Journal Articles

TAA/TSA-based approaches

Cancer vaccines based on tumor-associated (TAA) or tumor-specific (TSA) antigens derived from germline genes, oncogenic viruses or endogenous retroviruses

PRAME peptide-specific CD8(+) T cells represent the predominant response against leukemia-associated antigens (LAAs) in healthy individuals

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Antigen-specific T cells isolated from healthy individuals (HIs) have shown great therapeutic potential upon adoptive transfer for the treatment of viremia in immunosuppressed patients. The lack of comprehensive data on the prevalence and characteristics of leukemia associated antigen (LAA)-specific T cells in HIs still limits such an approach for tumor therapy. Therefore, we have investigated T cell responses against prominent candidates comprising WT1, PRAME, Survivin, NY-ESO and p53 by screening PBMCs from HIs using intracellular IFN-gamma staining following provocation with LAA peptide mixes. Here, we found predominantly poly-functional effector/effector memory CCR7(-) /CD45RA(+/-) /CD8(+) LAA peptide-specific T cells with varying CD95 expression in 34 of 100 tested HIs, whereas CD4(+) T cells responses were restricted to 5. Most frequent LAA peptide-specific T cell responses were directed against WT1 and PRAME peptides with a prevalence of 20% and 17%, respectively, showing the highest magnitude (0.16% +/- 0.22% (mean+/-SD)) for PRAME peptides. Cytotoxicity of PRAME peptide-specific T cells was demonstrated by specific killing of PRAME peptide-pulsed T2 cells. Furthermore, the proliferative capacity of PRAME peptide-specific T cells was confined to HIs responsive towards PRAME peptide challenge corroborating the accuracy of the screening results. In conclusion, we identified PRAME as a promising target antigen for adoptive leukemia therapy. This article is protected by copyright. All rights reserved.

Author Info: (1) Experimental Transfusion Medicine, Medical Faculty Carl Gustav Carus, TU Dresden, Germany. Institute for Transfusion Medicine Dresden, German Red Cross Blood Donation Service North-East, Dresden

Author Info: (1) Experimental Transfusion Medicine, Medical Faculty Carl Gustav Carus, TU Dresden, Germany. Institute for Transfusion Medicine Dresden, German Red Cross Blood Donation Service North-East, Dresden, Germany. (2) Experimental Transfusion Medicine, Medical Faculty Carl Gustav Carus, TU Dresden, Germany. Institute for Transfusion Medicine Dresden, German Red Cross Blood Donation Service North-East, Dresden, Germany. (3) Center for Regenerative Therapies Dresden (CRTD), Dresden, Germany. (4) German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), Dresden, Germany. Center for Regenerative Therapies Dresden (CRTD), Dresden, Germany. Institute of Immunology, Medical Faculty, TU Dresden, Dresden, Germany. National Center for Tumor Diseases, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany. (5) German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), Dresden, Germany. Center for Regenerative Therapies Dresden (CRTD), Dresden, Germany. Department of Medicine 1, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany. National Center for Tumor Diseases, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany. (6) Experimental Transfusion Medicine, Medical Faculty Carl Gustav Carus, TU Dresden, Germany. Institute for Transfusion Medicine Dresden, German Red Cross Blood Donation Service North-East, Dresden, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), Dresden, Germany. Center for Regenerative Therapies Dresden (CRTD), Dresden, Germany. (7) Experimental Transfusion Medicine, Medical Faculty Carl Gustav Carus, TU Dresden, Germany. Institute for Transfusion Medicine Dresden, German Red Cross Blood Donation Service North-East, Dresden, Germany.

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Morphological changes induced by Intraprostatic PSA-based vaccine in prostate Cancer biopsies (phase I clinical trial)

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Immunotherapy is a novel treatment for many tumors including prostate cancer. Little is known about the histological changes in prostate biopsies caused by the prostatic-specific antigen (PSA)-based vaccine. This study evaluated the histopathological effects in prostate biopsies of recombinant fowlpox (rF) virus-based vaccine engineered to present the PSA and three costimulatory molecules (collectively labeled as PSA-TRICOM). This vaccine has shown that it can break tolerance of the PSA, and its administration directly into a tumor enables the affected tumor cells to act as antigen-presenting cells activating new T-cells, and broadening the immune response to recognize and kill tumor. We studied 10 patients with recurrent prostate cancer who had failed radiation therapy and/or androgen-deprivation therapy. Pre- and post-treatment biopsies were compared. Post-treatment biopsies induced 8 cases with residual adenocarcinoma despite evidences treatment effect and inflammation, two cases did not show any residual tumor; and only one case did not have any inflammatory infiltrate or any evidenced treatment effect. The inflammatory infiltrate varied from mild to severe, and was composed of mononuclear cells. Greater numbers amount of infiltrating CD8+ lymphocytes were identified around prostatic glands and within the epithelial lining. The most remarkable feature was the presence of increased eosinophils around the glands and stroma. Three cases showed areas of necrosis surrounded by lymphocytes and palisading epithelioid macrophages arranged in granuloma-like pattern with multinucleated giant cells. This description of l these morphological changes induced by the PSA-TRICOM will help to interpret the results of future intratumoral vaccine therapy trials.

Author Info: (1) Translational Surgical Pathology, Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD. Electronic address: mjmerino@mail.nih.gov. (2) Urologic Oncology Branch, CCR, NCI, NIH, Bethesda, MD. (3)

Author Info: (1) Translational Surgical Pathology, Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD. Electronic address: mjmerino@mail.nih.gov. (2) Urologic Oncology Branch, CCR, NCI, NIH, Bethesda, MD. (3) Translational Surgical Pathology, Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD. (4) Translational Surgical Pathology, Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD. (5) Laboratory of Tumor Immunology and Biology, CCR, NCI, NIH, Bethesda, MD. (6) Laboratory of Tumor Immunology and Biology, CCR, NCI, NIH, Bethesda, MD.

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Developing Anti-HER2 Vaccines: Breast Cancer Experience

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Breast cancer accounts for more than one million new cases annually and is the leading cause of death in women globally. HER2 overexpression induces cellular and humoral immune responses against the HER2 protein and is associated with higher tumour proliferation rates. Trastuzumab-based therapies are effectively and widely used as standard of care in HER2-amplified/overexpressed breast cancer patients; one cited mechanism of action is the induction of passive immunity and antibody-dependent cellular cytotoxicity against malignant breast cancer cells. These findings drove the efforts to generate antigen-specific immunotherapy to trigger the patient's immune system to target HER2-overexpressing tumour cells, which led to the development of various vaccines against the HER2 antigen. This manuscript discusses the various anti-HER2 vaccine formulations and strategies and their potential role in the metastatic and adjuvant settings. This article is protected by copyright. All rights reserved.

Author Info: (1) Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Breast Medical Oncology, The University of

Author Info: (1) Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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Expression of KK-LC-1, a cancer/testis antigen, at non-tumour sites of the stomach carrying a tumour

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Kita-Kyushu lung cancer antigen-1 (KK-LC-1) is a cancer/testis antigen (CTA) and predominant target for cancer immunotherapy. Our previous study indicated that KK-LC-1 was expressed in 82% of gastric cancers, and also in 79% of early stage of gastric cancers, with a correlation to Helicobacter pylori (H. pylori) infection. In addition, we found that KK-LC-1 was occasionally expressed at non-tumour sites of stomachs carrying tumours. Here, we investigated the characteristics of KK-LC-1 expression at non-tumour sites and the clinical utility of these phenomena. The gene expression of KK-LC-1 was detected at the non-tumour sites including pyloric glands. The most detectable corpus/gland subset had a KK-LC-1 expression rate of 77% in the pyloric gland of the lower corpus where H. pylori preferentially exists. KK-LC-1 expression rates were 67% or 32% with or without intestinal metaplasia, which also induced by H. pylori, respectively. Consequently, KK-LC-1 would be detected at the pre-cancerous condition of the stomach, and may be a useful marker to predict gastric cancer.

Author Info: (1) Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Japan. fukuyam@insti.kitasato-u.ac.jp. (2) Department of Surgery, Sagamihara National Hospital, Sagamihara, Japan. (3) Division of Biomedical

Author Info: (1) Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Japan. fukuyam@insti.kitasato-u.ac.jp. (2) Department of Surgery, Sagamihara National Hospital, Sagamihara, Japan. (3) Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Japan. (4) Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Japan. (5) Second Department of Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan. (6) Department of Surgery, School of Medicine, Kitasato University, Sagamihara, Japan. (7) Department of Surgery, School of Medicine, Kitasato University, Sagamihara, Japan. Division of Surgery, Kitasato University Medical Center, Kitamoto, Japan. (8) Division of Surgery, Kitasato University Medical Center, Kitamoto, Japan. (9) Department of Surgery, School of Medicine, Kitasato University, Sagamihara, Japan. Division of Surgery, Kitasato University Medical Center, Kitamoto, Japan. (10) Division of Gastroenterology, Kitasato University Medical Center, Kitamoto, Japan. (11) Division of Pathology, Kitasato University Medical Center, Kitamoto, Japan. (12) Department of Gastroenterology, School of Medicine, Kitasato University, Sagamihara, Japan. (13) Moji Hospital, Kitakyushu, Japan. (14) Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Japan.

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Feasibility and Immune Response of WT1 Peptide Vaccination in Combination with OK-432 for Paediatric Solid Tumors

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BACKGROUND/AIM: Wilms' tumor 1 (WT1) peptide-based vaccination has been reported for its potential usefulness in targeting several cancers. The adjuvant drug OK-432 is known to have potent immunomodulation and therapeutic properties when applied in cancer treatment and may, thus, be important to trigger the appropriate immunological response in paediatric patients with a solid tumor that are vaccinated with a WT1 peptide. PATIENTS AND METHODS: Paediatric patients with a solid tumor were vaccinated with a WT1 peptide and OK-432 once every 2 weeks, for a total of seven times. RESULTS: Of the 24 patients, 18 completed the scheduled vaccinations. Sixteen patients had local skin symptoms and/or fever. In 1 patient, anaphylactic symptoms emerged at the time of the final injection, but these quickly subsided after the treatment. WT1-specific immunological responses were observed in 4 patients (22.2%). WT1 and HLA class I expression were confirmed in 100% and 85% of primary tumors, respectively. CONCLUSION: WT1 peptide vaccine therapy combined with OK-432 appears to be relatively safe for children. However further studies in a larger number of patients are necessary to confirm its safety and efficacy.

Author Info: (1) Center for Advanced Cell Therapy, Shinshu University Hospital, Nagano, Japan. Department of Paediatrics, Shinshu University School of Medicine, Nagano, Japan. (2) Center for Advanced

Author Info: (1) Center for Advanced Cell Therapy, Shinshu University Hospital, Nagano, Japan. Department of Paediatrics, Shinshu University School of Medicine, Nagano, Japan. (2) Center for Advanced Cell Therapy, Shinshu University Hospital, Nagano, Japan ryu@shinshu-u.ac.jp. Department of Paediatrics, Shinshu University School of Medicine, Nagano, Japan. (3) Center for Advanced Cell Therapy, Shinshu University Hospital, Nagano, Japan. Department of Paediatrics, Shinshu University School of Medicine, Nagano, Japan. (4) Center for Advanced Cell Therapy, Shinshu University Hospital, Nagano, Japan. (5) Department of Regenerative Medicine, Kanazawa Medical University, Ishikawa, Japan. (6) Department of Laboratory Medicine, Shinshu University Hospital, Nagano, Japan. (7) Department of Gastroenterology and Hepatology, The Jikei University School of Medicine, Chiba, Japan. (8) Department of Advanced Immunotherapeutics, Osaka University Graduate School of Pharmaceutical Sciences, Osaka, Japan. (9) Department of Functional Diagnostic Science, Graduate School of Medicine, Osaka University, Osaka, Japan. (10) Department of Paediatrics, Shinshu University School of Medicine, Nagano, Japan. (11) Department of Regenerative Medicine, Kanazawa Medical University, Ishikawa, Japan.

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WT1-pulsed Dendritic Cell Vaccine Combined with Chemotherapy for Resected Pancreatic Cancer in a Phase I Study

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BACKGROUND/AIM: Wilms' tumor 1 (WT1) is a tumor-associated antigen highly expressed in cancer. We examined the safety of WT1-peptide pulsed dendritic cell (WT1-DC) vaccine in combination with chemotherapy in patients with surgically resected pancreatic cancer. PATIENTS AND METHODS: Eight patients with resectable pancreatic cancer undergoing surgery either combined with S-1 or S-1 plus gemcitabine therapy were enrolled. Immunohistochemical analysis of WT1 was performed in 34 cases of pancreatic cancer. RESULTS: No serious side-effects were observed, except grade I fever in five and grade I reactions at the injection site in all patients. WT1-specific cytotoxic T-lymphocytes were detected in seven patients, and WT1 and human leukocyte antigen class I antigens were positive in all 34 cases. CONCLUSION: Our study clarified the safety and potential acquisition of immunity after vaccination targeting WT1. Further efficacy of WT1-DC vaccine to improve prognosis would be determined by a prospective clinical trial for resectable pancreatic cancer.

Author Info: (1) Center for Advanced Cell Therapy, Shinshu University Hospital, Matsumoto, Japan ryu@shinshu-u.ac.jp. (2) Shinshu Cancer Center, Shinshu University Hospital, Matsumoto, Japan. (3) Department of Regenerative

Author Info: (1) Center for Advanced Cell Therapy, Shinshu University Hospital, Matsumoto, Japan ryu@shinshu-u.ac.jp. (2) Shinshu Cancer Center, Shinshu University Hospital, Matsumoto, Japan. (3) Department of Regenerative Medicine, Kanazawa Medical University, Ishikawa, Japan. (4) Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan. (5) Department of Gastroenterology and Hepatology, The Jikei University School of Medicine, Kashiwa, Japan. (6) Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Sakamoto, Japan. (7) Department of Advanced Immunotherapeutics, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Japan. (8) Department of Advanced Immunotherapeutics, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Japan. (9) Department of Functional Diagnostic Science, Graduate School of Medicine, Osaka University, Suita, Japan. (10) Department of Regenerative Medicine, Kanazawa Medical University, Ishikawa, Japan.

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A phase I/Ib study of OTSGC-A24 combined peptide vaccine in advanced gastric cancer

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BACKGROUND: We conducted a phase I/Ib, open-label, single-arm trial to assess the safety, tolerability and optimal scheduling regimen of OTSGC-A24 cancer vaccine in patients with advanced gastric cancer. METHODS: Patients with advanced gastric cancer with HLA-A*24:02 haplotype were included in this study. OTSGC-A24 was administered at 1 mg in 3-weekly (3w), 2-weekly (2w), and weekly (1w) cohorts to evaluate the safety, immunological response and schedule. Based on the highest specific cytotoxic T lymphocyte (CTL) induction rate at 4 weeks, using the ELISPOT test, cohorts were expanded to define the optimal dosing schedule for OTSGC-A24. RESULTS: In this study, 24 advanced gastric cancer patients with HLA-A*24:02 haplotype were enrolled and treated in 3 cohorts (3w cohort: 3; 2w cohort: 11 and 1w cohort: 10 patients). The most common adverse events were decreased appetite (29%), diarrhea (21%), myalgia (25%). The most common treatment-related adverse event was injection site erythema (25%). No dose-limiting toxicities were observed in any cohort and OTSGC-A24 was well tolerated. Positive CTL responses after vaccination were observed in 15 patients (75%) at 4 weeks: 3w cohort (33%), 2w cohort (88%), 1w cohort (78%). At 12 weeks, 18 patients had responded (90%); 3w cohort (100%), 2w cohort (100%), 1w cohort (78%). The best radiological was stable disease (40%). Median progression free survival was 1.7 months (95% CI: 1.4 to 3.5) and median overall survival was 5.7 months (95% CI 3.8 to 8.6). CONCLUSIONS: OTSGC-A24 combined peptide cancer vaccine was well tolerated. Significant responses in CTL were observed and the recommended phase 2 dose is 1 mg OTSGC-A24 sub-cutaneous, every 2 weeks. Although no radiological response was observed, a respectable overall survival was achieved, consistent with other immunotherapy agents being investigated in gastric cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01227772 , Date registered: 21 Oct 2010.

Author Info: (1) Department of Haematology-Oncology, National University Health System, 5 Lower Kent Ridge Road, Main Building Level 2, Singapore, S119074, Singapore. (2) Yonsei Cancer Center, Seoul

Author Info: (1) Department of Haematology-Oncology, National University Health System, 5 Lower Kent Ridge Road, Main Building Level 2, Singapore, S119074, Singapore. (2) Yonsei Cancer Center, Seoul, South Korea. (3) Wakayama Medical University Hospital, Wakayama, Japan. (4) Wakayama Medical University Hospital, Wakayama, Japan. (5) Cancer Science Institute, National University of Singapore, Singapore, Singapore. Department of Gastrointestinal Tract Surgery, Fukushima Medical University, Fukushima, Japan. (6) Yonsei Cancer Center, Seoul, South Korea. (7) Yonsei Cancer Center, Seoul, South Korea. (8) Department of Gastrointestinal Tract Surgery, Fukushima Medical University, Fukushima, Japan. Department of Advanced Cancer Immunotherapy, Fukushima Medical University, Fukushima, Japan. Department of Progressive DOHaD Research, Fukushima Medical University, Fukushima, Japan. (9) Cancer Science Institute, National University of Singapore, Singapore, Singapore. (10) Department of Haematology-Oncology, National University Health System, 5 Lower Kent Ridge Road, Main Building Level 2, Singapore, S119074, Singapore. wei_peng_yong@nuhs.edu.sg. Cancer Science Institute, National University of Singapore, Singapore, Singapore. wei_peng_yong@nuhs.edu.sg.

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Phase Ib trial of folate binding protein (FBP)-derived peptide vaccines, E39 and an attenuated version, E39': An analysis of safety and immune response

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In this randomized phase Ib trial, we tested combining the E39 peptide vaccine with a vaccine created from E39', an attenuated version of E39. Patients with breast or ovarian cancer, who were disease-free after standard of care therapy, were enrolled and randomized to one of three arms. Arm EE received six E39 inoculations; arm EE' received three E39 inoculations followed by three E39'; and arm E'E received three E39' inoculations, followed by three E39. Within each arm, the first five patients received 500mug of peptide and the remainder received 1000mug. Patients were followed for toxicity, and immune responses were measured. This initial analysis after completion of the primary vaccination series has confirmed the safety of both vaccines. Immune analyses suggest incorporating the attenuated version of the peptide improves immune responses and that sequencing of E39 followed by E39' might produce the optimal immune response. TRIAL REGISTRATION: NCT02019524.

Author Info: (1) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1484, Houston, TX 77030, United States. Electronic address

Author Info: (1) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1484, Houston, TX 77030, United States. Electronic address: tjvreeland@mdanderson.org. (2) Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1155 Pressler St, Unit 1354, Houston, TX 77030, United States. Electronic address: jlitton@mdanderson.org. (3) Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1434, Houston, TX 77030, United States. Electronic address: nqiao@mdanderson.org. (4) Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1434, Houston, TX 77030, United States. Electronic address: avphilips@mdanderson.org. (5) Department of Stem Cell Transplantation and Cellular Therapy, The University of MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 423, Houston, TX 77030, United States. Electronic address: galatras@mdanderson.org. (6) Department of Surgery, San Antonio Military Medical Center, 3551 Roger Brooke Dr, San Antonio, TX 78234, United States. Electronic address: diane.f.hale.mil@mail.mil. (7) Department of Surgery, San Antonio Military Medical Center, 3551 Roger Brooke Dr, San Antonio, TX 78234, United States. Electronic address: Doreen.o.jackson.mil@mail.mil. (8) Department of Surgery, San Antonio Military Medical Center, 3551 Roger Brooke Dr, San Antonio, TX 78234, United States. Electronic address: Kaitlin.m.peace.mil@mail.mil. (9) Department of Surgery, San Antonio Military Medical Center, 3551 Roger Brooke Dr, San Antonio, TX 78234, United States. Electronic address: Julia.m.greene.mil@mail.mil. (10) Department of Surgery, Womack Army Medical Center, 2817 Reilly Rd, Fort Bragg, NC 28310, United States. Electronic address: john.s.berry.mil@mail.mil. (11) Department of Surgery, San Antonio Military Medical Center, 3551 Roger Brooke Dr, San Antonio, TX 78234, United States. Electronic address: Guy.t.clifton.mil@mail.mil. (12) Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814, United States. (13) Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1434, Houston, TX 77030, United States. Electronic address: emittendorf@bwh.harvard.edu.

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Activity of Mesothelin-specific Chimeric Antigen Receptor T cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial

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Pancreatic ductal adenocarcinoma (PDAC) is resistant to T-cell mediated immunotherapy. We engineered T cells to transiently express an mRNA encoding a chimeric antigen receptor (CAR) specific for mesothelin-a protein that is over-expressed by PDAC cells. We performed a phase 1 study to evaluate the safety and efficacy of adoptive cell therapy with autologous mesothelin-specific CAR T cells (CARTmeso cells) in 6 patients with chemotherapy-refractory metastatic PDAC. Patients were given intravenous CARTmeso cells 3 times weekly for 3 weeks. None of the patients developed cytokine release syndrome or neurologic symptoms and there were no dose limiting toxicities. Disease stabilized in 2 patients, with progression-free survival times of 3.8 and 5.4 months. We used FDG-positron emission tomography/computed tomography imaging to monitor the metabolic active volume (MAV) of individual tumor lesions. The total MAV remained stable in 3 patients and decreased by 69.2% in 1 patient with biopsy-proven mesothelin expression; in this patient, all liver lesions had a complete reduction in FDG uptake at 1 month compared to baseline, although there was no effect on the primary PDAC. Transient CAR expression was detected in patients' blood after infusion and led to expansion of new immunoglobulin G proteins. Our results provide evidence for the potential anti-tumor activity of mRNA CARTmeso cells, as well as PDAC resistance to the immune response.

Author Info: (1) Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Electronic

Author Info: (1) Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Electronic address: gregory.beatty@uphs.upenn.edu. (2) Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. (3) Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA. (4) Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. (5) Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA. (6) Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA. (7) Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA. (8) Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. (9) Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA. (10) Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA. (11) Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA. (12) Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA. (13) Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA. (14) Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA. (15) Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

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Engineered T lymphocytes eliminate lung metastases in models of pancreatic cancer

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Pancreatic cancer is known as one of the most lethal cancers in the world. A majority of advanced stage pancreatic cancer patients are diagnosed with distant metastasis and given poor prognoses, calling for a better therapeutic option. Mesothelin, which is overexpressed in pancreatic cancer and other solid tumors, is a potential target for pancreatic cancer immunotherapy. Adoptive transfer of T cells engineered with chimeric antigen receptors (CART cells) was effective for treating CD19-positive leukemia, but it is more difficult for CART cells to eliminate solid tumors. Because distal metastasis is an important malignant behavior of solid tumors, we investigated whether meso-CART cells exert anti-tumor effects against distant metastases. After expressing meso-CAR in human primary T lymphocytes, the resultant meso-CART cells released cytokines in response to and exhibited cytolytic effects on mesothelin-positive tumor cells in vitro. Injection of meso-CART cells into tumor-bearing mice moderately delayed subcutaneous tumor growth and eliminated lung metastases. This is the first study to show that meso-CART cells are effective against lung metastases induced by intravenous injection of pancreatic tumor cells. Our results suggest that meso-CART cells may be an effective clinical treatment for mesothelin-positive primary and metastatic tumors in pancreatic cancer patients.

Author Info: (1) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. (2) Department of

Author Info: (1) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. (2) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. (3) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. (4) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. (5) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. (6) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. (7) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. (8) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. (9) Beijing Vitalstar Biotechnology Co., Ltd., Beijing, China. (10) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. (11) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China. (12) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.

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