Michael P. O’Leary

From Benchtop to Bedside: A Review of Oncolytic Virotherapy

Oncolytic viruses (OVs) demonstrate the ability to replicate selectively in cancer cells, resulting in antitumor effects by a variety of mechanisms, including direct cell lysis and indirect cell death through immune-mediate host responses. Although the mechanisms of action of OVs are still not fully understood, major advances have been made in our understanding of how OVs function and interact with the host immune system, resulting in the recent FDA approval of the first OV for cancer therapy in the USA. This review provides an overview of the history of OVs, their selectivity for cancer cells, and their multifaceted mechanism of antitumor action, as well as strategies employed to augment selectivity and efficacy of OVs. OVs in combination with standard cancer therapies are also discussed, as well as a review of ongoing human clinical trials.

Complications of Feeding Jejunostomy Tubes in Patients with Gastroesophageal Cancer.

BackgroundFeeding jejunostomy tubes (FJT) in patients undergoing resection of gastroesophageal cancers facilitate perioperative nutrition. Data regarding FJT use and complications are limited.Study designA single institution review was performed for patients who underwent perioperative FJT placement for gastrectomy or esophagogastrectomy from 2007 to 2015. FJT-related and unrelated complications were evaluated.ResultsFJTs were inserted for total/completion gastrectomy (nu2009=u200949/117, 41.9xa0%), proximal gastrectomy (nu2009=u20097/117, 6.0xa0%), or esophagogastrectomy (nu2009=u200961/117, 52.1xa0%). Ninety percent (nu2009=u2009106/117) of patients used an FJT at some time point. Although the majority of patients (75.2xa0%) used FJTs after discharge, 8.5xa0% (nu2009=u200910/117) never used the FJT and 10.3xa0% (nu2009=u200912/117) used the FJT only during hospitalization. Overall, 44.4xa0% (nu2009=u200952/117) had FJT-related complications, including dislodgement (nu2009=u200922), clogging (nu2009=u200913), and leakage (nu2009=u20096). The majority of FJT complications were resolved by telephone triage (13.5xa0%) or bedside/clinic intervention (57.7xa0%), but 3.4xa0% required operative intervention for small bowel obstruction (nu2009=u20093) and hemorrhage (nu2009=u20091). FJT complications were more common with gastrectomy than esophagogastrectomy (53.6 vs. 36.0xa0%), perhaps related to longer FJT use in gastrectomy patients (71 vs. 38xa0days).ConclusionsFJT-related complications are common, occurring more frequently after gastrectomy than esophagogastrectomy. In most patients, complications can be managed by simple measures, rarely requiring operative intervention. Nevertheless, the need for FJTs should be carefully considered to balance nutritional benefits with the risks of insertion and usage.

Oncolytic herpes simplex virus kills stem-like tumor-initiating colon cancer cells

Stem-like tumor-initiating cells (TICs) are implicated in cancer progression and recurrence, and can be identified by sphere-formation and tumorigenicity assays. Oncolytic viruses infect, replicate in, and kill a variety of cancer cells. In this study, we seek proof of principle that TICs are susceptible to viral infection. HCT8 human colon cancer cells were subjected to serum-free culture to generate TIC tumorspheres. Parent cells and TICs were infected with HSV-1 subtype NV1066. Cytotoxicity, viral replication, and Akt1 expression were assessed. TIC tumorigenicity was confirmed and NV1066 efficacy was assessed in vivo. NV1066 infection was highly cytotoxic to both parent HCT8 cells and TICs. In both populations, cell-kill of >80% was achieved within 3 days of infection at a multiplicity of infection (MOI) of 1.0. However, the parent cells required 2-log greater viral replication to achieve the same cytotoxicity. TICs overexpressed Akt1 in vitro and formed flank tumors from as little as 100 cells, growing earlier, faster, larger, and with greater histologic atypia than tumors from parent cells. Treatment of TIC-induced tumors with NV1066 yielded tumor regression and slowed tumor growth. We conclude that colon TICs are selected for by serum-free culture, overexpress Akt1, and are susceptible to oncolytic viral infection.

Novel oncolytic chimeric orthopoxvirus causes regression of pancreatic cancer xenografts and exhibits abscopal effect at a single low dose

BackgroundPancreatic ductal adenocarcinoma (PDAC) has been increasing by 0.5% per year in the United States. PDAC portends a dismal prognosis and novel therapies are needed. This study describes the generation and characterization of a novel oncolytic chimeric orthopoxvirus for the treatment of pancreatic cancer.MethodsAfter chimerization and high-throughput screening, CF33 was chosen from 100 new chimeric orthopoxvirus isolates for its ability to kill pancreatic cancer cells. In vitro cytotoxicity was assayed in six pancreatic cancer cell lines. In vivo efficacy and toxicity were evaluated in PANC-1 and MIA PaCa-2 xenograft models.ResultsCF33 caused rapid killing of six pancreatic cancer cells lines in vitro, releasing damage-associated molecular patterns, and regression of PANC-1 injected and non-injected distant xenografts in vivo after a single low intratumoral dose of 103 plaque-forming units. Using luciferase imaging, CF33 was noted to preferentially replicate in tumors which corresponds to the low viral titers found in solid organs.ConclusionThe low dose of CF33 required to treat pancreatic cancer in this preclinical study may ease the manufacturing and dosing challenges currently facing oncolytic viral therapy.

The Comprehensive Complication Index: a New Measure of the Burden of Complications After Hyperthermic Intraperitoneal Chemotherapy

ABSTRACTBackgroundCytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) are complex surgeries with multiple comorbidities. The Clavien–Dindo classification (CDC) is the most commonly used method to report surgical morbidity, but limits it to the highest-grade complication. The Comprehensive Complication Index (CCI) is a score ranging from 0 to 100, calculated using all 30-day complications and their treatment after abdominal surgery. The aim of this study is to assess the CCI’s validity in the HIPEC patient population.MethodsA review of our institutional cytoreduction database from 2009 to 2015 was undertaken. Patient demographics, pathology, Peritoneal Carcinomatosis Index (PCI), complications and their treatments, and length of stay (LOS) were reviewed. The CCI was calculated for each patient. Linear regression was used to assess whether the CCI and CDC were predictors of LOS.ResultsOf 157 patients reviewed, 110 (70.1%) underwent HIPEC. The majority were female (77, 66.9%), and the mean age was 53.7 years. Mean PCI was 13.2 [interquartile range (IQR) 7–18]. Median CDC was grade 2 (IQR 0–2), and only 9.8% had CDC of grade 4 or higher. Mean CCI was 21.4, while the median was 20.9 (IQR 0–30.8). Mean LOS was 16.2 days, while the median was 11 days (IQR 8–15 days). The CCI strongly correlated with LOS with coefficient of 0.46 [95% confidence interval (CI) 0.38–0.54, pxa0=xa00.000].ConclusionsThe CCI is an adequate tool to capture all complications and their overall burden in patients having undergone HIPEC. This study shows that the CCI can predict LOS and could be used to quantify and compare the burden of multiple complications.

Association of Fluid Administration With Morbidity in Cytoreductive Surgery With Hyperthermic Intraperitoneal Chemotherapy

Importance Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal cancers can be associated with significant complications. Randomized trials have demonstrated increased morbidity with liberal fluid regimens in abdominal surgery. Objective To investigate the association of intraoperative fluid administration and morbidity in patients undergoing CRS/HIPEC. Design, Setting, and Participants A retrospective analysis of information from a prospectively collected institutional database was conducted at a National Cancer Institute–designated comprehensive cancer center. A total of 133 patients from April 15, 2009, to June 23, 2016, with primary or secondary peritoneal cancers were included. Exposures Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Main Outcomes and Measures Morbidity associated with intraoperative fluid management calculated by the comprehensive complication index, which uses a formula combining all perioperative complications and their severities into a continuous variable from 0 to 100 in each patient. Results Of the 133 patients identified, 38% and 37% had diagnoses of metastatic appendiceal and colorectal cancers, respectively. Mean age was 54 (interquartile range [IQR], 47-64) years, and mean peritoneal cancer index was 13 (IQR, 7-18). Mitomycin and platinum-based chemotherapeutic agents were used in 96 (72.2%) and 37 (27.8%) of the patients, respectively. Mean intraoperative fluid (IOF) rate was 15.7 (IQR, 11.3-18.7) mL/kg/h. Mean comprehensive complication index (CCI) was 26.0 (IQR, 8.7-36.2). On multivariate analysis, age (coefficient, 0.32; 95% CI, 0.01-0.64; Pu2009=u2009.04), IOF rate (coefficient, 0.97; 95% CI, 0.19-1.75; Pu2009=u2009.02), and estimated blood loss (coefficient, 0.02; 95% CI, 0.01-0.03; Pu2009=u2009.002) were independent predictors of increased CCI. In particular, patients who received greater than the mean IOF rate experienced a 43% increase in the CCI compared with patients who received less than the mean IOF rate (31.5 vs 22.0; Pu2009=u2009.02). Conclusions and Relevance Intraoperative fluid administration is associated with a significant increase in perioperative morbidity in patients undergoing CRS/HIPEC. Fluid administration protocols that include standardized restrictive fluid rates can potentially help to mitigate morbidity in patients undergoing CRS/HIPEC.

Mesenteric Lymphadenectomy in Well-Differentiated Appendiceal Neuroendocrine Tumors

BACKGROUND: Surgical resection is the primary therapy for local and locally advanced appendiceal neuroendocrine tumors. The role of mesenteric lymphadenectomy in these patients is undefined. OBJECTIVE: The purpose of this study was to define the role and prognostic significance of mesenteric lymphadenectomy. DESIGN: This was a retrospective, observational study. SETTINGS: A population-based cohort from the National Cancer Institute Surveillance, Epidemiology, and End Results registry (January 1988 to November 2013) was used. PATIENTS: Patients with well-differentiated neuroendocrine tumors and nonmixed histologies undergoing surgical resection were included. MAIN OUTCOME MEASURES: The risk of lymph node metastases as a function of tumor size and overall survival with respect to lymph node count and tumor size was measured. Lymph node cut-point was determined using the Contal and O’Quigely method. RESULTS: Of the 573 patients who met the inclusion criteria, 64% were women, 79% were white, and 76% were <60 years of age. Seventy percent of the tumors were ⩽2u2009cm, and 77% were lymph node negative. Median lymph nodes retrieved were 0 (interquartile range, 0–14). The probability of nodal metastases was 2.7% in tumors ⩽1.0u2009cm, 31.0% in tumors 1.1 to 2.0u2009cm, and 64.0% in tumors >2.0u2009cm. The probability of a positive lymph node increased with increasing lymph node count up to 26 lymph nodes. An ideal cut-point of 12 lymph nodes was identified by statistical modeling. After adjustment in the multivariable model, the group with 12 or fewer lymph nodes examined had significantly worse overall survival (HR = 4.33 (95% CI, 1.54–12.15); p = 0.005; 5-year survival, 88% versus 96%) than the group with more than 12 lymph nodes examined. LIMITATIONS: Analysis was limited by the variables available in the database. CONCLUSIONS: This is the largest study to date that looks at prognostic significance of lymph node count for well-differentiated appendiceal neuroendocrine tumors. Overall survival was worse where 12 or fewer lymph nodes were identified for tumors >1u2009cm. See Video Abstract at http://links.lww.com/DCR/A352.

Therapeutic oncolytic viruses: clinical advances and future directions

Purpose of review The present review will highlight recent advances in the clinical application of oncolytic viral therapy. Recent findings Until recently, oncolytic viral researchers saw the immune system as an enemy that would clear the virus from the bloodstream. However, researchers now understand that sustained responses are seen in those patients with more robust antitumor immune responses. Much of the current focus in oncolytic viral research is trained on manipulation of the immune system to affect cancer cell killing in the tumor microenvironment and to facilitate durable systemic antitumor immunity. Many investigators have demonstrated synergistic effects of checkpoint inhibition and other immune therapies with viral administration. At the same time, insertion of various markers enables noninvasive deep tissue imaging. Finally, following regulatory approval in the United States and Europe, unbridled clinical use of T-VEC for patients with metastatic melanoma is also generating large volumes of patient data that will help elucidate strengths and weaknesses of oncolytic viral therapy. Perhaps the most telling sign of the fields future is a seismic shift in clinical trials with more investigators combining virus and immunotherapies. Summary This article reviews the current state of therapeutic oncolytic viruses in clinical use, and explores future directions of the field.

Base Excess as a Predictor of Complications in Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy

BackgroundBase excess is important in assessing metabolic status. Postoperative management in patients undergoing cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal malignancies can be a challenge, and we therefore sought to investigate perioperative predictors of overall morbidity in CRS/HIPEC patients at our institution.MethodsPatients who underwent CRS/HIPEC from 2012 to 2016 were identified retrospectively from a prospectively collected institutional database. Patient demographics and perioperative variables were obtained and the comprehensive complication index (CCI) was calculated for each patient in order to assess perioperative morbidity. Stepwise linear regression analyses were performed, with CCI as the outcome variable.ResultsA total of 72 CRS/HIPEC patients had recorded base excesses in the first 48xa0h postoperatively. Mean immediate postoperative base excess was −6.0xa0mmol/L (interquartile range [IQR] −8 to −4.1), mean delta base excess at 48xa0h was +4.3xa0mmol/L (IQR +2.1 to +6.2), and mean CCI was 25.2 (IQR 8.7–36.7). On multivariate analysis, delta base excess was the only significant predictor of CCI, demonstrating a protective effect (pxa0=xa00.001). In patients who experienced less than the mean delta base excess of +4.3xa0mmol/L, lower delta base excess was an independent predictor of complications (pxa0<xa00.001).ConclusionsDelta base excess is an independent predictor of morbidity in patients undergoing CRS/HIPEC. A delta base excess of greater than +4.3xa0mmol/L at 48xa0h may be an appropriate goal for resuscitation of CRS/HIPEC patients in the immediate postoperative period. Standardized protocols to correct the base deficit in CRS/HIPEC patients during the early postoperative period can potentially help mitigate perioperative morbidity.

Endogenous Akt Activity Promotes Virus Entry and Predicts Efficacy of Novel Chimeric Orthopoxvirus in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high recurrence rate and poor prognosis. Here, we describe a novel, chimeric orthopoxvirus (CF33) that efficiently kills TNBC. Cytotoxicity was assayed in vitro in four TNBC cell lines. Viral replication was examined through standard plaque assay. Two orthotopic TNBC xenograft models were generated in athymic nude mice and were injected with CF33 intratumorally. CF33 was effective in vitro with potent cytotoxicity and efficient intracellular replication observed in TNBC lines with phosphatidylinositol 3-kinase (PI3K)/Akt pathway mutations that resulted in endogenous phospho-Akt (p-Akt) activity (BT549, Hs578T, and MDA-MB-468). Relative resistance to CF33 by wild-type PI3K/Akt pathway cell line MDA-MB-231 was overcome using higher MOI. The virus was effective in vivo with significant tumor size reduction in both xenograft models. Mechanistically, CF33 appears to share similar properties to vaccinia virus with respect to Akt-mediated and low-pH-mediated viral entry. In summary, CF33 demonstrated potent antitumoral effect in vitro and in vivo, with the most potent effect predicted by the presence of endogenous Akt activity in the TNBC cell line. Further investigation of its mechanism of action as well as genetic modifications to enhance its natural viral tropism are warranted for preclinical development.