Endoscopic Ultrasound-guided Fine-needle Injection Research Articles

Abstract A048: Enhancing the immune response in locally advanced pancreatic cancer (LAPC) with intratumoral endoscopic ultrasound-guided fine needle injection of large surface area microparticle paclitaxel (LSAM-PTX)

Abstract Background: The complex tumor microenvironment (TME) of locally advanced pancreatic cancer (LAPC) is resistant to immune effector cell infiltration and drug bioavailability, limiting the effectiveness of current systemic therapies. Large Surface Area Microparticle Paclitaxel (LSAM-PTX) was developed for intratumoral (IT) injection to solid tumors to provide a paclitaxel depot at therapeutic levels with a prolonged residence time. We previously reported enhanced tumor kill in LAPC subjects receiving two monthly IT LSAM-PTX injections and demonstrated immunomodulation in the TME. Multiplex immunofluorescence (mIF) performed on pre-treatment biopsy tissue and post-LSAM-PTX resection showed increases in densities of effector T cells and NK cells and decreases in myeloid derived suppressor cells (MDSC). To further evaluate immunomodulation following IT LSAM-PTX therapy, blood samples were obtained for immunophenotyping using flow cytometry (NCT03077685). Methods: Pretreatment samples were obtained from subjects administered four injections (n=14) and at visits throughout the treatment period and up to six months post first LSAM-PTX injection. Flow cytometric analysis was performed using three panels to evaluate absolute counts and percentages of up to 45 immunophenotypes. Results: Treatment with four IT injections of LSAM-PTX (ongoing median overall survival = 12.6 months; follow-up = 12.2 months) was associated with increases in peripheral lymphocytes during the treatment period. An enhancement of immune subsets associated with anti-tumor effector functions was found, including significant increases in circulating CD3+ and CD4+ cells (p=0.0012 and 0.002 respectively) which is consistent with the 4-fold increase in CD4+helper T cells detected in the TME of resected tissue. A significant increase in LAG3+CD8+ T cells was seen following treatment initiation (p=0.048) marking early T cell activation. Increases in circulating CD8+ T cells, B cells, and NK cells were seen during the treatment period corresponding with effector T cells and NK cells increases (4.8-fold increase in density) within the TME. Six months following treatment initiation there was a significant decrease in circulating Treg cells (p=0.0183) and a decrease in peripheral immunosuppressive G-MDSC, consistent with the reduction in MDSC measured in the TME. Notably, systemic taxane toxicities, including immunosuppression, were not reported following IT LSAM-PTX and negligible amounts of paclitaxel were found in blood samples. Conclusion: Immunophenotyping of blood from LAPC subjects treated with IT LSAM-PTX demonstrates immunomodulation to a phenotype associated with anti-tumor immune effects, including favorable immunosurveillance, and is consistent with changes found in the TME in resected tissues. Immunosuppressive cell types typically associated with poor outcomes were reduced at six months. Anti-tumor immunomodulation without immunosuppression suggests that IT LSAM-PTX may be amenable to combination with immunotherapy. Citation Format: Andrew E. Hendifar, Max M. Wattenberg, Holly A. Maulhardt, Alyson M. Marin, Alison E. Wendt, Shelagh J. Verco, Gere S. diZerega. Enhancing the immune response in locally advanced pancreatic cancer (LAPC) with intratumoral endoscopic ultrasound-guided fine needle injection of large surface area microparticle paclitaxel (LSAM-PTX) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A048.

Local Sustained Chemotherapy of Pancreatic Cancer Using Endoscopic Ultrasound-Guided Injection of Biodegradable Thermo-Sensitive Hydrogel.

Endoscopic ultrasound-guided fine-needle injection (EUS-FNI) offers a promising minimally invasive approach for locally targeted management of advanced pancreatic cancer. However, the efficacy is limited due to the rapid plasma clearance of chemotherapeutic agents. Injectable hydrogels can form drug release depots, which provide a feasible solution for optimizing targeted chemotherapy through EUS-FNI. A drug delivery system was developed, consisting of gemcitabine (GEM) and thermo-sensitive hydrogel (PLGA-PEG-PLGA, PPP). The injectability, gel formation ability, biocompatibility and sustained drug delivery properties of PPP hydrogel were verified in vitro and in vivo. The effects of GEM/PPP hydrogel on cell proliferation, invasion, metastasis, and apoptosis were explored through co-culturing with PANC-1 cells. The therapeutic effects of GEM/PPP hydrogel on xenograft mice were compared with those of GEM, ethanol and polidocanol using the precisely targeted EUS-FNI technology. Tumor sections were examined by H&E, Ki-67, and TUNEL staining. GEM/PPP hydrogel exhibited excellent injectability, biocompatibility, and the capability of sustained drug delivery for up to 7 days by forming a gel triggered by body temperature. It demonstrated the best therapeutic effects, significantly reducing proliferation, invasion and migration of PANC-1 cells while promoting apoptosis. After precise injection using EUS-FNI technology, GEM/PPP hydrogel resulted in a reduction of tumor weight by up to 75.96% and extending the survival period by 14.4 days with negligible adverse effects. Pathological examination revealed no systemic toxicity and significant apoptosis and minimal proliferation as well. The combination of GEM/PPP hydrogel and EUS-FNI technology provides an optimal approach of precise chemotherapy for pancreatic cancer, builds a bridge for clinical translation of basic research, and brings great hope for innovation of minimally invasive treatment modalities. The first-hand EUS image data obtained in this study also serves as a crucial reference for future clinical trials.

Early phase trial of intracystic injection of large surface area microparticle paclitaxel for treatment of mucinous pancreatic cysts.

Background and study aims Mucinous pancreatic cystic lesions (PCLs) have the potential for malignant transformation, for which the only accepted curative modality is surgery. A novel intracystic therapy with large surface area microparticle paclitaxel (LSAM-PTX) may treat PCLs without local or systemic toxicities. Safety and preliminary efficacy of LSAM-PTX for the treatment of PCLs administered by endoscopic ultrasound-guided fine-needle injection (EUS-FNI) was evaluated. Patients and methods Ten subjects with confirmed PCLs (size > 1.5 cm) received intracystic LSAM-PTX via EUS-FNI at volumes equal to those aspirated from the cyst in sequential cohorts at 6, 10, and 15 mg/mL in a standard "3 + 3" dose-escalation protocol. The highest dose with acceptable safety and tolerability was taken into the confirmatory phase where nine additional subjects received two injections of LSAM-PTX 12 weeks apart. Subjects were followed for 6 months after initial LSAM-PTX treatment for endpoints including: adverse events (AEs), tolerability, pharmacokinetic analysis of systemic paclitaxel drug levels, and change in cyst volume. Results Nineteen subjects completed the study. No dose-limiting toxicities, treatment-related serious AEs, or clinically significant laboratory changes were reported. Systemic paclitaxel concentrations did not exceed 3.5 ng/mL at any timepoint measured and fell below 1 ng/mL by Week 2, supporting the lack of systemic toxicity. By Week 24 a cyst volume reduction (10-78 %) was seen in 70.6 % of subjects. Conclusions Intracystic injection of LSAM-PTX into mucinous PCLs resulted in no significant AEs, a lack of systemic absorption, and resulted in reduction of cyst volume over a 6month period.

Evaluation of the feasibility of intrapancreatic delivery of drug-loaded microparticles via EUS-guided fine needle injection using a swine model.

Background and study aims Patients with pancreatic cancer often have locally advanced or metastatic disease and are not candidates for curative surgery. Polymer-based microparticles (MPs) represent a drug delivery system that offers sustained release of a chemotherapeutic drug after intralesional injection for local tumor management. The aim of this study was to determine the feasibility of endoscopic ultrasound-guided fine-needle injection (EUS-FNI) of drug-loaded MPs tagged with a fluorophore and fiducial markers for locating the injection site. Secondary aims were to determine the tissue-specific effects of MPs. Methods Five pigs underwent EUS with selection of an injection site within the pancreas that was marked by placing fiducial markers prior to the MPs injection. EUS-FNI of either blank microparticles (BMPs), containing no drug, or gemcitabine-loaded microparticles (GMPs) was performed. A saline flush containing Spot Endoscopic Marker was used to expel any residual MPs in the needle shaft and tattoo the injection site. Results A green fluorescent protein flashlight was used to successfully identify the site of MP injection sites in the dissected pancreas. Frozen sections of pig pancreas demonstrated a defined deposit, confirming the delivery of the MPs. Finally, fluorescence microscopy showed activation of caspase-mediated cell death in pancreases of animals that received injections of GMPs. Conclusions This pilot study demonstrated that fiducial marker placement and pancreatic EUS-FNI of MPs was successful in all pigs with no animals demonstrating pancreatitis. Further studies are needed to determine the role for intralesional injection of drug-loaded MPs in borderline resectable or unresectable pancreatic cancer.

Endoscopic Ultrasound-Guided Fine-Needle Injection of Hydrogen Peroxide into the Pancreas: Feasibility and Tolerability Study Using a Survival Porcine Model

Hydrogen peroxide (H2O2) has been reported to be an effective radiation sensitizer for various cancers. A combination therapy comprising fine-needle injection (FNI) of H2O2 under endoscopic ultrasound (EUS) guidance and chemoradiation might improve treatment outcomes of pancreatic cancer; however, there have been no reports thus far. The aims of this study were to evaluate the feasibility and safety of EUS-FNI of H2O2 into the pancreas using a porcine survival model. EUS-FNI was performed in the pancreas of six pigs, which were randomly divided into three groups based on the solution injected: group 1, 2 mL of sodium hyaluronate (control); group 2, 0.5 mL of H2O2; group 3, 2 mL of H2O2. To evaluate any adverse events, blood tests and computed tomography (CT) were performed before and after FNI, as well as days 3 and 7 subsequently. The pigs were necropsied on day 7. Histologic evaluation was performed according to the criteria for experimental acute pancreatitis. EUS-FNI was successful in all pigs. CT immediately after FNI revealed gas formation in the FNI area in groups 2 and 3. No adverse events were revealed by blood tests and CT. Histologic evaluations revealed pancreatitis scores of 5 and 5 in group 1, 7 and 7 in group 2 and 14 and 15 in group 3. EUS-FNI of H2O2 into the pancreas is feasible; however, it could cause pancreatitis. FNI of H2O2 into only the pancreatic tumor might be ideal in minimizing possible adverse events.

Local drug delivery to a human pancreatic tumor via a newly designed multiple injectable needle

Endoscopic ultrasound-guided fine needle injection (EUS-FNI) has been proposed as a novel technique for local delivery of antitumor agents to refractory tumors, including pancreatic cancer. However, the present outcome of this strategy remains insufficient, and further improvements as well as novel agents and injection devices are required. The aim of the study was to determine the feasibility of a newly designed 'multiple injectable needle' (MIN) for EUS-FNI and the resulting improvements in the drug distribution to the tumor in comparison with straight-type needles. Human pancreatic cancer BxPC-3 cells or orthotopic tumor were transplanted subcutaneously into athymic rats. Ethanol was injected into subcutaneous tumors using a MIN or straight-type needle. Sequential sections of subcutaneous tumors were stained with hematoxylin and eosin, and tumors and injury areas were quantified using ImageJ software. In the orthotopic tumors, injection of the outer needle of the MIN, advancement of the inner needle and ethanol infusion were monitored by EUS. Injury volume of subcutaneous tumors using a MIN was greater than that with the straight-type needles, except for large tumors. Injecting process using MIN was monitored with endoscopic ultrasound (EUS). This study showed improvement in the drug distribution in a tumor, following injection with MIN compared to straight-type needles, suggesting the novel device to be feasible for use in EUS-FNI.

CLINICAL EVALUATION OF DENDRITIC CELLS VACCINATION FOR ADVANCED CANCER PATIENTS AT FUKUSHIMA MEDICAL UNIVERSITY

Dendritic cells (DCs) are powerful antigen-presenting cells (APCs) that have attracted attention in recent years from the viewpoint of DC vaccine therapy against cancer. However, the existence of a strongly immunosuppressed state in cancer-bearing individuals inhibits DC maturation, which is one of the problems facing anti-cancer DC vaccine therapy. Isolated DCs loaded with tumor antigen ex vivo and administered as a cellular vaccine have been found to induce protective and therapeutic anti-tumor immunity in experimental animals. In clinical trials of DC vaccination for cancer patients, induction of anti-tumor immune responses and tumor regression has been observed. In this study, eighty-one advanced cancer patients unsuccessfully treated by established treatment in individual cases were selected between January 2002 and May 2007 at Fukushima Medical University. The usefulness of DC therapy was investigated by intradermal injection of peptide pulsed DCs for an overall objective response rate of 28.0%. Furthermore, direct injection of immature DCs into tumor extracted an overall objective response rate of 35.7%, and especially 40.0% for advanced pancreatic cancer by using endoscopic ultrasound-guided fine-needle injection technique as a novel approach. These results indicate that DC-based vaccination could be a promising treatment modality for various cancers, however multiple hurdles must be cleared before the development of an affordable DC-based vaccination can be used worldwide.

Signal transduction of vitamin K3 for pancreas cancer therapy

We characterized molecular mechanisms of vitamin K3 (VK3)-induced inhibition of proliferation to evaluate VK3 effectiveness in treating advanced pancreatic cancer. A novel endoscopic drug delivery system, ultrasound injection technique, was used to study local effects of VK3. VK3 inhibited pancreas cancer cell growth by rapid phosphorylation of growth factor receptor and cellular signal factors such as extracellular signal-regulated kinase. VK3 also activated apoptosis, and apoptosis inhibitor antagonized the apoptosis pathway without inhibiting cell growth. Thiol antioxidant treatment completely abrogated VK3-induced ERK but not JNK phosphorylation or inhibition of proliferation. Non-thiol antioxidant did not affect ERK phosphorylation or growth inhibitory actions. Arylation was considered the main mechanism of VK3-induced growth inhibition through ERK activation. VK3 may lead to favorable outcomes in the treatment of pancreatic tumors. Detection of ERK phosphorylation in tissue is important to predict VK3 effect. Endoscopic ultrasound-guided fine-needle injection may be beneficial for treating pancreatic cancer with VK3.

Signal transduction of vitamin K3 for pancreas cancer therapy

We characterized molecular mechanisms of vitamin K3 (VK3)-induced inhibition of proliferation to evaluate VK3 effectiveness in treating advanced pancreatic cancer. A novel endoscopic drug delivery system, ultrasound injection technique, was used to study local effects of VK3. VK3 inhibited pancreas cancer cell growth by rapid phosphorylation of growth factor receptor and cellular signal factors such as extracellular signal-regulated kinase. VK3 also activated apoptosis, and apoptosis inhibitor antagonized the apoptosis pathway without inhibiting cell growth. Thiol antioxidant treatment completely abrogated VK3-induced ERK but not JNK phosphorylation or inhibition of proliferation. Non-thiol antioxidant did not affect ERK phosphorylation or growth inhibitory actions. Arylation was considered the main mechanism of VK3-induced growth inhibition through ERK activation. VK3 may lead to favorable outcomes in the treatment of pancreatic tumors. Detection of ERK phosphorylation in tissue is important to predict VK3 effect. Endoscopic ultrasound-guided fine-needle injection may be beneficial for treating pancreatic cancer with VK3.

Phase I trial of preoperative intratumoral injection of immature dendritic cells and OK‐432 for resectable pancreatic cancer patients

To determine the feasibility, safety and histological change of preoperative endoscopic ultrasound-guided fine-needle injection (PEU-FNI) of immature DCs (iDCs) with OK-432 in pancreatic cancer patients. Nine patients enrolled in the trial (DC group) and were compared with 15 patients operated on without iDC injection (non-DC group). Adverse events of PEU-FNI and postoperative complications were evaluated according to CTC-AE ver.3.0 and the Clavien-Dindo classification/ISGPF definition, respectively. Histological changes within the tumor and lymph nodes were evaluated by immunohistochemical examination of infiltrating inflammatory cells (CD4+, CD8+, Foxp3+ and CD83+). There were no severe toxicities following PEU-FNI, except for one transient grade 3 fever, and there were no significant differences in the incidence of postoperative complications between the two groups. Colliquative necrosis and diffusely scattered TUNEL-positive cells were observed at the injection sites. CD83+ cells significantly accumulated in the regional lymph nodes of the DC group as well as Foxp3+ cells in the regional and distant lymph nodes. The two DC group patients, one of which was stage IV with distant lymph node metastasis, survived more than 5 years without requiring adjuvant theraphy. PEU-FNI was feasible and safe, and further study needs to confirm and enhance antitumor responses.

Signal transduction of vitamin K3 for pancreas cancer therapy

We characterized molecular mechanisms of vitamin K3 (VK3)-induced inhibition of proliferation to evaluate VK3 effectiveness in treating advanced pancreatic cancer. A novel endoscopic drug delivery system, ultrasound injection technique, was used to study local effects of VK3. VK3 inhibited pancreas cancer cell growth by rapid phosphorylation of growth factor receptor and cellular signal factors such as extracellular signal-regulated kinase. VK3 also activated apoptosis, and apoptosis inhibitor antagonized the apoptosis pathway without inhibiting cell growth. Thiol antioxidant treatment completely abrogated VK3-induced ERK but not JNK phosphorylation or inhibition of proliferation. Non-thiol antioxidant did not affect ERK phosphorylation or growth inhibitory actions. Arylation was considered the main mechanism of VK3-induced growth inhibition through ERK activation. VK3 may lead to favorable outcomes in the treatment of pancreatic tumors. Detection of ERK phosphorylation in tissue is important to predict VK3 effect. Endoscopic ultrasound-guided fine-needle injection may be beneficial for treating pancreatic cancer with VK3.

A Combination Therapy of Gemcitabine With Immunotherapy for Patients With Inoperable Locally Advanced Pancreatic Cancer

Dendritic cell (DC) therapy frequently induces a measurable immune response. However clinical responses are seen in a minority of patients, presumably due to insufficient expansion of antigen-specific cytotoxic T lymphocytes (CTLs) capable of eradicating tumor cells. To increase therapeutic efficacy of DC-based vaccination, we have undertaken the first clinical trial involving a combination therapy of gemcitabine (GEM) with immunotherapy for patients with inoperable locally advanced pancreatic cancer. Patients (n = 5) received the treatment course, which consisted of intravenous GEM administration at 1000 mg/m (day 1) and the endoscopic ultrasound-guided fine-needle injection of OK432-pulsed DCs into a tumor, followed by intravenous infusion of lymphokine-activated killer cells stimulated with anti-CD3 monoclonal antibody (CD3-LAKs) (day 4), at 2-week intervals. No serious treatment-related adverse events were observed during the study period. Three of the 5 patients demonstrated effective responses to this clinical trial; 1 had partial remission and 2 had long stable disease more than 6 months. In the patient with partial remission, it has been shown that DC-based vaccination combined with GEM administration induces tumor antigen-specific CTLs. This combined therapy was considered to be synergistically effective and may have a role in the therapy of pancreatic cancer for inducing tumor antigen-specific CTLs.

Endoscopic ultrasound guided fine needle injection (EUS-FNI) of nanoliposomes loaded with Curcumin and si-RNA into porcine pancreas

Endoscopic ultrasound guided fine needle injection (EUS-FNI) of nanoliposomes loaded with Curcumin and si-RNA into porcine pancreas

Review: Endoscopic ultrasound-guided fine needle injection for cancer therapy: The evolving role of therapeutic endoscopic ultrasound

Endoscopic ultrasound (EUS) is central to the diagnosis and staging of many malignancies, but now has an evolving role in cancer therapy. EUS-guided fine needle injection (FNI) is already used for palliative interventions such as treatment of pain through nerve blockade and to guide biliary decompression when conventional ERCP is not possible. More recently, EUS-FNI has been used to deliver specific anti-tumor agents for pancreatic cyst ablation and local control of tumor growth in patients with unresectable solid malignancies. The agents used to date include ethanol, brachytherapy seeds, and chemotherapeutic agents such as paclitaxel. In addition, FNI of new immunomodulating cell cultures such as mixed lymphocyte and dendritic cell cultures has also been reported, as has FNI of several different viral vectors for antitumor therapy. Although experience with these agents remains preliminary, EUS-FNI is a minimally invasive approach to deliver local antitumor agents, and is likely to have an expanding role in cancer therapy.

The Safety and Feasibility of Endoscopic Ultrasound Guided Fine Needle Injection (EUS-FNI) of Local Biologic Anti-Tumor Agents (BAA) in Patients with Advanced Pancreatic Carcinoma (APC)

Background: Despite numerous trials evaluating a variety of chemotherapeutic agents, the prognosis of pancreatic cancer remains poor. The recent development of BAA has lead to the possibility of augmenting these treatments. EUS-FNI allows for the local delivery of a variety of antitumor therapies, including BAA, in the treatment of APC. Aim: The purpose of this study was to determine the safety and feasibility of using EUS-FNI for delivering BAA in patients with APC. Methods: We retrospectively identified all patients at our institution from 5/95 to 11/07 receiving EUS-FNI with BAA for the treatment of APC.

Combined treatment with immunotherapy and chemotherapy using endoscopic ultrasonography guided injection for locally advanced pancreatic carcinoma

13503 Background: Dendritic cells (DCs) play a pivotal role in T cell-mediated immunity. Usually, mature DCs were cultured using resected tumor tissue, but for inoperable cases, this method is impractical. The injection of immature DCs into the tumor after appropriate chemotherapy is reasonable, if DCs come to maturity capturing the specific cancer antigen . The aim of this study is to assess the toxicity and efficacy of combined treatment with immunotherapy and chemotherapy for locally advanced pancreatic carcinoma. Methods: Five patients with pathologically confirmed pancreatic ductal carcinoma using EUS-FNA were enrolled, median age 56 years (range, 46–70 years). All cases without distant metastasis were diagnosed as surgically unresectable . Patients underwent leukapheresis, immature DCs were prepared from peripheral blood by a culture with granulocyte macrophage colony-stimulating factor and interleukin 4. Lymphokine-activated killer (LAK) were also prepared from peripheral blood. Immature DCs were injected biweekly in the mass by endoscopic ultrasound-guided fine needle injection (EUS-FNI), LAK were administered intravenously. Patients received the treatment of gemcitabine 1000 mg / m2 by intravenous injection 3 days before the immunotherapy. One course with 6 times combined therapy was continued until the judgment of progressive diseases (PD) was given. The toxicity and efficacy of this treatment were assessed. We also assessed whether tumor associated antigen (TAA)-specific IFN-?producing cells increase after treatment. Results: Hematological toxicity occurred in one case, leucopenia of grade 2. No severe toxicities of grade 3 to 4 occurred. One had a partial response (PR), stable disease (SD) was observed in 2 patients for more than 6 months (long-term SD). PR patient could undergo curative operation after this therapy. The number of TAA-specific IFN-?producing cells in PR patient increased 12-fold higher than that seen before treatments. Conclusions: These results support the safety and efficacy of combined treatment with immunotherapy and chemotherapy for locally advanced pancreatic ductal carcinoma. This treatment may be a useful for the treatment of pancreatic ductal carcinoma. No significant financial relationships to disclose.

Endoscopic Ultrasound-Guided Fine Needle Injection of Immature Dendritic Cells into Advanced Pancreatic Carcinoma Refractory to Gemcitabine: A Pilot Study

Background and Aim: Immunotherapy against cancer has been investigated using different type of immune cells and the crucial role of dendritic cells (DCs) for the induction of primary T-cell-dependent immune responses was established. Intratumorally injected immature DCs would acquire and process tumor antigens in situ, migrate to regional lymphoid organs, and initiate a significant tumor specific immune response. The aim of this pilot study is to determine the feasibility, safety and clinical response of endoscopic ultrasound (EUS)-guided fine needle injection (FNI) of immature DC into the pancreatic cancer that had progressed to a metastatic disease after repeated systemic administration of gemcitabine D. Patients and Methods: Six patients with unresectable pancreatic cancer that had been unsuccessfully treated with gemcitabine were enrolled: all 6 patients in stage IVb with multiple liver metastasis, in whom 2 with malignant ascites. Immature DCs were generated from peripheral monocytes of patients with granulocyte-macrophage-colony stimulating factor and interleukin-4. Patients received intratumoral injection of 10 billion or more immature DC at 2-3 sites using EUS-guided FNI. Physical and laboratory examinations were performed to assess potential vaccine toxicity. Clinical endpoints included CA 19-9, tumor response and survival. Results: All DC injections were well tolerated without any clinical toxicity. The level of CA19-9 was decreased in 3 patients, mixed responses was observed in 3 (2 with malignant ascites) and the median survival of patients was 8 months. Conclusion: Direct injection of immature DC into the pancreatic tumor resulted in the generation of a potent antitumor immune response as evidenced by decreased CA19-9 levels and prolonged survival. Therefore intratumoral DC injection is a viable alternative to peripheral DC vaccination therapy for unresectable pancreatic cancer.

Recombinant toxin DAB389EGF is cytotoxic to human pancreatic cancer cells

Few malignancies have frustrated the persistent efforts of the oncologist like pancreatic cancer. Pancreatic cancer is usually unresectable at the time of diagnosis because of metastasis or local extension. Despite the aggressive nature of this deadly disease, systemic treatment options are limited. Even the recent introduction of the deoxycytidine analogue gemcitabine does not extend median survival of responders beyond a year. Clearly, alternative, more effective regimens are needed for treating pancreatic carcinoma. In pancreatic cancer, there is overexpression of growth factors and growth factor receptors, including epidermal growth factor receptor (EGFR). Targeted toxins consist of a targeting polypeptide covalently linked to a peptide toxin. DAB389EGF is a fusion protein composed of the catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor (EGF). The authors have previously shown that DAB389EGF is selectively toxic to EGFR-overexpressing cells, including human brain tumour and lung carcinoma cell lines. Pancreatic adenocarcinoma should be responsive to this fusion protein based on its EGFR overexpression. However, the cytotoxic effect of DAB389EGF on human pancreatic carcinoma cell lines has yet to be explored. The authors describe preliminary data showing the potent cytotoxicity of DAB389EGF to human pancreatic carcinoma cell lines. Because of the nonspecific toxicity to liver and kidney (which possess EGFR) of systemic administration, they also propose a potential novel drug delivery system for direct toxin implantation into pancreatic tumours using endoscopic ultrasound guided fine-needle injection (EUS-FNI). Hopefully, the use of these targeted therapeutic approaches in combination with other modalities may further extend survival and quality of life in patients with pancreatic adenocarcinoma.