Therapeutic effect of haploidentical peripheral blood stem cell treatment on relapsed/refractory ovarian cancer.

The traditional immunotherapy is limited on relapsed/refractory metastatic ovarian cancer because tumors cause immunosuppression. Since new therapeutic strategies to improve clinical outcomes for patients with relapsed/refractory metastatic ovarian carcinoma are needed, the aim of this study was to evaluate the therapeutic effect of haploidentical peripheral blood stem cells (haplo-PBSCs) adoptive treatment on relapsed/refractory ovarian cancer. Thirteen patients with advanced stage of ovarian cancer and refractory history after surgery and chemotherapy were treated with interleukin-2 activated haplo-PBSCs donated by their parents or children. Clinical outcomes including therapeutic response by measuring tumor size changes using CT scanning, CA-125 levels and survival times were evaluated. T and NK cell population in patients before and after treatment was detected by flow cytometry analysis. The median follow-up time after haplo-PBSCs adoptive treatment was 14 months. At the time of the last follow-up, the median overall survival after haplo-PBSCs adoptive treatment was 9.1 months. Ten patients (76.9%) achieved a relief of symptoms, including abdominal distention, ache, fatigue, and poor appetite. During the first 2 months after treatment, CA125 levels decreased in 10 patients (76.9%). Five patients (38.5%) had a stable disease and 1 patient (8%) had partial response. T cell population (CD3+CD4+ and CD3+CD8+) and CD3-CD16+CD56+ NK cells were increased in patients after haplo-PBSCs adoptive treatment. Our study reveals that haplo-PBSCs adoptive treatment is associated with an anti-tumor effect and increasing immune responses in patients with relapsed/refractory ovarian cancer.

A Phase IB Trial of Autologous Cytokine-Induced Killer Cells in Combination with Sintilimab, Monoclonal Antibody Against Programmed Cell Death-1, plus Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer.

INTRODUCTION: Can the Cytokine-induced killer (CIK) cells in combination with immune checkpoint inhibitor further improve the efficacy of chemotherapy in non-small cell lung cancer (NSCLC) patients? What are the adverse reactions of this combination therapy? But these problems are not clear. Therefore, we conducted a phase 1b trial to evaluate the safety and efficacy of autologous CIK cells therapy combined with Sintilimab, antibody against programmed cell death-1, plus chemotherapy in untreated, advanced NSCLC patients. PATIENTS AND METHODS: Patients with stage IIIB/IIIC/IV NSCLC received Sintilimab, platinum-based doublet chemotherapy, and CIK cells every 3 weeks for 4 cycles, then maintenance treatment with Sintilimab in squamous and with Sintilimab plus pemetrexed in non-squamous NSCLC until disease progression or unacceptable toxicity or 2 years. The primary endpoints were safety and objective response rate (ORR). RESULTS: Thirty-four patients received the treatment. 94.1% of patients experienced treatment-related adverse events (TRAEs). Grade 3 or greater TRAEs occurred in 64.7% of patients. One (2.9%) patient died of grade 5 immune-related pneumonia. The ORR and DCR were 82.4% (95% CI, 65.5%-93.2%) and 100.0% (95% CI, 89.7%-100.0%), respectively. Objective responses were evaluated in 14 of 15 non-squamous patients (93.3%; 95% CI, 68.1%-99.8%) and in 14 of 19 squamous patients (73.7%; 95% CI, 48.8%-90.9%). Median PFS was 19.3 months (95% CI, 8.3 months to not available). CONCLUSION: Autologous CIK cells immunotherapy in combination with Sintilimab plus chemotherapy was well tolerable and showed encouraging efficacy in patients with previously untreated, advanced NSCLC (ClinicalTrials.gov number, NCT03987867).

Ferritin as a diagnostic, differential diagnostic, and prognostic marker for immune-related adverse events.

OBJECTIVE: Distinguishing immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) from the AEs caused by chemotherapy, targeted therapy, or infection is highly difficult. This study offers new insights into evaluating the diagnosis, differential diagnostic, and prognostic value of ferritin for irAEs induced by ICIs. METHODS: From December 1, 2018, to April 1, 2019, we examined 318 patients with malignant tumors who received serum ferritin monitoring. The cohort comprised 231 patients treated with PD-1 inhibitor or combination with chemotherapy, and 87 patients treated with chemotherapy. Of the 231 patients, 90 had irAEs (irAE group), 70 had non-irAEs (non-irAE group), 67 had no AEs (no irAE-non irAE group), and 4 had unclassified AEs. In the 87 patients, 60 had AEs (AE group), and 27 had no AEs (no AE group). Statistical analyses were conducted with nonparametric Mann-Whitney tests. RESULTS: At the onset of AEs in the irAE group, ferritin (normal range, 35-150 µg/L) rose to a median of 927 µg/L (range, 117-17,825 µg/L) from 86 µg/L at baseline (range, 29-421 µg/L) (P < 0.001). Ferritin levels at the onset of AEs in the irAE group were significantly higher than those in the non-irAE group (median, 81 µg/L; range, 32-478 µg/L) (P < 0.001) and the AE group (median, 103 µg/L; range, 23-712 µg/L) (P < 0.001). After treatment in the irAE group, ferritin continuously decreased to a normal range in recovered patients, showed no significant changes in stable patients, and continued to rise in patients who died. CONCLUSIONS: Ferritin can be used as a diagnostic, differential diagnostic, and prognostic marker for irAEs in patients treated with ICIs.

T-cell receptor gene therapy targeting melanoma-associated antigen-A4 by silencing of endogenous TCR inhibits tumor growth in mice and human.

Genetically engineered T cells expressing a T-cell receptor (TCR) are powerful tools for cancer treatment and have shown significant clinical effects in sarcoma patients. However, mismatch of the introduced TCR α/ß chains with endogenous TCR may impair the expression of transduced TCR, resulting in an insufficient antitumor capacity of modified T cells. Here, we report the development of immunotherapy using human lymphocytes transduced with a codon-optimized melanoma-associated antigen (MAGE)-A4 and HLA-A*2402-restricted TCR, which specifically downregulate endogenous TCR by small interfering RNA (si-TCR). We evaluated the efficacy of this immunotherapy in both NOD-SCID mice and uterine leiomyosarcoma patients. Our results revealed that transduced human lymphocytes exhibited high surface expression of the introduced tumor-specific TCR, enhanced cytotoxic activity against antigen-expressing tumor cells, and increased interferon-γ production by specific MAGE-A4 peptide stimulation. Retarded tumor growth was also observed in NOD-SCID mice inoculated with human tumor cell lines expressing both MAGE-A4 and HLA-A*2402. Furthermore, we report the successful management of a case of uterine leiomyosarcoma treated with MAGE-A4 si-TCR/HLA-A*2402 gene-modified T cells. Our results indicate that the TCR-modified T cell therapy is a promising novel strategy for cancer treatment.

Identification of SUV39H2 as a potential oncogene in lung adenocarcinoma.

BACKGROUND: SUV39H2 (suppressor of variegation 3-9 homolog 2), which introduces H3K9me3 to induce transcriptional repression, has been reported to play critical roles in heterochromatin maintenance, DNA repair, and recently, carcinogenesis. Dysregulation of SUV39H2 expression has been observed in several types of cancers. However, neither the genomic landscape nor the clinical significance of SUV39H2 in lung adenocarcinoma has been probed comprehensively. METHODS: In this research, we conducted bioinformatics analysis to primarily sort out potential genes with dysregulated expressions. After we identified SUV39H2, RNA-seq was performed for a high-throughput evaluation of altered gene expression and dysregulated pathways, followed by a series of validations via RT-qPCR and bioinformatics analyses. Finally, to assess the potential oncogenic role of SUV39H2, we employed the invasion assay and clone formation assay in vitro and tumorigenesis assays in mouse models in vivo. RESULTS: Through bioinformatics analyses, we found that SUV39H2 underwent a severe upregulation in the tumor tissue, which was also confirmed in the surgically removed tissues. Overexpression of SUV39H2 was mainly associated with its amplification and with shorter patient overall survival. Then, the RNA-seq demonstrated that TPM4, STOM, and OPTN might be affected by the loss of function of SUV39H2. Finally, in vitro and in vivo experiments with SUV39H2 knockdown all suggested a potential role of SUV39H2 in both carcinogenesis and metastasis. CONCLUSIONS: SUV39H2 expression was elevated in lung adenocarcinoma. TPM4, OPTN, and STOM were potentially regulated by SUV39H2. SUV39H2 might be a potential oncogene in lung adenocarcinoma, mediating tumorigenesis and metastasis.

Prognostic value of pretreatment inflammatory biomarkers in advanced lung adenocarcinoma patients receiving first-line pemetrexed/platinum doublet.

Inflammation is a new hallmark feature of cancer initiation and progression. We aimed to investigate the association between inflammatory response biomarkers and progression-free survival and overall survival in advanced lung adenocarcinoma patients treated with first-line pemetrexed and platinum doublet chemotherapy. Patients hospitalized between April 2012 and March 2015 were enrolled and eliminated according to the inclusion and exclusion criteria. The pretreatment neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, derived neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio were calculated. Besides the well-established clinical prognostic factors, the prognostic values of the four markers were evaluated by the Kaplan-Meier method and Cox's proportional hazards regression model. A total of 78 patients were enrolled in this study. Elevated neutrophil-to-lymphocyte ratio and derived neutrophil-to-lymphocyte ratio were correlated with poor treatment response ( p = 0.014, 0.012, respectively). A high pretreatment neutrophil-to-lymphocyte ratio, derived neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio, as well as low lymphocyte-to-monocyte ratio, were associated with worse progression-free survival and overall survival. Multivariate analysis revealed that high neutrophil-to-lymphocyte ratio (hazard ratio = 2.056; 95% confidence interval, 1.281-3.299; p = 0.003) and ≥3 metastasis organs (hazard ratio = 1.989; 95% confidence interval, 1.069-3.702; p = 0.030) were independent prognostic factors for progression-free survival. Meanwhile, high neutrophil-to-lymphocyte ratio (hazard ratio = 5.540; 95% confidence interval, 2.974-10.321; p < 0.001) and habitual smoking (hazard ratio = 2.806; 95% confidence interval, 1.509-5.221; p = 0.001) were independent prognostic factors for overall survival. In conclusion, Pretreatment neutrophil-to-lymphocyte ratio was an independent prognostic factor for advanced lung adenocarcinoma patients treated with first-line pemetrexed/platinum doublet chemotherapy. Elevated pretreatment derived neutrophil-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio might be potential biomarkers for poorer responses to chemotherapy. To verify these findings, larger well-designed prospective studies are needed.