The Experts below are selected from a list of 360 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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identification of neoantigen reactive tumor infiltrating Lymphocytes in primary bladder cancer
Journal of Immunology, 2019Co-Authors: Vid Leko, Zhili Zheng, Todd D Prickett, Jared J Gartner, Lucas A Mcduffie, Andrea B Apolo, Piyush K Agarwal, Steven A RosenbergAbstract:Immune checkpoint inhibitors are effective in treating a variety of malignancies, including metastatic bladder cancer. A generally accepted hypothesis suggests that immune checkpoint inhibitors induce tumor regressions by reactivating a population of endogenous Tumor-Infiltrating Lymphocytes (TILs) that recognize cancer neoantigens. Although previous studies have identified neoantigen-reactive TILs from several types of cancer, no study to date has shown whether neoantigen-reactive TILs can be found in bladder tumors. To address this, we generated TIL cultures from patients with primary bladder cancer and tested their ability to recognize tumor-specific mutations. We found that CD4+ TILs from one patient recognized mutated C-terminal binding protein 1 in an MHC class II-restricted manner. This finding suggests that neoantigen-reactive TILs reside in bladder cancer, which may help explain the effectiveness of immune checkpoint blockade in this disease and also provides a rationale for the future use of adoptive T cell therapy targeting neoantigens in bladder cancer.
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outcomes of adoptive cell transfer with tumor infiltrating Lymphocytes for metastatic melanoma patients with and without brain metastases
Journal of Immunotherapy, 2018Co-Authors: Gautam U Mehta, Stephanie L Goff, Udai S Kammula, James Chihhsin Yang, Steven A Rosenberg, Donald E White, Parisa Malekzadeh, Thomas E Shelton, John A Butman, Richard M SherryAbstract:Brain metastases cause significant morbidity and mortality in patients with metastatic melanoma. Although adoptive cell therapy (ACT) with Tumor-Infiltrating Lymphocytes (TIL) can achieve complete and durable remission of advanced cutaneous melanoma, the efficacy of this therapy for brain metastases is unclear. Records of patients with M1c melanoma treated with ACT using TIL, including patients with treated and untreated brain metastases, were analyzed. Treatment consisted of preparative chemotherapy, autologous TIL infusion, and high-dose interleukin-2. Treatment outcomes, sites of initial tumor progression, and overall survival were analyzed. Among 144 total patients, 15 patients with treated and 18 patients with untreated brain metastases were identified. Intracranial objective responses (OR) occurred in 28% patients with untreated brain metastases. The systemic OR rates for patients with M1c disease without identified brain disease, treated brain disease, and untreated brain disease, and were 49%, 33% and 33%, respectively, of which 59%, 20% and 16% were durable at last follow-up. The site of untreated brain disease was the most likely site of initial tumor progression (61%) in patients with untreated brain metastases. Overall, we found that ACT with TIL can eliminate small melanoma brain metastases. However, following TIL therapy these patients frequently progress in the brain at a site of untreated brain disease. Patients with treated or untreated brain disease are less likely to achieve durable systemic ORs following TIL therapy compared with M1c disease and no history of brain disease. Melanoma brain metastases likely require local therapy despite the systemic effect of ACT.
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diversity of mutated antigen recognition by tumor infiltrating Lymphocytes from patients with metastatic melanoma
Journal for ImmunoTherapy of Cancer, 2015Co-Authors: Jessica S Crystal, Mona Elgamil, Todd D Prickett, Jared J Gartner, Maria R Parkhurst, Yongchen Lu, Alena Gros, Yong Li, Kasia Trebskamcgowan, Steven A RosenbergAbstract:The adoptive cell transfer (ACT) of autologous tumor infiltrating Lymphocytes (TIL) can mediate durable, complete tumor regression in approximately 20% of patients with metastatic melanoma. Recent observations suggest that autologous melanoma TIL administered to multiple patients in ACT protocols can recognize 1 or more tumor-specific somatic mutations, findings facilitated by recent advances in whole exome sequencing and RNA-seq methods.
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personalized immunotherapy for non small cell lung cancer through identification of tumor specific mutations by next generation sequencing and adoptive transfer of tumor infiltrating Lymphocytes that recognize neoantigens
Journal for ImmunoTherapy of Cancer, 2015Co-Authors: Kenichi Hanada, Robert Somerville, Paul F Robbins, Steven A Rosenberg, Todd D Prickett, Jared J Gartner, Christopher Chow, Raul Gil Hoyos, Katherine Hogan, James Chihhsin YangAbstract:Meeting abstracts Patients with metastatic melanoma can be successfully treated with adoptive transfer of tumor infiltrating Lymphocytes (TIL). In 93 patients with over 5 year follow-up, the overall response rate was 56% and 20% achieved durable complete responses persisting in excess of 7 years.
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impact of a recombinant fowlpox vaccine on the efficacy of adoptive cell therapy with tumor infiltrating Lymphocytes in a patient with metastatic melanoma
Journal of Immunotherapy, 2009Co-Authors: Franz O Smith, Steven A Rosenberg, John R Wunderlich, Jacob A Klapper, Mark E DudleyAbstract:A patient with metastatic melanoma who had progressive disease after prior surgical resections, high dose interleukin-2, and anti-cytotoxic T lymphocyte antigen-4 antibody received sequential treatments with autologous tumor infiltrating Lymphocytes that recognized the gp100 melanocyte differentiation antigen. Although no clinical response was seen when cells were administered alone, an objective clinical response to therapy was seen with tumor infiltrating Lymphocytes administered together with a highly immunogenic fowlpox vaccine expressing a gp100: 209-217 (210M) epitope. Persistence of the transferred antigen-specific Lymphocytes in the peripheral blood was observed only after adoptive cell therapy plus administration of vaccine. Cell proliferation in vitro was further stimulated by additional vaccine and interleukin-2. The patient has an ongoing partial response at 10 months after the last treatment.
Peter H Watson - One of the best experts on this subject based on the ideXlab platform.
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tumor infiltrating Lymphocytes predict response to anthracycline based chemotherapy in estrogen receptor negative breast cancer
Breast Cancer Research, 2011Co-Authors: Nathan R West, Katy Milne, Pauline T Truong, Nicol Macpherson, Brad H Nelson, Peter H WatsonAbstract:Introduction Infiltration of breast tumors by Tumor-Infiltrating Lymphocytes (TIL) has been associated with sensitivity to anthracycline-based chemotherapy. However, it is unclear whether this is true within the estrogen receptor-alpha (ER)-negative subset of breast tumors that frequently manifest high TIL levels.
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tumor infiltrating Lymphocytes predict response to anthracycline based chemotherapy in estrogen receptor negative breast cancer
Breast Cancer Research, 2011Co-Authors: Nathan R West, Katy Milne, Pauline T Truong, Nicol Macpherson, Brad H Nelson, Peter H WatsonAbstract:Introduction Infiltration of breast tumors by Tumor-Infiltrating Lymphocytes (TIL) has been associated with sensitivity to anthracycline-based chemotherapy. However, it is unclear whether this is true within the estrogen receptor-alpha (ER)-negative subset of breast tumors that frequently manifest high TIL levels.
David L Rimm - One of the best experts on this subject based on the ideXlab platform.
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pd l1 expression correlates with tumor infiltrating Lymphocytes and response to neoadjuvant chemotherapy in breast cancer
Cancer immunology research, 2015Co-Authors: Hallie Wimberly, Jason R Brown, Kurt A Schalper, Herbert Haack, Matthew Ren Silver, Christian Nixon, Veerle Bossuyt, Lajos Pusztai, Donald R Lannin, David L RimmAbstract:Programmed death 1 ligand 1 (PD-L1) is an immune regulatory molecule that limits antitumor immune activity. Targeting of PD-L1 and other immune checkpoint proteins has shown therapeutic activity in various tumor types. The expression of PD-L1 and its correlation with response to neoadjuvant chemotherapy in breast cancer has not been studied extensively. Our goal was to assess PD-L1 expression in a cohort of breast cancer patients treated with neoadjuvant chemotherapy. Pretreatment biopsies from 105 patients with breast cancer from Yale New Haven Hospital that subsequently received neoadjuvant chemotherapy were assessed for PD-L1 protein expression by automated quantitative analysis with a rabbit monoclonal antibody (E1L3N) to the cytoplasmic domain of PD-L1. In addition, Tumor-Infiltrating Lymphocytes (TIL) were assessed on hematoxylin and eosin slides. PD-L1 expression was observed in 30% of patients, and it was positively associated with hormone-receptor-negative and triple-negative status and high levels of TILs. Both TILs and PD-L1 measured in the epithelium or stroma predicted pathologic complete response (pCR) to neoadjuvant chemotherapy in univariate and multivariate analyses. However, because they are strongly associated, TILs and PD-L1 cannot both be included in a significant multivariate model. PD-L1 expression is prevalent in breast cancer, particularly hormone-receptor-negative and triple-negative patients, indicating a subset of patients that may benefit from immune therapy. Furthermore, PD-L1 and TILs correlate with pCR, and high PD-L1 predicts pCR in multivariate analysis.
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pd l1 expression correlates with tumor infiltrating Lymphocytes and response to neoadjuvant chemotherapy in breast cancer
Cancer immunology research, 2015Co-Authors: Hallie Wimberly, Jason R Brown, Kurt A Schalper, Herbert Haack, Matthew Ren Silver, Christian Nixon, Veerle Bossuyt, Lajos Pusztai, Donald R Lannin, David L RimmAbstract:Programmed death 1 ligand 1 (PD-L1) is an immune regulatory molecule that limits anti-tumor immune activity. Targeting of PD-L1 and other immune checkpoint proteins has shown therapeutic activity in various tumor types. The expression of PD-L1 and its correlation with response to neoadjuvant chemotherapy in breast cancer has not been studied extensively. Our goal was to assess PD-L1 expression in a cohort of breast cancer patients treated with neoadjuvant chemotherapy.Pre-treatment biopsies from 105 breast cancer patients from Yale New Haven Hospital that subsequently received neoadjuvant chemotherapy were assessed for PD-L1 protein expression by automated quantitative analysis (AQUA) with a rabbit monoclonal antibody (E1L3N) to the cytoplasmic domain. Additionally, tumor infiltrating Lymphocytes (TILs) were assessed on H&E slides.PD-L1 expression was observed in 30% of patients and it was positively associated with hormone receptor negative and triple-negative status and high levels of TILs. Both TILs and PD-L1 measured in the epithelium or stroma predicted pathological complete response (pCR) to neoadjuvant chemotherapy in univariate and multivariate analysis. However, since they are strongly associated, TILs and PD-L1 cannot both be included in a significant multivariate model.PD-L1 expression is prevalent in breast cancer, particularly hormone receptor negative and triple-negative patients, indicating a subset of patients which may benefit from immune therapy. Furthermore, PD-L1 and TILs correlate with pCR and high PD-L1 predicts pCR in multivariate analysis.
Sherene Loi - One of the best experts on this subject based on the ideXlab platform.
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tumor infiltrating Lymphocytes and prognosis a pooled individual patient analysis of early stage triple negative breast cancers
Journal of Clinical Oncology, 2019Co-Authors: Sherene Loi, Sylvia Adams, Damien Drubay, Giancarlo Pruneri, Prudence A Francis, Magali Lacroixtriki, Heikki Joensuu, Maria Vittoria Dieci, Sunil BadveAbstract:PurposeThe aim of the current study was to conduct a pooled analysis of studies that have investigated the prognostic value of Tumor-Infiltrating Lymphocytes (TILs) in early-stage triple negative b...
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tumor infiltrating Lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2 positive and triple negative primary breast cancers
Journal of Clinical Oncology, 2015Co-Authors: Carsten Denkert, Sherene Loi, Gunter Von Minckwitz, Jan C Brase, Bruno Valentin Sinn, Stephan Gade, Ralf Kronenwett, Berit M Pfitzner, Christoph SalatAbstract:Purpose Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy. To investigate the immunogenicity of human epidermal growth factor receptor 2 (HER2) –positive and triple-negative (TN) breast cancers (BCs), we evaluated Tumor-Infiltrating Lymphocytes (TILs) and immunologically relevant genes in the neoadjuvant GeparSixto trial. Patients and Methods GeparSixto investigated the effect of adding carboplatin (Cb) to an anthracycline-plus-taxane combination (PM) on pathologic complete response (pCR). A total of 580 tumors were evaluated before random assignment for stromal TILs and lymphocyte-predominant BC (LPBC). mRNA expression of immune-activating (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21) as well as immunosuppressive factors (IDO1, PD-1, PD-L1, CTLA4, FOXP3) was measured in 481 tumors. Results Increased levels of stromal TILs predicted pCR in univariable (P < .001) and multivariable analyses (P < .001). pCR rate was 59.9% in LPBC and 33.8% for non-LPBC (P < .001). pC...
Mark E Dudley - One of the best experts on this subject based on the ideXlab platform.
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randomized prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor infiltrating Lymphocytes for patients with metastatic melanoma
Journal of Clinical Oncology, 2016Co-Authors: Stephanie L Goff, David N Danforth, Daniel Zlott, Robert Somerville, Richard M Sherry, James Chihhsin Yang, Mark E Dudley, John R Wunderlich, Deborah Citrin, Udai S KammulaAbstract:PurposeAdoptive cell transfer, the infusion of large numbers of activated autologous Lymphocytes, can mediate objective tumor regression in a majority of patients with metastatic melanoma (52 of 93; 56%). Addition and intensification of total body irradiation (TBI) to the preparative lymphodepleting chemotherapy regimen in sequential trials improved objective partial and complete response (CR) rates. Here, we evaluated the importance of adding TBI to the adoptive transfer of Tumor-Infiltrating Lymphocytes (TIL) in a randomized fashion.Patients and MethodsA total of 101 patients with metastatic melanoma, including 76 patients with M1c disease, were randomly assigned to receive nonmyeloablative chemotherapy with or without 1,200 cGy TBI before transfer of Tumor-Infiltrating lymphcytes. Primary end points were CR rate (as defined by Response Evaluation Criteria in Solid Tumors v1.0) and overall survival (OS). Clinical and laboratory data were analyzed for correlates of response.ResultsCR rates were 24% in bo...
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tumor infiltrating Lymphocytes genetically engineered with an inducible gene encoding interleukin 12 for the immunotherapy of metastatic melanoma
Clinical Cancer Research, 2015Co-Authors: Ling Zhang, Richard M Sherry, Mark E Dudley, Richard A Morgan, Joal D Beane, Zhili Zheng, Sadik H Kassim, Azam V Nahvi, Lien T Ngo, Giao Q PhanAbstract:Purpose: Infusion of interleukin-12 (IL12) can mediate antitumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the antitumor activity of adoptively transferred human Tumor-Infiltrating Lymphocytes (TILs) genetically engineered to secrete single-chain IL12 selectively at the tumor site. Experimental Design: Thirty-three patients with metastatic melanoma were treated in a cell dose–escalation trial of autologous TILs transduced with a gene encoding a single-chain IL12 driven by a nuclear factor of the activated T cells promoter (NFAT.IL12). No IL2 was administered. Results: The administration of 0.001 to 0.1 × 10 9 NFAT.IL12–transduced TILs to 17 patients resulted in a single, objective response (5.9%). However, at doses between 0.3 and 3 × 10 9 cells, 10 of 16 patients (63%) exhibited objective clinical responses. The responses tended to be short, and the administered IL12-producing cells rarely persisted at 1 month. Increasing cell doses were associated with high serum levels of IL12 and IFNγ as well as clinical toxicities, including liver dysfunction, high fevers, and sporadic life-threatening hemodynamic instability. Conclusions: In this first-in-man trial, administration of TILs transduced with an inducible IL12 gene mediated tumor responses in the absence of IL2 administration using cell doses 10- to 100-fold lower than conventional TILs. However, due to toxicities, likely attributable to the secreted IL12, further refinement will be necessary before this approach can be safely used in the treatment of cancer patients. Clin Cancer Res; 21(10); 2278–88. ©2015 AACR .
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randomized selection design trial evaluating cd8 enriched versus unselected tumor infiltrating Lymphocytes for adoptive cell therapy for patients with melanoma
Journal of Clinical Oncology, 2013Co-Authors: Mark E Dudley, Robert Somerville, Colin Gross, Young Hong, Nicholas Schaub, Shannon F Rosati, Donald E White, Debbie Ann N Nathan, Nicholas P Restifo, Seth M SteinbergAbstract:Purpose Adoptive cell therapy (ACT) with autologous Tumor-Infiltrating Lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown. Patients and Methods Patients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8+-enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points. Results Thirty-four patients received unselected young TILs with a median of 8.0% CD4+ Lymphocytes, and 35 patients received CD8+-enriched TILs with a median of 0.3% CD4+ Lymphocytes. One month after TIL infusion, patients who received CD8+-enriched TILs had significantly fewer CD4+ peripheral blood Lymphocytes (P = .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [RECIST]), a...
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cd8 enriched young tumor infiltrating Lymphocytes can mediate regression of metastatic melanoma
Clinical Cancer Research, 2010Co-Authors: Mark E Dudley, Udai S Kammula, Richard M Sherry, James Chihhsin Yang, Giao Q Phan, Colin Gross, Michelle M Langhan, Marcos R Garcia, Marybeth S Hughes, Deborah CitrinAbstract:Purpose: Tumor‐infiltrating Lymphocytes (TIL) and interleukin (IL)-2 administered following lymphodepletion can cause the durable complete regression of bulky metastatic melanoma in patients refractory to approved treatments. However, the generation of a unique tumor-reactive TIL culture for each patient may be prohibitively difficult. We therefore investigated the clinical and immunologic impact of unscreened, CD8+ enriched “young” TIL. Experimental Design: Methods were developed for generating TIL that minimized the time in culture and eliminated the individualized tumor-reactivity screening step. Thirty-three patients were treated with these CD8+ enriched young TIL and IL-2 following nonmyeloablative lymphodepletion (NMA). Twenty-three additional patients were treated with CD8+ enriched young TIL and IL-2 after lymphodepletion with NMA and 6 Gy of total body irradiation. Results: Young TIL cultures for therapy were successfully established from 83% of 122 consecutive melanoma patients. Nineteen of 33 patients (58%) treated with CD8+ enriched young TIL and NMA had an objective response (Response Evaluation Criteria in Solid Tumors) including 3 complete responders. Eleven of 23 patients (48%) treated with TIL and 6 Gy total body irradiation had an objective response including 2 complete responders. At 1 month after TIL infusion the absolute CD8+ cell numbers in the periphery were highly correlated with response. Conclusions: This study shows that a rapid and simplified method can be used to reliably generate CD8+ enriched young TIL for administration as an individualized therapy for advanced melanoma, and may allow this potentially effective treatment to be applied at other institutions and to reach additional patients. Clin Cancer Res; 16(24); 6122–31. ©2010 AACR .
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impact of a recombinant fowlpox vaccine on the efficacy of adoptive cell therapy with tumor infiltrating Lymphocytes in a patient with metastatic melanoma
Journal of Immunotherapy, 2009Co-Authors: Franz O Smith, Steven A Rosenberg, John R Wunderlich, Jacob A Klapper, Mark E DudleyAbstract:A patient with metastatic melanoma who had progressive disease after prior surgical resections, high dose interleukin-2, and anti-cytotoxic T lymphocyte antigen-4 antibody received sequential treatments with autologous tumor infiltrating Lymphocytes that recognized the gp100 melanocyte differentiation antigen. Although no clinical response was seen when cells were administered alone, an objective clinical response to therapy was seen with tumor infiltrating Lymphocytes administered together with a highly immunogenic fowlpox vaccine expressing a gp100: 209-217 (210M) epitope. Persistence of the transferred antigen-specific Lymphocytes in the peripheral blood was observed only after adoptive cell therapy plus administration of vaccine. Cell proliferation in vitro was further stimulated by additional vaccine and interleukin-2. The patient has an ongoing partial response at 10 months after the last treatment.
