David L. Bartlett

The complex immune tumour microenvironment requires an equally complex immunotherapy approach, especially when the cancer-immune set point is non-inflamed. Oncolytic viruses expressing immune activating cytokines might optimally modify the immune microenvironment and improve the antitumour effects. In this study, we have explored a variety of IL-2 constructs expressed by a tumour-selective oncolytic vaccinia virus, designed to maintain IL-2 in the tumour microenvironment to reduce systemic toxicity. An IL-2 construct combining a glycosylphosphatidylinositol (GPI) anchor with a rigid peptide linker leads to functional IL-2 expression on the tumour cell surface and in the tumour microenvironment. This virus construct effectively modifies the cancer-immune set point and treats a variety of murine tumour models with no toxic side effects. In combination with PD-1/PD-L1 blockade this virus cures most of the mice with a high tumour burden. This combination represents a treatment for cancers which are to date unresponsive to immunotherapy.

Oncolytic viruses (OVs), either occurring naturally or through genetic engineering, can selectively infect, replicate in, and kill cancer cells, while leaving normal cells (almost) unharmed

Both anti-PD1/PD-L1 therapy and oncolytic virotherapy have demonstrated promise, yet have exhibited efficacy in only a small fraction of cancer patients. Here we hypothesized that an oncolytic poxvirus would attract T cells into the tumour, and induce PD-L1 expression in cancer and immune cells, leading to more susceptible targets for anti-PD-L1 immunotherapy. Our results demonstrate in colon and ovarian cancer models that an oncolytic vaccinia virus attracts effector T cells and induces PD-L1 expression on both cancer and immune cells in the tumour. The dual therapy reduces PD-L1⁺ cells and facilitates non-redundant tumour infiltration of effector CD8⁺, CD4⁺ T cells, with increased IFN-γ, ICOS, granzyme B and perforin expression. Furthermore, the treatment reduces the virus-induced PD-L1⁺ DC, MDSC, TAM and Treg, as well as co-inhibitory molecules-double-positive, severely exhausted PD-1⁺CD8⁺ T cells, leading to reduced tumour burden and improved survival. This combinatorial therapy may be applicable to a much wider population of cancer patients.

The impact of histopathologic features on oncologic outcomes for patients with peritoneal metastases from goblet cell carcinoid (GCC) undergoing multimodality therapy, including cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC), is unknown. This study prospectively analyzed 43 patients with GCC undergoing CRS-HIPEC between 2005 and 2013. Pathology slides were re-reviewed to classify GCC into histologic subtypes according to the Tang classification. Kaplan-Meier survival curves and multivariate Cox-regression models identified prognostic factors affecting oncologic outcomes. The 43 patients in this study underwent 50 CRS-HIPEC procedures for peritoneal metastases from GCC, and the majority received neoadjuvant and/or adjuvant systemic chemotherapy. The GCC demonstrated an aggressive phenotype with frequent lymph node and peritoneal metastases without systemic dissemination. The majority of the patients had Tang B GCC. The estimated median overall survival times after surgery for the patients with Tang A, B, and C GCC were respectively 59, 22, and 13 months. In a multivariate Cox-regression analysis, poor survival was associated with patients who had Tang B or C GCC, those undergoing incomplete macroscopic resection, and those with symptoms at the time of CRS-HIPEC. The patients with Tang A GCC demonstrated oncologic outcomes similar to those with intermediate-grade (American Joint Committee on Cancer [AJCC] grade 2) disseminated mucinous appendiceal neoplasms, whereas the patients with Tang B and C GCC demonstrated survival rates similar to or worse than those with high-grade (AJCC grade 3) disseminated mucinous appendiceal neoplasms. Tang classification is an independent prognostic factor for poor survival after multimodality therapy for GCC. Patients with Tang C GCC demonstrate limited survival and are not ideal candidates for a surgical approach.

Modulation of chemokines in the tumor microenvironment enhances oncolytic virotherapy for colorectal cancer

311 Background: The role of RT following PD for PDA remains controversial due to ambiguity in the definition of R0/R1 margin status in existing clinical trials. Recent data suggest that increased margin clearance (MC) is associated with improved survival after PD for PDA, however the role of adjuvant radiotherapy (ADRT) in patients with known MC is undefined. We sought to analyze the influence of ADRT on outcomes of PD for PDA based on MC data. Methods: We retrospectively identified 326 patients with MC data (in mm) who underwent PD between 2002-2014. Recurrence-free (RFS) and overall survival (OS) was determined by Kaplan-Meier analysis. Hazard ratios (HR) were calculated by Cox multivariate regression analysis on significant variables. Results: Mean age was 68 yrs and 55% were male. Median follow-up was 21 mos (IQR 12-34 mos). ADRT was administered to 87 patients (27%). Median RFS and OS for the entire cohort was 14 mos and 25 mos. On univariate analysis, ADRT was not associated with improved median RFS (13 vs. 14 mos; p = NS) or OS (23 vs. 27 mos; p = NS), but increasing MC was associated with prolonged median RFS [10 (0mm) vs. 13 (0-1mm) vs. 23 mos ( > 1mm); p < 0.02 for all pairs] and OS [16 (0mm) vs. 23 (0-1mm) vs. 40 mos ( > 1mm); p < 0.01 for all pairs]. After controlling for sex, BMI, neoadjuvant therapy, LVI, PNI, lymph node ratio > 0.2, tumor size > 2.5cm, and adjuvant chemotherapy, increasing MC was independently associated with improved OS [HR 0.680; p = 0.034 (0-1mm); HR 0.451; p < 0.001 ( > 1mm), compared to 0mm]. Patients were subsequently stratified into 3 groups based on MC [0mm (n = 73); 0-1mm (n = 118); > 1mm (n = 135)]. ADRT was administered less frequently to patients with greater MC [0mm (n = 29; 41%); 0-1mm (n = 36; 31%); > 1mm (n = 22; 16%); p < 0.001]. Even when stratified by MC, ADRT was not associated with improved RFS [10 vs. 9 mos (0mm); 13 vs. 12 mos (0-1mm); 21 vs. 23 mos ( > 1mm); p = NS for all pairs] or OS [16 vs. 18 mos (0mm); 24 vs. 23 mos (0-1mm); 33 vs. 42 mos ( > 1mm); p = NS for all pairs]. Conclusions: ADRT is not associated with improved RFS or OS following PD for PDA regardless of MC. The use of RT following PD for PDA should be re-examined.

Background High-grade (HG) mucinous appendiceal neoplasms (MAN) have a worse prognosis than low-grade histology. Our objective was to assess the safety and efficacy of cytoreductive surgery with...

We have armed a tumor-selective oncolytic vaccinia virus (vvDD) with the chemokine (CK) CXCL11, in order to enhance its ability to attract CXCR3⁺ antitumor CTLs and possibly NK cells to the tumor microenvironment (TME) and improve its therapeutic efficacy. As expected, vvDD-CXCL11 attracted high numbers of tumor-specific T cells to the TME in a murine AB12 mesothelioma model. Intratumoral virus-directed CXCL11 expression enhanced local numbers of CD8⁺ CTLs and levels of granzyme B, while reducing expression of several suppressive molecules, TGF-β, COX2, and CCL22 in the TME. Unexpectedly, we observed that vvDD-CXCL11, but not parental vvDD, induced a systemic increase in tumor-specific IFNγ-producing CD8⁺ T cells in the spleen and other lymph organs, indicating the induction of systemic antitumor immunity. This effect was associated with enhanced therapeutic efficacy and a survival benefit in tumor-bearing mice treated with vvDD-CXCL11, mediated by CD8⁺ T cells and IFNγ, but not CD4⁺ T cells. These results demonstrate that intratumoral expression of CXCL11, in addition to promoting local trafficking of T cells and to a lesser extent NK cells, has a novel function as a factor eliciting systemic immunity to cancer-associated antigens. Our data provide a rationale for expressing CXCL11 to enhance the therapeutic efficacy of oncolytic viruses (OVs) and cancer vaccines.

Background Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemoperfusion (HIPEC) is routinely used to treat certain peritoneal carcinomatoses (PC), but it can be associated with...