Treatment Of Other Tumors Research Articles

Bioengineer mesenchymal stem cell for treatment of glioma by IL‐12 mediated microenvironment reprogramming and nCD47‐SLAMF7 mediated phagocytosis regulation of macrophages

AbstractHigh expression of cellular self‐activated immunosuppressive molecules and extensive infiltration of suppressive immune cells in the tumor microenvironment are the main factors contributing to glioma's resistance to immunotherapy. Nonetheless, technology to modify the expression of glioma cellular self‐molecules through gene editing requires further development. This project advances cell therapy strategies to reverse the immunosuppressive microenvironment of glioma (TIME). Bone marrow‐derived mesenchymal stem cells (MSCs) are engineered to express bioactive proteins and demonstrate tumor‐homing characteristics upon activation by TGF‐β. These MSCs are designed to secrete the anti‐tumor immune cytokine IL‐12 and the nCD47‐SLAMF7 fusion protein, which regulates T‐cell activity and macrophage phagocytosis. The engineered MSCs are then injected in situ into the glioma site, circumventing the blood‐brain barrier to deliver high local concentrations of bioactive proteins. This approach aims to enhance the M1 polarization of infiltrating macrophages, stimulate macrophage‐mediated tumor cell phagocytosis, activate antigen‐presenting cells, and promote effector CD8+ T cell infiltration, effectively controlling glioma. Additionally, the engineered MSCs may serve as a universal treatment for other tumors that express TGF‐β at high levels. This study proposes a novel treatment strategy for the clinical management of glioma patients.

Cannabinoids in the treatment of glioblastoma.

Glioblastoma (GBM) is the most prevalent primary malignant tumor of the nervous system. While the treatment of other neoplasms is increasingly more efficacious the median survival rate of GBM patients remains low and equals about 14 months. Due to this fact, there are intensive efforts to find drugs that would help combat GBM. Nowadays cannabinoids are becoming more and more important in the field of cancer and not only because of their properties of antiemetic drugs during chemotherapy. These compounds may have a direct cytotoxic effect on cancer cells. Studies indicate GBM has disturbances in the endocannabinoid system-changes in cannabinoid metabolism as well as in the cannabinoid receptor expression. The GBM cells show expression of cannabinoid receptors 1 and 2 (CB1R and CB2R), which mediate various actions of cannabinoids. Through these receptors, cannabinoids inhibit the proliferation and invasion of GBM cells, along with changing their morphology. Cannabinoids also induce an intrinsic pathway of apoptosis in the tumor. Hence the use of cannabinoids in the treatment of GBM may be beneficial to the patients. So far, studies focusing on using cannabinoids in GBM therapy are mainly preclinical and involve cell lines and mice. The results are promising and show cannabinoids inhibit GBM growth. Several clinical studies are also being carried out. The preliminary results show good tolerance of cannabinoids and prolonged survival after administration of these drugs. In this review, we describe the impact of cannabinoids on GBM and glioma cells in vitro and in animal studies. We also provide overview of clinical trials on using cannabinoids in the treatment of GBM.

Applications of Focused Ultrasound for the Treatment of Glioblastoma: A New Frontier.

Simple SummaryGlioblastoma (GBM) is a common primary brain tumor with a short median overall survival despite aggressive treatment with resection, chemotherapy, and radiation therapy. Focused ultrasound (FUS) represents a promising new therapeutic approach for treatment of GBM. Unlike imaging forms of ultrasound, FUS can successfully penetrate the skull surrounding the brain, allowing for non-invasive ablation of tumor tissue. FUS can also temporarily disrupt the blood–brain barrier, a microvascular network that prohibits diffusion of most therapeutic agents, allowing chemotherapeutic drugs to penetrate the tumor. Other modalities are under investigation and include means of stimulating the immune system and sensitizing tumors to radiation therapy. The feasibility and safety of transcranial FUS has been illustrated in animal models and clinical trials. Precise results can be obtained under guidance from magnetic resonance imaging, limiting side effects. Successful outcomes from clinical trials will likely continue to motivate investigation and innovation of FUS technology for GBM.Glioblastoma (GBM) is an aggressive primary astrocytoma associated with short overall survival. Treatment for GBM primarily consists of maximal safe surgical resection, radiation therapy, and chemotherapy using temozolomide. Nonetheless, recurrence and tumor progression is the norm, driven by tumor stem cell activity and a high mutational burden. Focused ultrasound (FUS) has shown promising results in preclinical and clinical trials for treatment of GBM and has received regulatory approval for the treatment of other neoplasms. Here, we review the range of applications for FUS in the treatment of GBM, which depend on parameters, including frequency, power, pulse duration, and duty cycle. Low-intensity FUS can be used to transiently open the blood–brain barrier (BBB), which restricts diffusion of most macromolecules and therapeutic agents into the brain. Under guidance from magnetic resonance imaging, the BBB can be targeted in a precise location to permit diffusion of molecules only at the vicinity of the tumor, preventing side effects to healthy tissue. BBB opening can also be used to improve detection of cell-free tumor DNA with liquid biopsies, allowing non-invasive diagnosis and identification of molecular mutations. High-intensity FUS can cause tumor ablation via a hyperthermic effect. Additionally, FUS can stimulate immunological attack of tumor cells, can activate sonosensitizers to exert cytotoxic effects on tumor tissue, and can sensitize tumors to radiation therapy. Finally, another mechanism under investigation, known as histotripsy, produces tumor ablation via acoustic cavitation rather than thermal effects.

The Role of ATRA, Natural Ligand of Retinoic Acid Receptors, on EMT-Related Proteins in Breast Cancer: Minireview.

The knowledge of the structure, function, and abundance of specific proteins related to the EMT process is essential for developing effective diagnostic approaches to cancer with the perspective of diagnosis and therapy of malignancies. The success of all-trans retinoic acid (ATRA) differentiation therapy in acute promyelocytic leukemia has stimulated studies in the treatment of other tumors with ATRA. This review will discuss the impact of ATRA use, emphasizing epithelial-mesenchymal transition (EMT) proteins in breast cancer, of which metastasis and recurrence are major causes of death.

Association between oncology drug review times and public funding recommendations.

99 Background: New oncology drugs undergo detailed review of clinical, economic, and patient data. Thoroughly assessing these data can require lengthy review processes, in the absence of accelerated approval pathways. The aim of this study was to assess how cancer drug review times impact public funding recommendations. Methods: Drugs reviewed by Canada’s health technology assessment body, the pan-Canadian Oncology Drug Review (pCODR), from April 2012 to November 2020 were included in this study. Data was collected including Health Canada approval date, initial and final funding recommendations, treatment intent, drug class, clinical indication (tumour type) and incremental cost-effectiveness ratios (ICER). Univariable and multivariable analyses were used to determine the association between funding recommendations and review times. Results: Of the 227 applications submitted to pCODR, 168 had received positive funding recommendations. Amongst the total drug applications, 24 (14.3%) drugs were intended for the treatment of thoracic cancers, 19 (11.3%) for gastrointestinal cancers, 17 (10.1%) for genitourinary cancers, 17 (10.1%) for breast cancer, and 91 (54.2%) for other tumour sites. Median time from pCODR submission to final recommendation was longer for drugs indicated for the treatment of lung and breast cancer compared to those indicated for treatment of other tumours (223 vs. 212 vs. 203 days, respectively; Kruskal-Wallis p = 0.0322). Drugs with longer review times were more likely to receive a negative pCODR recommendation, even when adjusting for ICER (157 vs 298 days, Wilcoxon p-value = 0.0003). There was no association between positive or negative funding recommendation and tumour type. Conclusions: Oncology drugs with longer review times are less likely to receive recommendation for public funding in Canada. Addressing factors contributing to variance in review times and standardizing the review process can ensure equitable access to cancer drugs.

A Spherical Joint Robotic End-Effector for the Expanded Endoscopic Endonasal Approach

The endonasal transsphenoidal approach allows surgeons to access the pituitary gland through the natural orifice of the nose. Recently, surgeons have also described an Expanded Endoscopic Endonasal Approach (EEEA) for the treatment of other tumours around the base of the brain. However, operating in this way with nonarticulated tools is technically very difficult and not widely adopted. The goal of this study is to develop an articulated end-effector for a novel handheld robotic tool for the EEEA. We present a design and implementation of a 3.6[Formula: see text]mm diameter, three degrees-of-freedom, tendon-driven robotic end-effector that, contrary to rigid instruments which operate under fulcrum, will give the surgeon the ability to reach areas on the surface of the brain that were previously inaccessible. We model the end-effector kinematics in simulation to study the theoretical workspace it can achieve prior to implementing a test-bench device to validate the efficacy of the end-effector. We find promising repeatability of the proposed robotic end-effector of 0.42[Formula: see text]mm with an effective workspace with limits of [Formula: see text], which is greater than conventional neurosurgical tools. Additionally, although the tool’s end-effector has a small enough diameter to operate through the narrow nasal access path and the constrained workspace of EEEA, it showcased promising structural integrity and was able to support approximately a 6N load, despite a large deflection angle the limiting of which is scope of future work. These preliminary results indicate the end-effector is a promising first step towards developing appropriate handheld robotic instrumentation to drive EEEA adoption.

An exploratory study of CT-guided percutaneous radiofrequency ablation for stage I thymoma

BackgroundThymoma is a rare tumor that originates from thymic epithelial cells and is usually associated with myasthenia gravis. Radiofrequency ablation (RFA) is a minimally invasive and curative treatment for other tumors, but RFA has not been used for the early treatment of thymoma.MethodsThe current study included 13 patients with stage I thymoma who were not candidates for surgical resection or video-assisted thoracoscopic surgery (VATS). All patients underwent first-line CT-guided percutaneous RFA. The feasibility and therapeutic effects of the intervention were thoroughly documented.ResultsAll tumors were completely ablated (13 / 13, 100%). During follow-up (median 80.5 months, range, 64.6–116.9 months), only 1 of the 13 patients had recurrence of thymoma (1 / 13, 7.7%) at 35.5 months after the initial ablation. There were no surgery-related deaths after RFA treatment. The most common complications were fever (13 / 13, 100%) and pain (13 / 13, 100%). There was only one patient who occurred severe puncture-related bleeding during the procedure that needed blood transfusion and intravascular embolization of the punctured-injured vessel.ConclusionCT-guided percutaneous RFA for treatment of stage I thymoma is associated with minor trauma, few complications and good treatment outcomes.

Targeting ERBB2 (HER2) Amplification Identified by Next-Generation Sequencing in Patients With Advanced or Metastatic Solid Tumors Beyond Conventional Indications.

PURPOSEHuman epidermal growth factor receptor 2 (HER2) is an effective therapeutic target in breast and gastric and gastroesophageal junction cancers. However, less is known about the prevalence of ERBB2 (HER2) amplification and the efficacy of HER2-targeted treatment in other tumors.PATIENTS AND METHODSWe assessed HER2 amplification status among 5,002 patients with advanced disease (excluding breast cancer) who underwent next-generation sequencing. We evaluated the clinical benefit of HER2-targeted therapy by measuring the time-dependent overall survival (OS) from the genomic testing results, progression-free survival (PFS), and PFS during HER2-targeted therapy (PFS2) compared with PFS during prior therapy (PFS1).RESULTSOverall, 122 patients (2.4%) had HER2 amplification, including patients with endometrial (5.3%), bladder (5.2%), biliary or gallbladder (4.9%), salivary (4.7%), and colorectal cancer (3.6%). Forty patients (38%) with nongastric, nongastroesophageal junction, or nonesophageal cancers received at least one line of HER2-targeted therapy. Patients receiving HER2-targeted therapy had a median OS of 18.6 months, compared with 10.9 months for patients who did not receive HER2-targeted therapy (P = .070). On multivariable analysis, HER2-targeted therapy was significantly associated with increased OS (hazard ratio, 0.5; 95% CI, 0.27 to 0.93; P = .029), regardless of sex, age, or number of prior lines of treatment. The PFS2-to-PFS1 ratio was 1.3 or greater in 21 (57%) of 37 patients who received HER2-targeted therapy not in the first line of systemic treatment, and the median PFS2 and PFS1 times were 24 and 13 weeks, respectively (P < .001).CONCLUSIONHER2 amplifications using next-generation sequencing can be identified in a variety of tumor types. HER2-targeted therapy may confer clinical benefit in tumor types other than those for which HER2 inhibitors are approved.

Improving Magnetofection of Magnetic Polyethylenimine Nanoparticles into MG-63 Osteoblasts Using a Novel Uniform Magnetic Field

This study aimed to improve the magnetofection of MG-63 osteoblasts by integrating the use of a novel uniform magnetic field with low molecular weight polyethylenimine modified superparamagnetic iron oxide nanoparticles (PEI-SPIO-NPs). The excellent characteristics of PEI-SPIO-NPs such as size, zeta potential, the pDNA binding and protective ability were determined to be suitable for gene delivery. The novel uniform magnetic field enabled polyethylenimine-modified superparamagnetic iron oxide nanoparticles/pDNA complexes (PEI-SPIO-NPs/pDNA complexes) to rapidly and uniformly distribute on the surface of MG-63 cells, averting local transfection and decreasing disruption of the membrane caused by the centralization of positively charged PEI-SPIO-NPs, thereby increasing the effective coverage of magnetic gene carriers during transfection, and improving magnetofection efficiency. This innovative uniform magnetic field can be used to determine the optimal amount between PEI-SPIO-NPs and pDNA, as well as screen for the optimal formulation design of magnetic gene carrier under the homogenous conditions. Most importantly, the novel uniform magnetic field facilitates the transfection of PEI-SPIO-NPs/pDNA into osteoblasts, thereby providing a novel approach for the targeted delivery of therapeutic genes to osteosarcoma tissues as well as a reference for the treatment of other tumors.

CT-guided percutaneous radiofrequency ablation in the treatment of stage I thymoma.

e18287 Background: Thymoma is an uncommon tumor originating from the epithelial cells of the thymic epithelium. It is commonly associated with myasthenia gravis. Though surgical resection might provide the hope of curing thymoma, potential risks of invasive trauma and post operation complications still exists. Video-assisted thoracoscopic surgery (VATS) has many advantages over traditional surgery including minor trauma. However, surgeons operating the equipment to perform VATS need to be highly specifically trained. Although CT-guided percutaneous radiofrequency ablation (RFA) has emerged as a minimally invasive and curative treatment in other tumors, it has never been used in the treatment of stage I thymoma. Methods: The current study enrolled 13 patients with stage I thymomas whom refused open surgery or VATS. As a result, all patients received first-line CT-guided percutaneous RFA as treatment. The procedure was clearly described and displayed for clinical promoting. Results: The feasibility and treatment effectiveness were also recorded. The median time of ablation was 15 mins (range, 10 - 20 mins). Minimum blood loss was associated with the puncture. All lesions were completely ablated (13/13, 100%). Only one patient out of thirteen had thymoma recurrence at 35.5 months after initial ablation treatment (1/13, 7.7%) at follow-up period (median 80.5 months, range, 64.6-116.9 months). There was no procedure-related death after RFA treatment. Myasthenia gravis was cured in most patients (10/13,76.9%), alleviated in 3 patients (23.1%). The most common complications recorded were fever (13/13, 100%), incisional pain (13/13, 100%), nausea (38.5%), pleural effusion (69.2%), pneumothorax (69.2%) and hemoptysis (84.6%). Conclusions: It is clinically applicable for CT-guided percutaneous RFA to be considered as a safe and effective treatment in stage I thymoma.

Lymph cancer chemotherapy: delivery of doxorubicin-gemcitabine prodrug and vincristine by nanostructured lipid carriers.

PurposeRadiation and chemotherapy are the most common course of treatment for B-cell lymphoma. Doxorubicin (DOX), gemcitabine (GEM), and vincristine (VCR) are the commonly used antilymphoma chemotherapeutic drugs. The aim of this study is to construct a novel drug delivery system for the combination delivery of the three drugs on lymphoma.Materials and methodsDOX–GEM prodrug was synthesized. Novel nanostructured lipid carriers (NLCs) containing DOX–GEM prodrug and VCR were prepared and used to treat B-cell lymphoma through in vivo treatment to a lymph cancer animal model. The systemic toxicity of the nanomedicine was also evaluated during the treatment.ResultsDOX–GEM prodrug and VCR-loaded NLCs (DOX–GEM VCR NLCs) exhibited the highest antitumor effect in B-cell lymphoma cells and lymphoma animal xenografts when compared with the single drug-loaded NLCs and the drug solutions.ConclusionIt could be concluded that the highest antitumor effect can be achieved by the system due to the stable drug-loading capacity, attractive anticancer therapeutic effects, and reduced toxicities in human Burkitt’s lymphoma cell line and mice-bearing cancer model. The resulting DOX–GEM VCR NLCs could be an efficient antilymph cancer agent and could be developed further for the treatment of other tumors.

Autophagy inhibition enhances colorectal cancer apoptosis induced by dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235.

Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway performs a central role in tumorigenesis and is constitutively activated in many malignancies. As a novel dual PI3K/mTOR inhibitor currently undergoing evaluation in a phase I/II clinical trial, NVP-BEZ235 indicates a significant antitumor efficacy in diverse solid tumors, including colorectal cancer (CRC). Autophagy is a catabolic process that maintains cellular homeostasis and reduces diverse stresses through lysosomal recycling of the unnecessary and damaged cell components. This process is also observed to antagonize the antitumor efficacy of PI3K/mTOR inhibitor agents such as NVP-BEZ235, via apoptosis inhibition. In the present study, we investigated anti-proliferative and apoptosis-inducing ability of NVP-BEZ235 in SW480 cells and the crosstalk between autophagy and apoptosis in SW480 cells treated with NVP-BEZ235 in combination with an autophagy inhibitor. The results revealed that, NVP-BEZ235 effectively inhibit the growth of SW480 cells by targeting the PI3K/mTOR signaling pathway and induced apoptosis. The inhibition of autophagy with 3-methyladenine or chloroquine inhibitors in combination with NVP-BEZ235 in SW480 cells enhanced the apoptotic rate as componets to NVP-BEZ235 alone. In conclusion, the findings provide a rationale for chemotherapy targeting the PI3K/mTOR signaling pathway presenting a potential therapeutic strategy to enhance the efficacy of dual PI3K/mTOR inhibitor NVP-BEZ235 in combination with an autophagy inhibitor in CRC treatment and treatment of other tumors.

DDEL-13TARGETED INTERLEUKIN-13-LIPOSOMES-MAGNIVEST-DOXORUBICIN FOR DETECTION AND TREATMENT OF GLIOMA IN EARLY STAGE

Malignant glioma in central nervous system (CNS) is a challenge to detect/treat due to the blood-brain barrier (BBB) that prohibits most chemicals like anti-cancer agents to penetrate. Furthermore, to detect brain cancer, magnetic resonance image (MRI) contrast agent such as Magnevist (Gd/DTPA) is limited to the cases where the BBB is significantly compromised by the cancer because Gd-DTPA itself is not able to cross the BBB. As a result, the cancer boundary presented by Gd-DTPA-enhanced MRI reflects only the extent where BBB is compromised instead of all the cancer-infiltrated regions. For the malignant glioma in early stage when it is smaller than 2 mm, which is even none detectable by Gd-DTPA-enhanced MRI because the BBB is intact when tumor is less than 2 mm. It is critical to develop a delivery system that carries targeted MRI contrast agent with drug alongside, which could penetrate brain tissue, detect and treat glioma in early stage concomitantly. Previous work demonstrated: 1) IL-13Rα2 was over-expressed in glioma, 2) IL-13-liposomes-doxrubinsine inhibited an intracranial glioma growth and 3) IL-13-liposomes-Gd/DTPA as a MRI contrast agent enhanced and detected infiltrating glioma. Based on these findings we hypothesized that IL-13-liposome encapsulating Gd-DTPA and doxorubicin (Dox) will be a theranostic agent for detection and treatment of gliomas. To test our hypothesis, glioma U251 and glioma stem cells T3691 and athymic nude mice with intracranial glioma were selected as our in vitro and in vivo model. IL-13-liposomes-Gd/DTPA-Dox was developed and characterized. Its application in vitro and in vivo has been evaluated through targeted MRI guided drug delivery. Our results provided the evidence that corresponded with our hypothesis. We predicted that the development of IL-13-liposomes-Gd/Dox will not only lead a translation into clinical neuro-oncology, but also into treatment of other tumors like colon cancer metastasis and adrenocortical carcinoma, which overexpressed IL-13Rα2.

P11.01 * THE ROLE OF SURGERY IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMAS

INTRODUCTION: Involvement of the central nervous system (CNS) by limphoma is an uncommon variant of extranodal non-Hodgkin lymphoma (NHL). The appearance of CNS disease years after complete remission of NHL can be attributed to recurrence of the original tumor or to a second neoplasm in genetically and immunologically predisposed patients. MATERIAL AND METHODS: A descriptive analysis of all Primary Central Nervous System Lymphomas (PCNSL) treated in our institution since 1990 has been carried out. All patients have histologically confirmed PCNSL, and extent of the disease was studied with body CT scan and bone marrow biopsy. 15 cases were diagnosed, all without evidence of distant disease. RESULTS: The mean age at diagnosis was 59.3 years, with a larger proportion of males and presence of HIV disease in 33% of all patients. During the 1990′s the percentage of craniectomies is greater than during the following decade, in which biopsies prevail and the craniectomies carried out correspond to unsuspected PCNSL. Six patients had a previous history of systemic neoplasm upon diagnosis of PCNSL. CONCLUSIONS: Upon the suspicion of PCL, a stereotactic biopsy should be performed to confirm diagnosis. Biopsies of CNS lesions that appear syncronically or after treatment of other neoplasms have proven that PCNSL should be considered in the differential diagnosis of second tumors. PCNSL as a second primary tumor after extranodal NHL is a rare entity, yet such possibility should be taken into account and considered in the differential diagnosis with local relapse. In the case of metastases, treatment would have a palliative approach, whereas in second primary tumors curative treatment is attempted, with different prognostic implications.

PARP inhibitor olaparib increases the oncolytic activity of dl922-947 in in vitro and in vivo model of anaplastic thyroid carcinoma

PARP inhibitors are mostly effective as anticancer drugs in association with DNA damaging agents. We have previously shown that the oncolytic adenovirus dl922-947 induces extensive DNA damage, therefore we hypothesized a synergistic antitumoral effect of the PARP inhibitor olaparib in association with dl922-947. Anaplastic thyroid carcinoma was chosen as model since it is a particularly aggressive tumor and, because of its localized growth, it is suitable for intratumoral treatment with oncolytic viruses.Here, we show that dl922-947 infection induces PARP activation, and we confirm in vitro and in vivo that PARP inhibition increases dl922-947 replication and oncolytic activity. In vitro, the combination with olaparib exacerbates the appearance of cell death markers, such as Annexin V positivity, caspase 3 cleavage, cytochrome C release and propidium iodide permeability. In vivo, we also observed a better viral distribution upon PARP inhibition. Changes in CD31 levels suggest a direct effect of olaparib on tumor vascularization and on the viral distribution within the tumor mass. The observation that PARP inhibition enhances the effects of dl922-947 is highly promising not only for the treatment of anaplastic thyroid carcinoma but, in general, for the treatment of other tumors that could benefit from the use of oncolytic viruses.

Polymalic acid-based nano biopolymers for targeting of multiple tumor markers: an opportunity for personalized medicine?

Tumors with similar grade and morphology often respond differently to the same treatment because of variations in molecular profiling. To account for this diversity, personalized medicine is developed for silencing malignancy associated genes. Nano drugs fit these needs by targeting tumor and delivering antisense oligonucleotides for silencing of genes. As drugs for the treatment are often administered repeatedly, absence of toxicity and negligible immune response are desirable. In the example presented here, a nano medicine is synthesized from the biodegradable, non-toxic and non-immunogenic platform polymalic acid by controlled chemical ligation of antisense oligonucleotides and tumor targeting molecules. The synthesis and treatment is exemplified for human Her2-positive breast cancer using an experimental mouse model. The case can be translated towards synthesis and treatment of other tumors.

Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?

Tumors with similar grade and morphology often respond differently to the same treatment because of variations in molecular profiling. To account for this diversity, personalized medicine is developed for silencing malignancy associated genes. Nano drugs fit these needs by targeting tumor and delivering antisense oligonucleotides for silencing of genes. As drugs for the treatment are often administered repeatedly, absence of toxicity and negligible immune response are desirable. In the example presented here, a nano medicine is synthesized from the biodegradable, non-toxic and non-immunogenic platform polymalic acid by controlled chemical ligation of antisense oligonucleotides and tumor targeting molecules. The synthesis and treatment is exemplified for human Her2-positive breast cancer using an experimental mouse model. The case can be translated towards synthesis and treatment of other tumors.

Low-Dose Nilotinib and Imatinib Combination In CML Patients, With Failure, Suboptimal Response Or Treatment Intolerance To First Line Imatinib Treatment. A Pilot Study

IntroductionIntroduction of tyrosine kinase inhibitors (TKI) as first-line therapy has reduced mortality related to CML in the last 10 years. According to IRIS study probability of maintaining CCyR to 5 years with imatinib is 63%. Therefore 30-35% of patients will require alternative treatment for primary, secondary resistance or intolerance to treatment. Nilotinib has shown to be 20 times more potent than imatinib in cells expressing unmutated BCR / ABL and is effective against up to 30 different mutations present in the imatinib resistant patient. It now has a role as first line CML therapy or second line in the case of imatinib failure. Drug combinations are common in the treatment of other neoplasms, preclinical studies showed that nilotinib has a synergistic effect when used in conjunction with imatinib, for inducing apoptosis and decreases cell proliferation without relevant toxicity. Combination of these two drugs has been used in the treatment of gastrointestinal stromal tumor (GIST) and in at least 2 reported cases of CML, with good results and without increased toxicity.Low-dose nilotinib in combination with low-dose imatinib appears to be another option for patients with failure, suboptimal response or intolerance to imatinib therapy. In this pilot and prospective study, we analyzed the effectiveness and tolerability of this combination. ObjectiveTo evaluate cytogenetic and molecular response to low-dose imatinib and nilotinib combined treatment in CML patients with failure, suboptimal response or intolerance to imatinib therapy and the potential toxicity of the combination. MethodsCML patients with failure, suboptimal response or intolerance to imatinib therapy were evaluated. Cytogenetic analysis, quantitative PCR for BCR/ABL and evaluation for mutations were performed at baseline. All patients received treatment as follows: imatinib 200 mg daily and nilotinib 300 mg daily for 6 months. Quantitative PCR for BCR/ABL was performed at 3 months, and cytogenetic analysis and quantitative PCR for BCR/ABL at 6 months. If hematologic progression occurred, stepwise dose escalation of imatinib 200 mg and nilotinib 150-300 mg monthly was permitted until a maximum dose of 800 or 750 mg each. Kolmogorov-Smirnov was use to test for normality, T-test, Friedman test and Q Cochran were used for parametric and non parametric variables respectively. ResultsTen patients were included, 6 men and 4 women, median age of 38 years (27-68). Median time from diagnosis was 65.8 (13.7-149.3) months, and time of previous imatinib treatment was 60.8 (30.0-113.3) months; with a median imatinib dose of 400 mg (400-800), 80% had treatment failure and 20% suboptimal response according to European Leukemia Net criteria. No patients with treatment intolerance were included. Mutations were detected in 40% of patients. At baseline only 2 patients had complete cytogenetic response, at 6 months 6 patients had complete cytogenetic response (p=0.046), at 6 months 40% of patients had achieved major molecular response (p=0.039). Mean percentage of BCR/ABL transcripts detected by quantitative PCR before treatment and at 3 and 6 months was 15.62% IS (SD±18.39), 7.25% IS (SD± 8.48) and 1.05% IS (SD± 1.32) respectively, with a significant difference, p= 0.045. The most frequent side effect was rash in 4 patients; with mild severity and complete response to antihistaminic treatment in all cases. One patient had to be withdrawn from the study after 3 months of treatment because of grade 4 thrombocytopenia. None of the patients presented disease progression. ConclusionOur results support the information that preclinical studies showed, that nilotinib has a synergistic effect when used in conjunction with imatinib. Low-dose imatinib and nilotinib combination is an effective and safe treatment alternative for some patients with failure, suboptimal response or intolerance to imatinib monotherapy at standard dose. Disclosures:Off Label Use: Nilotinib and imatinib at low dose.

Vaccination for invasive canine meningioma induces in situ production of antibodies capable of antibody-dependent cell-mediated cytotoxicity.

Malignant and atypical meningiomas are resistant to standard therapies and associated with poor prognosis. Despite progress in the treatment of other tumors with therapeutic vaccines, this approach has not been tested preclinically or clinically in these tumors. Spontaneous canine meningioma is a clinically meaningful but underutilized model for preclinical testing of novel strategies for aggressive human meningioma. We treated 11 meningioma-bearing dogs with surgery and vaccine immunotherapy consisting of autologous tumor cell lysate combined with toll-like receptor ligands. Therapy was well tolerated, and only one dog had tumor growth that required intervention, with a mean follow up of 585 days. IFN-γ-elaborating T cells were detected in the peripheral blood of 2 cases, but vaccine-induced tumor-reactive antibody responses developed in all dogs. Antibody responses were polyclonal, recognizing both intracellular and cell surface antigens, and HSP60 was identified as one common antigen. Tumor-reactive antibodies bound allogeneic canine and human meningiomas, showing common antigens across breed and species. Histologic analysis revealed robust infiltration of antibody-secreting plasma cells into the brain around the tumor in posttreatment compared with pretreatment samples. Tumor-reactive antibodies were capable of inducing antibody-dependent cell-mediated cytotoxicity to autologous and allogeneic tumor cells. These data show the feasibility and immunologic efficacy of vaccine immunotherapy for a large animal model of human meningioma and warrant further development toward human trials.

Abstract 1811: Cancer/testis antigens: Comprehensive expression analysis and correlation with survival in glioblastoma.

Abstract Glioblastoma (GBM) is a highly invasive and aggressive tumor which confers a dismal prognosis despite advances of current therapy. Cancer vaccines have been utilized as treatment of other tumors and might be an option for brain tumors. Cancer/testis (CTA) genes represent promising targets for immunotherapeutic approaches. They are expressed in tumors and expression in normal tissues is exclusively or preferentially restricted to testis. The expression of 31 CTA genes was investigated in 48 glioblastomas and 5 normal brain samples using RT-PCR. A tissue microarray was made and expression of a CTA was detected by immunohistochemical staining. Among the genes with no expression in normal brain CTA1 (57%), CTA2 (54%), CTA3 (44%) and CTA4 (15%) were the most expressed in glioblastomas. At least one of these four selected CTA genes was found expressed in 86% of the GBM cases. Coexpression of two, three and four CTA genes occurred in 25%, 17% and 5% of the examined GBM cases, respectively. CTA4 protein expression was identified in 13% (12/92) of GBM and was negative in all anaplastic astrocytomas (0/15), diffuse astrocytomas (0/48), pilocytic astrocytomas (0/38) and normal brain samples (0/40) evaluated. We found that CTA2-positive GBMs and tumors expressing 3-4 CTA genes presented a significantly better outcome (P = 0.032; hazards ratio = 0.53; 95% CI; 0.28 to 1.0 and P = 0.017, hazards ratio = 0.36; 95% CI, 0.17 to 0.74; respectively). Furthermore, multivariate survival analysis revealed that coexpression of 3-4 CTA genes (P = 0.044, hazards ratio = 0.3, 95%CI = 0.093-0.963), radiotherapy (P = 0.010, hazards ratio = 0.16, 95%CI = 0.04-0.65) and chemotherapy (P = 0.001, hazards ratio = 0.10, 95% CI = 0.03-0.41) remained as independent predictors of overall survival. In conclusion, CTAs are potential targets for immunotherapy in patients with GBM, 86% of the cases examined expressed at least one of four selected CTA genes. The presence of 3-4 CTA genes was associated with better survival, suggesting that these genes might elicit an immune response against GBM. Supported by FAPESP(Grant 2010/20218-2 and 2011/15118-1). Citation Format: Marcelo Freitas, Thaís P. Biassi, Suzana M.F Malheiros, João N. Stávale, Fernando T. Zamunér, Maria D.F.S Begnami, Fernando A. Soares, André L. Vettore. Cancer/testis antigens: Comprehensive expression analysis and correlation with survival in glioblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1811. doi:10.1158/1538-7445.AM2013-1811