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

An Anti-CLL-1 Antibody-Drug Conjugate for the Treatment of Acute Myeloid Leukemia

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PURPOSE: The treatment of acute myeloid leukemia (AML) has not significantly changed in 40 years. Cytarabine and anthracyclinebased chemotherapy induction regimens (7 + 3) remain the standard of care, and most patients have poor long-term survival. The re-approval of Mylotarg, an anti-CD33-calicheamicin antibody-drug conjugate (ADC), has demonstrated ADCs as a clinically validated option to enhance the effectiveness of induction therapy. We are interested in developing a next generation ADC for AML to improve upon the initial success of Mylotarg. EXPERIMENTAL DESIGN: The expression pattern of CLL-1 and its hematopoietic potential were investigated. A novel anti-CLL-1-ADC, with a highly potent pyrrolobenzodiazepine (PBD) dimer conjugated through a self-immolative disulfide linker, was developed. The efficacy and safety profiles of this ADC were evaluated in mouse xenograft models and in cynomolgus monkeys. RESULTS: We demonstrate that CLL-1 shares similar prevalence and trafficking properties that make CD33 an excellent ADC target for AML, but lacks expression on hematopoietic stem cells that hampers current CD33 targeted ADCs. Our anti-CLL-1-ADC is highly effective at depleting tumor cells in AML xenograft models and lacks target independent toxicities at doses that depleted target monocytes and neutrophils in cynomolgus monkeys. CONCLUSIONS: Collectively, our data suggest that an anti-CLL-1-ADC has the potential to become an effective and safer treatment for AML in humans, by reducing and allowing for faster recovery from initial cytopenias than the current generation of ADCs for AML.

Author Info: (1) Translational Oncology & Cancer Signaling, Genentech Inc. (2) Translational Oncology, Genentech, Inc. (3) In Vivo Pharmacology, Genentech. (4) Research and Early Development, Genentech, Inc

Author Info: (1) Translational Oncology & Cancer Signaling, Genentech Inc. (2) Translational Oncology, Genentech, Inc. (3) In Vivo Pharmacology, Genentech. (4) Research and Early Development, Genentech, Inc. (5) Translational Oncology, Genentech, Inc. (6) Research and Early Development, Genentech, Inc. (7) Research and Early Development, Genentech, Inc. (8) Antibody Engineering, Genentech, Inc. (9) Antibody Engineering, Genentech, Inc. (10) Pathology, Genentech. (11) Genentech, Inc. (12) Safety Assessment, Genentech, Inc. (13) Research and Early Development, Genentech, Inc. (14) Safety Assessment, Amgen, Inc. (15) Oncology Clinical Science, Genentech Inc. (16) Genentech, Inc. (17) Safety Assessment, Genentech. (18) Genentech, Inc. (19) Research and Early Development, Genentech, Inc. polson@gene.com.

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TLS11a Aptamer/CD3 Antibody Anti-Tumor System for Liver Cancer

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New therapeutic approaches are needed for hepatocellular carcinoma (HCC), which is the most common primary malignancy of the liver. Bispecific T-cell engagers (BiTE) can effectively redirect T cells against tumors and show a strong anti-tumor effect. However, the potential immunogenicity, complexity, and high cost significantly limit their clinical application. In this paper, we used the hepatoma cells-specific aptamer TLS11a and anti-CD3 for to establish an aptamer/antibody bispecific system (AAbs), TLS11a/CD3, which showed advantages over BiTE and can specifically redirect T cells to lyse tumor cells. TLS11a-SH and anti-CD3-NH2 were crosslinked with sulfosuccinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (sulfo-SMCC). T cell activation, proliferation, and cytotoxicity of TLS11a/CD3 were analyzed by flow cytometry. Cytokine array was used to detect cytokine released from activated T cells. Hepatoma xenograft model was used to monitor the tumor volume and survival. TLS11a/CD3 could specifically bind hepatoma cells (H22) and T cells, activated T cells to mediate antigen-specific lysis of H22 cells in vitro, and effectively inhibited the growth of implanted H22 tumors as well as prolonged mice survival. TLS11a/CD3 could simultaneously target hepatoma cells and T cells, specifically guide T cells to kill tumor cells, and enhance the anti-tumor effect of T cells both in vitro and in vivo.

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13)

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13)

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Survival analysis of multiple peptide vaccination for the selection of correlated peptides in urological cancers

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Peptide-based cancer vaccines are able to induce strong immune responses, but their clinical results are unsatisfactory. To determine clinically correlated peptides, we analyzed survival data from urological cancer patients treated by personalized peptide vaccination (PPV), in which different multiple peptides were used for individual patients based on human leukocyte antigen (HLA) type and pre-existing immunity. Survival data were obtained from a database of 265 urological cancer patients treated in 5 clinical PPV trials comprising 154 patients with castration-resistant prostate cancer (CRPC) and 111 patients with advanced urothelial cancer (UC). The expression of tumor-associated antigens (TAAs) was evaluated in 10 prostate cancer tissues, 4 metastatic lymph nodes from prostate cancer and 10 UC tissues using immunohistochemical staining. The clinical efficacy of individual peptides for overall survival was evaluated by the Cox proportional hazards regression model. All TAAs coding candidate peptides used in PPV treatment were expressed in tumor cells from prostate cancer and UC samples except for p56Lck in both, and PSA, PAP and PSMA in the UC samples. Patients with the following peptides had a significantly longer survival than patients without the peptides (Hazard ratio < 1.0, 95% confidence intervals < 1.0 and P < 0.05): SART3-109, PTHrP-102, HNPRL-140, SART3-302 and Lck-90 in CRPC patients, and EGF-R-800, Lck-486, PSMA-624, CypB-129 and SART3-734 in advanced UC patients, respectively. Correlated peptides selected using both survival data and pre-existing immunity for PPV treatment may enhance the clinical benefits for urological cancer patients. This article is protected by copyright. All rights reserved.

Author Info: (1) Cancer Vaccine Center. (2) Cancer Vaccine Center. (3) Department of Pathology. (4) Department of Urology. (5) Cancer Vaccine Center. (6) Division of Cancer Vaccines

Author Info: (1) Cancer Vaccine Center. (2) Cancer Vaccine Center. (3) Department of Pathology. (4) Department of Urology. (5) Cancer Vaccine Center. (6) Division of Cancer Vaccines in Research Center for Innovative Cancer Therapy. (7) Cancer Vaccine Center. (8) Bio-statistics Center, Kurume University School of Medicine, Kurume, Japan. (9) Cancer Vaccine Center.

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Cancer testis antigens as immunogenic and oncogenic targets in breast cancer

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Breast cancer cells frequently express tumor-associated antigens that can elicit immune responses to eradicate cancer. Cancer-testis antigens (CTAs) are a group of tumor-associated antigens that might serve as ideal targets for cancer immunotherapy because of their cancer-restricted expression and robust immunogenicity. Previous clinical studies reported that CTAs are associated with negative hormonal status, aggressive tumor behavior and poor survival. Furthermore, experimental studies have shown the ability of CTAs to induce both cellular and humoral immune responses. They also demonstrated the implication of CTAs in promoting cancer cell growth, inhibiting apoptosis and inducing cancer cell invasion and migration. In the current review, we attempt to address the immunogenic and oncogenic potential of CTAs and their current utilization in therapeutic interventions for breast cancer.

Author Info: (1) Department of Physical Therapy, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA. Department of Pathology, South Egypt Cancer

Author Info: (1) Department of Physical Therapy, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA. Department of Pathology, South Egypt Cancer Institute, Assiut University, Assiut 71111, Egypt.

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Massive expression of germ cell-specific genes is a hallmark of cancer and a potential target for novel treatment development

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Cancer cells have been found to frequently express genes that are normally restricted to the testis, often referred to as cancer/testis (CT) antigens or genes. Because germ cell-specific antigens are not recognized as "self" by the innate immune system, CT-genes have previously been suggested as ideal candidate targets for cancer therapy. The use of CT-genes in cancer therapy has thus far been unsuccessful, most likely because their identification has relied on gene expression in whole testis, including the testicular somatic cells, precluding the detection of true germ cell-specific genes. By comparing the transcriptomes of micro-dissected germ cell subtypes, representing the main developmental stages of human spermatogenesis, with the publicly accessible transcriptomes of 2617 samples from 49 different healthy somatic tissues and 9232 samples from 33 tumor types, we here discover hundreds of true germ cell-specific cancer expressed genes. Strikingly, we found these germ cell cancer genes (GC-genes) to be widely expressed in all analyzed tumors. Many GC-genes appeared to be involved in processes that are likely to actively promote tumor viability, proliferation and metastasis. Targeting these true GC-genes thus has the potential to inhibit tumor growth with infertility being the only possible side effect. Moreover, we identified a subset of GC-genes that are not expressed in spermatogonial stem cells. Targeting of this GC-gene subset is predicted to only lead to temporary infertility, as untargeted spermatogonial stem cells can recover spermatogenesis after treatment. Our GC-gene dataset enables improved understanding of tumor biology and provides multiple novel targets for cancer treatment.

Author Info: (1) Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. (2) Department of Oncogenomics, Academic

Author Info: (1) Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. (2) Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. (3) Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. (4) Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. (5) Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. g.hamer@amc.uva.nl.

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MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial

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BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 mug MAGE-A3 antigen plus 420 mug CpG 7909 reconstituted in AS01B to a total volume of 0.5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28.0 months [IQR 23.3-35.5] in the MAGE-A3 group and 28.1 months [23.7-36.9] in the placebo group. Median disease-free survival was 11.0 months (95% CI 10.0-11.9) in the MAGE-A3 group and 11.2 months (8.6-14.1) in the placebo group (hazard ratio [HR] 1.01, 0.88-1.17, p=0.86). In the GS-positive population, median disease-free survival was 9.9 months (95% CI 5.7-17.6) in the MAGE-A3 group and 11.6 months (5.6-22.3) in the placebo group (HR 1.11, 0.83-1.49, p=0.48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment. INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.

Author Info: (1) Department of Dermatooncology, Hotel Dieu Nantes University Hospital, Nantes, France. (2) Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. (3) Queensland Melanoma

Author Info: (1) Department of Dermatooncology, Hotel Dieu Nantes University Hospital, Nantes, France. (2) Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. (3) Queensland Melanoma Project, Discipline of Surgery, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia. (4) Melanoma Sarcoma Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. (5) Service d'Oncologie Medicale, Hopital Francois Mitterrand, Pau, France. (6) Skin Cancer Center Hannover, Department of Dermatology, Hannover Medical School, Hannover, Germany. (7) Petrov Research Institute of Oncology, St Petersburg, Russia. (8) Department of Soft Tissue, Bone Sarcoma, and Melanoma, Maria Sklodowska-Curie Institute, Oncology Center, Warsaw, Poland. (9) Department of Dermatology and Skin Cancers, La Timone APHM Hospital, Aix-Marseille University, Marseille, France. (10) Department of Skin and Soft Tissue Tumours, National Cancer Institute, Kiev, Ukraine. (11) Swissmed Centrum Zdrowia, Gdansk, Poland; Department of Surgical Oncology, Gdansk Medical University, Gdansk, Poland. (12) Dermatology Department, Hopital Robert Debre, Universite de Reims Champagne-Ardenne, Reims, France. (13) Department of Dermatology, Centre Hospitalier Universitaire, Tours, France; UFR de Medecine, Universite Francois-Rabelais, Tours, France. (14) Melanoma Immunology and Oncology Group, Centenary Institute, University of Sydney, Sydney, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia. (15) Dermato-oncology Department, General University Hospital, Prague, Czech Republic. (16) Columbus Clinic Center, Milan, Italy. (17) Division of Hematology & Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. (18) Departement de Dermatologie, Centre Hospitalier Universitaire, Hopital Saint-Eloi, Montpellier, France. (19) Department of Medical Oncology, Erasmus MC Cancer institute, Rotterdam, Netherlands. (20) Cancer Research Center, Moscow, Russia. (21) Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Seattle Cancer Care Alliance, University of Washington, Seattle, WA, USA. (22) Department of Oncology and Medical Radiology, Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine. (23) Centrum Medyczne Bienkowski, Klinika Chirurgii Plastycznej, Bydgoszcz, Poland; Department of Oncological Surgery, Oncology Center, Bydgoszcz, Poland. (24) Melanoma Unit, Dermatology Department, Hospital Clinic of Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain; Centro de Investigacion Biomedica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain. (25) Instituto de Oncologia Angel H Roffo, Universidad de Buenos Aires, Buenos Aires, Argentina. (26) Department of Dermatology, Venereology, and Allergology, University Hospital Schleswig-Holstein, Kiel, Germany. (27) Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands. (28) Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands. (29) GlaxoSmithKline, Rixensart, Belgium. Electronic address: fernando.x.ulloa-montoya@GSK.com. (30) GlaxoSmithKline, Rixensart, Belgium. (31) GlaxoSmithKline, Rixensart, Belgium; Immunology Translational Medicine, UCB, Brussels, Belgium. (32) GlaxoSmithKline, Rixensart, Belgium; Biostatistics Department, Janssen Research & Development, Beerse, Belgium. (33) GlaxoSmithKline, Rixensart, Belgium. (34) GlaxoSmithKline, Rixensart, Belgium; ViaNova Biosciences, Brussels, Belgium. (35) GlaxoSmithKline, Rixensart, Belgium. (36) GlaxoSmithKline, Rixensart, Belgium; Laboratoires Servier, Paris, France. (37) GlaxoSmithKline, Rixensart, Belgium; University Hospitals Leuven, Leuven, Belgium. (38) UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

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Spontaneous T-cell responses against the immune check point programmed-death-ligand 1 (PD-L1) in patients with chronic myeloproliferative neoplasms correlate with disease stage and clinical response

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The Chronic Myeloproliferative Neoplasms (MPN) are cancers characterized by hyperinflammation and immune deregulation. Concurrently, the expression of the immune check point programmed death ligand 1 (PD-L1) is induced by inflammation. In this study we report on the occurrence of spontaneous T cell responses against a PD-L1 derived epitope in patients with MPN. We show that 71% of patients display a significant immune response against PD-L1, and patients with advanced MPN have significantly fewer and weaker PD-L1 specific immune responses compared to patients with non-advanced MPN. The PD-L1 specific T cell responses are CD4(+) T cell responses, and by gene expression analysis we show that expression of PD-L1 is enhanced in patients with MPN. This could imply that the tumor specific immune response in MPN could be enhanced by vaccination with PD-L1 derived epitopes by boosting the anti-regulatory immune response hereby allowing tumor specific T cell to exert anti-tumor immunity.

Author Info: (1) Department of Hematology, Zealand University Hospital, Roskilde, Denmark. Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark. (2)

Author Info: (1) Department of Hematology, Zealand University Hospital, Roskilde, Denmark. Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark. (2) Department of Hematology, Rigshospitalet, Copenhagen, Denmark. (3) Department of Hematology, Zealand University Hospital, Roskilde, Denmark. (4) Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark. Department of Oncology, Copenhagen University, Herlev, Denmark. (5) Department of Hematology, Zealand University Hospital, Roskilde, Denmark. (6) Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark. Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.

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HER2-Based Immunotherapy for Breast Cancer

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Resistance to therapies and disease recurrences after surgery or treatment are common challenges in breast cancer management in clinic. Active immunotherapy using human epidermal growth factor receptor 2 (HER2)-targeted vaccines represents an attractive option in combating breast cancer. Different HER2-derived vaccines have been developed over the years. Many clinical trials have been carried out in evaluating HER2-based vaccines. The authors reviewed current literature on HER2-based vaccines in clinical trials. The trials covered in this mini-review represent some of the major trials published in the past 20 years regarding the clinical use and test of HER2 vaccines. Their focus is on trials using HER2 peptide vaccines as the majority of clinical trials initiated or published used HER2 peptide-based vaccines. Findings from combination therapy trials of HER2 peptide vaccines with other treatment modalities are also presented.

Author Info: (1) 1 Department of Breast Surgery, Affiliated Hospital of Hebei University , Baoding, China . (2) 2 Central Laboratory, Hebei Laboratory of Mechanism and Procedure

Author Info: (1) 1 Department of Breast Surgery, Affiliated Hospital of Hebei University , Baoding, China . (2) 2 Central Laboratory, Hebei Laboratory of Mechanism and Procedure of Cancer Radiotherapy and Chemotherapy, Affiliated Hospital of Hebei University , Baoding, China . (3) 3 Breast Medical Oncology, The University of Texas MD Anderson Cancer Center , Houston, Texas.

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Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1c259T cells in Synovial Sarcoma

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In a phase 1/2 clinical trial, 12 patients with metastatic synovial sarcoma were treated with autologous T cells engineered to express an affinity-enhanced TCR recognizing a NY-ESO-1 derived peptide. Six of 12 patients responded (1 CR, 5 PR). The NY-ESO-1c259 T cells expanded significantly in responding patients, persisted long-term, remained polyfunctional, and were enriched in central memory and stem cell memory phenotypes. TCR sequencing revealed the presence of a broad initial and persisting TCR repertoire derived from multiple phenotypes, and raised questions regarding a T cell model based on hierarchical, linear differentiation.

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In a phase 1/2 clinical trial, 12 patients with metastatic synovial sarcoma were treated with autologous T cells engineered to express an affinity-enhanced TCR recognizing a NY-ESO-1 derived peptide. Six of 12 patients responded (1 CR, 5 PR). The NY-ESO-1c259 T cells expanded significantly in responding patients, persisted long-term, remained polyfunctional, and were enriched in central memory and stem cell memory phenotypes. TCR sequencing revealed the presence of a broad initial and persisting TCR repertoire derived from multiple phenotypes, and raised questions regarding a T cell model based on hierarchical, linear differentiation.

We evaluated safety and activity of autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T cell receptor (TCR) recognizing an HLA-A2-restricted NY-ESO-1/LAGE-1a-derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1c259 T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1c259 T cells were present post-infusion in all patients and persisted for at least 6 months in all responders. Most infused NY-ESO-1c259 T cells exhibited an effector memory phenotype following the ex vivo expansion, but the persisting pools comprised largely central memory and stem cell memory subsets, which remained polyfunctional and showed no evidence for T cell exhaustion despite persistent tumor burdens. Next generation sequencing of endogenous TCRs in CD8+ NY-ESO-1c259 T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1c259 T cells produced a continuing supply of effector cells to mediate sustained, clinically meaningful antitumor effects.

Author Info: (1) Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College dangelos@mskcc.org. (2) Adaptimmune (United Kingdom). (3) NIH. (4) Pediatric Oncology

Author Info: (1) Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College dangelos@mskcc.org. (2) Adaptimmune (United Kingdom). (3) NIH. (4) Pediatric Oncology Branch, National Cancer Institute. (5) Pediatric Oncology Branch, National Institutes of Health. (6) Tumor Microenvironment and Metastasis Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute. (7) Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania. (8) Department of Medicine, Memorial Sloan Kettering Cancer Center. (9) Adaptimmune (United Kingdom). (10) Adaptimmune (United Kingdom). (11) Adaptimmune (United Kingdom). (12) Translational Sciences, Adaptimmune (United Kingdom). (13) Adaptimmune. (14) Adaptimmune (United Kingdom). (15) Adaptimmune. (16) Immunology, Adaptimmune (United Kingdom). (17) Adaptimmune (United Kingdom). (18) Biomarkers and Companion Diagnostic, Adaptimmune (United Kingdom). (19) NIH. (20) Parker Institute for Cancer Immunotherapy. (21) Clinical Development, Adaptimmune (United Kingdom). (22) Adaptimmune (United Kingdom). (23) Adaptimmune (United Kingdom). (24) Clinical, Adaptimmune (United Kingdom). (25) Clinical Development, Adaptimmune (United Kingdom). (26) Clinical Development, Adaptimmune (United Kingdom). (27) Stanford Cancer Institute and Department of Pediatrics, Stanford University.

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Latest developments in MUC1 immunotherapy

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Currently, there is renewed interest in attempting to recruit the host immune system to eliminate cancers, and within this renewed activity, MUC1 continues to arouse interest. MUC1 has been considered a possible therapeutic target for the past 30 years as it is up-regulated, aberrantly glycosylated and its polarization is lost in many adenocarcinomas. Moreover, MUC1 is expressed by some haematopoietic cancers, including acute myeloid leukaemia and myeloma. Although multiple clinical trials have been initiated and immune responses have been documented, effective clinical benefit worthy of approval for general application has not as yet been achieved. However, this does not appear to have quelled the interest in MUC1 as a therapeutic target, as shown by the increase in the number of MUC1-based clinical trials initiated in 2017 ( Figure 1). As with all translational studies, incorporating new relevant research findings into therapeutic strategy is difficult. Decisions are made to commit to a specific strategy based on the information and data available when the trial is initiated. However, the time required for preclinical studies and early trials can render the founding concept not always appropriate for proceeding to a larger definitive trial. Here, we summarize the attempts made, to date, to bring MUC1 into the world of cancer immunotherapy and discuss how research findings regarding MUC1 structure and function together with expanded knowledge of its interactions with the tumour environment and immune effector cells could lead to improved therapeutic approaches.

Author Info: (1) Breast Cancer Biology Lab, School of Cancer and Pharmaceutical Sciences, King's College London, London, U.K. joyce.taylor-papadimitriou@kcl.ac.uk. (2) Breast Cancer Biology Lab, School of Cancer

Author Info: (1) Breast Cancer Biology Lab, School of Cancer and Pharmaceutical Sciences, King's College London, London, U.K. joyce.taylor-papadimitriou@kcl.ac.uk. (2) Breast Cancer Biology Lab, School of Cancer and Pharmaceutical Sciences, King's College London, London, U.K. (3) Breast Cancer Biology Lab, School of Cancer and Pharmaceutical Sciences, King's College London, London, U.K. (4) Breast Cancer Biology Lab, School of Cancer and Pharmaceutical Sciences, King's College London, London, U.K.

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