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Biomedical subjects

S L Woo

Publications and source records attributed to S L Woo.

At least 19 recordsLinked to original sources
PubMed2001

Precision of ACL tunnel placement using traditional and robotic techniques.

The objective of this study was to examine the precision of ACL tunnel placement using: (1) CASPAR (orto MAQUET GmbH Co. KG)--an active robotic system, and (2) four orthopedic surgeons with various levels of experience (between 100 and 3,500 ACL reconstructions). The robotic system and each surgeon drilled tunnels for ACL reconstruction in 10 plastic knees (total n = 50) that included a reference cube in the medial aspect of the proximal tibia and distal femur. For the robotic system, the placement of each tunnel was planned preoperatively using custom software and CT data for each femur and tibia. The robotic system then drilled the tunnels in the femur and tibia based on the preoperative plan. For the surgeons, tunnel placement was accomplished using their preferred technique, which was based on the one-incision arthroscopic technique. The distribution of intra-articular points on the tibia was contained within a sphere of radius 2.0 mm (robot system), 2.1 mm (Fellow 1), 2.4 mm (Fellow 2), 3.4 mm (Experienced Surgeon 1), or 2.0 mm (Experienced Surgeon 2). On the femur, no significant differences in the distribution of intra-articular points could be demonstrated between the robotic system (2.1 mm), Fellow 1 (4.5 mm), Fellow 2 (4.1 mm), Experienced Surgeon 1 (2.3 mm), and Experienced Surgeon 2 (3.0 mm). The direction of the tunnels drilled in the femur and tibia was different with the robotic and traditional techniques. However, the robotic system had the most consistent tunnel directions, while the surgeons' tunnels were more dispersed. Variation in surgeon precision of tunnel placement for ACL reconstruction is greater on the femur than the tibia, and this can be correlated with experience. Our data also suggest that the robotic system has the same precision as the most experienced surgeons.

Anterior Cruciate Ligament↗
PubMed2001

Auto-regulated hepatic insulin gene expression in type 1 diabetic rats.

Paradigms of insulin gene therapy for type 1 diabetes should incorporate vigorous control for insulin gene expression to be effective in correcting postprandial hyperglycemia and to be safe in preventing fasting hypoglycemia. We hypothesize that hepatic insulin gene expression auto-regulated positively by glucose and negatively by insulin might be both effective and safe in the treatment of type 1 diabetes. Expression of the glucose 6-phosphatase (G6Pase) gene in the liver is both stimulated by glucose and suppressed by insulin. The G6Pase promoter incorporated with intronic enhancers of the aldolase B gene was used to direct insulin gene expression in the liver of streptozotocin-induced diabetic nude rats. In the treated animals, blood insulin levels were elevated after feeding, and nonfasting hyperglycemia was significantly reduced. Glucose tolerance testing also illustrated that the treated animals exhibited accelerated glucose utilization rates. Upon fasting, blood glucose was reduced to normoglycemic range within 4 h and maintained at that level during the prolonged fasting of 16 h. No hypoglycemia was observed in any treated animals at any time throughout the fasting period, as blood insulin gradually declined to the normal range. These results suggest that auto-regulated hepatic insulin expression can potentially be developed as an effective and safe treatment modality for type 1 diabetes.

Adenoviridae↗
PubMed2001

Intratumoral adenovirus-mediated suicide gene transfer for hepatic metastases from colorectal adenocarcinoma: results of a phase I clinical trial.

Animal studies have shown that direct injection of an adenoviral vector (Adv.RSV-tk) expressing the herpes thymidine kinase gene into established tumors in the liver, followed by systemic ganciclovir administration, was effective in inducing tumor necrosis. Toxicities were minimal at therapeutically effective vector doses, although severe hepatic necroinflammation was seen at much higher supratherapeutic doses. We conducted a clinical phase I trial in patients with metastatic colorectal adenocarcinoma in the liver to assess the safety of intratumoral Adv.RSV-tk injection (escalating doses) followed by intravenous ganciclovir (fixed dose). The vector was injected into a metastatic tumor in the liver under local anesthesia by percutaneous needle placement with concurrent ultrasonographic monitoring to prevent injection or leakage into adjacent normal liver structures. We treated 16 patients in five dose level cohorts of Adv.RSV-tk, from 1.0x10(10) to 1.0x10(13) virus particles per patient. Hepatic toxicities were low, with transient grade 1 elevations in serum aminotransferase levels in 3 of 16 patients. Other toxicities were also transient: grade 2-3 fevers in 5 of 16 patients, grade 3 thrombocytopenia in 1 of 16 patients, and grade 2 leucopenia in 3 of 16 patients. These results indicate that Adv.RSV-tk can be safely administered by percutaneous intratumoral injection in patients with hepatic metastases at doses up to 1.0x10(13) virus particles per patient, and can provide the basis for future clinical trials involving intratumoral adenoviral vector injection.

Adenocarcinoma↗
PubMed2001

A method for measuring joint kinematics designed for accurate registration of kinematic data to models constructed from CT data.

A method for measuring three-dimensional kinematics that incorporates the direct cross-registration of experimental kinematics with anatomic geometry from Computed Tomography (CT) data has been developed. Plexiglas registration blocks were attached to the bones of interest and the specimen was CT scanned. Computer models of the bone surface were developed from the CT image data. Determination of discrete kinematics was accomplished by digitizing three pre-selected contiguous surfaces of each registration block using a three-dimensional point digitization system. Cross-registration of bone surface models from the CT data was accomplished by identifying the registration block surfaces within the CT images. Kinematics measured during a biomechanical experiment were applied to the computer models of the bone surface. The overall accuracy of the method was shown to be at or below the accuracy of the digitization system used. For this experimental application, the accuracy was better than +/-0.1mm for position and 0.1 degrees for orientation for linkage digitization and better than +/-0.2mm and +/-0.2 degrees for CT digitization. Surface models of the radius and ulna were constructed from CT data, as an example application. Kinematics of the bones were measured for simulated forearm rotation. Screw-displacement axis analysis showed 0.1mm (proximal) translation of the radius (with respect to the ulna) from supination to neutral (85.2 degrees rotation) and 1.4mm (proximal) translation from neutral to pronation (65.3 degrees rotation). The motion of the radius with respect to the ulna was displayed using the surface models. This methodology is a useful tool for the measurement and application of rigid-body kinematics to computer models.

Arthrography↗
PubMed2001

Hepatic insulin expression improves glycemic control in type 1 diabetic rats.

Low levels of hepatic insulin production have been shown to prevent lethal ketoacidosis associated with type 1 diabetes. To assess the beneficial effects of sustained hepatic production of insulin on glycemic control in type 1 diabetes, we have employed the adenovirus-mediated gene delivery system to transfer an engineered rat preproinsulin gene to the livers of streptozotocin-induced diabetic nude rats. Hepatic insulin production resulted in the reduction of blood glucose in treated diabetic rats, the degree of blood glucose reduction correlated with both the vector dose and the level of hepatic insulin expression. At moderate vector doses, 0.3-0.7 ng/ml of plasma insulin was produced in treated diabetic animals, resulting in significant reduction of nonfasting hyperglycemia and improvement in glucose tolerance. Furthermore, these animals maintained euglycemia after 12-h fast. At higher vector doses, greater than 1 ng/ml of plasma insulin was produced, completely reversing nonfasting hyperglycemia in treated rats. However, all of the treated animals developed severe hypoglycemia upon fasting. This study has defined the maximal tolerable level of hepatic insulin production that is sufficient to reduce the degree and ameliorate the adverse effects of nonfasting hyperglycemia without risk of fasting hypoglycemia in type 1 diabetic rats.

Amino Acid Sequence↗
PubMed2001

Hepatic insulin production for type 1 diabetes.

Type 1 diabetes, along with its long-term complications, imposes a serious impact on public health. In spite of the development and application of various insulin formulations, exogenous insulin neither achieves the same degree of glycemic control as that provided by endogenous insulin, nor prevents the long-term complications associated with type 1 diabetes. As an alternative strategy, insulin gene transfer is being explored to restore endogenous insulin production in type 1 diabetes. Sustained hepatic insulin production has been shown to reverse ketonuria, prevent ketoacidosis, improve body weight gain and significantly ameliorate the adverse effects of insulin deficiency in diabetic animals. However, to achieve adequately regulated insulin production in response to changes in blood glucose concentrations remains a major hurdle. This article will review the most recent advances made to address this crucial limitation. In addition, based on the significance of maintaining basal plasma insulin for management of type 1 diabetes, we discuss the feasibility of developing basal hepatic insulin production as an auxiliary treatment to current insulin therapy for achieving tight glycemic control in type 1 diabetes.

Animals↗
PubMed2001

Therapeutic elastase inhibition by alpha-1-antitrypsin gene transfer limits neointima formation in normal rabbits.

PURPOSE: Alpha-1-antitrypsin (AAT) is the major circulating elastase inhibitor. Deficiency of elastase inhibition leads to emphysema and vascular abnormalities including accelerated neointima. Because recent evidence suggests that tissue AAT levels determine inhibitory function, the authors hypothesize that local tissue-based expression of AAT limits elastase activity sufficiently to guide arterial response to injury. MATERIALS AND METHODS: Rabbit common femoral arteries were injured by mechanical overdilation and treated with buffer, viral control, or an adenovirus expressing AAT (Ad/AAT). After 3 and 28 days, intima-to-media (I/M) ratios were evaluated. Additionally, early changes in elastase inhibition potential (3 d), extracellular elastin and collagen content (3 d), and local macrophage and neutrophil infiltration (7 d) were determined. RESULTS: Ad/AAT significantly decreased neointima formation after mechanical dilation injury after 28 days: buffer controls exhibited mean I/M ratios of 0.76 +/- 0.06, whereas viral controls reached 0.77 +/- 0.09; in contrast, Ad/AAT reduced I/M ratios to 0.44 +/- 0.06. Both early elastin and collagen content were preserved in the Ad/AAT group relative to controls. The Ad/AAT group also reversed the local inflammation that characterized viral controls. CONCLUSIONS: This strategy demonstrates that local increases in elastase inhibition potential promote a neointima-resistant small-caliber artery, which may offer new promise in management of patients undergoing angioplasty.

Angioplasty↗
PubMed2001

Structure and function of the healing medial collateral ligament in a goat model.

In this study knee joint function with a healing medial collateral ligament (MCL) at six weeks was examined with a robotic/universal force-moment sensor testing system during the application of two loading conditions: (1) 5 Nm valgus moment and (2) 67 N anterior load. Additionally the structural properties of the femur-MCL-tibia complex and the mechanical properties of the MCL substance were determined by uniaxial tensile tests. The histological appearance of the healing MCL was also observed. At 30 degrees and 60 degrees of knee flexion, valgus rotation of the healing knee was significantly increased compared to the sham. The in situ force in the healing MCL was significantly lower (34+/-17 N vs 54+/-12 N) at the same flexion angles (50+/-10 N vs 62+/-7 N). The anterior translation of the knee had returned to normal values at 30 degrees and 60 degrees of knee flexion. However, no differences could be found between the corresponding in situ forces in the healing MCL at all flexion angles examined during application of an anterior load. The stiffness of the healing group (52.5+/-19.4 N/mm) was significantly lower than the sham group (80.3+/-26.4 N/mm) (p<0.04). The modulus of the healing group was also significantly decreased (p<0.05). The findings suggest that the tensile properties of the healing goat MCL and valgus knee rotation have not returned to normal at six weeks after an isolated MCL rupture, however, anterior translation appeared to return to sham levels.

Animals↗
PubMed2001

Effect of capsular injury on acromioclavicular joint mechanics.

BACKGROUND: Traumatic disruption of the acromioclavicular joint capsule is associated with pain and instability after the injury and may lead to degenerative joint disease. The objective of this study was to quantify the effect of transection of the acromioclavicular joint capsule on the kinematics and the in situ forces in the coracoclavicular ligaments in response to external loading conditions. METHODS: Eleven fresh-frozen human cadaveric shoulders were tested with use of a robotic/universal force-moment sensor testing system. The shoulders were subjected to three loading conditions (an anterior, posterior, and superior load of 70 N) in their intact state and after transection of the acromioclavicular joint capsule. RESULTS: Transection of the capsule resulted in a significant (p < 0.05) increase in anterior translation (6.4 mm) and posterior translation (3.6 mm) but not in superior translation (1.6 mm). The effect of capsule transection on the forces in the coracoclavicular ligaments was also significant (p < 0.05) in response to anterior and posterior loading but not in response to superior loading. However, differences were found between the forces in the trapezoid and conoid ligaments. Under an anterior load, the mean in situ force (and standard deviation) in the trapezoid increased from 14 +/- 14 N to 25 +/- 19 N, while the mean force in the conoid increased from 15 +/- 14 N to 49 +/- 23 N, or 227%. In contrast, in response to a posterior load, the mean in situ force in the trapezoid increased from 23 +/- 15 N to 38 +/- 23 N, or 66% (p < 0.05), while the mean force in the conoid increased only 9%. CONCLUSIONS AND CLINICAL RELEVANCE: The large differences in the change of force in the conoid and trapezoid ligaments suggest that these ligaments should not be considered as one structure when surgical treatment is considered. Furthermore, transection of the capsule resulted in a shift of load to the coracoclavicular ligaments, which may render the intact coracoclavicular ligaments more likely to fail with anterior or posterior loading. The results of the present study also suggest that the intact coracoclavicular ligaments cannot compensate for the loss of capsular function during anterior-posterior loading as occurs in type-II acromioclavicular joint injuries.

Acromioclavicular Joint↗
PubMed2000

Thrombomodulin overexpression to limit neointima formation.

BACKGROUND-These studies were initiated to confirm that high-level thrombomodulin overexpression is sufficient to limit neointima formation after mechanical overdilation injury. METHODS AND RESULTS-An adenoviral construct expressing thrombomodulin (Adv/RSV-THM) was created and functionally characterized in vitro and in vivo. The impact of local overexpression of thrombomodulin on neointima formation 28 days after mechanical overdilation injury was evaluated. New Zealand White rabbit common femoral arteries were treated with buffer, viral control, or Adv/RSV-THM and subjected to mechanical overdilation injury. The treated vessels (n=4 per treatment) were harvested after 28 days and evaluated to determine intima-to-media (I/M) ratios. Additional experiments were performed to determine early (7-day) changes in extracellular elastin and collagen content; local macrophage, T-cell, and neutrophil infiltration; and local thrombus formation as potential contributors to the observed impact on 28-day neointima formation. The construct significantly decreased neointima formation after mechanical dilation injury in this model. By histological analysis, buffer controls exhibited mean I/M ratios of 0.76+/-0.06%, whereas viral controls reached 0.77+/-0.08%; in contrast, Adv/RSV-THM reduced I/M ratios to 0.47+/-0.06%. Local inflammatory infiltrate decreased in the Adv/RSV-THM group relative to controls, whereas matrix remained relatively preserved. Rates of early thrombus formation also decreased in Adv/RSV-THM animals. CONCLUSIONS-This construct thus offers a viable technique for promoting a locally neointima-resistant small-caliber artery via decreased thrombus bulk, normal matrix preservation, and decreased local inflammation without the inflammatory damage that has limited many other adenoviral applications.

Animals↗
PubMed2000

Adenovirus-mediated gene transfer of endostatin in vivo results in high level of transgene expression and inhibition of tumor growth and metastases.

Inhibition of angiogenesis has been shown to be an effective strategy in cancer therapy in mice. However, its widespread application has been hampered by difficulties in the large-scale production of the antiangiogenic proteins. This limitation may be resolved by in vivo delivery and expression of the antiangiogenic genes. We have constructed a recombinant adenovirus that expresses murine endostatin that is biologically active both in vitro, as determined in endothelial cell proliferation assays, and in vivo, by suppression of angiogenesis induced by vascular endothelial growth factor 165. Persistent high serum levels of endostatin (605-1740 ng/ml; mean, 936 ng/ml) were achieved after systemic administration of the vector to nude mice, which resulted in significant reduction of the growth rates and the volumes of JC breast carcinoma and Lewis lung carcinoma (P < 0.001 and P < 0.05, respectively). In addition, the endostatin vector treatment completely prevented the formation of pulmonary micrometastases in Lewis lung carcinoma (P = 0.0001). Immunohistochemical staining of the tumors demonstrated a decreased number of blood vessels in the treatment group versus the controls. In conclusion, the present study clearly demonstrates the potential of vector-mediated antiangiogenic gene therapy as a component in cancer therapy.

Adenoviridae↗
PubMed2000

Importance of the medial meniscus in the anterior cruciate ligament-deficient knee.

The incidence of meniscal tears in the chronically anterior cruciate ligament-deficient knee is increased, particularly in the medial meniscus because it performs an important function in limiting knee motion. We evaluated the role of the medial meniscus in stabilizing the anterior cruciate ligament-deficient knee and hypothesized that the resultant force in the meniscus is significantly elevated in the anterior cruciate ligament-deficient knee. To test this hypothesis, we employed a robotic/universal force-moment sensor testing system to determine the increase in the resultant force in the human medial meniscus in response to an anterior tibial load following transection of the anterior cruciate ligament. We also measured changes in the kinematics of the knee in multiple degrees of freedom following medial meniscectomy in the anterior cruciate ligament-deficient knee. In response to a 134-N anterior tibial load, the resultant force in the medial meniscus of the anterior cruciate ligament-deficient knee increased significantly compared with that in the meniscus of the intact knee; it increased by a minimum of 10.1 N (52%) at full knee extension to a maximum of 50.2 N (197%) at 60 degrees of flexion. Medial meniscectomy in the anterior cruciate ligament-deficient knee also caused a significant increase in anterior tibial translation in response to the anterior tibial load, ranging from an increase of 2.2 mm at full knee extension to 5.8 mm at 60 degrees of flexion. Conversely, coupled internal tibial rotation in response to the load decreased significantly, ranging from a decrease of 2.5 degrees at 15 degrees of knee flexion to 4.7 degrees at 60 degrees of flexion. Our data confirm the hypothesis that the resultant force in the medial meniscus is significantly greater in the anterior cruciate ligament-deficient knee than in the intact knee when the knee is subjected to anterior tibial loads. This indicates that the demand on the medial meniscus in resisting anterior tibial loads is increased in the anterior cruciate ligament-deficient knee compared with in the intact knee, suggesting a mechanism for the increased incidence of medial meniscal tears observed in chronically anterior cruciate ligament-deficient patients. The large changes in kinematics due to medial meniscectomy in the anterior cruciate ligament-deficient knee confirm the important role of the medial meniscus in controlling knee stability. These findings suggest that the reduction of resultant force in the meniscus may be a further motive for reconstructing the anterior cruciate ligament, with the goal of preserving meniscal integrity.

Aged↗
PubMed2000

Significance of changes in the reference position for measurements of tibial translation and diagnosis of cruciate ligament deficiency.

Measurements of tibial translation in response to an external load are used in clinical and laboratory settings to diagnose and characterize knee-ligament injuries. Before these measurements can be quantified, a reference position of the knee must be established (defined as the position of the knee with no external forces or moments applied). The objective of this study was to determine the effects of cruciate ligament deficiency on this reference position and on subsequent measurements of tibial translation and, in so doing, to establish a standard of kinematic measurement for future biomechanical studies. Thirty-six human cadaveric knees were studied with a robotic/universal force-moment sensor testing system. The reference positions of the intact and posterior cruciate ligament-deficient knees of 18 specimens were determined at full extension and at 30, 60, 90, and 120 degrees of flexion, and the remaining five-degree-of-freedom knee motion was unrestricted. Subsequently, under a 134-N anterior-posterior load, the resulting knee kinematics were measured with respect to the reference positions of the intact and posterior cruciate ligament-deficient knees. With posterior cruciate ligament deficiency, the reference position of the knee moved significantly in the posterior direction, reaching a maximal shift of 9.3 +/- 3.8 mm at 90 degrees of flexion. For the posterior cruciate ligament-deficient knee, posterior tibial translation ranged from 13.0 +/- 3.4 to 17.7 +/- 3.6 mm at 30 and 90 degrees, respectively, when measured with respect to the reference positions of the intact knee. When measured with respect to the reference positions of the posterior cruciate ligament-deficient knee, these values were significantly lower, ranging from 11.7 +/- 4.3 mm at 30 degrees of knee flexion to 8.4 +/- 4.8 mm at 90 degrees. A similar protocol was performed to study the effects of anterior cruciate ligament deficiency on 18 additional knees. With anterior cruciate ligament deficiency, only a very small anterior shift in the reference position was observed. Overall, this shift did not significantly affect measurements of tibial translation in the anterior cruciate ligament-deficient knee. Thus, when the tibial translation in the posterior cruciate ligament-injured knee is measured when the reference position of the intact knee is not available, errors can occur and the measurement may not completely reflect the significance of posterior cruciate ligament deficiency. However, there should be less corresponding error when measuring the tibial translation of the anterior cruciate ligament-injured knee because the shift in reference position with anterior cruciate ligament deficiency is too small to be significant. We therefore recommend that in the clinical setting, where the reference position of the knee changes with injury, comparison of total anterior-posterior translation with that of the uninjured knee can be a more reproducible and accurate measurement for assessing cruciate-ligament injury, especially in posterior cruciate ligament-injured knees. Similarly, in biomechanical testing where tibial translations are often reported for the ligament-deficient and reconstructed knees, a fixed reference position should be chosen when measuring knee kinematics. If such a standard is set, measurements of knee kinematics will more accurately reflect the altered condition of the knee and allow valid comparisons between studies.

Anterior Cruciate Ligament Injuries↗
PubMed2000

Mechanical behavior of two hamstring graft constructs for reconstruction of the anterior cruciate ligament.

We compared the mechanical behavior of two common hamstring graft constructs that are frequently used for reconstruction of the anterior cruciate ligament-Graft A: quadrupled semitendinosus tendon fixed with titanium button/polyester tape and suture/screw post, and Graft B: a double semitendinosus and double gracilis tendon fixed with a cross pin and two screws over washers. The experimental protocol used to evaluate each graft construct included stress relaxation (with and without preconditioning), cyclic loading, and a tensile load-to-failure test. The amount of stress relaxation without preconditioning was 60.6% for Graft A and 53.8% for Graft B. With preconditioning, it significantly decreased (p < 0.05) to 48.7 and 42.3%, respectively. Elongation of the graft construct in response to 100 cycles of loading (20-150 N) was 1.8 and 0.6% of the original length for Grafts A and B, respectively. However, after a series of five cyclic loading tests, the residual permanent elongation for each construct was 3.8 +/- 1.2 and 0.3 +/- 0.2 mm, a significant difference (p < 0.05) between the two graft constructs. Further analysis found more than 90% of the permanent elongation in the proximal and distal regions of Graft A, which consisted of polyester tape tied to a titanium button (proximal) and sutures tied around a screw post (distal). The tensile load-to-failure tests also revealed significant differences (p < 0.05) between the two graft constructs. Linear stiffness was 32 +/- 1 and 119 +/- 19 Nmm and ultimate load was 415 +/- 36 and 658 +/- 128 N for Grafts A and B, respectively. For Graft A, the polyester tape consistently failed; for Graft B, slippage or tearing from the washers was the mode of failure. We conclude that a quadruple-hamstring graft fixed over a cross pin proximally and with metal washers distally (Graft B) has less permanent elongation in response to cyclic loading and has structural properties superior to those of a graft construct that includes suture and tape material (Graft A). The large permanent elongation following repetitive loading of a graft construct with tape and suture material during the early postoperative period is of concern.

Aged↗
PubMed2000

Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors.

Between December 1996 and September 1998, 13 patients with advanced recurrent malignant brain tumors (9 with glioblastoma multiforme, 1 with gliosarcoma, and 3 with anaplastic astrocytoma) were treated with a single intratumoral injection of 2 x 10(9), 2 x 10(10), 2 x 10(11), or 2 x 10(12) vector particles (VP) of a replication-defective adenoviral vector bearing the herpes simplex virus thymidine kinase gene driven by the Rous sarcoma virus promoter (Adv.RSVtk), followed by ganciclovir (GCV) treatment. The VP to infectious unit ratio was 20:1. Our primary objective was to determine the safety of this treatment. Injection of Adv.RSVtk in doses <==2 x 10(11) VP, followed by GCV, was safely tolerated. Patients treated with the highest dose, 2 x 10(12) VP, exhibited central nervous system toxicity with confusion, hyponatremia, and seizures. One patient is living and stable 29.2 months after treatment. Two patients survived >25 months before succumbing to tumor progression. Ten patients died within 10 months of treatment, 9 from tumor progression and 1 with sepsis and endocarditis. Neuropathologic examination of postmortem tissue demonstrated cavitation at the injection site, intratumoral foci of coagulative necrosis, and variable infiltration of the residual tumor with macrophages and lymphocytes.

Adenoviridae↗
PubMed2000

Rejection of disseminated metastases of colon carcinoma by synergism of IL-12 gene therapy and 4-1BB costimulation.

In an orthotopic model of metastatic colon carcinoma established in the liver of mice, we have previously shown that the natural killer (NK) cells were the major effectors after intratumoral delivery of a recombinant adenovirus expressing the murine IL-12 gene. However, tumor cure and long-term survival were achieved only in a minority of animals. In the present study, we generated an effective antitumoral CD8(+ ) T-cell response by the combination of IL-12 gene therapy and systemic delivery of an agonistic monoclonal antibody against 4-1BB, a costimulatory molecule expressed on activated T cells. In the IL-12 plus anti-4-1BB combination treatment, the effective dose of IL-12 could even be reduced even up to 18-fold and still achieved a better efficacy than the maximal dose of either treatment alone. We further demonstrate that the innate and the adaptive antitumoral immune responses were synergistic, as animals bearing hepatic as well as multiple pulmonary metastases were quantitatively cured of their diseases after IL-12 gene therapy + anti-4-1BB combination treatment. Both NK and CD8(+) T cells were necessary in maintaining the long-term antitumor immunity, as depletion of either cell type in the cured animals abolished their abilities to reject tumor cells implanted at distal sites. These results indicate that synergism between innate and adaptive immune responses may be effectively exploited to treat patients with metastatic diseases.

4-1BB Ligand↗