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Adoptive Cell Transfer
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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.
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.
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.