Intelligent biogenic pH-sensitive and amine-responsive color-changing label for real-time monitoring of shrimp freshness.

BACKGROUND: This study developed an intelligent, pH-sensitive and amine-responsive colorimetric label based on chitosan, whey protein and thymol blue by controlling the pH value of the film-forming solution. The obtained label was used to monitor shrimp freshness in real time. The results of this study offer a new approach for developing highly intelligent biogenic labels for freshness monitoring during seafood preservation and processing. RESULTS: The pH 2.0 chitosan-whey protein-thymol blue (CWT-pH 2.0) label exhibited remarkable properties, including the highest tensile strength (5.90 MPa), excellent thermal stability, low water solubility (27.80%) and highly sensitive color responsiveness. The characterization techniques of scanning electron microscopy, X-ray diffraction and Fourier transform infrared spectroscopy confirmed the effective immobilization of thymol blue within the film-forming matrix through hydrogen bonding. Furthermore, the CWT-pH 2.0 label demonstrated visible color changes in the presence of volatile ammonia concentrations ranging from 25 to 25 000 ppm. Consequently, the label successfully facilitated real-time monitoring of shrimp freshness during storage at 4 °C. Importantly, the release rate of thymol blue from the label in food simulants was minimal, measuring only 2.53%. CONCLUSION: The CWT-pH 2.0 label exhibits significant potential as a highly intelligent biogenic label for freshness monitoring in seafood preservation and processing. © 2023 Society of Chemical Industry.

Programmed cell death-1 inhibitor combination treatment for recurrent proficient mismatch repair/ miscrosatellite-stable type endometrial cancer: A case report.

BACKGROUND: Endometrial cancer (EC) is one of the most common cancers of the female reproductive tract, and the incidence is increasing rapidly. Immunotherapy using programmed cell death-1 (PD-1) inhibitors is an emerging research topic and treatment strategy for refractory gynecological malignancies. However, clinical management of EC with checkpoint inhibitors requires improvement. Herein, we discuss a case of refractory proficient mismatch repair (pMMR)/miscrosatellite-stable (MSS) EC treated with a combination of PD-1 and angiogenesis inhibitors and offer a review of the pathophysiology and clinical outcomes based on previous studies. CASE SUMMARY: A 62-year-old woman diagnosed with invasive or metastatic EC in 2015 was treated with six courses of chemotherapy and refused further radiotherapy. Four years later, she developed chest pain, and lung biopsy indicated thyroid transcription factor-1 (-), Napsin A (-), estrogen receptor (+), progesterone receptor (+), anaplastic lymphoma kinase (D5F3) (-), and receptor tyrosine kinase (D4D6) (-) metastatic EC. Genetic testing results showed low tumor mutation burden, pMMR, PD ligand 1 (-), MSS, and HLA-class 1 heterogeneous disease. The patient was started on toripalimab combined with nab-paclitaxel for seven cycles (every 3 wk), but this regimen was terminated because of an intolerable chemotherapy adverse event. The disease progressed in 2020, and the patient's treatment was switched from nab-paclitaxel to anlotinib, while immunotherapy using toripalimab was continued. The patient achieved a major partial response with well-tolerated toxicities, and treatment is ongoing. CONCLUSION: Molecular testing is advised for clinical classifications of EC owing to its high heterogeneity. In this case, the patient had pMMR/MSS EC and achieved a positive outcome with combination PD-1 inhibitor treatment. These results warrant further clinical exploration.

College of American Pathologists Tumor Regression Grading System for Long-Term Outcome in Patients with Locally Advanced Rectal Cancer.

BACKGROUND: The National Comprehensive Cancer Network's Rectal Cancer Guideline Panel recommends American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) system to evaluate pathologic response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC). Yet, the clinical significance of the AJCC/CAP TRG system has not been fully defined. MATERIALS AND METHODS: This was a multicenter, retrospectively recruited, and prospectively maintained cohort study. Patients with LARC from one institution formed the discovery set, and cases from external independent institutions formed a validation set to verify the findings from discovery set. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed by Kaplan-Meier analysis, log-rank test, and Cox regression model. RESULTS: The discovery set (940 cases) found, and the validation set (2,156 cases) further confirmed, that inferior AJCC/CAP TRG categories were closely /ccorrelated with unfavorable survival (OS, DFS, LRFS, and DMFS) and higher risk of disease progression (death, accumulative relapse, local recurrence, and distant metastasis) (all p < .05). Significantly, pairwise comparison revealed that any two of four TRG categories had the distinguished survival and risk of disease progression. After propensity score matching, AJCC/CAP TRG0 category (pathological complete response) patients treated with or without adjuvant chemotherapy displayed similar survival of OS, DFS, LRFS, and DMFS (all p > .05). For AJCC/CAP TRG1-3 cases, adjuvant chemotherapy treatment significantly improved 3-year OS (90.2% vs. 84.6%, p < .001). Multivariate analysis demonstrated the AJCC/CAP TRG system was an independent prognostic surrogate. CONCLUSION: AJCC/CAP TRG system, an accurate prognostic surrogate, appears ideal for further strategizing adjuvant chemotherapy for LARC. IMPLICATIONS FOR PRACTICE: The National Comprehensive Cancer Network recommends the American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) four-category system to evaluate the pathologic response to neoadjuvant treatment for patients with locally advanced rectal cancer; however, the clinical significance of the AJCC/CAP TRG system has not yet been clearly addressed. This study found, for the first time, that any two of four AJCC/CAP TRG categories had the distinguished long-term survival outcome. Importantly, adjuvant chemotherapy may improve the 3-year overall survival for AJCC/CAP TRG1-3 category patients but not for AJCC/CAP TRG0 category patients. Thus, AJCC/CAP TRG system, an accurate surrogate of long-term survival outcome, is useful in guiding adjuvant chemotherapy management for rectal cancer.

A microRNA disease signature associated with lymph node metastasis of lung adenocarcinoma.

Background: Lymph node metastasis (LNM) of lung cancer is an important factor associated with prognosis. Dysregulated microRNAs (miRNAs) are becoming a new powerful tool to characterize tumorigenesis and metastasis. We have developed and validated a miRNA disease signature to predict LNM in lung adenocarcinoma (LUAD). Method: LUAD miRNAs and clinical data from The Cancer Genome Atlas (TCGA) were obtained and divided randomly into training (n = 259) and validation (n = 83) cohorts. A miRNA signature was built using least absolute shrinkage and selection operator (LASSO) (λ =-1.268) and logistic regression model. The performance of the miRNA signature was evaluated using the area under curve (AUC) of receiver operating characteristic curve (ROC). We performed decision curve analysis (DCA) to assess the clinical usefulness of the signature. We also conducted a miRNA-regulatory network analysis to look for potential genes engaged in LNM in LUAD. Result: Thirteen miRNAs were selected to build our miRNA disease signature. The model showed good calibration in the training cohort, with an AUC of 0.782 (95% CI: 0.725-0.839). In the validation cohort, AUC was 0.691 (95% CI: 0.575-0.806). DCA demonstrated that the miRNA signature was clinically useful. Conclusion: The miRNA disease signature can be used as a noninvasive method to predict LNM in patients with lung adenocarcinoma objectively and the signature achieved high accuracy for prediction.

Genetically engineered T cells for cancer immunotherapy.

T cells in the immune system protect the human body from infection by pathogens and clear mutant cells through specific recognition by T cell receptors (TCRs). Cancer immunotherapy, by relying on this basic recognition method, boosts the antitumor efficacy of T cells by unleashing the inhibition of immune checkpoints and expands adaptive immunity by facilitating the adoptive transfer of genetically engineered T cells. T cells genetically equipped with chimeric antigen receptors (CARs) or TCRs have shown remarkable effectiveness in treating some hematological malignancies, although the efficacy of engineered T cells in treating solid tumors is far from satisfactory. In this review, we summarize the development of genetically engineered T cells, outline the most recent studies investigating genetically engineered T cells for cancer immunotherapy, and discuss strategies for improving the performance of these T cells in fighting cancers.

Excessive activated T-cell proliferation after anti-CD19 CAR T-cell therapy.

Excessive activated T-cell proliferation was observed in vivo in one patient after an anti-CD19-chimeric antigen receptor (CAR) T-cell infusion. The patient, who had chemotherapy refractory and CD19+ diffuse large B-cell lymphoma (DLBCL), received an anti-CD19 CAR T-cell infusion following conditioning chemotherapy (fludarabine/cyclophosphamide). The lymphocyte count in the peripheral blood (PB) increased to 77 × 109/L on day 13 post infusion, and the proportion of CD8+ actived T cells was 93.06% of the lymphocytes. Then, the patient suffered from fever and hypoxaemia. Significant increases in serum cytokine, lactate dehydrogenase, aspartate aminotransferase (AST), alanine transaminase (ALT), and glutamic-oxalacetic transaminase (γ-GT) levels were observed. A high-throughput sequencing analysis for T-cell receptors (TCRs) and whole-genome sequencing were used to explore the mechanisms underlying this excessive T-cell proliferation. TCR diversity was demonstrated, but no special gene mutation was found. The patient was found to be infected with the John Cunningham polyomavirus (JCV). It cannot be ruled out the bystander activation pathway induced by JCV infections related the excessive activated T-cell proliferation. Although the clinical and laboratory data do not fully explain the reason for excessive T-cell proliferation after the anti-CD19 CAR T-cell infusion, the risk of this type of toxicity should be emphasized. This study was registered at www.clinicaltrials.gov as NCT01864889.

Chimeric antigen receptor modified T-cells for cancer treatment.

T cells engineered with the chimeric antigen receptor (CAR) are rapidly emerging as an important immunotherapy for hematologic malignancies. The anti-cluster of differentiation (CD)19 CAR-T cell therapy has been remarkably successful against refractory/relapsed acute lymphoblastic leukemia (ALL), and a complete remission rate as high as 90% was observed, in both children and adults. Although the achievement of clinical efficacy using CAR-T cell therapy for solid tumors has encountered several obstacles that were associated with the multiple mechanisms contributing to an immunosuppressive microenvironment, investigators are exploring more optimized approaches to improve the efficiency of CAR-T in solid tumors. In addition, cytokine release syndrome (CRS) and neurotoxicity following CAR-T cell therapy can be severe or even fatal; therefore, the management of these toxicities is significant. Herein, we briefly review the structure of CAR-T and some novel CAR designs, the clinical application of CAR-T cell therapies, as well as the assessment and management of toxicities.

Cocktail treatment with EGFR-specific and CD133-specific chimeric antigen receptor-modified T cells in a patient with advanced cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is one of the most fatal malignant tumors with increasing incidence, mortality, and insensitivity to traditional chemo-radiotherapy and targeted therapy. Chimeric antigen receptor-modified T cell (CART) immunotherapy represents a novel strategy for the management of many malignancies. However, the potential of CART therapy in treating advanced unresectable/metastatic CCA is uncharted so far. CASE PRESENTATION: In this case, a 52-year-old female who was diagnosed as advanced unresectable/metastatic CCA and resistant to the following chemotherapy and radiotherapy was treated with CART cocktail immunotherapy, which was composed of successive infusions of CART cells targeting epidermal growth factor receptor (EGFR) and CD133, respectively. The patient finally achieved an 8.5-month partial response (PR) from the CART-EGFR therapy and a 4.5-month-lasting PR from the CART133 treatment. The CART-EGFR cells induced acute infusion-related toxicities such as mild chills, fever, fatigue, vomiting and muscle soreness, and a 9-day duration of delayed lower fever, accompanied by escalation of IL-6 and C reactive protein (CRP), acute increase of glutamic-pyruvic transaminase and glutamic-oxalacetic transaminase, and grade 2 lichen striatus-like skin pathological changes. The CART133 cells induced an intermittent upper abdominal dull pain, chills, fever, and rapidly deteriorative grade 3 systemic subcutaneous hemorrhages and congestive rashes together with serum cytokine release, which needed emergent medical intervention including intravenous methylprednisolone. CONCLUSIONS: This case suggests that CART cocktail immunotherapy may be feasible for the treatment of CCA as well as other solid malignancies; however, the toxicities, especially the epidermal/endothelial damages, require a further investigation. TRIAL REGISTRATION: ClinicalTrials.gov NCT01869166 and NCT02541370 .

Adipose-derived mesenchymal stem cells ameliorate hyperglycemia through regulating hepatic glucose metabolism in type 2 diabetic rats.

Infusion of mesenchymal stem cells (MSCs) has been identified in the rapid alleviation in hyperglycemia of diabetic individuals, but the mechanism involved has not been adequately explained by these cells' potential role in modulating system insulin sensitivity and islet regeneration. In this study, we demonstrated adipose-derived mesenchymal stem cells (ASCs) produced significantly lower blood glucose via promoting hepatic glycogen synthesis and inhibiting hepatic glucose production within 24 h after infusion in T2DM rats. In vitro, HepG2 cells treated with palmitate (PA) were used as a model of hepatic glucose metabolism disorder to confirm that ASCs stimulates the phosphorylation of hepatic AMP-activated protein kinase (AMPK) to restores hepatic glucose metabolism in type 2 diabetes. In summary, this study indicated that ASCs improve hyperglycemia via regulating hepatic glucose metabolism. Additionally, the effect of ASCs on hepatic glucose metabolism depended on the AMPK signaling pathway. Thus, this is the new research of the molecular mechanisms of MSCs administration to improve glucose metabolism, and it may indicate a new treatment target of MSCs in T2DM.

Autologous T Cells Expressing CD30 Chimeric Antigen Receptors for Relapsed or Refractory Hodgkin Lymphoma: An Open-Label Phase I Trial.

Purpose: Relapsed or refractory Hodgkin lymphoma is a challenge for medical oncologists because of poor overall survival. We aimed to assess the feasibility, safety, and efficacy of CD30-targeting CAR T cells in patients with progressive relapsed or refractory Hodgkin lymphoma.Experimental Design: Patients with relapsed or refractory Hodgkin lymphoma received a conditioning chemotherapy followed by the CART-30 cell infusion. The level of CAR transgenes in peripheral blood and biopsied tumor tissues was measured periodically according to an assigned protocol by quantitative PCR (qPCR).Results: Eighteen patients were enrolled; most of whom had a heavy treatment history or multiple tumor lesions and received a mean of 1.56 × 107 CAR-positive T cell per kg (SD, 0.25; range, 1.1-2.1) in total during infusion. CART-30 cell infusion was tolerated, with grade ≥3 toxicities occurring only in two of 18 patients. Of 18 patients, seven achieved partial remission and six achieved stable disease. An inconsistent response of lymphoma was observed: lymph nodes presented a better response than extranodal lesions and the response of lung lesions seemed to be relatively poor. Lymphocyte recovery accompanied by an increase of circulating CAR T cells (peaking between 3 and 9 days after infusion) is a probable indictor of clinical response. Analysis of biopsied tissues by qPCR and immunohistochemistry revealed the trafficking of CAR T cells into the targeted sites and reduction of the expression of CD30 in tumors.Conclusions: CART-30 cell therapy was safe, feasible, and efficient in relapsed or refractory lymphoma and guarantees a large-scale patient recruitment. Clin Cancer Res; 23(5); 1156-66. ©2016 AACR.

Upregulation of CC Chemokine Receptor 7 (CCR7) Enables Migration of Xenogeneic Human Adipose-Derived Mesenchymal Stem Cells to Rat Secondary Lymphoid Organs.

BACKGROUND CC chemokine receptor 7 (CCR7) expression is vital for cell migration to secondary lymphoid organs (SLOs). Our previous work showed that inducing CCR7 expression enabled syngeneic mesenchymal stem cells (MSCs) to migrate into SLOs, resulting in enhanced immunosuppressive performance in mice. Given that human adipose-derived stem cells (hASCs) are widely used in clinical therapy, we further investigated whether upregulation of CCR7 enables xenogeneic hASCs to migrate to rat SLOs. MATERIAL AND METHODS hASCs rarely express CCR7; therefore, hASCs were transfected with lentivirus encoding rat CCR7 (rCCR7) plus green fluorescence protein (GFP) or GFP alone. CCR7 mRNA and cell surface expression of rCCR7-hASCs and GFP-hASCs were examined by reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry (FCM), respectively. The phenotype, differentiation, and proliferation capacity of each cell type was also determined. To examine migration, rCCR7-hASCs and GFP-hASCs were injected intravenously into Lewis rats, and the proportion of GFP-positive cells in the spleen and lymph nodes was determined with FCM. RESULTS mRNA and cell surface protein expression of CCR7 was essentially undetectable in hASCs and GFP-ASCs; however, CCR7 was highly expressed in rCCR7-ASCs. rCCR7-hASCs, GFP-hASCs, and hASCs shared a similar immunophenotype, and maintained the ability of multilineage differentiation and proliferation. In addition, the average proportion of GFP-positive cells was significantly higher following transplantation of rCCR7-hASCs compared with GFP-hASCs (p<0.01). CONCLUSIONS These results suggest that upregulation of rat CCR7 expression does not change the phenotype, differentiation, or proliferation capacity of hASCs, but does enable efficient migration of hASCs to rat SLOs.

Circulating tumor cells predict survival benefit from chemotherapy in patients with lung cancer.

BACKGROUND: This meta-analysis was to explore the clinical significance of circulating tumor cells (CTCs) in predicting the tumor response to chemotherapy and prognosis of patients with lung cancer. METHODS: We searched PubMed, Embase, Cochrane Database, Web of Science and reference lists of relevant articles. Our meta-analysis was performed by Stata software, version 12.0, with a random effects model. Risk ratio (RR), hazard ratio (HR) and 95% confidence intervals (CI) were used as effect measures. RESULTS: 8 studies, including 453 patients, were eligible for analyses. We showed that the disease control rate (DCR) in CTCs-negative patients was significantly higher than CTCs-positive patients at baseline (RR = 2.56, 95%CI [1.36, 4.82], p < 0.05) and during chemotherapy (RR = 9.08, CI [3.44, 23.98], p < 0.001). Patients who converted form CTC-negative to positive or persistently positive during chemotherapy had a worse disease progression than those with CTC-positive to negative or persistently negative (RR = 8.52, CI [1.66, 43.83], p < 0.05). Detection of CTCs at baseline and during chemotherapy also indicated poor overall survival (OS) (baseline: HR = 3.43, CI [2.21, 5.33], p<0.001; during chemotherapy: HR = 3.16, CI [2.23, 4.48], p < 0.001) and progression-free survival (PFS) (baseline: HR = 3.16, 95%CI [2.23, 4.48], p < 0.001; during chemotherapy: HR = 3.78, CI [2.33, 6.13], p < 0.001). CONCLUSIONS: Detection of CTCs in peripheral blood indicates poor tumor response to chemotherapy and poor prognosis in patients with lung cancer.

MicroRNAs: Novel immunotherapeutic targets in colorectal carcinoma.

Colorectal carcinoma (CRC) is one of the most common types of cancer worldwide and the prognosis for CRC patients with recurrence or metastasis is extremely poor. Although chemotherapy and radiation therapy can improve survival, there are still numerous efforts to be performed. Immunotherapy is frequently used, either alone or in combination with other therapies, for the treatment of CRC and is a safe and feasible way to improve CRC treatment. Furthermore, the significance of the immune system in the biology of CRC has been demonstrated by retrospective assessments of immune infiltrates in resected CRC tumors. MicroRNAs (miRNAs) are short, non-coding RNAs that can regulate multiple target genes at the post-transcriptional level and play critical roles in cell proliferation, differentiation and apoptosis. MiRNAs are required for normal immune system development and function. Nevertheless, aberrant expression of miRNAs is often observed in various tumor types and leads to immune disorders or immune evasion. The immunomodulatory function of miRNAs indicates that miRNAs may ultimately be part of the portfolio of anti-cancer targets. Herein, we will review the potential roles of miRNAs in the regulation of the immune response in CRC and then move on to discuss how to utilize different miRNA targets to treat CRC. We also provide an overview of the major limitations and challenges of using miRNAs as immunotherapeutic targets.

Treatment of CD20-directed Chimeric Antigen Receptor-modified T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an early phase IIa trial report.

Patients with relapsed or refractory non-Hodgkin lymphoma have a dismal prognosis. Chimeric Antigen Receptor (CAR)-modified T cells (CART cells) that targeted CD20 were effective in a phase I clinical trial for patients with advanced B-cell lymphomas. We performed a phase IIa trial to further assess the safety and efficacy of administering autologous anti-CD20 CART (CART-20) cells to patients with refractory or relapsed CD20+ B-cell lymphoma. Eleven patients were enrolled, and seven patients underwent cytoreductive chemotherapy to debulk the tumors and deplete the lymphocytes before receiving T-cell infusions. The overall objective response rate was 9 of 11 (81.8%), with 6 complete remissions (CRs) and 3 partial remissions; no severe toxicity was observed. The median progression-free survival lasted for >6 months, and 1 patient had a 27-month continuous CR. A significant inverse correlation between the levels of the CAR gene and disease recurrence or progression was observed. Clinically, the lesions in special sites, specifically the spleen and testicle, were refractory to CART-20 treatment. Collectively, these results together with our data from phase I strongly demonstrated the feasibility and efficacy of CART-20 treatment in lymphomas and suggest large-scale patient recruitment in a future study. This study was registered at www.clinicaltrials.org as NCT01735604.

Wnt/ß-catenin signaling pathway in lung cancer stem cells is a potential target for the development of novel anticancer drugs.

PURPOSE: In the present study, we have analyzed the regulation of Wnt/ß-catenin signaling in lung adenocarcinoma stem cells (CSCs), that are responsible for tumor recurrence. METHODS: Lung cancer samples were studied for the presence of cancer stem like cells and analyzed by flow cytometry. Then, the sorted cells were analyzed for the stem cell surface markers and Wnt/ß-catenin signaling pathways. Moreover, the sorted side population (SP) and non-SP cells were also subjected to drug resistance assay. RESULTS: Western blot analysis showed that the protein level of ß-catenin was highly upregulated in fluorescence activated cells (FACs) sorted SP cells which led to elevated expression of stem cell protein Oct-4 that is responsible for SP cells' self-renewal. RT-PCR revealed that the relative mRNA expression level of Wnt target gene cyclin D was significantly higher (p<0.01) in SP cells, enhancing thus the cell proliferation rate and clone formation efficiency. In addition, the matrigel invasion assay revealed that SP cells were highly invasive than non-SP cells. CONCLUSION: In the present study we demonstrated that lung adenocarcinoma samples contain a small population of tumor-initiating SP cells which possess the characteristic features of CSCs. Wnt/ß-catenin mediated increased expression of ß-catenin, Oct-4 and cyclin D in SP cells but not in non-SP cells was also observed. FACs-purified SP cells are resistant to a number of chemotherapeutic drugs. Our data suggest that the use of novel anticancer drugs, targeting Wnt/ß-catenin signaling pathways, may help eradicate the lung cancers stem cells.

Effects of the Four-Herb Compound ANBP on Wound Healing Promotion in Diabetic Mice.

Wound healing is a troublesome problem in diabetic patients. Besides, there is also an increased risk of postsurgical wound complications for diabetic patient. It has been revealed that traditional Chinese medicine may promote healing and inhibit scar formation, while the changes of morphology and physiology of wounds on such medicine treatment still remain elusive. In this study, we first used the ultralow temperature preparation method to produce mixed superfine powder from Agrimonia pilosa (A), Nelumbo nucifera (N), Boswellia carteri (B), and Pollen typhae (P), named as ANBP. Applying ANBP on 40 streptozotocin (STZ)-induced diabetic C57BL/6 mice (4-6 weeks, 20 ± 2 g), we observed that the wound healing process was accelerated and the wound healing time was shortened (14 days, P < .05). Pathological observation using hematoxylin-eosin staining indicated that inflammatory cells were reduced (P < .05) while the thickness of granulation tissue and length of epithelial tongue were increased (P < .05). The vascular density was increased on 7 and 14 days after ANBP treatment. Masson and Sirius red staining showed that, at the early stage of trauma, the expressions of Col I and Col III, especially Col III, were increased in the ANBP group (P < .05). Studies in vitro demonstrated that tubular formation was significantly increased after ANBP treatment on human vascular endothelial cells in a dose-dependent way. Taken together, our studies revealed that ANBP treatment could accelerate wound healing, promote vascularization, and inhibit inflammation, suggesting the potential clinic application of ANBP for diabetes mellitus and refractory wounds.

Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia.

We conducted a clinical trial to assess the feasibility and efficacy of CD33-directed chimeric antigen receptor-modified T cells (CART-33) for the treatment of refractory acute myeloid leukemia (AML). A 41-year-old male patient with AML was enrolled and received a total of 1.12 × 10(9) autologous CART-33 cells, of which ~38% were transduced with CAR. The CART-33 infusion alone induced rigorous chills and fevers; drastic fluctuations of his preexisting pancytopenia; elevated serum cytokine levels, including interleukin (IL)-6, IL-8, tumor necrosis factor-α, and interferon-γ; slight transient hyperbilirubinemia within 2 weeks; a subsequent intermittent moderate fever; and reversed fluctuation of the pancytopenia. A marked decrease of blasts in the bone marrow was observed on examination 2 weeks after therapy, and there was a gradual increase until florid disease progression occurred at 9 weeks after the cell infusion. These observations warrant further research on CART-33 treatment in refractory AML and may spur efforts to extend the CART-33-induced tumor burden to the preparation of other intensive strategies, such as hematopoietic stem cell transplantation. This study is registered at www.ClinicalTrials.gov as NCT01864902.

Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells.

We conducted a trial testing a CD20-specific CAR coupled with CD137 and the CD3ζ moiety in patients with chemotherapy refractory advanced diffuse large B cell lymphomas (DLBCL). Seven patients were enrolled. One of the two patients with no bulky tumor obtained a 14-month durable and ongoing complete remission by cell infusion only, and another attained a 6-month tumor regression. Four of five patients with bulky tumor burden were evaluable for clinical efficacy, three of which attained 3- to 6-month tumor regression. Delayed toxicities related to cell infusion are directly correlated to tumor burden and tumor-harboring sites, and mainly included cytokine release symptoms, tumor lysis symptoms, massive hemorrhage of the alimentary tract and aggressive intrapulmonary inflammation surrounding extranodal lesions. These results show firstly that anti-CD20 CART cells can cause prolonged tumor regression in combination with debulking conditioning regimens for advanced DLBCL. This study is registered at www.clinicaltrials.gov as NCT01735604.