Subjective Cognitive Decline in a Registry Sample: Relation to Psychiatric History, Loneliness, and Personality.

BACKGROUND: With the increasing focus on prevention of Alzheimer's disease, there is need for characterization of preclinical populations. Local participant registries offer an opportunity to facilitate research engagement via remote data collection, inform recruitment, and characterize preclinical samples, including individuals with subjective cognitive decline. OBJECTIVES: We sought to characterize subjective cognitive decline in a registry sample, as related to psychiatric history and related variables, including personality and loneliness, quality of life, and factors related to dementia risk (e.g., family history of dementia). DESIGN, SETTING, PARTICIPANTS: Participants were 366 individuals (mean age=67.2 (range 50-88), 65% female, 94% white, 97% non-Hispanic or Latino, 82% with at least a bachelor's degree) with no reported history of mild cognitive impairment or dementia. All participants had expressed interest in research, primarily via community outreach events and prior research involvement. Data was collected via electronic surveys, distributed using REDCap. Electronic questionnaires included questions on demographic variables, subjective cognitive decline, quality of life, loneliness, and personality. RESULTS: There was a high prevalence of risk factors for dementia in the registry sample (68% with family history of dementia, 31% with subjective cognitive decline). Subjective cognitive decline was more common in women and associated with history of depression, but not with family history of dementia. Subjective cognitive decline was also associated with lower conscientiousness and lower emotional stability, as well as higher loneliness and lower quality of life. Among participants who endorsed a psychiatric history, most reported onset more than 10 years prior, rather than within the last 10 years. CONCLUSIONS: Subjective cognitive decline in a registry sample may be more strongly associated with longstanding psychiatric and personality variables, rather than family history of dementia, adding to the literature on characterization of subjective cognitive decline across different settings. These findings highlight the acceptability of remote data collection and the potential of registries to inform recruitment by characterizing registrants, which may help to stratify dementia risk and match participants to eligible trials.

Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE).

Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE). 129 patients were randomly assigned 2:1 to Pexa-Vec plus BSC vs. BSC alone. Pexa-Vec was given as a single intravenous (IV) infusion followed by up to 5 IT injections. The primary endpoint was OS. Secondary endpoints included overall response rate (RR), time to progression (TTP) and safety. A high drop-out rate in the control arm (63%) confounded assessment of response-based endpoints. Median OS (ITT) for Pexa-Vec plus BSC vs. BSC alone was 4.2 and 4.4 months, respectively (HR, 1.19, 95% CI: 0.78-1.80; p = .428). There was no difference between the two treatment arms in RR or TTP. Pexa-Vec was generally well-tolerated. The most frequent Grade 3 included pyrexia (8%) and hypotension (8%). Induction of immune responses to vaccinia antigens and HCC associated antigens were observed. Despite a tolerable safety profile and induction of T cell responses, Pexa-Vec did not improve OS as second-line therapy after sorafenib failure. The true potential of oncolytic viruses may lie in the treatment of patients with earlier disease stages which should be addressed in future studies. ClinicalTrials.gov: NCT01387555.

"Feeling More Self-Confident, Cheerful and Safe". Experiences from a Health-Promoting Intervention in Community Dwelling Older Adults - A Qualitative Study.

OBJECTIVES: Studies show that regular exercise in combination with nutritional support can be effective in managing sarcopenia, which is age-related involuntary loss of skeletal muscle mass and strength. Qualitative investigations of participants' experiences from interventions in this domain are scarce. In this study, we explored older persons' experiences from an intervention designed to prevent sarcopenia, with the aim of capturing the participants' thoughts and opinions. DESIGN: A qualitative study embedded in the multicenter randomized clinical trial The Vitality and Vigor in the Elderly study, VIVE2. Focus group interviews were conducted. Manifest and latent content analyses were performed. PARTICIPANTS: Community dwelling older adults (n=20) 71-86 years of age with minor limitations in mobility. RESULTS: The experiences from the intervention were categorized and interpreted in one overall theme "Feeling more self-confident, cheerful and safe". The theme encompasses the categories psychological effects of participating in the intervention, physical effects of participating in the intervention, the importance of social support and the importance of a tailored set-up. The participants described their motives for participating in the intervention as being based on concerns regarding the negative health effects of continuing a sedentary lifestyle, difficulties of getting started on their own and lack of confidence in accomplishing change on their own. Participants also expressed that one main objective for participating was to lose weight. CONCLUSION: In this study we have captured the experiences of older adults with minor mobility limitations who participated in a lifestyle intervention. The experiences are interpreted in one overall theme "Feeling more self-confident, cheerful and safe". The central understanding of the participants' experiences was that the intervention affected them in several ways, both psychologically and physically, and that supporting factors included the social support, which became a prerequisite for success. A noticeable finding was the discrepancy between the motive of the participants, to lose weight, and the aim of the study, to improve muscle function. The expectation to lose weight seems to reflect what is commonly known as to be healthy. To our knowledge, at least in Sweden, there are no campaigns or public information highlighting the risks of sarcopenia and the complex issue of if, and when weight loss is desirable for older individuals. This finding highlights the importance of providing such information to this target group. The findings in this study provide valuable knowledge for research teams, practitioners and decision makers when designing and setting objectives for health-promoting interventions for older individuals.

Physical Performance and Serum 25(OH)vitamin D Status in Community Dwelling Old Mobility Limited Adults: A Cross-Sectional Study.

OBJECTIVES: To examine the potential association between serum 25(OH) vitamin D and the performance on the Short Physical Performance Battery (SPPB) including the sub-components; five repeated chair stands test, 4 meters walk test and balance in older mobility-limited community-dwelling men and women. DESIGN: A cross sectional study was performed in American and Swedish subjects who were examined for potential participation in a combined exercise and nutrition intervention trial. Logistic regression analysis and linear regression analyses were performed to evaluate the association for 25(OH)D with the overall score on the SBBP, chair stand, gait speed and balance. PARTICIPANTS: Community-dwelling (mean age 77.6 ± 5.3 years) mobility limited American (n=494) and Swedish (n=116) females (59%) and males. MEASUREMENTS: The SPPB (0-12 points) includes chair stand (s), gait speed (m/s) and a balance test. Mobility limitation i.e., SPPB score ≤ 9 was an inclusion criterion. A blood sample was obtained to measure serum 25(OH)vitamin D concentrations. RESULTS: No clear association of 25(OH)D with SPPB scores was detected either when 25(OH)D was assessed as a continuous variable or when categorized according to serum concentrations of <50, 50-75 or <75 nmol/L. However, when analyzing the relationship between 25(OH)D and seconds to perform the chair stands, a significant quadratic relationship was observed. Thus, at serum levels of 25(OH)D above 74 nmol/L, higher concentrations appeared to be advantageous for the chair stand test, whereas for serum levels below 74 nmol/L this association was not observed. CONCLUSION: This cross- sectional study lacked clear association between serum 25(OH)D and physical performance in mobility limited adults. A potentially interesting observation was that at higher serum levels of 25(OH)D a better performance on the chair stand test was indicated.

Effect of Structured Physical Activity and Nutritional Supplementation on Physical Function in Mobility-Limited Older Adults: Results from the VIVE2 Randomized Trial.

OBJECTIVES: The interactions between nutritional supplementation and physical activity on changes in physical function among older adults remain unclear. The primary objective of this study was to examine the impact of nutritional supplementation plus structured physical activity on 400M walk capacity in mobility-limited older adults across two sites (Boston, USA and Stockholm, Sweden). DESIGN: All subjects participated in a physical activity program (3x/week for 24 weeks), involving walking, strength, balance, and flexibility exercises. Subjects were randomized to a daily nutritional supplement (150kcal, 20g whey protein, 800 IU vitamin D) or placebo (30kcal, non-nutritive). SETTING: Participants were recruited from urban communities at 2 field centers in Boston MA USA and Stockholm SWE. PARTICIPANTS: Mobility-limited (Short Physical Performance Battery (SPPB) ≤9) and vitamin D insufficient (serum 25(OH) D 9 - 24 ng/ml) older adults were recruited for this study. MEASUREMENTS: Primary outcome was gait speed assessed by the 400M walk. RESULTS: 149 subjects were randomized into the study (mean age=77.5±5.4; female=46.3%; mean SPPB= 7.9±1.2; mean 25(OH)D=18.7±6.4 ng/ml). Adherence across supplement and placebo groups was similar (86% and 88%, respectively), and was also similar across groups for the physical activity intervention (75% and 72%, respectively). Both groups demonstrated an improvement in gait speed with no significant difference between those who received the nutritional supplement compared to the placebo (0.071 and 0.108 m/s, respectively (p=0.06)). Similar effects in physical function were observed using the SPPB. Serum 25(OH)D increased in supplemented group compared to placebo 7.4 ng/ml versus 1.3 ng/ml respectively. CONCLUSION: Results suggest improved gait speed following physical activity program with no further improvement with added nutritional supplementation.

Accelerometer Assessment of Physical Activity and Its Association with Physical Function in Older Adults Residing at Assisted Care Facilities.

OBJECTIVES: To describe levels of physical activity among older adults residing at assisted care facilities and their association with physical function. DESIGN: Cross-sectional analysis. SETTING: Assisted care facilities within the greater Boston, MA area. PARTICIPANTS: Older adults aged 65 years and older (N = 65). MEASUREMENTS: Physical Activity Level (PAL) as defined by quartiles from accelerometry (counts and steps), Short Physical Performance Battery (SPPB) Score, gait speed, and handgrip strength. RESULTS: Participants in the most active accelerometry quartile engaged in 25 minutes/week of moderate to vigorous physical activity (MVPA) and walked 2,150 steps/day. These individuals had an SPPB score, 400 meter walk speed, and handgrip strength that was 3.7-3.9 points, 0.3-0.4 meters/second, and 4.5-5.1 kg greater respectively, than individuals in the lowest activity quartile, who engaged in less than 5 min/wk of MVPA or took fewer than 460 steps/day. CONCLUSION: Despite engaging in physical activity levels far below current recommendations (150 min/week of MVPA or > 7000 steps/day), the most active older adults in this study exhibited clinically significant differences in physical function relative to their less active peers. While the direction of causality cannot be determined from this cross-sectional study, these findings suggest a strong association between PAL and physical function among older adults residing in an assisted care facility.

Synergistic anti-tumor effects between oncolytic vaccinia virus and paclitaxel are mediated by the IFN response and HMGB1.

Recent developments in the field of oncolytic or tumor-selective viruses have meant that the clinical applications of these agents are now being considered in more detail. Like most cancer therapies it is likely that they will be used primarily in combination with other therapeutics. Although several reports have shown that oncolytic viruses can synergize with chemotherapies within an infected cancer cell, it would be particularly important to determine whether factors released from infected cells could enhance the action of chemotherapies at a distance. Here, we demonstrate in vitro synergy between oncolytic vaccinia and taxanes. However, we also show, for the first time, that this synergy is at least partly due to the release of factors from the infected cells that are capable of sensitizing surrounding cells to chemotherapy. Several cellular factors were identified as being mediators of this bystander effect, including type I interferon released soon after infection and high-mobility group protein B1 (HMGB1) released after cell death. This represents the first description of these mechanisms for beneficial interactions between viral and traditional tumor therapies. These data may provide a direct basis for the design of clinical trials with agents currently in the clinic, as well as providing insight into the development of next generation viral vectors.

Oncolytic and immunostimulatory efficacy of a targeted oncolytic poxvirus expressing human GM-CSF following intravenous administration in a rabbit tumor model.

Targeted oncolytic poxviruses hold promise for the treatment of cancer. Arming these agents with immunostimulatory cytokines (for example, granulocyte-monocyte colony-stimulating factor; GM-CSF) can potentially increase their efficacy and/or alter their safety. However, due to species-specific differences in both human GM-CSF (hGM-CSF) activity and poxviruses immune avoidance proteins, the impact of hGM-CSF expression from an oncolytic poxvirus cannot be adequately assessed in murine or rat tumor models. We developed a rabbit tumor model to assess toxicology, pharmacodynamics, oncolytic efficacy and tumor-specific immunity of hGM-CSF expressed from a targeted oncolytic poxvirus JX-963. Recombinant purified hGM-CSF protein stimulated a leukocyte response in this model that paralleled effects of the protein in humans. JX-963 replication and targeting was highly tumor-selective after i.v. administration, and intratumoral replication led to recurrent, delayed systemic viremia. Likewise, hGM-CSF was expressed and released into the blood during JX-963 replication in tumors, but not in tumor-free animals. hGM-CSF expression from JX-963 was associated with significant increases in neutrophil, monocyte and basophil concentrations in the peripheral blood. Finally, tumor-specific cytotoxic T lymphocytes (CTL) were induced by the oncolytic poxvirus, and expression of hGM-CSF from the virus enhanced both tumor-specific CTL and antitumoral efficacy. JX-963 had significant efficacy against both the primary liver tumor as well as metastases; no significant organ toxicity was noted. This model holds promise for the evaluation of immunostimulatory transgene-armed oncolytic poxviruses, and potentially other viral species.

Gene therapy progress and prospects cancer: oncolytic viruses.

The past 2 years have seen several major advances in oncolytic virotherapy. Studies on the interaction between viruses, immune responses and tumor microenvironment have provided important insight, while clinical trials have shown promise. This review summarizes key findings in this field over the past 2 years, and provides directions for future success.

E1A-expressing adenoviral E3B mutants act synergistically with chemotherapeutics in immunocompetent tumor models.

The majority of clinical trials evaluating replication-selective oncolytic adenoviruses utilized mutants with immunomodulatory E3B genes deleted, likely contributing to the attenuated efficacy. We investigated whether an intact immune response could contribute to the observed improved efficacy in response to combinations with chemotherapeutics. Seven carcinoma cell lines were evaluated by combining viral mutants; dl309 (DeltaE3B), dl704 (DeltaE3gp19K), dl312 (DeltaE1A) or wild-type Ad5 with the commonly used clinical drugs cisplatin and paclitaxel. Synergistic effects on cell death were determined by generation of combination indexes in cultured cells. In vivo tumor growth inhibition was achieved by virotherapy alone and was most efficacious with wild-type virus and least with the DeltaE3B mutant. Significantly higher efficacy was observed when the viruses were combined with drugs. The greatest enhancement of tumor inhibition was in combination with the DeltaE3B mutant restoring potency to that of Ad5 wild-type levels, observed only in animals with intact immune response. Increases in infectivity, viral gene expression and replication were identified as potential mechanisms contributing to the synergistic effects. Our results suggest that the attenuation of DeltaE3B mutants can be overcome by low doses of chemotherapeutics only in the presence of an intact immune response indicating a role for T-cell-mediated functions.

Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie-adenoviral receptor in normal liver.

We administered an adenoviral vector, Onyx-015, into the hepatic artery of patients with metastatic colorectal cancer involving the liver. Thirty-five patients enrolled in this multi-institutional phase I/II trial received up to eight arterial infusions of up to 2 x 10(12) viral particles. Hepatic toxicity was the primary dose-limiting toxicity observed in preclinical models. However, nearly 200 infusions of this adenoviral vector were administered directly into the hepatic artery without significant toxicity. Therefore, we undertook this analysis to determine the impact of repeated adenoviral exposure on hepatic function. Seventeen patients were treated at our institution, providing a detailed data set on the changes in hepatic function following repeated exposure to adenovirus. No changes in hepatic function occurred with the first treatment of Onyx-015 among these patients. Transient increases in transaminase levels occurred in one patient starting with the second infusion and transient increases in bilirubin was observed in two patients starting with the fifth treatment. These changes occurred too early to be explained by viral-mediated lysis of hepatocytes. In addition, viremia was observed starting 3-5 days after the viral infusion in half of the patient, but was not associated with hepatic toxicity. To further understand the basis for the minimal hepatic toxicity of adenoviral vectors, we evaluated the replication of adenovirus in primary hepatocytes and tumor cells in culture and the expression of the coxsackie-adenoviral receptor (CAR) in normal liver and colon cancer metastatic to the liver. We found that adenovirus replicates poorly in primary hepatocytes but replicates efficiently in tumors including tumors derived from hepatocytes. In addition, we found that CAR is localized at junctions between hepatocytes and is inaccessible to hepatic blood flow. CAR is not expressed on tumor vasculature but is expressed on tumor cells. Spatial restriction of CAR to the intercellular space in normal liver and diminished replication of adenovirus in hepatocytes may explain the minimal toxicity observed following repeated hepatic artery infusions with Onyx-015.

Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF.

Targeted oncolytic viruses and immunostimulatory therapeutics are being developed as novel cancer treatment platforms. These approaches can be combined through the expression of immunostimulatory cytokines from targeted viruses, including adenoviruses and herpesviruses. Although intratumoral injection of such viruses has been associated with tumor growth inhibition, eradication of distant metastases was not reported. The major limitations for this approach to date have been (1) inefficient intravenous virus delivery to tumors and (2) the lack of predictive, immunocompetent preclinical models. To overcome these hurdles, we developed JX-594, a targeted, thymidine kinase(-) vaccinia virus expressing human GM-CSF (hGM-CSF), for intravenous (i.v.) delivery. We evaluated two immunocompetent liver tumor models: a rabbit model with reproducible, time-dependent metastases to the lungs and a carcinogen-induced rat liver cancer model. Intravenous JX-594 was well tolerated and had highly significant efficacy, including complete responses, against intrahepatic primary tumors in both models. In addition, whereas lung metastases developed in all control rabbits, none of the i.v. JX-594-treated rabbits developed detectable metastases. Tumor-specific virus replication and gene expression, systemically detectable levels of hGM-CSF, and tumor-infiltrating CTLs were also demonstrated. JX-594 holds promise as an i.v.-delivered, targeted virotherapeutic. These two tumor models hold promise for the optimization of this approach.

Functional interactions of antiapoptotic proteins and tumor necrosis factor in the context of a replication-competent adenovirus.

Replication-selective oncolytic adenoviruses hold promise, but novel mechanisms must be identified to maximize intratumoral virus persistence, spread and therapeutic transgene-carrying capacity while maintaining safety. One of the main approaches to engineering cancer-selectivity has been to delete a viral gene that is theoretically expendable in cancer cells. Results with this approach have been mixed, however, as evidenced by controversy over Onyx-015 (E1B-55kD(-)) selectivity. We hypothesized that the functional redundancy between viral gene products might limit selectivity and/or potency with this approach. Antiviral immune inducers of apoptosis (eg TNF-alpha) have not been thoroughly investigated in previous studies. We therefore explored whether deletion of functionally redundant viral genes, E1B-19kD and E3B, both independently antagonize TNF-alpha, could lead to enhanced oncolytic potency while maintaining selectivity. Since tumors have numerous blocks in apoptotic pathways, we hypothesized that deletion of one or both gene regions would result in cancer-selectivity in the presence of TNF-alpha. We have previously shown that the E1B-19kD deletion resulted in enhanced viral spread in vitro and in immunocompetent tumor models in vivo. In contrast, the impact of E3B deletion, especially its in vitro selectivity and potency, was not thoroughly characterized, although it resulted in rapid immune-mediated viral clearance in vivo. Furthermore, previous publications indicated that double-deleted mutants have selectivity but unsatisfactory efficacy. We compared the selectivity and potency of E1B-19kD(-), E3B(-) and E1B-19kD(-)/E3B(-) mutants to wild-type adenovirus. In cancer cells, the E1B-19kD(-) mutant had superior replication, spread and cytolysis (+) or (-) TNF-alpha; deletion of both E1B-19kD and E3B was relatively deleterious. In normal cells without TNF-alpha, similar results were obtained. In contrast, all three mutants were significantly inhibited in the presence of TNF-alpha. In immunocompetent mice, all three mutants were significantly inhibited in normal tissue. In tumors, only the E1B-19kD(-) mutant demonstrated enhanced replication, spread and antitumoral efficacy. Therefore, E1B-19kD deletion and E3B retention should be incorporated in oncolytic adenoviruses for enhanced safety and efficacy. In addition, functional redundant viral genes and their biological mediators/targets need to be carefully examined for the next generation of gene-deleted oncolytic viruses.

Genetically based therapeutics for cancer: similarities and contrasts with traditional drug discovery and development.

The field of molecular therapeutics is in its infancy and represents a promising and novel avenue for targeted cancer treatments. Like the small-molecule and antibody therapeutics before them, however, the genetic-based therapies will face significant research and development challenges in their maturation toward an approved cancer therapy. To facilitate this process, we outline and examine in this review the drug development process, briefly summarizing the research and development paradigms that have accompanied the recent successes of the small-molecule and antibody-based cancer therapeutics. Using this background, we compare and contrast the research and development experiences of small-molecule and antibody therapeutics with genetic-based cancer therapeutics, using oncolytic viruses as a defined example of an experimental molecular therapeutic for cancer.

Potentiation of radiation therapy by the oncolytic adenovirus dl1520 (ONYX-015) in human malignant glioma xenografts.

In spite of aggressive surgery, irradiation and/or chemotherapy, treatment of malignant gliomas remains a major challenge in adults and children due to high treatment failure. We have demonstrated significant cell lysis and antitumour activity of the E1B-55 kDa-gene-deleted adenovirus ONYX-015 (dl1520, CI-1042; ONYX Pharmaceuticals) in subcutaneous human malignant glioma xenografts deriving from primary tumours. Here, we show the combined efficacy of this oncolytic therapy with radiation therapy. Total body irradiation (5 Gy) of athymic nude mice prior to intratumoral injections of ONYX-015 1 x 10(8) PFU daily for 5 consecutive days yielded additive tumour growth delays in the p53 mutant xenograft IGRG88. Radiation therapy was potentiated in the p53 functional tumour IGRG121 with a 'subtherapeutic' dose of 1 x 10(7) PFU daily for 5 consecutive days, inducing significant tumour growth delay, 90% tumour regression and 50% tumour-free survivors 4 months after treatment. These potentiating effects were not due to increased adenoviral infectivity or replication. Furthermore, cell lysis and induction of apoptosis, the major mechanisms for adenoviral antitumour activity, did not play a major role in the combined treatment strategy. Interestingly, the oncolytic adenovirus seemed to accelerate radiation-induced tumour fibrosis. Potentiating antitumour activity suggests the development of this combined treatment for these highly malignant tumours.

Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer.

PURPOSE: Resistance to chemotherapy in ovarian cancer is frequently associated with mutations in the p53 gene. The adenovirus dl1520 (ONYX-015) with the E1B 55-kd gene deleted, allowing selective replication in and lysis of p53-deficient tumor cells, has shown preclinical efficacy against p53-deficient nude mouse-human ovarian carcinomatosis xenografts. PATIENTS AND METHODS: We undertook a phase I trial of intraperitoneal dl1520 in patients with recurrent ovarian cancer. Sixteen women with recurrent/refractory ovarian cancer received 35 cycles (median, two cycles) of dl1520 delivered on days 1 through 5 in four dose cohorts: 1 x 10(9) plaque forming units (pfu), 1 x 10(10) pfu, 3 x 10(10) pfu, and 1 x 10(11) pfu. RESULTS: The most common significant toxicities related to virus administration were flu-like symptoms, emesis, and abdominal pain. One patient receiving 1 x 10(10) pfu developed common toxicity criteria grade 3 abdominal pain and diarrhea, which was dose-limiting. The maximum-tolerated dose was not reached at 10(11) pfu, and at this dose level patients did not experience significant toxicity. There was no clear-cut evidence of clinical or radiologic response in any patient. Blood samples were taken for adenovirus DNA and neutralizing antibodies. Polymerase chain reaction data indicating presence of virus up to 10 days after the final (day 5) infusion of dl1520 are suggestive of continuing viral replication. CONCLUSION: This article therefore describes the first clinical experience with the intraperitoneal delivery of any replication-competent/-selective virus in cancer patients.

Efficient induction of apoptosis by ONYX-015 adenovirus in human colon cancer cell lines regardless of p53 status.

The ONYX-015 virus is a mutated adenovirus that in theory selectively replicates and induces cytolysis in tumor cells lacking functional p53. The present study investigated whether ONYX-015 viral infection alone or in combination with conventional chemotherapeutic agents could significantly increase apoptosis in human colon cancer cell lines, regardless of p53 status, compared to untreated cells. A pair of colon cancer cell lines that differ only in their p53 status (RKO with wild-type p53 and RKOp53 with deficient p53) was tested. Two chemotherapeutic agents, 5-fluorouracil (5-FU) and CPT-11, were tested in combination with ONYX-015. Final concentrations of these agents corresponded to peak plasma levels achievable in patients. ONYX-015 concentration was 10 p.f.u./cell. In RKO and RKOp53 cell lines, ONYX-015 viral infection alone or in combination with 5-FU or CPT-11 induced a significant increase in apoptosis compared to chemotherapeutic agents alone, regardless of p53 status. Moreover, the combination of ONYX-015 and chemotherapeutics induced more apoptosis than chemotherapeutics alone in the two colon cancer cell lines independently of their p53 status. We conclude that ONYX-015 virus infection alone or in combination with 5-FU or CPT-11 induced apoptosis in human colon cancer cell lines, independently of p53 status.

Oncolytic virotherapy for cancer with the adenovirus dl1520 (Onyx-015): results of phase I and II trials.

Replication-selective viral agents hold promise as a novel cancer treatment platform (virotherapy). dl1520 (Onyx-015, now CI-1042, Pfizer Corp., Groton, CT, USA), an E1B-55kD gene-deleted adenovirus, was the first such genetically engineered agent to be tested in humans. Over 250 cancer patients have now been treated on approximately ten clinical trials (phase I-III). The virus was generally well tolerated at doses of up to 2 x 10(12) particles by intratumoural, intraperitoneal, hepatic arterial and i.v. administration; no maximally-tolerated doses were identified following intra-vascular administration. Viral replication was tumour-selective and was documented after administration by all routes; however, viral replication was variable depending on tumour histology. Single agent efficacy has been relatively limited to date (0-14% local tumour regression rates). In combination with chemotherapy, however, encouraging antitumoural activity has been demonstrated. These clinical research results demonstrate the potential of this novel treatment platform, as well as the hurdles to be overcome. Novel replication-selective agents with improved potency are being developed.

Modeling and analysis of a virus that replicates selectively in tumor cells.

Replication-competent viruses have shown considerable promise in overcoming the inefficient gene transduction experienced by traditional gene therapy approaches to cancer treatment. The viruses infect tumor cells and replicate inside them, eventually causing lysis. Virus particles released during lysis are then able to infect other tumor cells, and, in this way, continuous rounds of infection and lysis allow the virus to spread throughout the tumor. Motivated by this novel cancer treatment, we formulate and analyse a system of partial differential equations that is essentially a radially-symmetric epidemic model embedded in a Stefan problem. We compare three, alternative virus-injection strategies: a fixed fraction of cells pre-infected with the virus are introduced throughout the entire tumor volume, within the tumor core, or within the tumor rim. For all three injection methods, simple and accurate conditions that predict whether the virus will control the tumor are derived.