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1.
mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer.
Cafri, G, Gartner, JJ, Zaks, T, Hopson, K, Levin, N, Paria, BC, Parkhurst, MR, Yossef, R, Lowery, FJ, Jafferji, MS, et al
The Journal of clinical investigation. 2020;(11):5976-5988
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Abstract
BACKGROUNDTherapeutic vaccinations against cancer have mainly targeted differentiation antigens, cancer-testis antigens, and overexpressed antigens and have thus far resulted in little clinical benefit. Studies conducted by multiple groups have demonstrated that T cells recognizing neoantigens are present in most cancers and offer a specific and highly immunogenic target for personalized vaccination.METHODSWe recently developed a process using tumor-infiltrating lymphocytes to identify the specific immunogenic mutations expressed in patients' tumors. Here, validated, defined neoantigens, predicted neoepitopes, and mutations of driver genes were concatenated into a single mRNA construct to vaccinate patients with metastatic gastrointestinal cancer.RESULTSThe vaccine was safe and elicited mutation-specific T cell responses against predicted neoepitopes not detected before vaccination. Furthermore, we were able to isolate and verify T cell receptors targeting KRASG12D mutation. We observed no objective clinical responses in the 4 patients treated in this trial.CONCLUSIONThis vaccine was safe, and potential future combination of such vaccines with checkpoint inhibitors or adoptive T cell therapy should be evaluated for possible clinical benefit in patients with common epithelial cancers.TRIAL REGISTRATIONPhase I/II protocol (NCT03480152) was approved by the IRB committee of the NIH and the FDA.FUNDINGCenter for Clinical Research, NCI, NIH.
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Rapid Generation of Sustainable HER2-specific T-cell Immunity in Patients with HER2 Breast Cancer using a Degenerate HLA Class II Epitope Vaccine.
Knutson, KL, Block, MS, Norton, N, Erskine, CL, Hobday, TJ, Dietz, AB, Padley, D, Gustafson, MP, Puglisi-Knutson, D, Mangskau, TK, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020;(5):1045-1053
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Abstract
PURPOSE Patients with HER2+ breast cancer benefit from trastuzumab-containing regimens with improved survival. Adaptive immunity, including cytotoxic T-cell and antibody immunity, is critical to clinical efficacy of trastuzumab. Because Th cells are central to the activation of these antitumor effectors, we reason that HER2 patients treated with trastuzumab may benefit by administering vaccines that are designed to stimulate Th-cell immunity. PATIENTS AND METHODS We developed a degenerate HER2 epitope-based vaccine consisting of four HLA class II-restricted epitopes mixed with GM-CSF that should immunize most (≥84%) patients. The vaccine was tested in a phase I trial. Eligible women had resectable HER2+ breast cancer and had completed standard treatment prior to enrollment and were disease free. Patients were vaccinated monthly for six doses and monitored for safety and immunogenicity. RESULTS Twenty-two subjects were enrolled and 20 completed all six vaccines. The vaccine was well tolerated. All patients were alive at analysis with a median follow-up of 2.3 years and only two experienced disease recurrence. The percent of patients that responded with augmented T-cell immunity was high for each peptide ranging from 68% to 88%, which led to 90% of the patients generating T cells that recognized naturally processed HER2 antigen. The vaccine also augmented HER2-specific antibody. Immunity was sustained in patients with little sign of diminishing at 2 years following the vaccination. CONCLUSIONS Degenerate HLA-DR-based HER2 vaccines induce sustainable HER2-specific T cells and antibodies. Future studies, could evaluate whether vaccination during adjuvant treatment with trastuzumab-containing regimens improves patient outcomes.
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Vitamin D status and the immune assessment in 22q11.2 deletion syndrome.
Legitimo, A, Bertini, V, Costagliola, G, Baroncelli, GI, Morganti, R, Valetto, A, Consolini, R
Clinical and experimental immunology. 2020;(3):272-286
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Abstract
22q11.2 deletion syndrome (22q11.2DS) is characterized by a heterogeneous phenotype, including alterations in phospho-calcium metabolism and immunodeficiency. We analyzed vitamin D status and the immune assessment, focusing on T cell subpopulations and dendritic cells (DCs) in a cohort of 17 pediatric 22q11.2DS patients and 17 age-matched healthy subjects. As antigen-presenting cells, DCs are the main target of vitamin D, promoting a tolerogenic T cell response. Patients were subdivided into three groups according to the parameters of phospho-calcium metabolism and serum levels of 25OHD: normal values, vitamin D deficiency and hypoparathyroidism. Different degrees of T cell deficiency, ranging from normal to partial T cell numbers, were observed in the cohort of patients. The group with vitamin D deficiency showed a significant reduction of naive T cells and a significant increase of central memory T cells compared to controls. In this group the number of circulating DCs was significantly reduced. DC decrease affected both myeloid and plasmacytoid DC subsets (mDCs and pDCs), with the most relevant reduction involving pDCs. A direct correlation between 25OHD levels and recent thymic emigrant (RTE) and DC number was identified. Despite the limited cohort analyzed, our results show that deficiency of the pDC subset in patients with 22q11.2DS may be included among the causative factors of the progressive increase of risk of autoimmune diseases in these patients. As most patients suffer from increased susceptibility to infections and heightened prevalence of autoimmune disorders, we suggest a potential role of vitamin D supplementation in preventing autoimmune or proinflammatory diseases in 22q11.2DS.
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Metabolic factors contribute to T-cell inhibition in the ovarian cancer ascites.
Gong, Y, Yang, J, Wang, Y, Xue, L, Wang, J
International journal of cancer. 2020;(7):1768-1777
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Abstract
Malignant ascites is one of the major clinical features of ovarian cancer, which serves as a carrier for the peritoneal dissemination of tumor cells and predicts a poor prognosis in patients. In the microenvironment of ovarian cancer ascites, antitumor immunity is suppressed, which enables the tumor cells to escape from immune surveillance. The metabolic factors, including hypoxia, nutrient deprivation and accumulation of metabolic products, contribute to the immunosuppressive status of malignant ascites. The malignant ascites and ovarian solid tumors exhibit differential metabolic profiles. In this review, we have summarized the most recent findings on the interaction between immune cells and metabolic factors in the ovarian cancer ascites. The effects of metabolic factors on the antitumor functions of T-cells in the malignant ascites were analyzed. Finally, we have discussed the potential directions for future research in this field.
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Gliadin-Induced Ex Vivo T-Cell Response in Dermatitis Herpetiformis: A Predictor of Clinical Relapse on Gluten Challenge?
Kalliokoski, S, Mansikka, E, de Kauwe, A, Huhtala, H, Saavalainen, P, Kurppa, K, Hervonen, K, Reunala, T, Kaukinen, K, Salmi, T, et al
The Journal of investigative dermatology. 2020;(9):1867-1869.e2
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Unconventional Peptide Presentation by Classical MHC Class I and Implications for T and NK Cell Activation.
Zajonc, DM
International journal of molecular sciences. 2020;(20)
Abstract
T cell-mediated immune recognition of peptides is initiated upon binding of the antigen receptor on T cells (TCR) to the peptide-MHC complex. TCRs are typically restricted by a particular MHC allele, while polymorphism within the MHC molecule can affect the spectrum of peptides that are bound and presented to the TCR. Classical MHC Class I molecules have a confined binding groove that restricts the length of the presented peptides to typically 8-11 amino acids. Both N- and C-termini of the peptide are bound within binding pockets, allowing the TCR to dock in a diagonal orientation above the MHC-peptide complex. Longer peptides have been observed to bind either in a bulged or zig-zag orientation within the binding groove. More recently, unconventional peptide presentation has been reported for different MHC I molecules. Here, either N- or C-terminal amino acid additions to conventionally presented peptides induced a structural change either within the MHC I molecule that opened the confined binding groove or within the peptide itself, allowing the peptide ends to protrude into the solvent. Since both TCRs on T cells and killer immunoglobulin receptors on Natural Killer (NK) cells contact the MHC I molecule above or at the periphery of the peptide binding groove, unconventionally presented peptides could modulate both T cell and NK cell responses. We will highlight recent advances in our understanding of the functional consequences of unconventional peptide presentation in cellular immunity.
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Cellular senescence and senescence-associated T cells as a potential therapeutic target.
Nakagami, H
Geriatrics & gerontology international. 2020;(2):97-100
Abstract
More than 50 years ago, Hayflick et al. found that no long-lived, proliferative cells remained in long-term cell culture experiments; this phenomenon is called "cellular senescence." This finding has allowed us to understand basic individual tissue aging and cancer inhibition from the view of cellular aging. Senescent cells survive and accumulate in the body, and secrete various inflammatory cytokines or chemokines, which is different from the cell fate in apoptosis. These phenomena describe the so-called senescence-associated secretory phenotype, and chronic inflammation and carcinogenesis are induced in the surrounding tissue through senescence-associated secretory phenotype factors. For example, senescence-associated T cells are an age-dependent CD4(+ ) T-cell subpopulation with a PD-1(+ ) memory phenotype; these cells do not proliferate in response to T-cell receptor stimulation, and produce abundant osteopontin, as well as inflammatory cytokines. Senescence-associated T cells are also increased in adipose tissue under a high-fat diet, which might be related to the progress of obesity or diabetes. These series of findings might allow us to connect senescent cells and tissue aging, leading to individual aging. Interestingly, the depletion of senescent cells in the body, called senolysis, successfully increases lifespan and attenuates age-related diseases. This novel therapy is now moving forward to translational research from the bench toward clinical trials. Geriatr Gerontol Int 2020; 20: 97-100.
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Adeno-Associated Viral Vectors for Homology-Directed Generation of CAR-T Cells.
Moço, PD, Aharony, N, Kamen, A
Biotechnology journal. 2020;(1):e1900286
Abstract
Immunotherapy with T cells expressing chimeric antigen receptors (CAR) is an emerging and promising treatment against refractory cancers. However, the currently adopted methods of modification of T cells pose a risk of insertional oncogenesis because lentiviral and retroviral vectors integrate the CAR transgene in a semi-random fashion. In addition, this therapy is only available using autologous cells, which create problems in production and limit the access for patients who have their T cells depleted. One modification method that shows the ability to overcome both drawbacks is the knock-in of the CAR simultaneously knocking-out genes that prevent allogeneic therapy, such as the endogenous T cell receptor. In this mini-review, the authors present recent efforts to develop safer universal CAR-T cells. More specifically, the combined application of target-directed nucleases, which create a double-strand break at a specific genome locus, and the delivery of CAR DNA via adeno-associated viral vectors for subsequent integration via homologous recombination and silencing of the targeted gene is focused on.
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MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19.
Bilezikian, JP, Bikle, D, Hewison, M, Lazaretti-Castro, M, Formenti, AM, Gupta, A, Madhavan, MV, Nair, N, Babalyan, V, Hutchings, N, et al
European journal of endocrinology. 2020;(5):R133-R147
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Abstract
The SARS-CoV-2 virus responsible for the COVID-19 pandemic has generated an explosion of interest both in the mechanisms of infection leading to dissemination and expression of this disease, and in potential risk factors that may have a mechanistic basis for disease propagation or control. Vitamin D has emerged as a factor that may be involved in these two areas. The focus of this article is to apply our current understanding of vitamin D as a facilitator of immunocompetence both with regard to innate and adaptive immunity and to consider how this may relate to COVID-19 disease. There are also intriguing potential links to vitamin D as a factor in the cytokine storm that portends some of the most serious consequences of SARS-CoV-2 infection, such as the acute respiratory distress syndrome. Moreover, cardiac and coagulopathic features of COVID-19 disease deserve attention as they may also be related to vitamin D. Finally, we review the current clinical data associating vitamin D with SARS-CoV-2 infection, a putative clinical link that at this time must still be considered hypothetical.
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T-cell agonists in cancer immunotherapy.
Choi, Y, Shi, Y, Haymaker, CL, Naing, A, Ciliberto, G, Hajjar, J
Journal for immunotherapy of cancer. 2020;(2)
Abstract
Cancer cells can evade immune surveillance in the body. However, immune checkpoint inhibitors can interrupt this evasion and enhance the antitumor activity of T cells. Other mechanisms for promoting antitumor T-cell function are the targeting of costimulatory molecules expressed on the surface of T cells, such as 4-1BB, OX40, inducible T-cell costimulator and glucocorticoid-induced tumor necrosis factor receptor. In addition, CD40 targets the modulation of the activation of antigen-presenting cells, which ultimately leads to T-cell activation. Agonists of these costimulatory molecules have demonstrated promising results in preclinical and early-phase trials and are now being tested in ongoing clinical trials. In addition, researchers are conducting trials of combinations of such immune modulators with checkpoint blockade, radiotherapy and cytotoxic chemotherapeutic drugs in patients with advanced tumors. This review gives a comprehensive picture of the current knowledge of T-cell agonists based on their use in recent and ongoing clinical trials.