Targeting cancer stem cells by using chimeric antigen receptor-modified T cells: a potential and curable approach for cancer treatment

Cancer stem cells (CSCs), a subpopulation of tumor cells, have self-renewal and multi-lineage differentiation abilities that play an important role in cancer initiation, maintenance, and metastasis. An accumulation of evidence indicates that CSCs can cause conventional therapy failure and cancer recurrence because of their treatment resistance and self-regeneration characteristics. Therefore, approaches that specifically and efficiently eliminate CSCs to achieve a durable clinical response are urgently needed. Currently, treatments with chimeric antigen receptor-modified T (CART) cells have shown successful clinical outcomes in patients with hematologic malignancies, and their safety and feasibility in solid tumors was confirmed. In this review, we will discuss in detail the possibility that CART cells inhibit CSCs by specifically targeting their cell surface markers, which will ultimately improve the clinical response for patients with various types of cancer. A number of viewpoints were summarized to promote the application of CSC-targeted CART cells in clinical cancer treatment. This review covers the key aspects of CSC-targeted CART cells against cancers in accordance with the premise of the model, from bench to bedside and back to bench.

Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers

This phase I clinical trial (NCT01935843) is to evaluate the safety, feasibility, and activity of chimeric antigen receptor-engineered T cell (CART) immunotherapy targeting human epidermal growth factor receptor 2 (HER2) in patients with advanced biliary tract cancers (BTCs) and pancreatic cancers (PCs). Eligible patients with HER2-positive (>50%) BTCs and PCs were enrolled in the trial. Well cultured CART-HER2 cells were infused following the conditioning treatment composed of nab-paclitaxel (100-200 mg/m) and cyclophosphamide (15-35 mg/kg). CAR transgene copy number in the peripheral blood was serially measured to monitor the expansion and persistence of CART-HER2 cells in vivo. Eleven enrolled patients received 1 to 2-cycle CART-HER2 cell infusion (median CAR T cell 2.1 × 10/kg). The conditioning treatment resulted in mild-to-moderate fatigue, nausea/vomiting, myalgia/arthralgia, and lymphopenia. Except one grade-3 acute febrile syndrome and one abnormal elevation of transaminase (>9 ULN), adverse events related to the infusion of CART-HER2 cells were mild-to-moderate. Post-infusion toxicities included one case of reversible severe upper gastrointestinal hemorrhage which occurred in a patient with gastric antrum invaded by metastasis 11 days after the CART-HER2 cell infusion, and 2 cases of grade 1-2 delayed fever, accompanied by the release of C-reactive protein and interleukin-6. All patients were evaluable for assessment of clinical response, among which 1 obtained a 4.5-months partial response and 5 achieved stable disease. The median progression free survival was 4.8 months (range, 1.5-8.3 months). Finally, data from this study demonstrated the safety and feasibility of CART-HER2 immunotherapy, and showed encouraging signals of clinical activity.

Clinical application of cytokines in acute iatrogenic radiation damage / 中华放射医学与防护杂志

Objective To explore the influence of hematopoietic growth factors on the TBI patients in the conditioning regimen for stem cell transplantation,and to evaluate the effect of cytokines on treatment of acute radiation disease.Methods The usage of hematopoietic growth factors,implantations and the side-effects of the patients and donors of TBI in the conditioning regimen for stem cell transplantation were retrospectively analysed from 1990 to 2012,and the effect and side-effects of cytokines on the hematopoietic function recovery and stem cell mobilization were observed.Results All patients recovered from their hematopoietic function except one died due to the side-effecs.The median time of white blood cell recover was 10 d in auto-SCT and 12 d in allo-SCT in the G-CSF group.The median day of platelet recovery was 11.67 ± 1.53 in rhIL-11 arm and 13.70 ±6.27 in no rhIL-11 arm in the auto-SCT group.The incidence rates of dental ulcer and diarrhea in the TBI patients were 48％ and 44％,respectively.The occurrence of side-effect was rare in the period of cytokines treatment,but was over 50％ during stem cell mobilization.Conclusions Cytokines play very important roles in the hematopoietic function recovery and stem cell mobilization in the TBI patients.

Detection of rearrangements of mixed lineage leukemia gene in acute leukemia patients / 白血病·淋巴瘤

Objective To explore the value of fluorescence in situ hybridization (FISH) and multiplex RT-PCR in the detection of mixed lineage leukemia (MLL) gene rearrangement in acute leukemia (AL) patients. Methods Dual-color MLL probe, multiplex RT-PCR and R or G banding techniques were used to detect the MLL gene rearrangement in 189 cases of AL.Results MLL gene rearrangements were detected in 9 cases (5.03 ％) by FISH,and 16 cases (8.47 ％) by multiplex RT-PCR,including MLL/AF9,MLL/AF10,MLL/AF6, MLL/AF7, MLL/ELL, MLL/PTD. R or G banding techniques could find 11q23 in 5 out of 189 patients (2.65 ％). There was no statistic difference in the incidence of 6 common MLL gene rearrangements between ALL (73 cases) and AML patients (116 cases) (P ＞ 0.05).Conclusion Multiplex RT-PCR is a powerful technique in the detection of MLL gene rearrangement for tentatively diagnosed AL.It could not only confirm translocation detected by conventional cytogenetic method, but also detect MLL partial tandem duplication which could not been detected by cytogenetic examination or FISH. It plays an important role in guiding therapy and predicting prognosis for AL.

Study on detection of common fusion genes in acute lymphoblastic leukemia / 白血病·淋巴瘤

[Objective] To investigate combined application of multiplex reverse transcription-polymerase chain reaction(mRT-PCR)and karyotype analysis detect of clonal chromosomal aberrations in acute lymphoblasfic leukemia (ALL),and explore the expression of common fusion genes.Methods 189 ALL patients were examined by multiplex RT-PCR and R or G banding techniques.[Results]10 fusion genes were detected in 69 out of 189 ALL patients(36.5％),including E2A/PBX1,TEL/AML1,BCR/ABL,MLL/AF4,MLL/AF6、MLL/AF9,MLL/AF10,MLL/ELL,SIL/TAL1,TLS/ERG.R or G banding techniques could find chromosome structural and numeracy abnormalities in 86 out of 152 patients (56.6％) available for analysis.Combination of mRT-PCR and R or G banding could raise the rate of detecting clonal chromosomal abnormalities to 69.3％.Fusion genes were detected in 33 out of 90 (36.7％) patients with adult ALL and 36out of 99 (36.4 ％) patients with children ALL,there were 22 patients with positive BCR/ABL but no TEL/AML1 in adult ALL group,while there were 24 patients with positive TEL/AML.1 and 2 with positive BCR/ABL in children ALL group.There was significant statistical difference for the expression of RCR/ABL and TEL/AML1 between adult ALL and children ALL (P＜0.01),but no difference for MLL related fusion gene,E2A/PBX1,SIL/TAL1 and TLS/ERG(P＞0.05).BCR/ABL and TEL/AML1 fusion gene could be detected in 66 ALL patients with normal karyotype (36.3％).[Conclusion]There were different biological characteristics between adults and children with ALL.mRT-PCR technique can quickly screen chromosome structural aberrations in patients with newly diagnosed leukemia.It is useful in detection of fusion genes in ALL with normal karyotypes and it would refine the karyotype analysis and provide imrootramt prognosis-relevant information.

GDP regimen as salvage treatment for relapsed refractory non-Hodgkin's lymphoma / 白血病·淋巴瘤

Objective To study the effect and safety of GDP regimens (gemcitabine,cisplatin,dexamethasone) as salvage chemotherapy in relapsed refractory non-Hodgkin’s lymphoma (NHL).Methods Clinical response and adverse effects of 34 NHL patients treated by GDP regimens were analyzed retrospectively.Results The overall response rate (ORR) was 52.9 ％ (18/34),there was no statistic difference between ORR in relapsed NHL [72.7 ％ (8/11)] and that in refractory ones [43.5 ％ (10/23)](P =0.11).The ORR for B-NHL was 64.0 ％ (16/25),while for T-NHL was 22.2 ％ (2/9),there was no statistic difference between them (P =0.052).The ORR for low risks groups was 66.7 ％ (6/9),while it for intermediate-risk and high-risk ones were 55.6 ％ (10/18) and 28.6 ％ (2/7),respectively,the effect of GDP regimens for low-risk group was better for high-risk ones,but there was no statistic difference (P =0.349).The incedience of Ⅲ-Ⅳ granulopenia reduced was 23.5 ％ (8/34) and there were no Ⅲ-Ⅳ gastrointestinal adverse reactions or liver and kidney toxicity.Conclusion GDP regimens were efficient and less toxic as second-line salvage chemotherapy.