Effect of anti-asthma Chinese medicine Chuankezhi on the anti-tumor activity of cytokine-induced killer cells

Chuankezhi(CKZ),a new Chinese medicine,plays an important role in immunoregulation.Cytokineinduced killer(CIK)cells have been commonly used for immunotherapy in recent years.In this study,we aimed to investigate the immunoregulatory effect of CKZ on CIK cells.Peripheral blood monocytes were isolated from healthy donors,and CIK cells were generated by culturing monocytes with interferon-gamma(IFN-γ)and interleukin 2.Different concentrations of CKZ were added on day 2.After incubation for 14days in culture,the antitumor effects of CIK cells were measured by cytotoxicity assay.Flow cytometry was used to explore the effect of CKZ on CIK cell immunophenotype,intracellular cytokine production,and apoptosis.The effect of CKZ on the antitumor activity of CIK cells in nude mice was also investigated.CKZ increased the percentage of CD3+CD56+CIK cells but did not significantly change the percentage of CD4+,CD8+,or CD4+CD25+CIK cells.CKZ-conditioned CIK cells showed a greater ability to kill tumor cells,as well as a higher frequency of IFN-γand TNF-αproduction,compared with the CIK cells in the control group.CKZ also suppressed the apoptosis of CIK cells in vitro.Furthermore,CKZ combined with CIK cells had a stronger suppressive effect on tumor growth in vivo than the CIK,CKZ,or normal saline control groups.Our results indicate that CKZ enhances the antitumor activity of CIK cells and is a potential medicine for tumor immunotherapy.

Safety of in vitro amplified HLA-haploidentical donor immune cell infusions for childhood malignancies

In vitro amplified human leukocyte antigen(HLA)-haploidentical donor immune cell infusion(HDICI)is not commonly used in children.Therefore,our study sought to evaluate its safety for treating childhood malignancies.Between September 2011 and September 2012,12 patients with childhood malignancies underwent HDICI in Sun Yat-sen University Cancer Center.The median patient age was 5.1 years(range,1.7-8.4 years).Of the 12 patients,9 had high-risk neuroblastoma(NB)[7 showed complete response(CR),1 showed partial response(PR),and 1 had progressive disease(PD)after multi-modal therapies],and 3 had Epstein-Barr virus(EBV)-positive lymphoproliferative disease(EBV-LPD).The 12 patients underwent a total of 92 HDICIs at a mean dose of 1.6×108immune cells/kg body weight:71 infusions with natural killer(NK)cells,8 with cytokine-induced killer(CIK)cells,and 13 with cascade primed immune cells(CAPRIs);83 infusions with immune cells from the mothers,whereas 9 with cells from the fathers.Twenty cases(21.7%)of fever,including 6 cases(6.5%)accompanied with chills and 1(1.1%)with febrile convulsion,occurred during infusions and were alleviated after symptomatic treatments.Five cases(5.4%)of mild emotion changes were reported.No other adverse events occurred during and after the completion of HDIDIs.Neither acute nor chronic graft versus host disease(GVHD)was observed following HDICIs.After a median of 5.0 months(range,1.0-11.5 months)of follow-up,the 2 NB patients with PR and PD developed PD during HDICIs.Of the other 7 NB patients in CR,2 relapsed in the sixth month of HDICIs,and 5 maintained CR with disease-free survival(DFS)ranging from 4.5 to 11.5 months(median,7.2months).One EBV-LPD patient achieved PR,whereas 2 had stable disease(SD).Our results show that HDICI is a safe immunotherapy for childhood malignancies,thus warranting further studies.

XELOX(capecitabine plus oxaliplatin)plus bevacizumab(anti-VEGF-A antibody)with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer:a multicenter,open-label,randomized,controlled,phase 3 trial

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer(mCRC),but the prognosis remains poor.This phase 3 trial(ClinicalTrials.gov:NCT03950154)assessed the efficacy and adverse events(AEs)of the combination of PD-1 blockade-activated DC-CIK(PD1-T)cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC.A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab(the control group,n=102)or the same regimen plus autologous PD1-T cell immunotherapy(the immunotherapy group,n=100)every 21 days for up to 6 cycles,followed by maintenance treatment with capecitabine and bevacizumab.The main endpoint of the trial was progression-free survival(PFS).The median follow-up was 19.5 months.Median PFS was 14.8 months(95%CI,11.6-18.0)for the immunotherapy group compared with 9.9 months(8.0-11.8)for the control group(hazard ratio[HR],0.60[95%CI,0.40-0.88];p=0.009).Median overall survival(OS)was not reached for the immunotherapy group and 25.6 months(95%CI,18.3-32.8)for the control group(HR,0.57[95%CI,0.33-0.98];p=0.043).Grade 3 or higher AEs occurred in 20.0%of patients in the immunotherapy group and 23.5%in the control groups,with no toxicity-associated deaths reported.The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

TES functions as a Mena-dependent tumor suppressor in gastric cancer carcinogenesis and metastasis

Background: In our previous study, we identified a candidate tumor suppressor gene, testin LIM domain protein (TES), in primary gastric cancer (GC). TES contains three LIM domains, which are specific interacting regions for the cell adhesion and cytoskeleton regulatory proteins. Mena is a known cytoskeleton regulator that regulates the assembly of actin filaments and modulates cell adhesion and motility by interacting with Lamellipodin (Lpd). Therefore, we hypothesized that TES plays a role as tumor suppressor in GC through interacting with Mena. This study aimed to investigate the tumor suppressive functions of TES in GC. Methods: We explored the tumor suppressive effect of TES in GC by in vitro cell proliferation assay, colony formation assay, cell cycle analysis, Transwell assays, and in vivo tumorigenicity and metastasis assays. The interaction of TES and Mena was investigated through immunoprecipitation-based mass spectrometry. We also analyzed the expression of TES and Mena in 172 GC specimens using immunohistochemistry and investigated the clinicopathological and prog-nostic significance of TES and Mena in GC. Results: TES suppressed GC cell proliferation and colony formation, induced cell cycle arrest, and inhibited tumorigenicity in vitro. Additionally, it inhibited GC cell migration and invasion in vitro and suppressed metastasis in vivo. TES interacted with Mena, and inhibited the interaction of Mena with Lpd. Transwell assays suggested that TES suppressed migration and invasion of GC cells in a Mena-dependent fashion. In GC patients with high Mena expression, the expression of TES was associated with tumor infiltration (P = 0.005), lymph node metastasis (P = 0.003), TNM stage (P = 0.003), and prognosis (P = 0.010). However, no significant association was observed in GC patients with low Mena expression. Conclusions: We believe that TES functions as a Mena-dependent tumor suppressor. TES represents a valuable prog-nostic marker and potential target for GC treatment.