The Experts below are selected from a list of 183552 Experts worldwide ranked by ideXlab platform
Steven A Rosenberg - One of the best experts on this subject based on the ideXlab platform.
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final common pathway of human Cancer immunotherapy targeting random somatic mutations
Nature Immunology, 2017Co-Authors: Eric Tran, Paul F Robbins, Steven A RosenbergAbstract:Effective clinical Cancer immunotherapies, such as administration of the cytokine IL-2, adoptive cell transfer (ACT) and the recent success of blockade of the checkpoint modulators CTLA-4 and PD-1, have been developed without clear identification of the immunogenic targets expressed by human Cancers in vivo. Immunotherapy of patients with Cancer through the use of ACT with autologous lymphocytes has provided an opportunity to directly investigate the antigen recognition of lymphocytes that mediate Cancer Regression in humans. High-throughput immunological testing of such lymphocytes in combination with improvements in deep sequencing of the autologous Cancer have provided new insight into the molecular characterization and incidence of anti-tumor lymphocytes present in patients with Cancer. Here we highlight evidence suggesting that T cells that target tumor neoantigens arising from Cancer mutations are the main mediators of many effective Cancer immunotherapies in humans.
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adoptive cell transfer as personalized immunotherapy for human Cancer
Science, 2015Co-Authors: Steven A Rosenberg, Nicholas P RestifoAbstract:Adoptive cell therapy (ACT) has multiple advantages compared with other forms of Cancer immunotherapy that rely on the active in vivo development of sufficient numbers of antitumor T cells with the functions necessary to mediate Cancer Regression. For use in ACT, large numbers of antitumor lymphocytes (up to 10 11 ) can be readily grown in vitro and selected for high-avidity recognition of the tumor, as well as for the effector functions required to mediate Cancer Regression. In vitro activation allows such cells to be released from the inhibitory factors that exist in vivo. Perhaps most importantly, ACT enables the manipulation of the host before cell transfer to provide a favorable microenvironment that better supports antitumor immunity. ACT is a “living” treatment because the administered cells can proliferate in vivo and maintain their antitumor effector functions. A major factor limiting the successful use of ACT in humans is the identification of cells that can target antigens selectively expressed on the Cancer and not on essential normal tissues. ACT has used either natural host cells that exhibit antitumor reactivity or host cells that have been genetically engineered with antitumor T cell receptors (TCRs) or chimeric antigen receptors (CARs). With the use of these approaches, ACT has mediated dramatic Regressions in a variety of Cancer histologies, including melanoma, cervical Cancer, lymphoma, leukemia, bile duct Cancer, and neuroblastoma. This Review will discuss the current state of ACT for the treatment of human Cancer, as well as the principles of effective treatment that point toward improvements in this approach.
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Phenotype and Function of T Cells Infiltrating Visceral Metastases from Gastrointestinal Cancers and Melanoma: Implications for Adoptive Cell Transfer Therapy
Journal of immunology (Baltimore Md. : 1950), 2013Co-Authors: Simon Turcotte, Mark E Dudley, John R Wunderlich, Alena Gros, Katherine Hogan, Eric Tran, Christian S. Hinrichs, Steven A RosenbergAbstract:Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate Cancer Regression in patients with metastatic melanoma, but whether this approach can be applied to common epithelial malignancies remains unclear. In this study, we compared the phenotype and function of TILs derived from liver and lung metastases from patients with gastrointestinal (GI) Cancers (n = 14) or melanoma (n = 42). Fewer CD3+ T cells were found to infiltrate GI compared with melanoma metastases, but the proportions of CD8+ cells, T cell differentiation stage, and expression of costimulatory molecules were similar for both tumor types. Clinical-scale expansion up to ∼50 × 109 T cells on average was obtained for all patients with GI Cancer and melanoma. From GI tumors, however, TIL outgrowth in high-dose IL-2 yielded 22 ± 1.4% CD3+CD8+ cells compared with 63 ± 2.4% from melanoma (p < 0.001). IFN-γ ELISA demonstrated MHC class I–mediated reactivity of TIL against autologous tumor in 5 of 7 GI Cancer patients tested (9% of 188 distinct TIL cultures) and in 9 of 10 melanoma patients (43% of 246 distinct TIL cultures). In these assays, MHC class I–mediated up-regulation of CD137 (4-1BB) expression on CD8+ cells suggested that 0–3% of TILs expanded from GI Cancer metastases were tumor-reactive. This study implies that the main challenge to the development of TIL adoptive cell transfer for metastatic GI Cancers may not be the in vitro expansion of bulk TILs, but the ability to select and enrich for tumor-reactive T cells.
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cell transfer immunotherapy for metastatic solid Cancer what clinicians need to know
Nature Reviews Clinical Oncology, 2011Co-Authors: Steven A RosenbergAbstract:Cancer immunotherapy using the adoptive transfer of autologous tumor-infiltrating lymphocytes results in objective Cancer Regression in 49-72% of patients with metastatic melanoma. In a pilot trial combining cell transfer with a maximum lymphodepleting regimen, complete durable responses were seen in 40% of patients, with complete responses ongoing beyond 3 to 7 years. Current approaches to cell transfer therapy using autologous cells genetically engineered to express conventional or chimeric T-cell receptors have mediated Cancer Regression in patients with metastatic melanoma, synovial sarcoma, neuroblastoma and refractory lymphoma. Adoptive cell transfer immunotherapy is a rapidly developing new approach to the therapy of metastatic Cancer in humans. This Review will emphasize the current available applications of cell transfer immunotherapy for patients with Cancer.
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antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of Cancer
Cancer Research, 2010Co-Authors: Rajeev K Shrimali, Nicholas P Restifo, Marc R Theoret, Zhiya Yu, Dhanalakshmi Chinnasamy, Steven A RosenbergAbstract:Abstract Adoptive cell transfer (ACT)–based immunotherapies can mediate objective Cancer Regression in animalmodels and in up to 70% of patients with metastatic melanoma; however, it remains unclear whether thetumor vasculature impedes the egress of tumor-specific T cells, thus hindering this immunotherapy. Disrup-tion of the proangiogenic interaction of vascular endothelial growth factor (VEGF) with its receptor (VEGFR-2)has been reported to “normalize” tumor vasculature, enhancing the efficacy of chemotherapeutic agents byincreasing their delivery to the tumor intersitium. We thus sought to determine whether disrupting VEGF/VEGFR-2 signaling could enhance the effectiveness of ACT in a murine Cancer model. The administration ofan antibody against mouse VEGF synergized with ACT to enhance inhibition of established, vascularized, B16melanoma (P = 0.009) and improve survival (P = 0.003). Additive effects of an antibody against VEGFR-2 inconjunction with ACT were seen in this model (P = 0.013). Anti-VEGF, but not anti–VEGFR-2, antibody sig-nificantly increased infiltration of transferred cells into the tumor. Thus, normalization of tumor vasculaturethrough disruption of the VEGF/VEGFR-2 axis can increase extravasation of adoptively transferred T cells intothe tumor and improve ACT-based immunotherapy. These studies provide a rationale for the exploration ofcombining antiangiogenic agents with ACT for the treatment of patients with Cancer.
Else Driehuis - One of the best experts on this subject based on the ideXlab platform.
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abstract ct075 fasting mimicking diet and hormone therapy modulates metabolic factors to promote breast Cancer Regression and reduce side effects
Cancer Research, 2020Co-Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Min Wei, Lorenzo FerrandoAbstract:Breast Cancer (BC) is the most common malignancy with 1.7 million new diagnoses/year and is responsible for more than 450,000 yearly deaths worldwide. Two thirds of BC express the estrogen receptor (ER) and/or progesterone receptor and are referred to as hormone receptor-positive (HR+) BC. Endocrine therapy (ET) is usually active in these tumors, although drug resistance and side effects limit its benefit. Growth factor signaling through the PI3K/AKT/mammalian target of rapamycin (mTOR) and MAP kinase axes enhances ER activity and is a key mechanism underlying endocrine resistance. Water-only fasting (fasting) or plant-based, low-calorie, carbohydrate- and protein-restricted fasting-mimicking diets (FMDs) reduce circulating growth factors, such as insulin and IGF1 Therefore, we hypothesized that these dietary interventions could be used to enhance the activity of ET and delay the occurrence of resistance. For our in vitro experiments we used the HR+ BC cell lines, MCF7, T47D, and ZR-75-1, as well as metastases-derived organoids from patients with HR+ BC. Our in vivo experiments in mouse xenografts of human BC cell lines, were conducted in six-to-eight-week old female NOD SCID or athymic Nude-FoxN1 mice treated with ET w/ or w/o 48-72 hours of fasting/FMD. We monitored tumor growth and mouse survival and collected tumor masses and blood to detect circulating levels of several growth factors, adipokines and cytokines. In vivo add back experiments with fasting-reduced factors were done with IGF1, insulin and leptin. Circulating growth factors and adipo-cytokines were also detected in blood samples from 36 patients with HR+ BC, who were enrolled in either one of two clinical trials (NCT03595540 and NCT03340935) assessing safety and feasibility of periodic FMD in Cancer patients. Patient nutritional status and response to treatment were also monitored in our clinical trials.We found that in HR+ BC models, periodic fasting or FMD enhanced tamoxifen and fulvestrant activity by lowering circulating IGF1, insulin, and leptin levels and by blocking AKT-mTOR signaling via EGR1 and PTEN upregulation. When fulvestrant was combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic FMD cycles promoted long-lasting tumour Regressions and reverted acquired resistance to this regime. Moreover, both fasting and FMD prevented tamoxifen-induced endometrial hyperplasia. In HR+ BC patients receiving ET, FMD cycles caused metabolic changes analogous to those observed in mice, including reduced leptin and IGF1 levels, which were found to remain low for extended periods. In mice, these long-lasting effects were associated with carryover antiCancer activity. Overall, our results provide the rationale for conducting further clinical studies of fasting-based dietary strategies as an adjuvant to ET w/ or w/o CDK4/6 inhibitors in patients with HR+ BC. Citation Format: Irene Caffa, Vanessa Spagnolo, Pamela Becherini, Francesca Valdemarin, Claudio Vernieri, Min Wei, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Lorenzo Ferrando, Luca Mastracci, Michele Cilli, Francesco Piacente, Anna Laura Cremonini, Mario Passalacqua, Valerio Vellone, Gabriele Zoppoli, Michele Cea, Giulia Salvadori, Salvatore Cortellino, Hans Clevers, Filippo De Braud, Alessandro Provenzani, Valter D. Longo, Alessio Nencioni. Fasting-mimicking diet and hormone therapy modulates metabolic factors to promote breast Cancer Regression and reduce side effects [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT075.
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fasting mimicking diet and hormone therapy induce breast Cancer Regression
Nature, 2020Co-Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Min WeiAbstract:Approximately 75% of all breast Cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast Cancer, periodic fasting or a fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour Regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast Cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-Cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast Cancer.
Mark E Dudley - One of the best experts on this subject based on the ideXlab platform.
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persistence of ctl clones targeting melanocyte differentiation antigens was insufficient to mediate significant melanoma Regression in humans
Clinical Cancer Research, 2015Co-Authors: Smita S Chandran, Luke D. Rothermel, Daniel J. Stephens, Bibhash C Paria, Abhishek K. Srivastava, Richard M Sherry, Mark E Dudley, John R Wunderlich, Robert Somerville, James Chihhsin YangAbstract:Purpose: Adoptive transfer of autologous tumor infiltrating lymphocytes (TIL) can mediate durable Cancer Regression in selected patients with metastatic melanoma. However, the tumor antigens associated with these favorable responses remain unclear. We hypothesized that a clinical strategy involving the iterative adoptive transfer of selected autologous antigen-specific T-cell clones could help systematically define immunologic targets associated with successful Cancer therapy, without the interpretative ambiguity of transferring polyclonal populations. Here, we evaluated the clinical efficacy of CD8 + T-cell clones specific for the melanocyte differentiation antigens (MDA), gp100 and MART-1, respectively. Experimental Design: We conducted two consecutive phase II clinical trials involving the adoptive transfer of highly selected autologous antigen-specific CD8 + T-cell clones against gp100 and MART-1, respectively. Fifteen patients with HLA-A2 + treatment-refractory metastatic melanoma received highly avid MDA-specific CD8 + T-cell clones specific for either gp100 ( n = 10) or MART-1 ( n = 5) with or without intravenous interleukin-2 (IL2) after a lymphodepleting myeloablative preparative regimen. Results: Of the 15 treated patients, we observed immune-mediated targeting of skin melanocytes in 11 patients (73%) and clonal engraftment in eight patients (53%) after cell transfer. There were only transient minor tumor Regressions observed, but no objective tumor responses based on Response Evaluation Criteria in Solid Tumor (RECIST) criteria. Conclusions: Despite successful clonal repopulation and evidence of in vivo antigen targeting, the poor therapeutic efficacy after the adoptive transfer of autologous MDA-specific T cells raises significant concerns regarding future immunotherapy efforts targeting this class of tumor antigens. Clin Cancer Res; 21(3); 534–43. ©2014 AACR.
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Phenotype and Function of T Cells Infiltrating Visceral Metastases from Gastrointestinal Cancers and Melanoma: Implications for Adoptive Cell Transfer Therapy
Journal of immunology (Baltimore Md. : 1950), 2013Co-Authors: Simon Turcotte, Mark E Dudley, John R Wunderlich, Alena Gros, Katherine Hogan, Eric Tran, Christian S. Hinrichs, Steven A RosenbergAbstract:Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate Cancer Regression in patients with metastatic melanoma, but whether this approach can be applied to common epithelial malignancies remains unclear. In this study, we compared the phenotype and function of TILs derived from liver and lung metastases from patients with gastrointestinal (GI) Cancers (n = 14) or melanoma (n = 42). Fewer CD3+ T cells were found to infiltrate GI compared with melanoma metastases, but the proportions of CD8+ cells, T cell differentiation stage, and expression of costimulatory molecules were similar for both tumor types. Clinical-scale expansion up to ∼50 × 109 T cells on average was obtained for all patients with GI Cancer and melanoma. From GI tumors, however, TIL outgrowth in high-dose IL-2 yielded 22 ± 1.4% CD3+CD8+ cells compared with 63 ± 2.4% from melanoma (p < 0.001). IFN-γ ELISA demonstrated MHC class I–mediated reactivity of TIL against autologous tumor in 5 of 7 GI Cancer patients tested (9% of 188 distinct TIL cultures) and in 9 of 10 melanoma patients (43% of 246 distinct TIL cultures). In these assays, MHC class I–mediated up-regulation of CD137 (4-1BB) expression on CD8+ cells suggested that 0–3% of TILs expanded from GI Cancer metastases were tumor-reactive. This study implies that the main challenge to the development of TIL adoptive cell transfer for metastatic GI Cancers may not be the in vitro expansion of bulk TILs, but the ability to select and enrich for tumor-reactive T cells.
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Cancer Regression and neurological toxicity following anti mage a3 tcr gene therapy
Journal of Immunotherapy, 2013Co-Authors: Richard A. Morgan, James Chihhsin Yang, Mark E Dudley, Alena Gros, Paul F Robbins, Nachimuthu Chinnasamy, Daniel Abatedaga, Zhili L Zheng, Steven A Feldman, Richard M SherryAbstract:Nine Cancer patients were treated with adoptive cell therapy using autologous anti-MAGE-A3 T-cell receptors (TCR)-engineered T cells. Five patients experienced clinical Regression of their Cancers including 2 on-going responders. Beginning 1-2 days postinfusion, 3 patients (#'s 5, 7, and 8) experienced mental status changes, and 2 patients (5 and 8) lapsed into comas and subsequently died. Magnetic resonance imagining analysis of patients 5 and 8 demonstrated periventricular leukomalacia, and examination of their brains at autopsy revealed necrotizing leukoencephalopathy with extensive white matter defects associated with infiltration of CD3(+)/CD8(+) T cells. Patient 7, developed Parkinson-like symptoms, which resolved over 4 weeks and fully recovered. Immunohistochemical staining of patient and normal brain samples demonstrated rare positively staining neurons with an antibody that recognizes multiple MAGE-A family members. The TCR used in this study recognized epitopes in MAGE-A3/A9/A12. Molecular assays of human brain samples using real-time quantitative-polymerase chain reaction, Nanostring quantitation, and deep-sequencing indicated that MAGE-A12 was expressed in human brain (and possibly MAGE-A1, MAGE-A8, and MAGE-A9). This previously unrecognized expression of MAGE-A12 in human brain was possibly the initiating event of a TCR-mediated inflammatory response that resulted in neuronal cell destruction and raises caution for clinical applications targeting MAGE-A family members with highly active immunotherapies.
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the stoichiometric production of il 2 and ifn γ mrna defines memory t cells that can self renew after adoptive transfer in humans
Science Translational Medicine, 2012Co-Authors: Anran Wang, Smita Chandran, Syed A Shah, Yu M Chiu, Biman C Paria, Tamara Aghamolla, Melissa M Alvarezdowning, Sanmeet Singh, Thomas Li, Mark E DudleyAbstract:Adoptive immunotherapy using ex vivo–expanded tumor-reactive lymphocytes can mediate durable Cancer Regression in selected melanoma patients. Analyses of these trials have associated the in vivo engraftment ability of the transferred cells with their antitumor efficacy. Thus, there is intensive clinical interest in the prospective isolation of tumor-specific T cells that can reliably persist after transfer. Animal studies have suggested that central memory CD8 + T cells (T CM ) have divergent capabilities including effector differentiation to target antigen and stem cell–like self-renewal that enable long-term survival after adoptive transfer. We sought to isolate human melanoma-specific T CM to define their in vivo fate and function after autologous therapeutic transfer to metastatic patients. To facilitate the high-throughput identification of these rare cells from patients, we report that T CM have a defined stoichiometric production of interleukin-2 (IL-2) and interferon-γ (IFN-γ) mRNA after antigen stimulation. Melanoma-specific T cells screened for high relative IL-2 production had a T CM phenotype and superior in vitro proliferative capacity compared to cells with low IL-2 production. To investigate in vivo effector function and self-renewal capability, we allowed melanoma-specific T CM to undergo in vitro expansion and differentiation into lytic effector clones and then adoptively transferred them back into their hosts. These clones targeted skin melanocytes in all five patients and persisted long term and reacquired parental T CM attributes in four patients after transfer. These findings demonstrate the favorable engraftment fitness for human T CM -derived clones, but further efforts to improve their antitumor efficacy are still necessary.
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gene therapy with human and mouse t cell receptors mediates Cancer Regression and targets normal tissues expressing cognate antigen
Blood, 2009Co-Authors: Laura A Johnson, Richard E Royal, Marybeth S Hughes, Udai S Kammula, Richard M Sherry, Mark E Dudley, Richard A. Morgan, Lydie Cassard, James C Yang, John R WunderlichAbstract:Gene therapy of human Cancer using genetically engineered lymphocytes is dependent on the identification of highly reactive T-cell receptors (TCRs) with antitumor activity. We immunized transgenic mice and also conducted high-throughput screening of human lymphocytes to generate TCRs highly reactive to melanoma/melanocyte antigens. Genes encoding these TCRs were engineered into retroviral vectors and used to transduce autologous peripheral lymphocytes administered to 36 patients with metastatic melanoma. Transduced patient lymphocytes were CD45RA− and CD45RO+ after ex vivo expansion. After infusion, the persisting cells displayed a CD45RA+ and CD45RO− phenotype. Gene-engineered cells persisted at high levels in the blood of all patients 1 month after treatment, responding patients with higher ex vivo antitumor reactivity than nonresponders. Objective Cancer Regressions were seen in 30% and 19% of patients who received the human or mouse TCR, respectively. However, patients exhibited destruction of normal melanocytes in the skin, eye, and ear, and sometimes required local steroid administration to treat uveitis and hearing loss. Thus, T cells expressing highly reactive TCRs mediate Cancer Regression in humans and target rare cognate–antigen-containing cells throughout the body, a finding with important implications for the gene therapy of Cancer. This trial was registered at www.ClinicalTrials.gov as NCI-07-C-0174 and NCI-07-C-0175.
James Chihhsin Yang - One of the best experts on this subject based on the ideXlab platform.
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persistence of ctl clones targeting melanocyte differentiation antigens was insufficient to mediate significant melanoma Regression in humans
Clinical Cancer Research, 2015Co-Authors: Smita S Chandran, Luke D. Rothermel, Daniel J. Stephens, Bibhash C Paria, Abhishek K. Srivastava, Richard M Sherry, Mark E Dudley, John R Wunderlich, Robert Somerville, James Chihhsin YangAbstract:Purpose: Adoptive transfer of autologous tumor infiltrating lymphocytes (TIL) can mediate durable Cancer Regression in selected patients with metastatic melanoma. However, the tumor antigens associated with these favorable responses remain unclear. We hypothesized that a clinical strategy involving the iterative adoptive transfer of selected autologous antigen-specific T-cell clones could help systematically define immunologic targets associated with successful Cancer therapy, without the interpretative ambiguity of transferring polyclonal populations. Here, we evaluated the clinical efficacy of CD8 + T-cell clones specific for the melanocyte differentiation antigens (MDA), gp100 and MART-1, respectively. Experimental Design: We conducted two consecutive phase II clinical trials involving the adoptive transfer of highly selected autologous antigen-specific CD8 + T-cell clones against gp100 and MART-1, respectively. Fifteen patients with HLA-A2 + treatment-refractory metastatic melanoma received highly avid MDA-specific CD8 + T-cell clones specific for either gp100 ( n = 10) or MART-1 ( n = 5) with or without intravenous interleukin-2 (IL2) after a lymphodepleting myeloablative preparative regimen. Results: Of the 15 treated patients, we observed immune-mediated targeting of skin melanocytes in 11 patients (73%) and clonal engraftment in eight patients (53%) after cell transfer. There were only transient minor tumor Regressions observed, but no objective tumor responses based on Response Evaluation Criteria in Solid Tumor (RECIST) criteria. Conclusions: Despite successful clonal repopulation and evidence of in vivo antigen targeting, the poor therapeutic efficacy after the adoptive transfer of autologous MDA-specific T cells raises significant concerns regarding future immunotherapy efforts targeting this class of tumor antigens. Clin Cancer Res; 21(3); 534–43. ©2014 AACR.
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Cancer Regression and neurological toxicity following anti mage a3 tcr gene therapy
Journal of Immunotherapy, 2013Co-Authors: Richard A. Morgan, James Chihhsin Yang, Mark E Dudley, Alena Gros, Paul F Robbins, Nachimuthu Chinnasamy, Daniel Abatedaga, Zhili L Zheng, Steven A Feldman, Richard M SherryAbstract:Nine Cancer patients were treated with adoptive cell therapy using autologous anti-MAGE-A3 T-cell receptors (TCR)-engineered T cells. Five patients experienced clinical Regression of their Cancers including 2 on-going responders. Beginning 1-2 days postinfusion, 3 patients (#'s 5, 7, and 8) experienced mental status changes, and 2 patients (5 and 8) lapsed into comas and subsequently died. Magnetic resonance imagining analysis of patients 5 and 8 demonstrated periventricular leukomalacia, and examination of their brains at autopsy revealed necrotizing leukoencephalopathy with extensive white matter defects associated with infiltration of CD3(+)/CD8(+) T cells. Patient 7, developed Parkinson-like symptoms, which resolved over 4 weeks and fully recovered. Immunohistochemical staining of patient and normal brain samples demonstrated rare positively staining neurons with an antibody that recognizes multiple MAGE-A family members. The TCR used in this study recognized epitopes in MAGE-A3/A9/A12. Molecular assays of human brain samples using real-time quantitative-polymerase chain reaction, Nanostring quantitation, and deep-sequencing indicated that MAGE-A12 was expressed in human brain (and possibly MAGE-A1, MAGE-A8, and MAGE-A9). This previously unrecognized expression of MAGE-A12 in human brain was possibly the initiating event of a TCR-mediated inflammatory response that resulted in neuronal cell destruction and raises caution for clinical applications targeting MAGE-A family members with highly active immunotherapies.
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Adoptive cell transfer: a clinical path to effective Cancer immunotherapy
Nature reviews. Cancer, 2008Co-Authors: Steven A Rosenberg, James Chihhsin Yang, Nicholas P Restifo, Richard A. Morgan, Mark E DudleyAbstract:Adoptive cell therapy (ACT) using autologous tumour-infiltrating lymphocytes has emerged as the most effective treatment for patients with metastatic melanoma and can mediate objective Cancer Regression in approximately 50% of patients. The use of donor lymphocytes for ACT is an effective treatment for immunosuppressed patients who develop post-transplant lymphomas. The ability to genetically engineer human lymphocytes and use them to mediate Cancer Regression in patients, which has recently been demonstrated, has opened possibilities for the extension of ACT immunotherapy to patients with a wide variety of Cancer types and is a promising new approach to Cancer treatment.
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ipilimumab anti ctla4 antibody causes Regression of metastatic renal cell Cancer associated with enteritis and hypophysitis
Journal of Immunotherapy, 2007Co-Authors: James Chihhsin Yang, Richard E Royal, Marybeth S Hughes, Udai S Kammula, Richard M Sherry, Suzanne L. Topalian, Catherine Levy, Kimberly B Suri, Tamika AllenAbstract:The inhibitory receptor CTLA4 has a key role in peripheral tolerance of T cells for both normal and tumor-associated antigens. Murine experiments suggested that blockade of CTLA4 might have antitumor activity and a clinical experience with the blocking antibody ipilimumab in patients with metastatic melanoma did show durable tumor Regressions in some patients. Therefore, a phase II study of ipilimumab was conducted in patients with metastatic renal cell Cancer with a primary end point of response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Two sequential cohorts received either 3 mg/kg followed by 1 mg/kg or all doses at 3 mg/kg every 3 weeks (with no intention of comparing cohort response rates). Major toxicities were enteritis and endocrine deficiencies of presumed autoimmune origin. One of 21 patients receiving the lower dose had a partial response. Five of 40 patients at the higher dose had partial responses (95% confidence interval for cohort response rate 4% to 27%) and responses were seen in patients who had previously not responded to IL-2. Thirty-three percent of patients experienced a grade III or IV immune-mediated toxicity. There was a highly significant association between autoimmune events (AEs) and tumor Regression (response rate = 30% with AE, 0% without AE). CTLA4 blockade with ipilimumab induces Cancer Regression in some patients with metastatic clear cell renal Cancer, even if they have not responded to other immunotherapies. These Regressions are highly associated with other immune-mediated events of presumed autoimmune origin by mechanisms as yet undefined.
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Cancer Regression in patients after transfer of genetically engineered lymphocytes
Science, 2006Co-Authors: Richard A. Morgan, Richard E Royal, Udai S Kammula, Richard M Sherry, James Chihhsin Yang, Mark E Dudley, John R Wunderlich, Suzanne L. Topalian, M S Hughes, Nicholas P RestifoAbstract:Through the adoptive transfer of lymphocytes after host immunodepletion, it is possible to mediate objective Cancer Regression in human patients with metastatic melanoma. However, the generation of tumor-specific T cells in this mode of immunotherapy is often limiting. Here we report the ability to specifically confer tumor recognition by autologous lymphocytes from peripheral blood by using a retrovirus that encodes a T cell receptor. Adoptive transfer of these transduced cells in 15 patients resulted in durable engraftment at levels exceeding 10% of peripheral blood lymphocytes for at least 2 months after the infusion. We observed high sustained levels of circulating, engineered cells at 1 year after infusion in two patients who both demonstrated objective Regression of metastatic melanoma lesions. This study suggests the therapeutic potential of genetically engineered cells for the biologic therapy of Cancer.
Irene Caffa - One of the best experts on this subject based on the ideXlab platform.
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abstract ct075 fasting mimicking diet and hormone therapy modulates metabolic factors to promote breast Cancer Regression and reduce side effects
Cancer Research, 2020Co-Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Min Wei, Lorenzo FerrandoAbstract:Breast Cancer (BC) is the most common malignancy with 1.7 million new diagnoses/year and is responsible for more than 450,000 yearly deaths worldwide. Two thirds of BC express the estrogen receptor (ER) and/or progesterone receptor and are referred to as hormone receptor-positive (HR+) BC. Endocrine therapy (ET) is usually active in these tumors, although drug resistance and side effects limit its benefit. Growth factor signaling through the PI3K/AKT/mammalian target of rapamycin (mTOR) and MAP kinase axes enhances ER activity and is a key mechanism underlying endocrine resistance. Water-only fasting (fasting) or plant-based, low-calorie, carbohydrate- and protein-restricted fasting-mimicking diets (FMDs) reduce circulating growth factors, such as insulin and IGF1 Therefore, we hypothesized that these dietary interventions could be used to enhance the activity of ET and delay the occurrence of resistance. For our in vitro experiments we used the HR+ BC cell lines, MCF7, T47D, and ZR-75-1, as well as metastases-derived organoids from patients with HR+ BC. Our in vivo experiments in mouse xenografts of human BC cell lines, were conducted in six-to-eight-week old female NOD SCID or athymic Nude-FoxN1 mice treated with ET w/ or w/o 48-72 hours of fasting/FMD. We monitored tumor growth and mouse survival and collected tumor masses and blood to detect circulating levels of several growth factors, adipokines and cytokines. In vivo add back experiments with fasting-reduced factors were done with IGF1, insulin and leptin. Circulating growth factors and adipo-cytokines were also detected in blood samples from 36 patients with HR+ BC, who were enrolled in either one of two clinical trials (NCT03595540 and NCT03340935) assessing safety and feasibility of periodic FMD in Cancer patients. Patient nutritional status and response to treatment were also monitored in our clinical trials.We found that in HR+ BC models, periodic fasting or FMD enhanced tamoxifen and fulvestrant activity by lowering circulating IGF1, insulin, and leptin levels and by blocking AKT-mTOR signaling via EGR1 and PTEN upregulation. When fulvestrant was combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic FMD cycles promoted long-lasting tumour Regressions and reverted acquired resistance to this regime. Moreover, both fasting and FMD prevented tamoxifen-induced endometrial hyperplasia. In HR+ BC patients receiving ET, FMD cycles caused metabolic changes analogous to those observed in mice, including reduced leptin and IGF1 levels, which were found to remain low for extended periods. In mice, these long-lasting effects were associated with carryover antiCancer activity. Overall, our results provide the rationale for conducting further clinical studies of fasting-based dietary strategies as an adjuvant to ET w/ or w/o CDK4/6 inhibitors in patients with HR+ BC. Citation Format: Irene Caffa, Vanessa Spagnolo, Pamela Becherini, Francesca Valdemarin, Claudio Vernieri, Min Wei, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Lorenzo Ferrando, Luca Mastracci, Michele Cilli, Francesco Piacente, Anna Laura Cremonini, Mario Passalacqua, Valerio Vellone, Gabriele Zoppoli, Michele Cea, Giulia Salvadori, Salvatore Cortellino, Hans Clevers, Filippo De Braud, Alessandro Provenzani, Valter D. Longo, Alessio Nencioni. Fasting-mimicking diet and hormone therapy modulates metabolic factors to promote breast Cancer Regression and reduce side effects [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT075.
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fasting mimicking diet and hormone therapy induce breast Cancer Regression
Nature, 2020Co-Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Min WeiAbstract:Approximately 75% of all breast Cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast Cancer, periodic fasting or a fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour Regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast Cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-Cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast Cancer.
