disease-like damage in a glucose-dependent manner. In addition, the nutrient-sensing function of mTOR is suppressed. It is observed that normal cells escape severe damage due to their inferior ability to compete for nutrients compared with cancer cells. This work provides a bioinspired strategy to selectively impede the metabolic action of cancer cells by taking advantage of their nutrient avidity.

Introduction: NPC2 is well known as a player for cholesterol transport. However, the biological role of NPC2 in cancer development and therapy is far from clear. Methods: Here, we explore the potential role of NPC2 in prognosis and immunotherapy across multiple cancer types by integrating RNA-seq data from TCGA and GTEx, protein data from CPTAC, and multiple web analysis databases. Results: Expression depiction between tumour and normal tissues indicated that NPC2 is overexpressed in the majority of the most common cancer types, including glioblastoma and pancreatic cancer, two cancers mostly difficult to diagnose and treat. Conclusion: Cancer stemness in glioblastoma is negatively associated with NPC2 level. NPC2 expression is positively correlated with immune cell infiltration and the expression of several immune checkpoints. IDH1 mutation in GBM is negatively correlated with NPC2 level, while a positive correlation has been found between TP53 mutation and NPC2 expression in pancreatic cancer. NPC2 is also correlated with levels of serum biomarkers used for diagnosis of pancreatic cancer.

Background

A novel conditioning regimen using helical tomotherapy (HT) was developed to deliver 10 Gy for total body irradiation (TBI) and simultaneously augment dose to 12 Gy for targeted dose boost to total marrow, central nervous system leukemia, and extramedullary disease sites in patients with high-risk or relapsed/refractory acute lymphoblastic leukemia (ALL) receiving haploidentical allogeneic hematopoietic stem cell transplantation (allo-HSCT). Fourteen patients were included, eight of these patients were in first complete remission (CR1), one was in CR2, one had a partial response and four patients had refractory disease at transplantation. The median delivered average dose was 11.395 Gy (range 10.06–12.17). The median planning target volume D95 was 8.2 Gy (range 7.52–9.01). The median delivered dose to skeleton bone with active bone marrow sites was 12.685 Gy (range 11.12–13.52). The results of this trial suggest that using HT TBI confers satisfactory immunosuppression and excellent eradication of malignant cells in patients with high-risk ALL undergoing allo-HSCT, especially in those with refractory ALL. After a median follow-up of 14.6 months (range 4–28), four patients experienced non-relapse mortality, ten patients are alive in durable CR including remission of extramedullary leukemic infiltration. One-year overall survival and disease-free survival rates post-transplantation were both 70.7%.

EGFR mutations companion diagnostics have been proved to be crucial for the efficacy of tyrosine kinase inhibitor targeted cancer therapies. To uncover multiple mutations occurred in minority of EGFR-mutated cells, which may be covered by the noises from majority of un-mutated cells, is currently becoming an urgent clinical requirement. Here we present the validation of a microfluidic-chip-based method for detecting EGFR multi-mutations at single-cell level. By trapping and immunofluorescently imaging single cells in specifically designed silicon microwells, the EGFR-expressed cells were easily identified. By in situ lysing single cells, the cell lysates of EGFR-expressed cells were retrieved without cross-contamination. Benefited from excluding the noise from cells without EGFR expression, the simple and cost-effective Sanger’s sequencing, but not the expensive deep sequencing of the whole cell population, was used to discover multi-mutations. We verified the new method with precisely discovering three most important EGFR drug-related mutations from a sample in which EGFR-mutated cells only account for a small percentage of whole cell population. The microfluidic chip is capable of discovering not only the existence of specific EGFR multi-mutations, but also other valuable single-cell-level information: on which specific cells the mutations occurred, or whether different mutations coexist on the same cells. This microfluidic chip constitutes a promising method to promote simple and cost-effective Sanger’s sequencing to be a routine test before performing targeted cancer therapy.

Mild acidic environment and tumor angiogenesis are two typical features. The specific response toward lower pH may increase the targeting ability both for drug delivery. Herein, we present a responding self-assembled nanoparticle that is tumor angiogenesis targeting and pH triggered based on a novel recognition peptide DP. DP is pH-responsive as well as the affinity ligand of tumor marker EGFR. Efficient drug delivery and in vitro therapy in cell level could be accelerated in the conditions of EGFR overexpression and a mild acidic environment. We believed that such responsive materials will open a new way to turn on target imaging diagnostics and specific cancer therapies.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

BACKGROUND:The prognosis of patients with relapsed B-lineage acute lymphocyte leukemia (B-ALL) after allogeneic hematopoietic stem cells transplantation(HSCT) is poor. It is difficult to obtain disease-free remission and long-term survival in these patients based on chemotherapy, donor leukocyte infusion (DLI) or molecular targeted therapy. Donor-derived anti-CD19 CAR-T(CAR 19) cells may obtain remission in these patients, but many still encounter relapse, especially CD19-negative relapse. CD123 is a surface marker not only associated with the progenitors of acute myeloid leukemia, but also found in progenitors of acute lymphoblastic leukemia. Recent studies have shown that CD123 is highly expressed in the patients with CD19-negative relapsed after CAR19 cells therapy. we developed a novel therapeutic strategy for to administer pooled donor-derived fourth generation CART cells targeting CD19 and CD123 respectively, to patients who relapsed following allogeneic HSCT to avoid CD19-negative relapse. In this study, we report three patients who received combination CARTs therapy achieved disease-free survival that at least more than 6 months (www.clinicaltrials.gov; #NCT03125577).

Background:CD19 targeting chimeric antigen receptor T cells(CART19) therapy have shown great therapeutic potential in relapsed and refractory B cell acute lymphoblastic leukemia (ALL), but associated with risk of life-threatening adverse effects as severe cytokine release syndrome (sCRS) and CAR-T-cell-related encephalopathy syndrome (CRES).It's been reported that high leukemia burden before CART therapy, and high does infused CART cells are associated with severity of CRS and CRES. To decrease the risk of severe adverse effect, we applied integrated therapeutic strategy of using fourth generation CART cells , reducing leukemia blasts burden in bone marrow, and decreasing the dose of infused CART cells (www.clinicaltrials.gov; #NCT03407859 and #NCT03125577 ).

ABSTRACTBackground: Tumor PD-L1 levels have predictive value in PD-1/PD-L1 checkpoint blockade therapies, yet biopsies can only provide baseline information. Whether PD-L1 expression on circulating tumor cells (CTCs) could serve as an alternative biomarker is of great interest.Design:We established an immunofluorescence assay for semi-quantitative assessment of the PD-L1 expression levels on CTCs with four categories (PD-L1negative, PD-L1low, PD-L1mediumand PD-L1high). 35 patients with different advanced gastrointestinal tumors were enrolled in a phase 1 trial of a PD-1 inhibitor, IBI308. The CTC numeration and the PD-L1 expression levels were analyzed.Results:Prior the treatment of IBI308, 97% (34/35) patients had CTCs, ranging from1 to 70 (median 7). 74% (26/35) had PD-L1positiveCTCs, and 60% (21/35) had at least one PD-L1highCTCs. The disease control (DC) rate in PD-L1highpatients (48%) is much higher than the others (14%). The group with at least 20% abundance of PD-L1highCTCs had even higher DC rate of 64% (9/14), with only 14% DC rate for the rest (3/21). We also observed that the count changes of total CTC, PD-L1postiveCTC and PD-L1highCTC correlate quite well with disease outcome (P<0.001, P = 0.002 and 0.007, respectively). In addition, the abundance of PD-L1highCTCs at baseline had predicative significance for progression free survival (PFS).Conclusions:We revealed that the abundance of PD-L1highCTCs at baseline might serve as a predictor to screen patients for PD-1/PD-L1 blockade therapies and measuring the dynamic changes of CTC could indicate the therapeutic response at early time.