The Experts below are selected from a list of 21942 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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metastasectomy following immunotherapy with Adoptive Cell Transfer for patients with advanced melanoma
Annals of Surgical Oncology, 2017Co-Authors: Nicholas D Klemen, Steven A Rosenberg, Paul L Feingold, Stephanie L Goff, Marybeth S Hughes, Udai S Kammula, James Chihhsin Yang, David S Schrump, Richard M SherryAbstract:Background Immunotherapeutic treatment strategies including Adoptive Cell Transfer (ACT) for metastatic melanoma are capable of mediating complete and durable responses, as well as partial responses and prolonged disease stabilization. Unfortunately, many patients ultimately develop progressive disease. The role of salvage metastasectomy in managing these patients has not been evaluated.
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Metastasectomy Following Immunotherapy with Adoptive Cell Transfer for Patients with Advanced Melanoma
Annals of surgical oncology, 2016Co-Authors: Nicholas D Klemen, Steven A Rosenberg, Paul L Feingold, Stephanie L Goff, Marybeth S Hughes, Udai S Kammula, James Chihhsin Yang, David S Schrump, Richard M SherryAbstract:Immunotherapeutic treatment strategies including Adoptive Cell Transfer (ACT) for metastatic melanoma are capable of mediating complete and durable responses, as well as partial responses and prolonged disease stabilization. Unfortunately, many patients ultimately develop progressive disease. The role of salvage metastasectomy in managing these patients has not been evaluated. Records of patients with metastatic melanoma treated with ACT at a single institution between 2000 and 2014 were reviewed. Patients with an objective response by RECIST criteria or disease stabilization of at least 6 months and who subsequently developed progressive melanoma and were managed with metastasectomy as the next therapeutic strategy were studied for progression-free survival (PFS) and overall survival (OS). Five additional clinical parameters were also reviewed for association with outcomes. Of 115 patients treated with ACT who met our response criteria and then developed progressive disease, 26 (23%) had surgery. There were no mortalities related to surgical intervention. Median follow-up after surgery was 62 months. Median PFS after surgery was 11 months and five-year OS was 57%. The development of a new site of metastasis after ACT was associated with poor PFS and OS. Surgery after immunotherapy is safe. Long PFS and OS can be achieved by metastasectomy in selected patients with progressive melanoma following treatment with ACT. Clinical variables important for patient selection for metastasectomy after immunotherapy remain largely undefined. Improvements in immunotherapeutic treatment strategies may increase the role of surgery for patients with advanced disease.
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abstract ot1 01 03 Adoptive Cell Transfer act using tumor infiltrating lymphocytes to target neoantigens in patients with metastatic breast cancer
Cancer Research, 2016Co-Authors: Stephanie L Goff, Robert Somerville, Steven A Feldman, Steven A RosenbergAbstract:Background: Adoptive Transfer of tumor infiltrating lymphocytes (TIL) can cure patients with metastatic melanoma, likely based on the recognition of mutated neoantigens (Robbins et al Nature Medicine 2013). Although immunogenic cancer antigens have been found in gastrointestinal cancers (Tran et al Science 2014), this has not been widely studied in patients with breast cancer. The presence of TIL on pathologic examination of triple-negative breast cancers is a positive prognostic marker for disease-free survival and overall survival. This pilot study investigates the ability to grow TIL from breast cancer metastases, to identify personalized non-synonymous mutations and potential neoantigens, and to Adoptively Transfer TIL into patients with breast cancer. Trial Design: This is a single-arm, non-randomized pilot study of Adoptive immunotherapy in patients with metastatic epithelial cancers with a cohort designated for those patients with breast cancer. Once screened for eligibility, patients undergo metastectomy to obtain tissue for culture of TIL and extensive in vitro studies will be performed to identify TIL cultures reactive to neoantigens. Once robust TIL have been identified, the patient is admitted to the National Institutes of Health Clinical Center for conditioning chemotherapy, TIL infusion and interleukin-2. Treatment and recovery generally entails about three weeks as an inpatient. Eligibility Criteria: Patients between the ages of 18 and 70 with metastatic breast cancer who have measurable metastatic disease with at least one lesion resectable with minimal morbidity. Patients must be refractory to standard systemic therapy and must have shown progression on at least two lines of chemotherapy prior to infusion of TIL. Patients must be of good performance status (ECOG 0-1) and have three or fewer brain metastases. In addition, patients must meet common hematologic and chemistry lab criteria. Given the nature of immunotherapy and the rigorous treatment, patients are ineligible for the following reasons: dependence on steroids, cardiac dysfunction, active infection, active major medical illness of the respiratory, cardiovascular or immune system. Specific Aims: The aims are both clinical and research oriented. Of greatest interest is to determine the ability of autologous TIL to mediate tumor regression in patients with metastatic breast cancer. We will also be examining the phenotypic and functional characteristics of TIL derived from breast cancer metastases. We will be attempting to identify non-synonymous immunogenic mutations within resected tumors. Statistical Methods and Trial Accrual: Twenty-one patients will be initially enrolled in the treatment phase of this cohort to assess toxicity and tumor responses. If two or more of the first 21 patients per groups shows a clinical response (PR or CR), accrual will continue to 41 patients, targeting a 20% goal for objective response. We have currently enrolled three patients on the screening phase of this trial and one patient on the treatment phase. Contact Information: National Cancer Institute Surgery Branch Immunotherapy Referral Office, irc@nih.gov, (301) 451-1929, (866) 820-4505 Toll Free. ClinicalTrials.gov: NCT01174121. Citation Format: Goff SL, Feldman SA, Somerville R, Rosenberg SA. Adoptive Cell Transfer (ACT) using tumor infiltrating lymphocytes to target neoantigens in patients with metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-01-03.
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Adoptive Cell Transfer as personalized immunotherapy for human cancer.
Science (New York N.Y.), 2015Co-Authors: Steven A Rosenberg, Nicholas P. RestifoAbstract:Adoptive Cell therapy (ACT) is a highly personalized cancer therapy that involves administration to the cancer-bearing host of immune Cells with direct anticancer activity. ACT using naturally occurring tumor-reactive lymphocytes has mediated durable, complete regressions in patients with melanoma, probably by targeting somatic mutations exclusive to each cancer. These results have expanded the reach of ACT to the treatment of common epithelial cancers. In addition, the ability to genetically engineer lymphocytes to express conventional T Cell receptors or chimeric antigen receptors has further extended the successful application of ACT for cancer treatment.
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Expression of New York esophageal squamous Cell carcinoma-1 in primary and metastatic melanoma.
Human pathology, 2013Co-Authors: Phyu P. Aung, Paul F Robbins, Steven A Rosenberg, Yen Chun Liu, Leomar Y. Ballester, Chyi-chia Richard LeeAbstract:New York esophageal squamous Cell carcinoma-1 (NY-ESO-1), a cancer testis antigen, is an ideal target for Adoptive Cell Transfer immunotherapy. Evidence from several clinical trials in melanoma and other malignancies shows the potential value of targeting the NY-ESO-1 antigen in immune-based therapy of metastatic tumors. However, the incidence of NY-ESO-1 expression in metastatic melanoma is unknown, and thus, it is unclear how many patients might benefit from this therapy. In this study, we analyzed NY-ESO-1 expression in 222 melanoma specimens, including 16 primary and 206 metastatic tumors. Our results support previous findings showing higher expression of NY-ESO-1 in metastatic (58/206; 28.2%) versus primary (0/16) tumors. In addition, our results show that the epithelioid subtype of melanoma has the highest incidence of NY-ESO-1 expression. These findings provide evidence of the value of this specific Adoptive Cell Transfer therapy for the treatment of metastatic melanoma.
Mark E Dudley - One of the best experts on this subject based on the ideXlab platform.
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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, Alena Gros, Katherine Hogan, Eric Tran, Christian S. Hinrichs, John R. Wunderlich, 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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Bioreactors get personal.
Oncoimmunology, 2012Co-Authors: Robert Somerville, Mark E DudleyAbstract:Adoptive Cell Transfer immunotherapy against melanoma is highly effective. However, this therapy has seen limited dissemination, mainly due to the complexity and costs of Cell expansion protocols. Two bioreactors have recently been described that simplify and streamline the production of individualized Cell therapies. Such bioreactors might increase the number of patients that get access to this promising therapeutic modality.
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Clinical scale rapid expansion of lymphocytes for Adoptive Cell Transfer therapy in the WAVE® bioreactor
Journal of translational medicine, 2012Co-Authors: Robert Somerville, Steven A Rosenberg, Laura Devillier, Maria R. Parkhurst, Mark E DudleyAbstract:To simplify clinical scale lymphocyte expansions, we investigated the use of the WAVE®, a closed system bioreactor that utilizes active perfusion to generate high Cell numbers in minimal volumes. We have developed an optimized rapid expansion protocol for the WAVE bioreactor that produces clinically relevant numbers of Cells for our Adoptive Cell Transfer clinical protocols. TIL and genetically modified PBL were rapidly expanded to clinically relevant scales in both static bags and the WAVE bioreactor. Both bioreactors produced comparable numbers of Cells; however the cultures generated in the WAVE bioreactor had a higher percentage of CD4+ Cells and had a less activated phenotype. The WAVE bioreactor simplifies the process of rapidly expanding tumor reactive lymphocytes under GMP conditions, and provides an alternate approach to Cell generation for ACT protocols.
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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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Adoptive Cell Transfer therapy.
Seminars in oncology, 2007Co-Authors: Mark E Dudley, Steven A RosenbergAbstract:Adoptive Cell Transfer therapy has developed into a potent and effective treatment for patients with metastatic melanoma. Current application of this therapy relies on the ex vivo generation of highly active, highly avid tumor-reactive lymphocyte cultures from endogenous tumor infiltrating lymphocytes or on the genetic engineering of Cells using antigen receptor genes to express de novo tumor antigen recognition. When autologous anti-tumor lymphocyte cultures are administered to patients with high-dose interleukin (IL)-2 following a lymphodepleting conditioning regimen, the Cells can expand in vivo, traffic to tumor, and mediate tumor regression and durable objective clinical responses. Current investigation seeks to improve the methods for generating and administering the lymphocyte cultures, and future clinical trials aim to improve durable response rates and extend the patient populations that are candidates for treatment.
Per Thor Straten - One of the best experts on this subject based on the ideXlab platform.
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Genome editing of tumor specific T Cells for sustained functionality in a suppressive tumor microenvironment
Journal for ImmunoTherapy of Cancer, 2015Co-Authors: Sara R Pedersen, Per Thor StratenAbstract:Meeting abstracts Solid tumors are known to be infiltrated by Cells of the immune system, and a positive prognostic value of tumor infiltrating CD8 T Cells are found in most cancers. Such tumor infiltrating lymphocytes (TIL) can be expanded by in vitro culture and used for Adoptive Cell Transfer (
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Adoptive Cell Transfer in the Treatment of Metastatic Melanoma
The Journal of investigative dermatology, 2009Co-Authors: Per Thor Straten, Jürgen C. BeckerAbstract:Adoptive Cell therapy (ACT) for metastatic cancer is the focus of considerable research effort. Rosenberg's laboratory demonstrated a 50% response rate in stage IV melanoma patients treated with in vitro expanded tumor-infiltrating lymphocytes (TILs) and high-dose IL-2 administered after nonmyeloablative conditioning (Dudley et al., 2002a). Because early attempts to use expanded TILs in melanoma therapy failed to demonstrate better efficacy than high-dose IL-2 (Rosenberg et al., 1994), the efficacy of TILs and nonmyeloablative conditioning in combination implies that patient conditioning is crucial to clinical success. The 2002 data represent a milestone in Cellular cancer therapy and a turning point for ACT in cancer treatment.
Paul F Robbins - One of the best experts on this subject based on the ideXlab platform.
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Expression of New York esophageal squamous Cell carcinoma-1 in primary and metastatic melanoma.
Human pathology, 2013Co-Authors: Phyu P. Aung, Paul F Robbins, Steven A Rosenberg, Yen Chun Liu, Leomar Y. Ballester, Chyi-chia Richard LeeAbstract:New York esophageal squamous Cell carcinoma-1 (NY-ESO-1), a cancer testis antigen, is an ideal target for Adoptive Cell Transfer immunotherapy. Evidence from several clinical trials in melanoma and other malignancies shows the potential value of targeting the NY-ESO-1 antigen in immune-based therapy of metastatic tumors. However, the incidence of NY-ESO-1 expression in metastatic melanoma is unknown, and thus, it is unclear how many patients might benefit from this therapy. In this study, we analyzed NY-ESO-1 expression in 222 melanoma specimens, including 16 primary and 206 metastatic tumors. Our results support previous findings showing higher expression of NY-ESO-1 in metastatic (58/206; 28.2%) versus primary (0/16) tumors. In addition, our results show that the epithelioid subtype of melanoma has the highest incidence of NY-ESO-1 expression. These findings provide evidence of the value of this specific Adoptive Cell Transfer therapy for the treatment of metastatic melanoma.
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transition of late stage effector t Cells to cd27 cd28 tumor reactive effector memory t Cells in humans after Adoptive Cell Transfer therapy
Blood, 2005Co-Authors: Daniel J. Powell, Paul F Robbins, Mark E Dudley, Steven A RosenbergAbstract:In humans, the pathways of memory T-Cell differentiation remain poorly defined. Recently, Adoptive Cell Transfer (ACT) of tumor-reactive T lymphocytes to metastatic melanoma patients after nonmyeloablative chemotherapy has resulted in persistence of functional, tumor-reactive lymphocytes, regression of disease, and induction of melanocyte-directed autoimmunity in some responding patients. In the current study, longitudinal phenotypic analysis was performed on melanoma antigen-specific CD8+ T Cells during their transition from in vitro cultured effector Cells to long-term persistent memory Cells following ACT to 6 responding patients. Tumor-reactive T Cells used for therapy were generally late-stage effector Cells with a CD27Lo CD28Lo CD45RA- CD62 ligand- (CD62L-) CC chemokine receptor 7- (CCR7-) interleukin-7 receptor αLo (IL-7RαLo) phenotype. After Transfer, rapid up-regulation and continued expression of IL-7Rα in vivo suggested an important role for IL-7R in immediate and long-term T-Cell survival. Although the tumor antigen-specific T-Cell population contracted between 1 and 4 weeks after Transfer, stable numbers of CD27+ CD28+ tumor-reactive T Cells were maintained, demonstrating their contribution to the development of long-term, melanoma-reactive memory CD8+ T Cells in vivo. At 2 months after Transfer, melanoma-reactive T Cells persisted at high levels and displayed an effector memory phenotype, including a CD27+ CD28+ CD62L- CCR7- profile, which may explain in part their ability to mediate tumor destruction. (Blood. 2005;105:241-250)
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Persistence of multiple tumor-specific T-Cell clones is associated with complete tumor regression in a melanoma patient receiving Adoptive Cell Transfer therapy.
Journal of immunotherapy (Hagerstown Md. : 1997), 2005Co-Authors: Juhua Zhou, Steven A Rosenberg, Mark E Dudley, Paul F RobbinsAbstract:The authors recently reported that Adoptive immunotherapy with autologous tumor-reactive tumor infiltrating lymphocytes (TILs) immediately following a conditioning nonmyeloablative chemotherapy regimen resulted in an enhanced clinical response rate in patients with metastatic melanoma. These observations led to the current studies, which are focused on a detailed analysis of the T-Cell antigen reactivity as well as the in vivo persistence of T Cells in melanoma patient 2098, who experienced a complete regression of all metastatic lesions in lungs and soft tissues following therapy. Screening of an autologous tumor Cell cDNA library using Transferred TILs resulted in the identification of novel mutated growth arrest-specific gene 7 (GAS7) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene transcripts. Direct sequence analysis of the expressed T-Cell receptor beta chain variable regions showed that the Transferred TILs contained multiple T-Cell clonotypes, at least six of which persisted in peripheral blood for a month or more following Transfer. The persistent T Cells recognized both the mutated GAS7 and GAPDH. These persistent tumor-reactive T-Cell clones were detected in tumor Cell samples obtained from the patient following Adoptive Cell Transfer and appeared to be represented at higher levels in the tumor sample obtained 1 month following Transfer than in the peripheral blood obtained at the same time. Overall, these results indicate that multiple tumor-reactive T Cells can persist in the peripheral blood and at the tumor site for prolonged times following Adoptive Transfer and thus may be responsible for the complete tumor regression in this patient.
Lorenzo Galluzzi - One of the best experts on this subject based on the ideXlab platform.
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Trial Watch: Adoptive Cell Transfer for anticancer immunotherapy.
Oncoimmunology, 2014Co-Authors: Erika Vacchelli, Wolf Hervé Fridman, Jérôme Galon, Eric Tartour, Laurence Zitvogel, Guido Kroemer, Alexander Eggermont, Lorenzo GalluzziAbstract:The expression "Adoptive Cell Transfer" (ACT) is commonly employed to indicate an immunotherapeutic regimen involving the isolation of autologous blood-borne or tumor-infiltrating lymphocytes, their selection/expansion/activation ex vivo, and their reinfusion into the patient, most often in the context of lymphodepleting pre-conditioning and in combination with immunostimulatory treatments. Optionally, the Cellular material for ACT is genetically manipulated before expansion to (1) target specific tumor-associated antigens; (2) endogenously express immunostimulatory molecules; and/or (3) persist for long periods upon reinfusion. Consistent efforts have been dedicated at the amelioration of this immunotherapeutic regimen throughout the past decade, resulting in the establishment of ever more efficient and safer ACT protocols. Accordingly, the number of clinical trials testing ACT in oncological indications does not cease to increase. In this Trial Watch, we summarize recent developments in this exciting area of research, covering both high-impact studies that have been published during the last 12 months and clinical trials that have been launched in the same period to evaluate the safety and therapeutic potential of ACT in cancer patients.
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Trial Watch: Adoptive Cell Transfer for anticancer immunotherapy.
Oncoimmunology, 2013Co-Authors: Erika Vacchelli, Wolf Hervé Fridman, Jérôme Galon, Eric Tartour, Laurence Zitvogel, Guido Kroemer, Alexander Eggermont, Lorenzo GalluzziAbstract:Adoptive Cell Transfer (ACT) represents a prominent form of immunotherapy against malignant diseases. ACT is conceptually distinct from dendritic Cell-based approaches (which de facto constitute Cellular vaccines) and allogeneic transplantation (which can be employed for the therapy of hematopoietic tumors) as it involves the isolation of autologous lymphocytes exhibiting antitumor activity, their expansion/activation ex vivo and their reintroduction into the patient. Re-infusion is most often performed in the context of lymphodepleting regimens (to minimize immunosuppression by host Cells) and combined with immunostimulatory interventions, such as the administration of Toll-like receptor agonists. Autologous Cells that are suitable for ACT protocols can be isolated from tumor-infiltrating lymphocytes or generated by engineering their circulating counterparts for the expression of transgenic tumor-specific T-Cell receptors. Importantly, lymphocytes can be genetically modified prior to re-infusion for increasing their persistence in vivo, boosting antitumor responses and minimizing side effects. Moreover, recent data indicate that exhausted antitumor T lymphocytes may be rejuvenated in vitro by exposing them to specific cytokine cocktails, a strategy that might considerably improve the clinical success of ACT. Following up the Trial Watch that we published on this topic in the third issue of OncoImmunology (May 2012), here we summarize the latest developments in ACT-related research, covering both high-impact studies that have been published during the last 13 months and clinical trials that have been initiated in the same period to assess the antineoplastic profile of this form of Cellular immunotherapy.
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Trial Watch: Adoptive Cell Transfer immunotherapy.
Oncoimmunology, 2012Co-Authors: Lorenzo Galluzzi, Erika Vacchelli, Alexander M.m. Eggermont, Wolf Hervé Fridman, Jérôme Galon, Catherine Sautès-fridman, Eric Tartour, Laurence Zitvogel, Guido KroemerAbstract:During the last two decades, several approaches for the activation of the immune system against cancer have been developed. These include rather unselective maneuvers such as the systemic administration of immunostimulatory agents (e.g., interleukin-2) as well as targeted interventions, encompassing highly specific monoclonal antibodies, vaccines and Cell-based therapies. Among the latter, Adoptive Cell Transfer (ACT) involves the selection of autologous lymphocytes with antitumor activity, their expansion/activation ex vivo, and their reinfusion into the patient, often in the context of lymphodepleting regimens (to minimize endogenous immunosuppression). Such autologous Cells can be isolated from tumor-infiltrating lymphocytes or generated by manipulating circulating lymphocytes for the expression of tumor-specific T-Cell receptors. In addition, autologous lymphocytes can be genetically engineered to prolong their in vivo persistence, to boost antitumor responses and/or to minimize side effects. ACT has recently been shown to be associated with a consistent rate of durable regressions in melanoma and renal Cell carcinoma patients and holds great promises in several other oncological settings. In this Trial Watch, we will briefly review the scientific rationale behind ACT and discuss the progress of recent clinical trials evaluating the safety and effectiveness of Adoptive Cell Transfer as an anticancer therapy.