Self-replicating RNA vaccines delivered by viral replicon particles (VRPs) induce strong immunity, but repeated dosing on short intervals may be limited by vector responses. In patient samples and mice, VRP-srRNA vaccination generated VRP-neutralizing antibodies and T-cell responses to replicase. In mice, a third dose at two-week intervals minimally boosted transgene immunity, and prior VRP exposure reduced responses to a different-transgene VRP. Optimized schedules or heterologous prime-boost may sustain immunogenicity.

The concurrent presence of COVID-19 infection in advanced cancer patients has increased the mortality since the compromised immunity was inevitably worsen. The role and clinical impact of autologous adoptive T cell immunotherapy (ACT) designed for anti-cancer treatment were not known in such circumstances. The safety and potential immune reconstitution of concurrent ACT in advanced cancer patients with active COVID-19 infection have yet unknown as well. The effect of infused ACT on the symptom severity manifestation should be summarized. In this respectively clinical observation study, patients were non-randomized enrolled from the two centers according to the regular therapeutic plans including stage IV cancer patients for scheduled ACT, chemotherapy, cancer patients with symptomatic COVID-19 but without ACT, neither cancer or non-ACT but symptomatic cases of COVID-19 infection. We have incorporated the age-adjusted Charlson comorbidity index (aCCI) for each patient to compare the prognosis of the three groups. All patients were planned for the scheduled standard anti-cancer therapeutic considerations, chemotherapy plus ACT as planned as well as the supportive care.The clinical efficacy and impact of ACT on cancer patients within the 3 months from the peripheral blood apheresis, dendritic cell (DC) and cytokine induced killer T cell (CIK-T ) infusion and subsequent co-existence of COVID-19 infection were recorded as the primary objective. During the same period, the cancer cases without ACT and others were collected to compare the occurrence of both severe and death rate respectively. There were 123 patients (35 of ACT, 23 of non-ACT, 65 of non-cancer) with similar aCCI. There were similar cohort-level COVID-19 in-hospital case fatality rates consistent with previously reported data for non-cancer (26.2

Supplementary Figure Legends 1-9 from HER2 Overexpression Elicits a Proinflammatory IL-6 Autocrine Signaling Loop That Is Critical for Tumorigenesis

Supplementary Figure 4 from HER2 Overexpression Elicits a Proinflammatory IL-6 Autocrine Signaling Loop That Is Critical for Tumorigenesis

Supplementary Figure 8 from HER2 Overexpression Elicits a Proinflammatory IL-6 Autocrine Signaling Loop That Is Critical for Tumorigenesis

Supplementary Methods from Antihelminth Compound Niclosamide Downregulates Wnt Signaling and Elicits Antitumor Responses in Tumors with Activating APC Mutations

Supplementary Figure 5 from HER2 Overexpression Elicits a Proinflammatory IL-6 Autocrine Signaling Loop That Is Critical for Tumorigenesis

Hepatocellular carcinoma (HCC) accounts for about 90% of all primary liver cancers and is the second leading cause of cancer-related deaths worldwide. The hypervascular nature of most HCC tumors underlines the importance of angiogenesis in the pathobiology of these tumors. Several angiogenic pathways have been identified as being dysregulated in HCC, suggesting they may be involved in the development and pathogenesis of HCC. These data provide practical targets for systemic treatments such as those targeting the vascular endothelial growth factor receptor and its ligand. However, the clinical relevance of other more recently identified angiogenic pathways in HCC pathogenesis or treatment remains unclear. Research into molecular profiles and validation of prognostic or predictive biomarkers will be required to identify the patient subsets most likely to experience meaningful benefit from this important class of agents.

NEO-102 is a novel chimeric IgG1 monoclonal antibody which recognizes a variant form of MUC5AC expressed specifically by human pancreatic and colorectal tumors. Preclinical models have demonstrated encouraging signs of anti-tumor activity through antibody-dependent cell-mediated cytotoxicity.This is a phase 1, dose-escalation trial of NEO-102 (Ensituximab) for patients with refractory pancreatic and colorectal cancer. The primary objective was to determine safety and tolerability of escalating doses of NEO-102. Secondary objectives were to assess pharmacokinetics, anti-tumor activity and biologic correlates. Patients whose tumors express NPC-1 antigen were eligible. Dose-escalation was performed in a 3 + 3 design at doses of 1.5, 2, 3 and 4 mg/kg.A total of 19 patients (4 pancreatic and 15 colon cancer) were enrolled at participating institutions in the treatment phase. Most common treatment-related adverse events included anemia, fatigue, fevers, chills and flushing. There was no detectable hemolysis. Of twelve patients evaluable for disease response, the response rate at week 8 included 5 patients with stable disease and 8 patients with progressive disease (PD). Treatment-related grade 3/4 hyperbilirubinemia and anemia were observed at 4 mg/m2. Reversible hypoxia at 3 mg/kg was a dose-limiting toxicity. The maximum tolerated dose was established at 3 mg/kg. Of 74 patients who underwent tissue screening, positive NPC-1 expression was 47 % in colon and 59 % in pancreatic cancer.Treatment with the NEO-102, in this first-in-human study, is well tolerated with a manageable safety profile. A maximum tolerated dose of 3 mg/kg has been established. Toxicity profile is typical for this therapeutic class and allows for combination with conventional cytotoxic therapies.

Most dendritic cell (DC)-based vaccines have loaded the DC with defined antigens, but loading with autologos tumor-derived antigens would generate DCs that activate personalized tumor-specific T-cell responses. We hypothesized that DC matured with an optimized combination of reagents and loaded with tumor-derived antigens using a clinically feasible electroporation strategy would induce potent antitumor immunity. We first studied the effects on DC maturation and antigen presentation of the addition of picibanil (OK432) to a combination of zoledronic acid, tumor necrosis factor-α, and prostaglandin E2. Using DC matured with the optimized combination, we tested 2 clinically feasible sources of autologous antigen for electroloading, total tumor mRNA or total tumor lysate, to determine which stimulated more potent antigen-specific T cells in vitro and activated more potent antitumor immunity in vivo. The combination of tumor necrosis factor-α/prostaglandin E2/zoledronic acid/OK432 generated DC with high expression of maturation markers and antigen-specific T-cell stimulatory function in vitro. Mature DC electroloaded with tumor-derived mRNA [mRNA electroporated dendritic cell (EPDC)] induced greater expansion of antigen-specific T cells in vitro than DC electroloaded with tumor lysate (lysate EPDC). In a therapeutic model of MC38-carcinoembryonic antigen colon cancer-bearing mice, vaccination with mRNA EPDC induced the most efficient anti-carcinoembryonic antigen cellular immune response, which significantly suppressed tumor growth. In conclusion, mature DC electroloaded with tumor-derived mRNA are a potent cancer vaccine, especially useful when specific tumor antigens for vaccination have not been identified, allowing autologous tumor, and if unavailable, allogeneic cell lines to be used as an unbiased source of antigen. Our data support clinical testing of this strategy.

T cell infiltration of colorectal cancer is associated with improved clinical outcome, underlining the importance of the immune system in cancer control; however, immune checkpoints, including the inhibitory T cell molecules CTLA-4 and PD-1 that temper the native immune response, mitigating autoimmunity, are coopted by tumors to facilitate escape from immune surveillance. Blockade of CTLA-4 and PD-1 and its ligand PD-L1, expressed by many tumors, have shown impressive activity in melanoma, renal cell carcinoma, and lung cancer. Immune checkpoint inhibition has been less well studied in colorectal cancer, but preclinical and clinical investigations are in progress.

La presente invention concerne des methodes permettant de reduire la probabilite pour un cancer ou un precancer de developper une resistance contre un agent anticancereux a visee therapeutique ou preventive. Lesdites methodes comprennent les etapes consistant a administrer a un sujet l'agent anticancereux a visee therapeutique ou preventive et un vaccin contenant un polynucleotide codant pour un polypeptide dont l'expression ou l'activation est correlee avec le developpement de la resistance du cancer ou du precancer a l'agent anticancereux a visee therapeutique ou preventive. Le vaccin peut contenir un polynucleotide codant pour un polypeptide HER3. L'invention concerne egalement des methodes d'utilisation du vaccin contenant le polynucleotide codant pour le polypeptide HER3 afin de traiter un cancer ou un precancer.

Background Crosstalk between malignant hepatocytes and the surrounding peritumoral stroma is a key modulator of hepatocarcinogenesis and therapeutic resistance. To examine the chemotherapy resistance of these two cellular compartments in vitro , we evaluated a well-established hepatic tumor cell line, HepG2, and an adult hepatic stellate cell line, LX2. The aim was to compare the chemosensitization potential of arsenic trioxide (ATO) in combination with sorafenib or fluorouracil (5-FU), in both hepatic tumor cells and stromal cells. Methods Cytotoxicity of ATO, 5-FU, and sorafenib, alone and in combination against HepG2 cells and LX2 cells was measured by an automated high throughput cell-based proliferation assay. Changes in survival and apoptotic signaling pathways were analyzed by flow cytometry and western blot. Gene expression of the 5-FU metabolic enzyme, thymidylate synthase, was analyzed by real time PCR. Results Both HepG2 and LX2 cell lines were susceptible to single agent sorafenib and ATO at 24 hr (ATO IC 50 : 5.3 μM in LX2; 32.7 μM in HepG2; Sorafenib IC 50 : 11.8 μM in LX2; 9.9 μM in HepG2). In contrast, 5-FU cytotoxicity required higher concentrations and prolonged (48–72 hr) drug exposure. Concurrent ATO and 5-FU treatment of HepG2 cells was synergistic, leading to increased cytotoxicity due in part to modulation of thymidylate synthase levels by ATO. Concurrent ATO and sorafenib treatment showed a trend towards increased HepG2 cytotoxicity, possibly due to a significant decrease in MAPK activation in comparison to treatment with ATO alone. Conclusions ATO differentially sensitizes hepatic tumor cells and adult hepatic stellate cells to 5-FU and sorafenib. Given the importance of both of these cell types in hepatocarcinogenesis, these data have implications for the rational development of anti-cancer therapy combinations for the treatment of hepatocellular carcinoma (HCC).