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CD19-targeted chimeric antigen receptor T (CAR-T) cells using murine single-chain variable fragment (scFv) has shown substantial clinical efficacy in treating relapsed/refractory acute lymphoblastic leukemia (R/R ALL). However, potential immunogenicity of the murine scFv domain may limit the persistence of CAR-T cells. In this study, we treated 52 consecutive subjects with R/R ALL with humanized CD19-specific CAR-T cells (hCART19s). Forty-six subjects achieved complete remission (CR) (N = 43) or CR with incomplete count recovery (CRi) (N = 3) within 1 month post infusion. During the follow-up with a median time of 20 months, the 1-year cumulative incidence of relapse was 25% (95% confidence interval [CI] 13-46), and 1-year event-free survival was 45% (95% CI 29-60). To the cutoff date, 20 patients presented CD19

Renal carcinoma shows a high risk of invasion and metastasis without effective treatment. Herein, we developed a chitosan (CS) nanoparticle‐mediated DNA vaccine containing an activated factor L‐Myc and a tumor‐specific antigen CAIX for renal carcinoma treatment. The subcutaneous tumor models were intramuscularly immunized with CS‐pL‐Myc/pCAIX or control vaccine, respectively. Compared with single immunization group, the tumor growth was significantly suppressed in CS‐pL‐Myc/pCAIX co‐immunization group. The increased proportion and mature of CD11c+ DCs, CD8+CD11c+ DCs and CD103+CD11c+ DCs were observed in the splenocytes from CS‐pL‐Myc/pCAIX co‐immunized mice. Furthermore, the enhanced antigen‐specific CD8+ T lymphocyte proliferation, cytotoxic T lymphocyte (CTL) responses, and multi‐functional CD8+ T cell induction were detected in CS‐pL‐Myc/pCAIX co‐immunization group compared with CS‐pCAIX immunization group. Of note, the depletion of CD8 T cells resulted in the reduction of CD8+ T cells or CD8+CD11c+ DCs and the loss of anti‐tumor efficacy induced by CS‐pL‐Myc/pCAIX vaccine, suggesting the therapeutic efficacy of the vaccine was required for CD8+ DCs and CD103+ DCs mediated CD8+ T cells responses. Likewise, CS‐pL‐Myc/pCAIX co‐immunization also significantly inhibited the lung metastasis of renal carcinoma models accompanied with the increased induction of multi‐functional CD8+ T cell responses. Therefore, these results indicated that CS‐pL‐Myc/pCAIX vaccine could effectively induce CD8+ DCs and CD103+ DCs mediated tumor‐specific multi‐functional CD8+ T cell responses and exert the anti‐tumor efficacy. This vaccine strategy offers a potential and promising approach for solid or metastatic tumor treatment., CS‐p‐L‐Myc/pCAIX vaccine activated the CD8+CD11c+ DCs and CD103+CD11c+ DCs, and activated CAIX‐specific CD8+ T cell proliferation, CTL responses, and multi‐functional CD8+ T cells (expressing TNF‐α, IL‐2, and IFN‐γ) in mouse tumor models. Moreover, the CD8+ T cell depletion resulted in the reduction of CD8+CD11c+ DCs and the loss of anti‐tumor activity of vaccine, suggesting that this therapeutic efficacy was required for CD8+CD11c+ DCs‐mediated multi‐functional CD8+ T cell responses. Therefore, this vaccine strategy may be a potential approach for primary solid or metastasis tumor therapy.

Introduction Anti-CD19 chimeric antigen receptor (CAR) -T cells, which recognize and kill both B lymphoblasts and normal B cells, result in B cell aplasia and humoral immunodeficiency. However, there were only a few detailed reports on the profile of immune reconstitution after anti-CD19 CAR-T cell therapy. Methods Thirty nine patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (ALL) receiving anti-CD19 CAR-T cell therapy were enrolled. Subjects died, relapsed, received other treatment, or lost to follow-up within 60 days post-infusion were excluded. 21 patients were finally selected. Laboratory and clinical data were collected for analysis of immune reconstitution. Results CD8+ cells were the first to recover with a median time on day 21(7-87), followed by CD16/CD56+ cells on day 28(14-87), and finally CD4+ cells with only 5(23.81%) patients recovered within 60 days post-infusion. CD4/CD8 ratio was inverted, sustaining for at least 1 year. B cell aplasia occurred in all patients and CD19+ cells returned to normal on a median time of day 79(41-118). All patients developed hypogammaglobulinemia with a median onset time of 2 weeks post-infusion. IgG recovered in 6 patients with a median time on day 184(89-346). IgM recovered on days 212, 242, and 346 in 3 patients. IgA recovered most slowly and remained low >1 year postinfusion. A total of 9 infections occurred in 6(28.57%) patients. Conclusions Our data showed prolonged reconstitution of immune function, especially humoral immunity, in R/R B cell ALL patients receiving anti-CD19 CAR-T cell therapy.

Prolonged hypersecretion of catecholamine induced by chronic stress may correlate with malignant progression of cancer. β2‐adrenergic receptor (β2‐AR) overexpressed in certain cancer cells may translate the signals from neuroendocrine system to malignant signals by interacting with oncoproteins, such as Her2. In the present study, we demonstrate that catecholamine stimulation activates the expression and proteolytic activity of ADAM10 by modulating the expression of miR‐199a‐5p and SIRT1 and also confirm that catecholamine induction triggers the activities of γ‐secretase, leading to shedding of Her2 extracellular domain (ECD) by ADAM10 and subsequent intramembranous cleavage of Her2 intracellular domain (ICD) by presenilin‐dependent γ‐secretase, nuclear translocation of Her2 ICD, and enhanced transcription of tumor metastasis‐associated gene COX‐2. Chronic stimulation of catecholamine strongly promotes the invasive activities of cancer cells in vitro and spontaneous tumor lung metastasis in mice. Furthermore, nuclear localization of Her2 was significantly correlated with overexpression of β2‐AR in human breast cancer tissues, indicating that catecholamine‐induced β2‐AR activation plays decisive roles in tumor metastasis. Our data also reveal that an unknown mechanism by which the regulated intramembrane proteolysis (RIP) initiated by β2‐AR‐mediated signaling controls a novel Her2‐mediated signaling transduction., In the present study, we demonstrated that catecholamine stimulation activates the expression and proteolytic activity of ADAM10 by modulating the expression of miR‐199a‐5p and SIRT1 and also confirm that catecholamine induction triggers the activities of γ‐secretase, leading to shedding of Her2 ECD by ADAM10 and subsequent intramembranous cleavage of Her2 ICD by presenilin‐dependent γ‐secretase, nuclear translocation of Her2 ICD, and enhanced transcription of tumor metastasis‐associated gene COX‐2. Chronic stimulation of catecholamine strongly promotes the invasive activities of cancer cells in vitro and spontaneous tumor lung metastasis in mice. Furthermore, the nuclear localization of Her2 was significantly correlated with overexpression of β2‐adrenergic receptor (β2‐AR) in human breast cancer tissues, indicating that catecholamine‐induced β2‐AR activation plays decisive roles in tumor metastasis.

Purpose Anti‐CD19 chimeric antigen receptor T (CAR‐T) cell therapy has demonstrated remarkable efficacy for refractory and relapsed diffuse large B cell lymphoma (R/R DLBCL). However, this therapy failed in nearly 25% patients mainly due to antigen loss. The authors performed a phase Ⅱ trial by coadministration of anti‐CD19 and anti‐CD20 CAR‐T cells treatment for R/R DLBCL and evaluated its efficacy and toxicity. Methods Totally 21 patients with DLBCL were enrolled in this study. The patients were conditioned with fludarabine and cyclophosphamide before the infusion of anti‐CD19 and anti‐CD20 CAR‐T cells. Treatment response, toxicity, and persistence were monitored continuously. Results Of the 21 patients received the treatment, the objective response rate (ORR) is 81.0% (95% confidence interval [CI], 58.1%‐94.6%) with four cases of bulk (4/5) and one case of testis involvement; 52.4% (95% CI, 29.8%‐74.3%) had a complete response (CR). Peak levels of anti‐CD19 and anti‐CD20 CAR cells were associated with response (P = .007 and .002). Grade 3‐4 cytokine release syndrome (CRS) and neurologic events occurred in 28.5% and 9.5% patients, respectively. Median overall survival (OS) and progression‐free survival (PFS) were 8.1 and 5.0 months, respectively. The maximum standard uptake value (SUVmax) of CD4/CD8 ratio before and after infusion were associated with responses, and the total lesion glycolysis (TLG) before infusion correlates with cytokines level. Conclusions Coadministration of anti‐CD19 and CD20 CAR‐T cells therapy for DLBCL is feasible with manageable toxicity. Cytokine markers are related to toxicity and SUVmax could predict efficacy. This trial was registered at www.clinicaltrials.gov as NCT03207178., In this study, we confirmed that combination of anti‐CD19 and anti‐CD20 CAR‐T cells therapy strategy was efficient (81% ORR and 52.4% CR respectively) for R/R DLBCL, and that the toxicities was transient and manageable. To our knowledge, this is the first report that combination of anti‐CD19 and anti‐CD20 double‐target CAR‐T cell therapy for R/R DLBCL, and our data demonstrated the feasibility of combination of anti‐CD19 and anti‐CD20 CAR‐T cells therapy for R/R DLBCL.

Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) can induce apoptosis in cancer cells while sparing normal cells, thereby leading to the development of TRAIL receptor agonists for cancer treatment. However, these agonist‐based therapeutics exhibit little clinical benefits due to the lack of biomarkers to predict whether patients are responsive to the treatment, as well as determine the resistance of cancer cells to TRAIL‐based agonists. Our previous study has demonstrated that ISG12a enhances TRAIL‐induced apoptosis and might serve as a biomarker to predict the TRAIL response. The downstream mechanism by which ISG12a augments TRAIL‐induced apoptosis remains to be elucidated. In this study, we found that ISG12a was localized in the mitochondria and nucleus and augmented TRAIL‐induced apoptosis through intrinsic apoptotic pathway. In addition, ISG12a interacted with NR4A1 and promoted its nuclear‐to‐cytoplasm translocation. Upon translocate to cytoplasm, NR4A1 targeted mitochondria and induced Bcl2 conformational change, thereby exposing its BH3 domain. Moreover, TRAIL treatment can induce NR4A1 expression through the activation of NF‐κB in TRAIL‐resistant Huh7 hepatoma cells. Knockdown of NR4A1 could overcome TRAIL resistance. However, in TRAIL‐sensitive LH86 liver cancer cells, TRAIL activated the Jun N‐terminal kinases signalling pathway. Overall, these results showed that both ISG12a and its interaction partner NR4A1 are involved in TRAIL‐mediated apoptosis in hepatoma cells.

Renal cell carcinoma (RCC) is a high metastasis tumour with less effective treatment available currently. Absent in melanoma 2 (AIM2) as a tumour suppressor might be used as a potential therapeutic target for RCC treatment. Here, we found that AIM2 expression was significantly decreased in RCC patient specimens and renal carcinoma cell lines (786‐O and OSRC‐2). To establish a safe and effective AIM2 gene delivery system, we formed the nanoparticles consisting of a folate grafted PEI600‐CyD (H1) nanoparticle‐mediated AIM2 gene (H1/pAIM2) as an effective delivery agent. Delivery of H1/pAIM2 in renal carcinoma cells could remarkably increase the expression of AIM2, and subsequently decrease cell proliferation, migration, and invasion as well as enhance cell apoptosis. In order to evaluate the therapeutic efficacy of AIM2 in vivo, H1/pAIM2 nanoparticles were injected intratumorally into 786‐O‐xenograft mice. Administration of H1/pAIM2 nanoparticles could inhibit the tumour growth as evidenced by reduced tumour volume and weight. Furthermore, Blockade of inflammasome activation triggered by H1/pAIM2 nanoparticles using inflammasome inhibitor YVAD‐CMK abrogated the anti‐tumoral activities of H1/AIM2. These results indicated the therapeutic effect of H1/pAIM2 nanoparticles was mainly attributable to its capability to enhance the inflammasome activation. H1/AIM2 nanoparticles might act as an efficient therapeutic approach for RCC treatment.

Chimeric antigen receptor T (CAR-T) cell therapy has shown promising results for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). The immune response induced by murine single-chain variable fragment (scFv) of the CAR may limit CAR-T cell persistence and thus increases the risk of leukemia relapse. In this study, we developed a novel humanized scFv from the murine FMC63 antibody. A total of 18 R/R ALL patients with or without prior murine CD19 CAR-T therapy were treated with humanized CD19-targeted CAR-T cells (hCART19s). After lymphodepletion chemotherapy with cyclophosphamide and fludarabine, the patients received a single dose (1 × 106 /kg) of autologous hCART19s infusion. Among the 14 patients without previous CAR-T therapy, 13 (92.9%) achieved complete remission (CR) or CR with incomplete count recovery (CRi) on day 30, whereas 1 of the 3 patients who failed a second murine CAR-T infusion achieved CR after hCART19s infusion. At day 180, the overall and leukemia-free survival rates were 65.8% and 71.4%, respectively. The cumulative incidence of relapse was 22.6%, and the nonrelapse mortality rate was 7.1%. During treatment, 13 patients developed grade 1-2 cytokine release syndrome (CRS), 4 patients developed grade 3-5 CRS, and 1 patient experienced reversible neurotoxicity. These results indicated that hCART19s could induce remission in patients with R/R B-ALL, especially in patients who received a reinfusion of murine CAR-T.

Angiogenesis, the process of new blood vessel formation and growth from already existing venules is critical in vascular development and homeostasis controlled by the balance of pro- and anti-angiogenic factors. Emerging evidence indicates the development, progression, and metastasis of various human cancers are strongly relied on angiogenesis. However, molecular mechanisms that underlie the complex regulation of angiogenic processes are still not fully elucidated. Recent studies revealed that microRNAs (miRNAs) were important regulators of tumor angiogenesis and the entire research in this area has entered into a so-called "miRNAs era." Thus, miRNAs might be important therapeutic targets or biomarkers for cancer. Due to the complexity of miRNA regulating mechanisms, how specific miRNAs intersect with and modulate tumor angiogenesis is still unclear. The conflicting results of the same miRNAs from different groups indicated that miRNAs might possess potent activity in a cell type or cell context specific manner. Here, we present a summary of latest advances in understanding the roles of angiogenic miRNAs as potential tools or targets in cancer therapy.

MicroRNAs (miRNAs), which are characterized by highly conserved and small non-coding RNAs, have been a hot spot regarding biological processes such as cellular proliferation, apoptosis and metabolism as well as cellular differentiation, signal transduction and carcinogenesis. MiRNA-106a (miR-106a), a member of the miR-17 family, has been validated to be aberrantly regulated in the diversity of tumors. The purpose of this review is supposed to deliver an intricate overview of miR-106a, including its role in cell proliferation, apoptosis, cell cycle, invasion and metastasis, involvement in drug resistance as well as its interactions with the target proteins and signaling pathways involved.

Replication-competent adenovirus (RCAd) has been used extensively in cancer gene therapy, and tumor-selection is critical for the use of replication-competent adenovirus. Here we investigated the anti-tumor characterization of oncolytic virus, whose E1A gene is under the control of a renal cell carcinoma specific promoter - the G250 promoter. The constructed oncolytic virus G250-Ki67 is armed with transgene of Ki67-siRNA, and G250-ZD55-Ki67 also with E1B-55 KD deleted. The tumor-specific expression of E1A and Ki67 was demonstrated by Western blot and immunohistochemistry staining, and the tumor-specific cytotoxicity was assessed by crystal violet staining and cell viability assays. The G250-Ki67 and G250-ZD55-Ki67 adenoviruses could express E1A protein in 786-O and OSRC cell lines but not in ACHN and HK-2 cell lines. The expression of Ki67 gene in 786-O and OSRC cell lines were suppressed by these adenoviruses. The cytotoxic effects induced by G250-ZD55-Ki67 and G250-Ki67 were more obvious on the 786-O cell lines than on the OSRC cell lines. Each group of adenoviruses could inhibit the proliferation of the 786-O cells and OSRC cells. However, the effects induced by G250-ZD55-Ki67 and G250-Ki67 on 786-O cells were stronger than on OSRC cells. Moreover, G250-ZD55-Ki67 had enhanced antitumor activities in these renal cancer cells compared with G250-Ki67. G250 promoter-derived CRAds carrying Ki67-siRNA could highly amplify and express Ki67-siRNA in renal cancer cells with expression of G250 antigen, inhibit renal cancer cells proliferation and induce apoptosis. These results demonstrated that the G250-specific oncolytic adenovirus expressing Ki67-siRNA is applicable for human renal clear cell cancer therapy.

Combinatorial therapy is the current trend of the development of novel cancer treatments due to the high heterogenous nature of solid tumors. In this study, we investigated the effects of the combined use of a conditionally replicating adenovirus carrying IL-24 (ZD55-IL-24) and radiotherapy on the proliferation and apoptosis of melanoma A375 cells in vitro and in vivo. Compared with either agent used alone, ZD55-IL-24 combined with radiotherapy significantly inhibited cell proliferation, accompanied with increased apoptosis. Radiotherapy did not affect the expression of IL-24 and E1A of ZD55-IL-24-treated cells, but increased the expression of Bax, promoted the activation of caspase-3, while decreasing Bcl-2 levels. Thus, this synergistic effect of ZD55-IL-24 in combination with radiotherapy provides a novel strategy for the development of melanoma therapies, and is a promising approach for further clinical development.

Despite significant improvements in diagnosis and innovations in the therapy of specific cancers, effective treatment of neoplastic diseases still presents major challenges. Recent studies have shown that conditionally replicating adenoviruses (CRAds) not only have the ability to destroy cancer cells but may also be potential vectors for the expression of therapeutic genes. Several studies in animal models have demonstrated that the combination of CRAds-mediated gene therapy and chemotherapy has greater therapeutic benefit than either treatment modality alone. In this review, an overview of specifications for a novel antitumor approach combining CRAd-gene therapy and chemotherapy is provided and recent progress in this field is discussed.