No abstract

Murine IgG3 anti-GD2 antibody m3F8 has shown anti-neuroblastoma activity in Phase I/II studies, where antibody-dependent cell-mediated cytotoxicity (ADCC) played a key role. Humanization of m3F8 should circumvent human anti-mouse antibody (HAMA) response and enhance its ADCC properties to reduce dosing and pain side effect. Chimeric 3F8 (ch3F8) and humanized 3F8 (hu3F8-IgG1 and hu3F8-IgG4) were produced and purified by protein A affinity chromatography. In vitro comparison was made with m3F8 and other anti-GD2 antibodies in binding, cytotoxicity, and cross-reactivity assays. In GD2 binding studies by SPR, ch3F8 and hu3F8 maintained K D comparable to m3F8. Unlike other anti-GD2 antibodies, m3F8, ch3F8 and hu3F8 had substantially slower k off. . Similar to m3F8, both ch3F8 and hu3F8 inhibited tumor cell growth in vitro, while cross-reactivity with other gangliosides was comparable to that of m3F8. Both peripheral blood mononuclear cell (PBMC)-ADCC and polymorphonuclear leukocytes (PMN)-ADCC of ch3F8 and hu3F8-IgG1 were more potent than m3F8. This superiority was consistently observed in ADCC assays, irrespective of donors or NK-92MI-transfected human CD16 or CD32, whereas complement mediated cytotoxicity (CMC) was reduced. As expected, hu3F8-IgG4 had near absent PBMC-ADCC and CMC. Hu3F8 and m3F8 had similar tumor-to-non tumor ratios in biodistribution studies. Anti-tumor effect against neuroblastoma xenografts was better with hu3F8-IgG1 than m3F8. In conclusion, humanizing m3F8 produced next generation anti-GD2 antibodies with substantially more potent ADCC in vitro and anti-tumor activity in vivo. By leveraging ADCC over CMC, they may be clinically more effective, while minimizing pain and HAMA side effects. A Phase I trial using hu3F8-IgG1 is ongoing.

Cervical cancer remains an important public health problem worldwide. New and effective therapeutic strategies targeting cervical cancer are urgently needed. Long non-coding RNAs (lncRNAs) are newly identified regulators in tumorigenesis and tumor progression. To investigate the role of lncRNA MEG3 in the development of cervical cancer, we examined MEG3 expression in 18 pairs of cervical cancer and matched adjacent non-neoplastic tissues. Real-time quantitative RT-PCR (qRT-PCR) results showed high expression levels of MEG3 in non-neoplastic tissues, but markedly lower levels in cancer tissues. We further investigated whether the restoration of MEG3 expression might affect the proliferation of cervical carcinoma cells. Ectopic expression of MEG3 inhibited the proliferation of human cervical carcinoma cells HeLa and C-33A in vitro. On the other hand, knockdown of MEG3 promoted the growth of well-differentiated cervical carcinoma HCC94 cells. Further investigation into the mechanisms responsible for the growth inhibitory effects revealed that overexpression of MEG3 resulted in the induction of G2/M cell cycle arrest and apoptosis. These results identified an important role of MEG3 in the molecular etiology of cervical cancer and implicated the potential application of MEG3 in cervical cancer therapy.

Background: Despite an increasing understanding about tumor mutation burden (TMB) in cancer immunity and cancer immunotherapy, the comprehensive cognition between TMB and efficiency of immune checkpoint inhibitors (ICIs) is still lacking. A systematic review and meta-analysis was conducted to evaluate the predictive value of TMB on efficacy of ICIs.Methods: Systematic literature search was conducted on PubMed, EMBASE, Web of Science and Cochrane Library up to June 16, 2019. Pooled odds ratio (OR) of objective response rate (ORR), hazard ratio (HR) of progression-free survival (PFS) and overall survival (OS) were estimated by inverse variance weighted fixed-effects model (I2 ≤ 50%) or DerSimonian-Laird random-effects model (I2 > 50%). In addition, heterogeneity analysis, sensitivity analysis, publication bias and subgroup analysis were conducted. Moreover, fractional polynomial regression was conducted to investigate the dose-response relationship between TMB cutoffs and efficacy of ICIs. Furthermore, we assessed ORR by TMB and programmed cell death ligand 1 (PD-L1) expression after layering each other in studies which the two could be both acquired.Results: Three thousand six hundred fifty-seven records were retrieved through database searching, and 29 studies with 4,431 patients were finally included in the meta-analysis. TMB high group had significantly improved ORR (pooled OR 3.31, 95% CI 2.61, 4.19, P < 0.001), PFS (pooled HR 0.59, 95% CI 0.49, 0.71, P < 0.001) and OS (pooled HR 0.68, 95% CI 0.53, 0.89, P = 0.004). Sensitivity analyses illustrated the results were stable, and publication bias was identified in ORR. Subgroup analyses showed the predictive value of TMB was significant in non-small-cell lung cancer (except for the OS) and melanoma. In addition, heterogeneity was substantial in targeted next generation sequencing group but tiny in whole exome sequencing group. Furthermore, TMB and PD-L1 expression were capable to predict improved ORR of ICIs after stratification of each other, with tiny heterogeneity.Conclusions: High tumor mutation burden predicted improved efficacy of immune checkpoint inhibitors in cancers, and targeted next generation sequencing for estimating tumor mutation burden in clinic should be standardized to eliminate heterogeneity in the future. Moreover, tumor mutation burden and programmed cell death ligand 1 expression were independent factors on predicting efficacy of immune checkpoint inhibitors.

Lobectomy, segmentectomy, and wedge resection are comparable oncologic procedures for patients with stage IA NSCLC that is 1.0 cm or smaller. For tumors from 1.1 to 2.0 cm, lobectomy and segmentectomy could lead to equivalent survival rates but showed better survival rates than that observed with wedge resection. For tumors from 2.1 to 3.0 cm, lobectomy is still the standard surgical procedure; for patients who are unsuitable candidates for lobectomy, segmentectomy and wedge resection show similar survival rates.

No abstract

Early stage lung cancer is routinely treated by lobectomy whenever clinically feasible, whereas the role of segmentectomy is controversial. The purpose of this study was to investigate the benefits of segmentectomy vs lobectomy for early stage lung cancer through a meta-analysis of published data. Eligible studies were identified from MEDLINE through February 2013. The manual selection of relevant studies was based on the summary analysis. We used published hazard ratios (HRs) if available or estimates from the published survival data. Lobectomy was chosen as the reference in all HR calculations. We compared the effect of segmentectomy and lobectomy for Stage I, Stage IA, Stage IA with tumours larger than 2 cm but smaller than 3 cm in size and Stage IA with tumours of 2 cm or smaller in 22 observational studies. The HRs of overall and cancer-specific survival indicated significant benefits of lobectomy for Stage I, Stage IA and Stage IA with tumours larger than 2 cm but smaller than 3 cm at 1.20 (95% confidence interval [CI] 1.04-1.38; P = 0.011), 1.24 (95% CI 1.08-1.42; P = 0.002) and 1.41 (95% CI 1.14-1.71; P = 0.001), respectively. For tumours 2 cm or smaller, segmentectomy provided an effect equivalent to that of lobectomy (HR 1.05; 95% CI 0.89-1.24; P = 0.550). No significant publication bias was detected in any part of the analysis. These findings should be interpreted in the context of the inherent limitations of meta-analyses of retrospective studies, including the heterogeneity of patient characteristics.

Clinical responses to immunotherapy have been associated with augmentation of preexisting immune responses, manifested by heightened inflammation in the tumor microenvironment. However, many tumors have a noninflamed microenvironment, and response rates to immunotherapy in melanoma have been <50%. We approached this problem by utilizing immunotherapy (CTLA-4 blockade) combined with chemotherapy to induce local inflammation. In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8 þ and CD4 þ T cells increasing the CD8/Foxp3 T-cell ratio. These changes were associated with improved survival of the mice. To translate these findings into a clinical setting, 26 patients with advanced melanoma were treated locally by isolated limb infusion with the nitrogen mustard alkylating agent melphalan followed by systemic administration of CTLA-4 blocking antibody (ipilimumab) in a phase II trial. This combination of local chemotherapy with systemic checkpoint blockade inhibitor resulted in a response rate of 85% at 3 months (62% complete and 23% partial response rate) and a 58% progression-free survival at 1 year. The clinical response was associated with increased T-cell infiltration, similar to that seen in the murine models. Together, our findings suggest that local chemotherapy combined with checkpoint blockade-based immunotherapy results in a durable response to cancer therapy.