31 results on '"Bot, Adrian"'
Search Results
2. A Critical Role for Fas-Mediated Off-Target Tumor Killing in T-cell Immunotherapy.
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Upadhyay R, Boiarsky JA, Pantsulaia G, Svensson-Arvelund J, Lin MJ, Wroblewska A, Bhalla S, Scholler N, Bot A, Rossi JM, Sadek N, Parekh S, Lagana A, Baccarini A, Merad M, Brown BD, and Brody JD
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- Animals, Antigens, Neoplasm immunology, Bystander Effect immunology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, CRISPR-Cas Systems, Disease Models, Animal, Gene Editing, Genetic Engineering, Humans, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods, Mice, Mice, Knockout, Neoplasms etiology, Neoplasms therapy, Receptors, Chimeric Antigen, T-Cell Antigen Receptor Specificity, Treatment Outcome, Xenograft Model Antitumor Assays, Cytotoxicity, Immunologic, Immunotherapy adverse effects, Immunotherapy methods, T-Lymphocytes immunology, T-Lymphocytes metabolism, fas Receptor metabolism
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T cell-based therapies have induced cancer remissions, though most tumors ultimately progress, reflecting inherent or acquired resistance including antigen escape. Better understanding of how T cells eliminate tumors will help decipher resistance mechanisms. We used a CRISPR/Cas9 screen and identified a necessary role for Fas-FasL in antigen-specific T-cell killing. We also found that Fas-FasL mediated off-target "bystander" killing of antigen-negative tumor cells. This localized bystander cytotoxicity enhanced clearance of antigen-heterogeneous tumors in vivo , a finding that has not been shown previously. Fas-mediated on-target and bystander killing was reproduced in chimeric antigen receptor (CAR-T) and bispecific antibody T-cell models and was augmented by inhibiting regulators of Fas signaling. Tumoral FAS expression alone predicted survival of CAR-T-treated patients in a large clinical trial (NCT02348216). These data suggest strategies to prevent immune escape by targeting both the antigen expression of most tumor cells and the geography of antigen-loss variants. SIGNIFICANCE: This study demonstrates the first report of in vivo Fas-dependent bystander killing of antigen-negative tumors by T cells, a phenomenon that may be contributing to the high response rates of antigen-directed immunotherapies despite tumoral heterogeneity. Small molecules that target the Fas pathway may potentiate this mechanism to prevent cancer relapse. This article is highlighted in the In This Issue feature, p. 521 ., (©2020 American Association for Cancer Research.)
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- 2021
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3. Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop.
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Bedognetti D, Ceccarelli M, Galluzzi L, Lu R, Palucka K, Samayoa J, Spranger S, Warren S, Wong KK, Ziv E, Chowell D, Coussens LM, De Carvalho DD, DeNardo DG, Galon J, Kaufman HL, Kirchhoff T, Lotze MT, Luke JJ, Minn AJ, Politi K, Shultz LD, Simon R, Thórsson V, Weidhaas JB, Ascierto ML, Ascierto PA, Barnes JM, Barsan V, Bommareddy PK, Bot A, Church SE, Ciliberto G, De Maria A, Draganov D, Ho WS, McGee HM, Monette A, Murphy JF, Nisticò P, Park W, Patel M, Quigley M, Radvanyi L, Raftopoulos H, Rudqvist NP, Snyder A, Sweis RF, Valpione S, Zappasodi R, Butterfield LH, Disis ML, Fox BA, Cesano A, and Marincola FM
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- Advisory Committees, Animals, Biomarkers, Tumor genetics, Biomarkers, Tumor immunology, Congresses as Topic, Disease Models, Animal, Humans, Medical Oncology organization & administration, Neoplasms genetics, Neoplasms immunology, Societies, Medical organization & administration, Treatment Outcome, Tumor Microenvironment genetics, Immunotherapy, Neoplasms therapy, Tumor Microenvironment immunology
- Abstract
Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host's response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14-15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual's recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4-5, 2019.
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- 2019
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4. In this issue: Role of immune cells and molecules in rheumatoid arthritis pathogenesis and cancer immunotherapy.
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Kumar H and Bot A
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- Animals, Humans, Immunity, Humoral, Neoplasms immunology, Signal Transduction, Arthritis, Rheumatoid immunology, Immunity, Cellular, Immunotherapy methods, Neoplasms therapy
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- 2018
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5. In this issue: Cancer immunity and immunotherapy.
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Kumar H and Bot A
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- Humans, Neoplasms diagnosis, Neoplasms metabolism, Immunity, Immunotherapy methods, Neoplasms immunology, Neoplasms therapy
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- 2017
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6. In this issue: Role of immune cells, immune modulating factors and immunotoxins in cancer immunotherapy.
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Kumar H and Bot A
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- Animals, Antigens, Neoplasm immunology, Humans, Immunity, Maternally-Acquired, Immunologic Surveillance, Molecular Targeted Therapy, Neoplasms immunology, Thyroid Hormones metabolism, Immune System, Immunologic Factors, Immunotherapy methods, Immunotoxins, Neoplasms therapy
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- 2017
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7. New Cancer Immunotherapy Agents in Development: a report from an associated program of the 31 st Annual Meeting of the Society for Immunotherapy of Cancer, 2016.
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Adusumilli PS, Cha E, Cornfeld M, Davis T, Diab A, Dubensky TW Jr, Evans E, Grogan JL, Irving BA, Leidner RS, Olwill SA, Soon-Shiong P, Triebel F, Tuck D, Bot A, Dansey RD, Drake CG, Freeman GJ, Ibrahim R, Patel S, and Chen DS
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- Cancer Vaccines immunology, Humans, Neoplasms immunology, Tumor Microenvironment drug effects, Cancer Vaccines therapeutic use, Immunotherapy, Neoplasms drug therapy, Tumor Microenvironment immunology
- Abstract
This report is a summary of 'New Cancer Immunotherapy Agents in Development' program, which took place in association with the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), on November 9, 2016 in National Harbor, Maryland. Presenters gave brief overviews of emerging clinical and pre-clinical immune-based agents and combinations, before participating in an extended panel discussion with multidisciplinary leaders, including members of the FDA, leading academic institutions and industrial drug developers, to consider topics relevant to the future of cancer immunotherapy.
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- 2017
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8. In this issue: Antibodies in pathogenesis and management of diseases.
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Kumar H and Bot A
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- Animals, Antibodies therapeutic use, Autoimmune Diseases therapy, B-Cell Activating Factor immunology, Complement System Proteins metabolism, Humans, Immunity, Humoral, Infections therapy, Phagocytosis, Rhinitis, Allergic, Seasonal therapy, Tumor Necrosis Factor Ligand Superfamily Member 13 immunology, Antibodies immunology, Autoimmune Diseases immunology, Immunotherapy methods, Infections immunology, Rhinitis, Allergic, Seasonal immunology
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- 2017
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9. In This Issue: Translational Opportunities for Antibodies: Therapeutics, Biomarkers, and Novel Targets.
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Bot A and Kumar H
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- Humans, Antibodies, Monoclonal therapeutic use, Biomarkers analysis, Immunotherapy methods
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- 2016
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10. Editorial: in this issue.
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Bot A
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- Animals, Autoimmune Diseases genetics, Humans, Antibodies therapeutic use, Autoimmune Diseases immunology, Autophagy immunology, Immunotherapy
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In this issue, we are hosting several reviews on topics of broad interests, such as therapeutic or prophylactic antibodies, and the role of autophagy in autoimmunity.
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- 2015
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11. Editorial: international reviews of immunology.
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Internati MC, Mirandola L, and Bot A
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- Animals, Antigens, Neoplasm immunology, Autoantigens immunology, Autoimmunity, Cytotoxicity, Immunologic, Humans, Neoplasms immunology, Tumor Escape, Tumor Microenvironment, Cancer Vaccines, Immunotherapy trends, Neoplasms therapy, T-Lymphocytes physiology
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- 2014
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12. Repositioning therapeutic cancer vaccines in the dawning era of potent immune interventions.
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Bot A, Marincola F, and Smith KA
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- Humans, Cancer Vaccines isolation & purification, Cancer Vaccines therapeutic use, Immunotherapy methods, Neoplasms therapy
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Based on lessons learned with various immune interventions, this review aims to provide a constructive framework for repositioning therapeutic cancer vaccination. Intensive research throughout the past decade has identified key hurdles interfering with the efficacy of cancer vaccines. The vaccination concept still holds promise if positioned appropriately in minimal residual disease and select early disease stage cancer indications. However, in advanced cancer, it must be integrated with complementary immune interventions to ensure reconstruction of a functional immune repertoire and simultaneous blockade of immune inhibiting mechanisms. Vaccination could render complex and integrative immune interventions simpler, safer and more effective. The near future will witness an explosion of activities in the cancer immunotherapy arena, witnessing a rational repositioning of vaccines rather than their extinction.
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- 2013
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13. JTM's Tumor immunology goes broad: announcing the Immunobiology and Immunotherapy section.
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Bot A, Marincola F, and Romero P
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- Humans, Neoplasms therapy, Immunotherapy, Neoplasms immunology, Publishing
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For the last four years the Journal of Translational Medicine (JTM) has hosted the Section of Tumor Immunology and Biological Cancer Therapy. Under the editorial leadership of Dr. Pedro Romero and with the direct support of the Society for Immunotherapy of Cancer (SITC), this section enriched the communication between basic immunological sciences and the clinical investigation arena in oncology. We are re-launching this Section of JTM, now entitled Immunobiology and Immunotherapy, succeeding Tumor Immunology and Biological Cancer Therapy. While aiming to build on the editorial success and focus of its predecessor, this novel Section will have a broader scope, hosting translational immunology topics pertaining to immunotherapy beyond oncology, including disciplines such as inflammation, autoimmunity, transplantation, metabolic disorders and others. As the vision of this re-launched Section of JTM broadens up to serve a communication need for translational immunologists involved with immunotherapy irrespectively of the therapeutic area, a novel and focused journal entitled Journal for Immunotherapy of Cancer (JITC) has just been initiated, sponsored by the SITC.
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- 2013
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14. In this issue: Nef, a lingering problem; are there better immunoglobulins for human use; and Takayasu arteritis, still a mystery.
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Bot A
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- Animals, Humans, Immunoglobulins therapeutic use, Immunotherapy methods, Takayasu Arteritis immunology, nef Gene Products, Human Immunodeficiency Virus immunology
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The current issue of the International Reviews of Immunology brings the latest in three different areas of basic and clinical immunology. First, there is the lingering question of residual HIV-related pathology in patients on chronic antiretroviral therapy. The specific role of Nef in the macrophage-mediated disease manifested through lymphoma, metabolic disease and neurological disorder, is extensively discussed. A second topic is a clinical immunology one, a critical perspective on the efficacy and safety profile of various preparations of immunoglobulin products currently prescribed for a range of immunodeficiencies. Surprisingly, the authors showed that while the available preparations are equivalent from efficacy standpoint, they differ from the standpoint of toxicity. The third subject is again, in the arena of clinical immunology and deals with a relatively rare yet extremely puzzling disease -Takayasu arteritis -with a pathogenesis that needs elucidation and a dire need for better treatments. The authors provide a state of the art in terms of genetic association, other factors possibly involved in the onset and progression of this unusual inflammatory disease of large arteries, and provide a perspective on current standard of care and potential usefulness of TNF-α blockade as therapy for Takayasu arteritis.
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- 2012
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15. A novel series of conferences tackling the hurdles confronting the translation of novel cancer immunotherapies.
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Bot A, Ahn M, Bosch M, Brockstedt D, Butterfield LH, Cornforth A, Harrop R, Kast WM, Koya R, Marincola F, Margolin K, McCoy C, Pawelec G, Rothman J, Ramirez-Montagut T, Schlom J, Srivastava P, Wallis S, Walter S, Wang E, and Waslif J
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- Biomarkers, Tumor metabolism, Cancer Vaccines immunology, Clinical Trials as Topic, Hematopoietic Stem Cells, Humans, Monitoring, Immunologic, Neoplastic Stem Cells pathology, Stem Cell Transplantation, Congresses as Topic, Immunotherapy, Neoplasms immunology, Neoplasms therapy, Translational Research, Biomedical
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While there has been significant progress in advancing novel immune therapies to the bedside, much more needs to be done to fully tap into the potential of the immune system. It has become increasingly clear that besides practical and operational challenges, the heterogeneity of cancer and the limited efficacy profile of current immunotherapy platforms are the two main hurdles. Nevertheless, the promising clinical data of several approaches point to a roadmap that carries the promise to significantly advance cancer immunotherapy. A new annual series sponsored by Arrowhead Publishers and Conferences aims at bringing together scientific and business leadership from academia and industry, to identify, share and discuss most current priorities in research and translation of novel immune interventions. This Editorial provides highlights of the first event held earlier this year and outlines the focus of the second meeting to be held in 2013 that will be dedicated to stem cells and immunotherapy.
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- 2012
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16. In this issue: harnessing immunity against difficult targets, through the CD40-CD40L pathway.
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Kornbluth RS and Bot A
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- Adaptive Immunity, Animals, Antigen Presentation, B-Lymphocytes immunology, Humans, Immunity, Innate, Infections drug therapy, Molecular Targeted Therapy, Neoplasms drug therapy, Receptor Cross-Talk, Signal Transduction immunology, Translational Research, Biomedical, CD40 Antigens immunology, CD40 Ligand immunology, Immunotherapy, Infections immunology, Neoplasms immunology
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This issue highlights translational aspects related to the CD40-CD40L pathway, a veritable master-switch at the interface between the innate and adaptive immunity. From direct targeting of CD40 onto tumor cells to licensing professional antigen presenting cells (APC), and from in vivo activation of immune effectors to enabling adoptive cell immune interventions, this pathway already shows translational promise in oncology and infectious diseases. In light of the pivotal nature and versatility of the target, the authors discuss a diverse range of options to design and advance novel, safe and effective immune interventions or combinatorial therapies involving CD40 agonistic engagement.
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- 2012
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17. In this issue: targeting Human Papilloma Virus-associated disease, from cervical to head and neck carcinoma…and more.
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Chiriva-Internati M, Kast WM, and Bot A
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- Animals, Autoimmune Diseases immunology, Carcinoma etiology, Carcinoma pathology, Head and Neck Neoplasms etiology, Head and Neck Neoplasms pathology, Humans, Papillomavirus Infections complications, Papillomavirus Vaccines, Autoimmune Diseases therapy, Carcinoma immunology, Complementary Therapies, Head and Neck Neoplasms immunology, Immunotherapy, Papillomavirus Infections immunology, Severe Combined Immunodeficiency immunology
- Abstract
This issue of the International Reviews of Immunology hosts a diverse range of topics, ranging from cancer immunotherapy, to severe combined immunodeficiency syndromes in man and alternative treatments for autoimmunity. The emphasis of the issue is on cervical and head and neck carcinoma, significantly related to Human Papilloma Viruses. While the development of anti-HPV prophylactic vaccines represents one of the most remarkable triumphs of modern medicine, there is much more to be done in terms of advancing safe and effective treatments for cervical and head-and-neck cancers. We also host a review on congenital severe combined immunodeficiencies, a field that allowed unprecedented insight into the connection between the immune system, microbes, autoimmunity and cancer. Last but not least, we host a review dedicated to critically analyzing alternative treatments for Inflammatory Bowel Disease, as adjuncts to conventional therapies, based on solid scientific evidence and complementary mechanism of action., (Copyright © Informa Healthcare USA, Inc.)
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- 2012
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18. A phase 1 study of a vaccine targeting preferentially expressed antigen in melanoma and prostate-specific membrane antigen in patients with advanced solid tumors.
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Weber JS, Vogelzang NJ, Ernstoff MS, Goodman OB, Cranmer LD, Marshall JL, Miles S, Rosario D, Diamond DC, Qiu Z, Obrocea M, and Bot A
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- Aged, Aged, 80 and over, Cytokines blood, Female, Humans, Male, Middle Aged, Treatment Outcome, Antigens, Neoplasm immunology, Antigens, Surface immunology, Cancer Vaccines, Glutamate Carboxypeptidase II immunology, Immunotherapy methods, Neoplasms immunology, Neoplasms therapy
- Abstract
Preferentially expressed antigen in melanoma (PRAME) and prostate-specific membrane antigen (PSMA) are tumor-associated antigens implicated in cellular differentiation, genetic stability, and angiogenesis. MKC1106-PP is an immunotherapeutic regimen cotargeting PRAME and PSMA, comprised of a recombinant plasmid (pPRA-PSM encoding fragments derived from both antigens) and 2 peptides (E-PRA and E-PSM derived from PRAME and PSMA, respectively). This multicenter study evaluated MKC1106-PP with a fixed plasmid dose and 2 different peptide doses, administered by intralymph node injection in a prime-boost sequence in human leukocyte antigen-A*0201 and tumor-antigen-positive patients with progressing metastatic solid tumors who had failed standard therapy. Immune monitoring was done by tetramer and enzymatic-linked immune spot analysis. The treatment was well tolerated, with no significant differences in safety, immune response, and clinical outcome relative to peptide doses. Fifteen of 24 evaluable patients showed an immune response, as defined by the expansion of PRAME-specific or PSMA-specific T cells in the blood. There were no partial or complete responses by the Response Evaluation Criteria in Solid Tumors. Seven patients showed stable disease (SD) for 6 months or longer, or prostate specific antigen decline: 4 of 10 with prostate carcinoma, 2 of 2 with renal clear cell carcinoma, and 1 of 10 with metastatic melanoma. In addition, there was an association between the induction and persistence of antigen-specific T cells in blood above baseline levels and disease control, defined as SD for 6 months or longer. These results support further development of MKC1106-PP in specific clinical indications.
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- 2011
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19. The role of T regulatory (Treg) cells in cancer immunity; management of HIV-associated inflammation; and characterization of the homing pathways undertaken by mesenchymal stromal cells. Editorial.
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Bot A
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- Animals, Cell Movement, Clinical Trials as Topic, HIV Enteropathy microbiology, Humans, Intestines microbiology, Mesenchymal Stem Cells cytology, Stem Cell Transplantation, T-Lymphocytes, Regulatory drug effects, Tumor Escape, HIV Enteropathy therapy, Immunotherapy trends, Mesenchymal Stem Cells metabolism, Neoplasms drug therapy, Neoplasms immunology, T-Lymphocytes, Regulatory immunology
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- 2010
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20. Lymph node-targeted immunotherapy mediates potent immunity resulting in regression of isolated or metastatic human papillomavirus-transformed tumors.
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Smith KA, Meisenburg BL, Tam VL, Pagarigan RR, Wong R, Joea DK, Lantzy L, Carrillo MA, Gross TM, Malyankar UM, Chiang CS, Da Silva DM, Kündig TM, Kast WM, Qiu Z, and Bot A
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- Animals, Cancer Vaccines administration & dosage, Cancer Vaccines immunology, Cancer Vaccines therapeutic use, Cell Transformation, Viral immunology, Combined Modality Therapy, Cytotoxins administration & dosage, Female, Human papillomavirus 16 immunology, Humans, Lymphocytes, Tumor-Infiltrating immunology, Mice, Mice, Inbred C57BL, Neoplasm Metastasis, Neoplasms immunology, Neoplasms prevention & control, Papillomavirus E7 Proteins metabolism, Tumor Burden immunology, Human papillomavirus 16 physiology, Immunity, Cellular physiology, Immunotherapy methods, Lymph Nodes immunology, Neoplasms pathology, Neoplasms therapy
- Abstract
Purpose: The goal of this study was to investigate the therapeutic potential of a novel immunotherapy strategy resulting in immunity to localized or metastatic human papillomavirus 16-transformed murine tumors., Experimental Design: Animals bearing E7-expressing tumors were coimmunized by lymph node injection with E7 49-57 antigen and TLR3-ligand (synthetic dsRNA). Immune responses were measured by flow cytometry and antitumor efficacy was evaluated by tumor size and survival. In situ cytotoxicity assays and identification of tumor-infiltrating lymphocytes and T regulatory cells were used to assess the mechanisms of treatment resistance in bulky disease. Chemotherapy with cyclophosphamide was explored to augment immunotherapy in late-stage disease., Results: In therapeutic and prophylactic settings, immunization resulted in a considerable expansion of E7 49-57 antigen-specific T lymphocytes in the range of 1/10 CD8(+) T cells. The resulting immunity was effective in suppressing disease progression and mortality in a pulmonary metastatic disease model. Therapeutic immunization resulted in control of isolated tumors up to a certain volume, and correlated with antitumor immune responses measured in blood. In situ analysis showed that within bulky tumors, T-cell function was affected by negative regulatory mechanisms linked to an increase in T regulatory cells and could be overcome by cyclophosphamide treatment in conjunction with immunization., Conclusions: This study highlights a novel cancer immunotherapy platform with potential for translatability to the clinic and suggests its potential usefulness for controlling metastatic disease, solid tumors of limited size, or larger tumors when combined with cytotoxic agents that reduce the number of tumor-infiltrating T regulatory cells.
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- 2009
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21. In this issue: shifting the focus to modern vaccinology.
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Bot A
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- Animals, Fetal Blood, Humans, Immunity, Stem Cell Transplantation, Viral Vaccines economics, Virus Diseases economics, Virus Diseases etiology, Virus Diseases immunology, Immunotherapy, Viral Vaccines immunology, Virus Diseases prevention & control
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- 2008
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22. Antigen-based immune modulation: DNA vectors and beyond.
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Bot A, Phillips WJ, and von Herrath M
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- Adjuvants, Immunologic, Animals, Humans, Peptides immunology, Recombinant Proteins immunology, Vaccines, DNA immunology, Genetic Vectors, Immunotherapy methods, Vaccines, DNA genetics
- Abstract
The ultimate goal for autoimmune immunotherapy is to achieve a specific downregulation or modification of autoaggressive immune responses while leaving in place the normal repertoire, capable of mediating antimicrobial responses. A multitude of preclinical studies, particularly during the last 15 years, raised hopes that self-antigens could be used to achieve the goal of specific immune modulation. Difficulties associated with the translation of this concept to the clinic revealed inherent limitations of antigen-based immune modulation. To increase the efficiency of antigen-dependent immune modulation, researchers started to investigate novel vectors for antigen delivery. Plasmid vectors, as opposed to protein antigens or peptides, have the ability to trigger prolonged production of limited amounts of antigen in the periphery. However, one complicating factor may be the inherent "danger" signal stimulated by the nature of the unmethylated CpG motifs on bacterial plasmid. Currently, various approaches are being explored to improve the efficacy of response while ameliorating the safety concerns of plasmids as immunotherapeutic tools. This manuscript offers a perspective on such efforts and outlines how the knowledge accumulated in the process will help scientists advance to the next generation of immunotherapeutics.
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- 2002
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23. Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL
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Roberts, Zachary J, Better, Marc, Bot, Adrian, Roberts, Margo R, and Ribas, Antoni
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Immunology ,Biotechnology ,Orphan Drug ,Rare Diseases ,Lymphoma ,Clinical Research ,Hematology ,Cancer ,Development of treatments and therapeutic interventions ,5.2 Cellular and gene therapies ,Antigens ,CD19 ,Humans ,Immunotherapy ,Adoptive ,Lymphoma ,Large B-Cell ,Diffuse ,Lymphoma ,Non-Hodgkin ,Mediastinal Neoplasms ,Receptors ,Antigen ,T-Cell ,T-Lymphocytes ,Treatment Outcome ,CAR T cells ,axicabtagene ciloleucel ,adoptive cell transfer therapy ,refractory DLBCL ,immunotherapy ,KTE-C19 ,Clinical Sciences ,Cardiovascular medicine and haematology - Abstract
The development of clinically functional chimeric antigen receptor (CAR) T cell therapy is the culmination of multiple advances over the last three decades. Axicabtagene ciloleucel (formerly KTE-C19) is an anti-CD19 CAR T cell therapy in development for patients with refractory diffuse large B cell lymphoma (DLBCL), including transformed follicular lymphoma (TFL) and primary mediastinal B cell lymphoma (PMBCL). Axicabtagene ciloleucel is manufactured from patients' own peripheral blood mononuclear cells (PBMC) during which T cells are engineered to express a CAR that redirects them to recognize CD19-expressing cells. Clinical trials have demonstrated the feasibility of manufacturing axicabtagene ciloleucel in a centralized facility for use in multicenter clinical trials and have demonstrated potent antitumor activity in patients with refractory DLBCL. Main acute toxicities are cytokine release syndrome and neurologic events. Axicabtagene ciloleucel holds promise for the treatment of patients with CD19-positive malignancies, including refractory DLBCL.
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- 2018
24. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma
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Neelapu, Sattva S, Locke, Frederick L, Bartlett, Nancy L, Lekakis, Lazaros J, Miklos, David B, Jacobson, Caron A, Braunschweig, Ira, Oluwole, Olalekan O, Siddiqi, Tanya, Lin, Yi, Timmerman, John M, Stiff, Patrick J, Friedberg, Jonathan W, Flinn, Ian W, Goy, Andre, Hill, Brian T, Smith, Mitchell R, Deol, Abhinav, Farooq, Umar, McSweeney, Peter, Munoz, Javier, Avivi, Irit, Castro, Januario E, Westin, Jason R, Chavez, Julio C, Ghobadi, Armin, Komanduri, Krishna V, Levy, Ronald, Jacobsen, Eric D, Witzig, Thomas E, Reagan, Patrick, Bot, Adrian, Rossi, John, Navale, Lynn, Jiang, Yizhou, Aycock, Jeff, Elias, Meg, Chang, David, Wiezorek, Jeff, and Go, William Y
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Rare Diseases ,Orphan Drug ,Lymphoma ,Patient Safety ,Clinical Research ,Hematology ,Clinical Trials and Supportive Activities ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,6.2 Cellular and gene therapies ,Adult ,Aged ,Antigens ,CD19 ,Biomarkers ,Disease-Free Survival ,Female ,Humans ,Immunotherapy ,Adoptive ,Interleukins ,Lymphoma ,Large B-Cell ,Diffuse ,Male ,Middle Aged ,Nervous System Diseases ,Neutropenia ,Receptors ,Antigen ,T-Cell ,Survival Rate ,T-Lymphocytes ,Young Adult ,Medical and Health Sciences ,General & Internal Medicine - Abstract
BackgroundIn a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.MethodsIn this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.ResultsAmong the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.ConclusionsIn this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).
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- 2017
25. Cytokines in the Treatment of Cancer
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Bot, Adrian and Minev, Boris R., editor
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- 2011
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26. New Cancer Immunotherapy Agents in Development: a report from an associated program of the 31st Annual Meeting of the Society for Immunotherapy of Cancer, 2016.
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Adusumilli, Prasad S., Cha, Edward, Cornfeld, Mark, Davis, Thomas, Diab, Adi, Dubensky Jr., Thomas W., Evans, Elizabeth, Grogan, Jane L., Irving, Bryan A., Leidner, Rom S., Olwill, Shane A., Soon-Shiong, Patrick, Triebel, Frederic, Tuck, David, Bot, Adrian, Dansey, Roger D., Drake, Charles G., Freeman, Gordon J., Ibrahim, Ramy, and Patel, Salil
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IMMUNOTHERAPY ,CANCER treatment ,DRUG development ,CONFERENCES & conventions - Abstract
This report is a summary of 'New Cancer Immunotherapy Agents in Development' program, which took place in association with the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), on November 9, 2016 in National Harbor, Maryland. Presenters gave brief overviews of emerging clinical and pre-clinical immune-based agents and combinations, before participating in an extended panel discussion with multidisciplinary leaders, including members of the FDA, leading academic institutions and industrial drug developers, to consider topics relevant to the future of cancer immunotherapy. [ABSTRACT FROM AUTHOR]
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- 2017
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27. Target discovery for T cell therapy: next steps to advance Immunotherapies.
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Bot, Adrian, Brewer, Joanna E., Eshhar, Zelig, Frankel, Stanley R., Hickman, Emma, Jungbluth, Achim A., Morgan, Richard, Peretz, Yoav, Radvanyi, Laszlo, Ramos, Carlos A., Robbins, Paul F., and Wucherpfennig, Kai W.
- Subjects
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T cells , *CELLULAR therapy , *LYMPHOCYTES , *LEUCOCYTES , *ORGANOTHERAPY - Abstract
Investigators from academia and industry gathered on August 14, 2014, in Boston at the Inaugural ImVacS conference entitled "Target Discovery for T Cell Therapy: Next Step to Advance Immunotherapies". Novel targets, discovery strategies and enabling technologies were presented and discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
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28. Antigen kinetics determines immune reactivity.
- Author
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Johansen, Pål, Storni, Tazio, Rettig, Lorna, Zhiyong Qiu, Der-Sarkissian, Ani, Smith, Kent A., Manolova, Vania, Lang, Karl S., Senti, Gabriela, Müllhaupt, Beat, Gerlach, Tilman, Speck, Roberto F., Bot, Adrian, and Kundig, Thomas M.
- Subjects
IMMUNOLOGY ,T cell receptors ,DENDRITIC cells ,ANTIGEN presenting cells ,IMMUNOTHERAPY ,IMMUNIZATION ,PREVENTIVE medicine - Abstract
A current paradigm in immunology is that the strength of T cell responses is governed by antigen dose, localization, and costimulatory signals. This study investigates the influence of antigen kinetics on CD8 T cell responses in mice. A fixed cumulative antigen dose was administered by different schedules to produce distinct dose-kinetics. Antigenic stimulation increasing exponentially over days was a stronger stimulus for CD8 T cells and antiviral immunity than a single dose or multiple dosing with daily equal doses. The same was observed for dendritic cell vaccination, with regard to T cell and anti-tumor responses, and for T cells stimulated in vitro. In conclusion, stimulation kinetics perse was shown to be a separate parameter of immunogenicity. These findings warrant a revision of current immunization models and have implications for vaccine development and immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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29. Stem cells and cancer immunotherapy: Arrowhead’s 2nd annual cancer immunotherapy conference
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Bot, Adrian, Chiriva-Internati, Maurizio, Cornforth, Andrew, Czerniecki, Brian J, Ferrone, Soldano, Geles, Kenneth, Greenberg, Philip D, Hurt, Elaine, Koya, Richard C, Manjili, Masoud H, Matsui, William, Morgan, Richard A, Palena, Claudia M, Powell Jr , Daniel J, Restifo, Nicholas P, Spencer, David M, Vizcardo, Raul, Wong, Albert J, Yang, Lili, and Yu, John
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Immunotherapy ,Cancer stem cells ,Hematopoietic stem cells ,Adoptive T cell therapy ,Antibodies ,Vaccines - Abstract
Investigators from academia and industry gathered on April 4 and 5, 2013, in Washington DC at the Arrowhead’s 2nd Annual Cancer Immunotherapy Conference. Two complementary concepts were discussed: cancer “stem cells” as targets and therapeutic platforms based on stem cells.
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- 2014
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30. Topics in This Issue: Cancer Testes Antigens, Immune Checkpoints, Inflammation Associated with Ischemia-Reperfusion and Integrin Targeting.
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Bot, Adrian and Chiriva-Internati, Maurizio
- Abstract
This issue of the International Reviews of Immunology is dedicated to several topics: cancer immunotherapy, and basic and translational aspects of immunity. Two reviews, one focused on breast and the other on lung cancer, highlight the need to redefine the cancer testes antigens (CTAs) as novel information regarding their expression profile and biological role emerges. Two other reviews showcase pivotal molecules that keep in check immunity at two different levels: the transcription factor autoimmune regulator (AIRE) important to negative selection of the T-cell repertoire, and CD22 that limits the antigen-initiated B-cell response. Two other articles focus on the debated role of Toll-like receptors (TLRs) and inflammation in general, in ischemia-reperfusion lesions that follow cardiovascular disorders and stroke. Last but not the least, this issue hosts a review that discusses the role and translational potential of the α4 integrin for the treatment of inflammatory bowel disease (IBD). [ABSTRACT FROM AUTHOR]
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- 2012
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31. In this Issue: Targeting Human Papilloma Virus-Associated Disease, from Cervical to Head and Neck Carcinoma... and more.
- Author
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Chiriva-Internati, Maurizio, Kast, W. Martin, and Bot, Adrian
- Subjects
IMMUNOTHERAPY ,CANCER treatment ,IMMUNOLOGICAL deficiency syndromes ,AUTOIMMUNITY ,PAPILLOMAVIRUSES - Abstract
This issue of the International Reviews of Immunology hosts a diverse range of topics, ranging from cancer immunotherapy, to severe combined immunodeficiency syndromes in man and alternative treatments for autoimmunity. The emphasis of the issue is on cervical and head and neck carcinoma, significantly related to Human Papilloma Viruses. While the development of anti-HPV prophylactic vaccines represents one of the most remarkable triumphs of modern medicine, there is much more to be done in terms of advancing safe and effective treatments for cervical and head-and-neck cancers. We also host a review on congenital severe combined immunodeficiencies, a field that allowed unprecedented insight into the connection between the immune system, microbes, autoimmunity and cancer. Last but not least, we host a review dedicated to critically analyzing alternative treatments for Inflammatory Bowel Disease, as adjuncts to conventional therapies, based on solid scientific evidence and complementary mechanism of action. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
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