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Steven A Rosenberg - One of the best experts on this subject based on the ideXlab platform.
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abstract lb 221 diversity of Tumor Infiltrating Lymphocyte recognition of diverse mutated antigens in cutaneous melanoma
Cancer Research, 2015Co-Authors: Jessica S Crystal, Steven A Rosenberg, Todd D Prickett, Jared J Gartner, Maria R Parkhurst, Alena Gros, Mona Elgamil, Paul F RobbinsAbstract:The adoptive transfer of autologous Tumor Infiltrating Lymphocytes (TIL) can mediate long term Tumor regression in some patients with metastatic melanoma. Recent observations suggest that autologous melanoma TIL administered to patients in adoptive T cell therapy (ACT) protocols may frequently recognize multiple Tumor-specific somatic mutations, findings that have been facilitated by advances in whole exome sequencing and RNAseq methods. In an attempt to evaluate the antigenic diversity of TIL and gain some insights into the potential association between the recognition of mutated antigens and clinical responses to TIL therapy, we analyzed between 7 and 30 individual cultures derived from resected melanoma Tumor fragments and pooled populations of administered TIL from each of 5 patients for their ability to recognize mutated antigens expressed by patients’ autologous Tumors. Two of the patients who were evaluated exhibited durable complete Tumor regressions, 1 exhibited a partial response, and 2 were non-responders to ACT. Screening assays were carried out by evaluating the interferon gamma release stimulated by the co-culture of autologous patient TIL with autologous dendritic cells or EBV transformed B cells transfected with mini-genes encoding mutated antigens identified by exomic sequencing of patient Tumors. Using this approach, we identified 10, 3, and 2 mutated antigens targeted by TIL from the 3 patients who responded to ACT. The TIL that were administered to 1 of the non-responders appeared to recognize at least 4 mutated antigens, whereas TIL administered to the second non-responder failed to recognize any of the mutated minigenes that were tested. Immuno-dominant mutated antigens that were recognized by the majority of the evaluated TIL fragment cultures, as well as the bulk population of infusion TIL, could be identified in each of the 4 patients in this study for whom mutated antigen targets could be identified. In addition, 1 or more sub-dominant mutated antigens that were recognized by one or a relatively small percentage of the screened TIL fragment cultures were identified from each of these same 4 patients. Future studies will be directed at developing methods for enriching T cells reactive with mutated epitopes from TIL or peripheral blood in an attempt to enhance the effectiveness of ACT for the treatment of patients with metastatic melanoma and that will hopefully lead to the development of effective therapies for the treatment of patients with other malignancies. Note: This abstract was not presented at the meeting. Citation Format: Jessica S. Crystal, Todd Prickett, Yong-Chen Lu, Jared J. Gartner, Maria Parkhurst, Alena Gros, Yong F. Li, Mona El-Gamil, Steven A. Rosenberg, Paul F. Robbins. Diversity of Tumor Infiltrating Lymphocyte recognition of diverse mutated antigens in cutaneous melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-221. doi:10.1158/1538-7445.AM2015-LB-221
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Tumor Infiltrating Lymphocyte therapy for metastatic melanoma analysis of Tumors resected for til
Journal of Immunotherapy, 2010Co-Authors: Stephanie L Goff, Mark E Dudley, John R Wunderlich, Steven A Rosenberg, Richard M. Sherry, Jacob A Klapper, Franz O Smith, Donald E White, Seth M Steinberg, James Chihhsin YangAbstract:Adoptive cell transfer of Tumor-Infiltrating Lymphocytes (TILs) can mediate objective Tumor regression in 49% to 72% of patients with many long-term durable responses. To undergo treatment a patient must have (1) a resectable Tumor from which (2) TIL can be generated that (3) exhibit Tumor-specific reactivity. From July 2002 to July 2007, 787 Tumors from 402 patients were processed for possible use in the generation of TIL, leading to the eventual treatment of 107 patients (27%). Viable TILs were generated in 376 patients (94%), and active, specific TILs were identified in 269 patients (67%). Patient demographics and Tumor characteristics were analyzed for possible prognostic factors for growth and activity. Gastrointestinal-derived TIL grew less frequently, whereas lymph node and lung-derived TIL exhibited specific activity more often. TIL that grew and exhibited specific reactivity were from Tumors that were larger in diameter and digests that had a higher percentage of Lymphocytes. Despite these considerations, active, specific TIL could be generated from almost any site of metastasis. As more centers begin exploring the use of adoptive transfer with TIL, this compendium may provide a framework for therapeutic decision making and future investigation.
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enrichment of cd8 cells from melanoma Tumor Infiltrating Lymphocyte cultures reveals Tumor reactivity for use in adoptive cell therapy
Journal of Immunotherapy, 2010Co-Authors: Peter A Prieto, Steven A Rosenberg, John R Wunderlich, Katherine H Durflinger, Mark E DudleyAbstract:Adoptive cell therapy (ACT) using Tumor-Infiltrating Lymphocytes (TIL) for metastatic melanoma has shown objective response rates as high as 72%. The successful application of this therapy requires the selection of unique Tumor-reactive Lymphocyte cultures for each patient. This is a technically and logistically difficult undertaking, and patients who do not have Tumor-reactive TIL are not considered eligible for treatment. To simplify the methods of TIL generation and extend TIL-based immunotherapy to additional patients, methods were developed to use unselected, minimally cultured ("young") TIL. Young TIL cultures contain a variable number of CD8(+), CD4(+), and CD3(-)CD56(+) natural killer cells. In this study we retrospectively investigated a role for these subsets in the clinical outcome of patients treated with TIL derived from selected microcultures. This analysis demonstrated a suggestive but nonsignificant association between the number of CD8(+) cells administered and Tumor regression. We therefore investigated the feasibility of selecting CD8(+) cells from young TIL cultures for ACT therapy. The available methods for clinical scale CD8(+) enrichment proved inadequate for TIL, so an optimized CD8(+) enrichment method was developed and is reported here. We observed that CD8 (+)enrichment of some TIL cultures revealed in vitro Tumor recognition that was not evident in bulk culture, and an improved in vitro recognition of Tumor in other TIL cultures. In addition, the enriched CD8(+) young TIL expanded more reliably and predictably in rapid expansions than the bulk TIL. Thus, optimized CD8(+) selection combines the benefits of antigen-selected TIL and young TIL for generating Lymphocyte cultures for ACT, and should be evaluated in cell transfer therapy protocols.
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generation of Tumor Infiltrating Lymphocyte cultures for use in adoptive transfer therapy for melanoma patients
Journal of Immunotherapy, 2003Co-Authors: Mark E Dudley, Thomas E Shelton, Jos Even, John R Wunderlich, Steven A RosenbergAbstract:The generation of T Lymphocytes with specific reactivity against Tumor antigens is a prerequisite for effective adoptive transfer therapies. Melanoma-specific Lymphocyte cultures can be established from Tumor Infiltrating Lymphocytes (TILs) by in vitro culture in high levels of IL-2. We have optimized methods for generating melanoma-reactive TIL cultures from small resected Tumor specimens. We report a retrospective analysis of 860 attempted TIL cultures from 90 sequential melanoma biopsy specimens from 62 HLA-A2+ patients. Multiple independent TIL derived from a single Tumor often exhibited substantial functional and phenotypic variation. Tumor specific activity was detected in TIL from 29 (81%) of 36 patients screened. TIL cultures selected for high activity were generally capable of large numerical expansion using a single round of a rapid expansion protocol. Limited clonal T-cell populations in an oligoclonal TIL culture could confer specific Tumor recognition in these highly selected, highly expanded TIL cultures. These methods were efficient at generating TILs suitable for adoptive transfer therapy.
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the waardenburg syndrome type 4 gene sox10 is a novel Tumor associated antigen identified in a patient with a dramatic response to immunotherapy
Cancer Research, 2002Co-Authors: Hung T Khong, Steven A RosenbergAbstract:In this study, we have identified, for the first time, the presence of de novo cellular immune reactivity against the transcription factor SOX10, using Tumor-Infiltrating Lymphocytes obtained from a patient who experienced a dramatic clinical response to immunotherapy. SOX10 acts as a critical transactivator of tyrosinase-related protein-2 during melanoblast development and a potent transactivator of micropthalmia-associated transcription factor, which is considered to be a master gene that controls the development and postnatal survival of melanocytes. Mutations in SOX10 result in Waardenburg syndrome type 4. The overlapping epitopes AWISKPPGV and SAWISKPPGV, designated SOX10: 332–340 and SOX10: 331–340, respectively, were recognized by Tumor-Infiltrating Lymphocyte clone M37 in an HLA-A2-restricted fashion.
Balazs Acs - One of the best experts on this subject based on the ideXlab platform.
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abstract p3 08 12 an open source automated Tumor Infiltrating Lymphocyte algorithm for prognosis in triple negative breast cancer
Cancer Research, 2020Co-Authors: Yalai Bai, Balazs Acs, Jon Zugazagoitia, Sandra Martinezmorilla, Fahad Shabbir Ahmed, David L RimmAbstract:Background: The presence of high TILs (Tumor Infiltrating Lymphocytes) have been shown to be predictive of response to chemotherapy and is also a prognostic factor associated with better outcome in breast cancer, especially in early stage triple-negative (TNBC) and HER2-positive breast cancers. TIL assessment, while now more standardized due to the efforts of Salgado and the International TIL Working Group (https://www.tilsinbreastcancer.org/), are still a subjective test with variability in evaluation that has prevented broad adoption. Given the advances in application of artificial intelligence to pathology images, we believe the next step for TILs is to make them automated and objective and to identify a standardized and meaning TIL cut-point. The aim of this study is to build an open source, HE N=87, Set C; N=183, and Set D; N=83) in both tissue microarray (TMA) and whole tissue section (WTS) format. Results: Using an optimal cut point (30%) derived from TNBC cohort training set A, patients with high eTILs% displayed an overall survival benefit (HR 0.4, p=0.0150). This algorithm was then applied in other three TNBC validation sets (Set B: HR=0.42, p=0.0033; Set C: HR=0.42, p=0.0127; Set D in TMA format: HR=0.39, p=0.0089). For Set D, we also tested WTS format which showed HR=0.23, (p=0.0155). The validation sets were combined to assess independence from clinical status in a multi-variable analysis where eTILs% was independently associated with improved overall survival (HR=0.35, p Citation Format: Yalai Bai, Balazs Acs, Jon Zugazagoitia, Sandra Martinez-Morilla, Fahad Shabbir Ahmed, David L. Rimm. An open source, automated Tumor Infiltrating Lymphocyte algorithm for prognosis in triple-negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-12.
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an open source automated Tumor Infiltrating Lymphocyte algorithm for prognosis in melanoma
Nature Communications, 2019Co-Authors: Balazs Acs, Fahad Shabbir Ahmed, Swati Gupta, Pok Fai Wong, Robyn D Gartrell, Jaya Sarin Pradhan, Emanuelle M Rizk, Bonnie Gould E Rothberg, Yvonne M SaengerAbstract:Assessment of Tumor Infiltrating Lymphocytes (TILs) as a prognostic variable in melanoma has not seen broad adoption due to lack of standardization. Automation could represent a solution. Here, using open source software, we build an algorithm for image-based automated assessment of TILs on hematoxylin-eosin stained sections in melanoma. Using a retrospective collection of 641 melanoma patients comprising four independent cohorts; one training set (N = 227) and three validation cohorts (N = 137, N = 201, N = 76) from 2 institutions, we show that the automated TIL scoring algorithm separates patients into favorable and poor prognosis cohorts, where higher TILs scores were associated with favorable prognosis. In multivariable analyses, automated TIL scores show an independent association with disease-specific overall survival. Therefore, the open source, automated TIL scoring is an independent prognostic marker in melanoma. With further study, we believe that this algorithm could be useful to define a subset of patients that could potentially be spared immunotherapy. Histology data exists for many cancer samples and the ability to automatically image this data may provide prognostic information. Here, the authors generated an algorithm to measure tumour Infiltrating Lymphocytes in melanoma histology specimens and show that the ratio of these immune cells to tumour cells has prognostic value.
Cara Haymaker - One of the best experts on this subject based on the ideXlab platform.
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distinct Tumor Infiltrating Lymphocyte landscapes are associated with clinical outcomes in localized non small cell lung cancer
Annals of Oncology, 2021Co-Authors: Lorenzo Federico, Cara Haymaker, Marieandree Forget, Daniel J Mcgrail, Salaheddine Bentebibel, Andrea Ravelli, Tatiana Karpinets, Peixin Jiang, Alexandre Reuben, Marcelo V NegraoAbstract:Background Despite the importance of Tumor-Infiltrating T Lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established. Patients and methods Fresh Tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features. Results While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8+ T cells expressing cytolytic enzymes, CD4+ T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with Tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient Tumors from The Cancer Genome Atlas. Conclusions Our study suggests that although the number of Infiltrating T cells is not associated with patient survival, the nature of the Infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.
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pulmonary resection for tissue harvest in adoptive Tumor Infiltrating Lymphocyte therapy safety and feasibility
Journal of Surgical Oncology, 2021Co-Authors: Erin M Corsini, Cara Haymaker, Kyle G Mitchell, Nicolas Zhou, Chantale Bernatchez, Marieandree Forget, Wayne L Hofstetter, Reza J Mehran, Ravi Rajaram, David C RiceAbstract:Background and objectives Adoptive T-cell therapies (ACTs) using expansion of Tumor-Infiltrating Lymphocyte (TIL) populations are of great interest for advanced malignancies, with promising response rates in trial settings. However, postoperative outcomes following pulmonary TIL harvest have not been widely documented, and surgeons may be hesitant to operate in the setting of widespread disease. Methods Patients who underwent pulmonary TIL harvest were identified, and postoperative outcomes were studied, including pulmonary, cardiovascular, infectious, and wound complications. Results 83 patients met inclusion criteria. Pulmonary TIL harvest was undertaken primarily via a thoracoscopy with a median operative blood loss and duration of 30 ml and 65 min, respectively. The median length of stay was 2 days. Postoperative events were rare, occurring in only five (6%) patients, including two discharged with a chest tube, one discharged with oxygen, one episode of urinary retention, and one blood transfusion. No reoperations occurred. The median time from TIL harvest to ACT infusion was 37 days. Conclusions Pulmonary TIL harvest is safe and feasible, without major postoperative events in our cohort. All patients were able to receive intended ACT infusion without delays. Therefore, thoracic surgeons should actively participate in ongoing ACT trials and aggressively seek to enroll patients on these protocols.
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successful Tumor Infiltrating Lymphocyte til growth from uveal melanoma um using a three signal 3 0 method
Journal of Clinical Oncology, 2020Co-Authors: Meredith S Pelster, Cara Haymaker, Patrick Hwu, Chantale Bernatchez, Marieandree Forget, Stephen K Gruschkus, Rodabe N Amaria, Dan S Gombos, Sapna Pradyuman PatelAbstract:3027Background: Metastatic UM is a rare cancer with poor response rates to systemic therapy. Adoptive transfer of patient-specific TIL may represent the best strategy for treatment. TIL are harvest...
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potential clinical application of Tumor Infiltrating Lymphocyte therapy for ovarian epithelial cancer prior or post resistance to chemotherapy
Cancer Immunology Immunotherapy, 2019Co-Authors: Donastas Sakellariouthompson, Cara Haymaker, Patrick Hwu, Marieandree Forget, Emily Hinchcliff, Joseph Celestino, Amir A Jazaeri, Chantale BernatchezAbstract:Immunotherapy has become a powerful treatment option for several solid Tumor types. The presence of Tumor-Infiltrating Lymphocytes (TIL) is correlated with better prognosis in ovarian cancer, pointing at the possibility to benefit from harnessing their anti-Tumor activity. This preclinical study explores the feasibility of adoptive cell therapy (ACT) with TIL using an improved culture method. TIL from high-grade serous ovarian cancer were cultured using a combination of IL-2 with agonistic antibodies targeting 4-1BB and CD3. The cells were phenotyped using flow cytometry in the fresh tissue and after expansion. Tumor reactivity was assessed against HLA-matched ovarian cancer cell lines via IFN-γ ELISPOT. Ovarian cancer is highly infiltrated with CD8+ TIL that are preferentially and robustly expanded with the addition of the agonistic antibodies. With a 95% success rate, the TIL are grown to ≥ 100 × 106 cells in 2–3 weeks without over differentiation. In addition, the CD8+ TIL grown with this method showed HLA-restricted Tumor recognition. These results indicate the viability of TIL ACT for refractory ovarian cancer by allowing for the large expansion of anti-Tumor TIL in a short time and consistent manner.
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btla marks a less differentiated Tumor Infiltrating Lymphocyte subset in melanoma with enhanced survival properties
OncoImmunology, 2015Co-Authors: Cara Haymaker, Krit Ritthipichai, Patrick Hwu, Chantale Bernatchez, Marieandree Forget, Francesco M Marincola, Jie Qing Chen, Hui Liu, Ena Wang, Laszlo RadvanyiAbstract:In a recent adoptive cell therapy (ACT) clinical trial using autologous Tumor-Infiltrating Lymphocytes (TILs) in patients with metastatic melanoma, we found an association between CD8+ T cells expressing the inhibitory receptor B- and T-Lymphocyte attenuator (BTLA) and clinical response. Here, we further characterized this CD8+BTLA+ TIL subset and their CD8+BTLA- counterparts. We found that the CD8+ BTLA+ TILs had an increased response to IL-2, were less-differentiated effector-memory (TEM) cells, and persisted longer in vivo after infusion. In contrast, CD8+BTLA- TILs failed to proliferate and expressed genes associated with T-cell deletion/tolerance. Paradoxically, activation of BTLA signaling by its ligand, herpes virus entry mediator (HVEM), inhibited T-cell division and cytokine production, but also activated the Akt/PKB pathway thus protecting CD8+BTLA+ TILs from apoptosis. Our results point to a new role of BTLA as a useful T-cell differentiation marker in ACT and a dual signaling molecule that curtails T-cell activation while also conferring a survival advantage for CD8+ T cells. These attributes may explain our previous observation that BTLA expression on CD8+ TILs correlates with clinical response to adoptive T-cell therapy in metastatic melanoma.
Marieandree Forget - One of the best experts on this subject based on the ideXlab platform.
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distinct Tumor Infiltrating Lymphocyte landscapes are associated with clinical outcomes in localized non small cell lung cancer
Annals of Oncology, 2021Co-Authors: Lorenzo Federico, Cara Haymaker, Marieandree Forget, Daniel J Mcgrail, Salaheddine Bentebibel, Andrea Ravelli, Tatiana Karpinets, Peixin Jiang, Alexandre Reuben, Marcelo V NegraoAbstract:Background Despite the importance of Tumor-Infiltrating T Lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established. Patients and methods Fresh Tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features. Results While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8+ T cells expressing cytolytic enzymes, CD4+ T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with Tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient Tumors from The Cancer Genome Atlas. Conclusions Our study suggests that although the number of Infiltrating T cells is not associated with patient survival, the nature of the Infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.
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pulmonary resection for tissue harvest in adoptive Tumor Infiltrating Lymphocyte therapy safety and feasibility
Journal of Surgical Oncology, 2021Co-Authors: Erin M Corsini, Cara Haymaker, Kyle G Mitchell, Nicolas Zhou, Chantale Bernatchez, Marieandree Forget, Wayne L Hofstetter, Reza J Mehran, Ravi Rajaram, David C RiceAbstract:Background and objectives Adoptive T-cell therapies (ACTs) using expansion of Tumor-Infiltrating Lymphocyte (TIL) populations are of great interest for advanced malignancies, with promising response rates in trial settings. However, postoperative outcomes following pulmonary TIL harvest have not been widely documented, and surgeons may be hesitant to operate in the setting of widespread disease. Methods Patients who underwent pulmonary TIL harvest were identified, and postoperative outcomes were studied, including pulmonary, cardiovascular, infectious, and wound complications. Results 83 patients met inclusion criteria. Pulmonary TIL harvest was undertaken primarily via a thoracoscopy with a median operative blood loss and duration of 30 ml and 65 min, respectively. The median length of stay was 2 days. Postoperative events were rare, occurring in only five (6%) patients, including two discharged with a chest tube, one discharged with oxygen, one episode of urinary retention, and one blood transfusion. No reoperations occurred. The median time from TIL harvest to ACT infusion was 37 days. Conclusions Pulmonary TIL harvest is safe and feasible, without major postoperative events in our cohort. All patients were able to receive intended ACT infusion without delays. Therefore, thoracic surgeons should actively participate in ongoing ACT trials and aggressively seek to enroll patients on these protocols.
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successful Tumor Infiltrating Lymphocyte til growth from uveal melanoma um using a three signal 3 0 method
Journal of Clinical Oncology, 2020Co-Authors: Meredith S Pelster, Cara Haymaker, Patrick Hwu, Chantale Bernatchez, Marieandree Forget, Stephen K Gruschkus, Rodabe N Amaria, Dan S Gombos, Sapna Pradyuman PatelAbstract:3027Background: Metastatic UM is a rare cancer with poor response rates to systemic therapy. Adoptive transfer of patient-specific TIL may represent the best strategy for treatment. TIL are harvest...
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potential clinical application of Tumor Infiltrating Lymphocyte therapy for ovarian epithelial cancer prior or post resistance to chemotherapy
Cancer Immunology Immunotherapy, 2019Co-Authors: Donastas Sakellariouthompson, Cara Haymaker, Patrick Hwu, Marieandree Forget, Emily Hinchcliff, Joseph Celestino, Amir A Jazaeri, Chantale BernatchezAbstract:Immunotherapy has become a powerful treatment option for several solid Tumor types. The presence of Tumor-Infiltrating Lymphocytes (TIL) is correlated with better prognosis in ovarian cancer, pointing at the possibility to benefit from harnessing their anti-Tumor activity. This preclinical study explores the feasibility of adoptive cell therapy (ACT) with TIL using an improved culture method. TIL from high-grade serous ovarian cancer were cultured using a combination of IL-2 with agonistic antibodies targeting 4-1BB and CD3. The cells were phenotyped using flow cytometry in the fresh tissue and after expansion. Tumor reactivity was assessed against HLA-matched ovarian cancer cell lines via IFN-γ ELISPOT. Ovarian cancer is highly infiltrated with CD8+ TIL that are preferentially and robustly expanded with the addition of the agonistic antibodies. With a 95% success rate, the TIL are grown to ≥ 100 × 106 cells in 2–3 weeks without over differentiation. In addition, the CD8+ TIL grown with this method showed HLA-restricted Tumor recognition. These results indicate the viability of TIL ACT for refractory ovarian cancer by allowing for the large expansion of anti-Tumor TIL in a short time and consistent manner.
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preclinical development of Tumor Infiltrating Lymphocyte therapy for metastatic colorectal cancer
Journal of Clinical Oncology, 2018Co-Authors: Donastas Sakellariouthompson, Patrick Hwu, Marieandree Forget, Jason Roszik, Kyle R Jackson, Young Uk Kim, Shadarra Crosby, Mark W Hurd, Zhiqin Jiang, Gregory LizeeAbstract:95Background: Immunotherapy has become an effective cancer therapy, particularly in the case of checkpoint blockade and adoptive T-cell therapy (ACT). ACT exploits the presence of Tumor-Infiltrating Lymphocytes (TIL) by exponentially expanding their numbers ex vivo and re-infusing them into the patient in an autologous setting. With the effectiveness of TIL therapy already well established in multiple phase II studies in melanoma, there is a push to translate it to other cancers in need of improved therapies. Colorectal cancer (CRC) is a cancer where the presence of TIL has been strongly correlated with increased survival. Metastatic CRC (mCRC) has a poor outcome with median overall survival of less than 3 years. At present anti-PD1 therapy is only active in the small subset of mCRC patients (4%) that are MSI-high. We sought to evaluate the ability to generate and characterize TIL from patients with mCRC to provide a rationale for future TIL therapy in this disease. Methods: To assess the feasibility of u...
Celine Naveaux - One of the best experts on this subject based on the ideXlab platform.
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FOXP1 negatively regulates Tumor Infiltrating Lymphocyte migration in human breast cancerResearch in context
Elsevier, 2019Co-Authors: Pushpamali De Silva, Soizic Garaud, Alexandre De Wind, Anaïs Boisson, Cinzia Solinas, Gert Van Den Eyden, Vinu Jose, Chunyan Gu-trantien, Edoardo Migliori, Celine NaveauxAbstract:Background: FOXP1, a transcriptional regulator of Lymphocyte development, is abnormally expressed in some human Tumors. This study investigated FOXP1-mediated regulation of Tumor Infiltrating Lymphocytes (TIL) in untreated primary breast cancer (BC). Methods: FOXP1 expression was analyzed in tissues from primary untreated breast Tumors, BC cell lines and the METABRIC gene expression BC dataset. Cytokine and chemokine expression and Lymphocyte migration in response to primary Tumor supernatants (SN) was compared between FOXP1hi and FOXP1lo primary BC. Finding: FOXP1 expression was higher in estrogen receptor positive compared to negative BC. FOXP1hi Tumors were significantly associated with lower TIL and fewer tertiary lymphoid structures (TLS) compared to FOXP1lo BC. Silencing FOXP1 in BC cell lines positively impacted cytokine and chemokine expression with the inverse effect associated with overexpression. CXCL9, CXCL10, CXCL11, CXCL13, CX3CL, CCL20, IL2, IL21, GZMB and IFNG expression decreased while IL10 and TGFβ increased in FOXP1hi compared to FOXP1lo primary BC. Lymphocyte migration using primary BC supernatants detected decreased mobility toward FOXP1hi supernatants. FOXP1lo BC expresses higher levels of chemokines driving TIL migration. The METABRIC gene expression dataset analysis show FOXP1 expression is associated with unfavorable BC outcomes. Interpretation: These data identify FOXP1 as an important negative regulator of immune responses in BC via its regulation of cytokine and chemokine expression. Fund: Belgian Fund for Scientific Research (FNRS 3.4513.12F) and Opération Télévie (7.4636.13F and 7.4609.15F), Fonds J.C. Heuson and Fonds Lambeau-Marteaux. Keywords: FOXP1, Breast cancer, Tumor Infiltrating Lymphocytes, Chemokines, Cytokine
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FOXP1 negatively regulates Tumor Infiltrating Lymphocyte migration in human breast cancer
EBioMedicine, 2018Co-Authors: Pushpamali De Silva, Soizic Garaud, Alexandre De Wind, Anaïs Boisson, Cinzia Solinas, Gert Van Den Eyden, Vinu Jose, Chunyan Gu-trantien, Edoardo Migliori, Celine NaveauxAbstract:Abstract Background FOXP1, a transcriptional regulator of Lymphocyte development, is abnormally expressed in some human Tumors. This study investigated FOXP1-mediated regulation of Tumor Infiltrating Lymphocytes (TIL) in untreated primary breast cancer (BC). Methods FOXP1 expression was analyzed in tissues from primary untreated breast Tumors, BC cell lines and the METABRIC gene expression BC dataset. Cytokine and chemokine expression and Lymphocyte migration in response to primary Tumor supernatants (SN) was compared between FOXP1hi and FOXP1lo primary BC. Finding FOXP1 expression was higher in estrogen receptor positive compared to negative BC. FOXP1hi Tumors were significantly associated with lower TIL and fewer tertiary lymphoid structures (TLS) compared to FOXP1lo BC. Silencing FOXP1 in BC cell lines positively impacted cytokine and chemokine expression with the inverse effect associated with overexpression. CXCL9, CXCL10, CXCL11, CXCL13, CX3CL, CCL20, IL2, IL21, GZMB and IFNG expression decreased while IL10 and TGFβ increased in FOXP1hi compared to FOXP1lo primary BC. Lymphocyte migration using primary BC supernatants detected decreased mobility toward FOXP1hi supernatants. FOXP1lo BC expresses higher levels of chemokines driving TIL migration. The METABRIC gene expression dataset analysis show FOXP1 expression is associated with unfavorable BC outcomes. Interpretation These data identify FOXP1 as an important negative regulator of immune responses in BC via its regulation of cytokine and chemokine expression. Fund Belgian Fund for Scientific Research (FNRS 3.4513.12F) and Operation Televie (7.4636.13F and 7.4609.15F), Fonds J.C. Heuson and Fonds Lambeau-Marteaux.
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Reliability of Tumor-Infiltrating Lymphocyte and tertiary lymphoid structure assessment in human breast cancer
Modern Pathology, 2017Co-Authors: Laurence Buisseret, Soizic Garaud, Gert Van Den Eyden, Alexandre De Wind, Sebastien Duquenne, Marco Fornili, Anaïs Boisson, Christine Desmedt, Xiaoxiao Wang, Celine NaveauxAbstract:The presence of Tumor-Infiltrating Lymphocytes (TIL), reflecting host immune activity, is frequently correlated with better clinical outcomes, particularly in HER2-positive and triple-negative breast cancer. Recent findings suggest that organization of immune infiltrates in tertiary lymphoid structures also has a beneficial effect on survival. This study investigated inter- and intra-observer variation in TIL assessment using conventional hematoxylin-eosin versus immunohistochemical staining to identify immune cells. Global, intraTumoral, and stromal TIL, as well as tertiary lymphoid structures were scored independently by experienced pathologists on full-face Tumor sections ( n =124). The fidelity of scoring infiltrates in core biopsies compared to surgical specimens, and pathological assessment compared to quantitative digital analysis was also evaluated. The inter-observer concordance correlation coefficient was 0.80 for global, 0.72 for intraTumoral, and 0.71 for stromal TIL, while the intra-observer concordance correlation coefficient was 0.90 for global, 0.77 for intraTumoral, and 0.89 for stromal TIL using immunohistochemical stains. Correlations were lower with hematoxylin-eosin stains, particularly for intraTumoral TIL, while global scores had the highest concordance correlation coefficients. Our study concluded that tertiary lymphoid structures are accurately and consistently scored using immunohistochemical but not hematoxylin-eosin stains. A strong association was observed between TIL in core biopsies and surgical samples ( R ^2=0.74) but this did not extend to tertiary lymphoid structures ( R ^2=0.26). TIL scored by pathologists and digital analysis were correlated but our analysis reveals a constant bias between these methods. These data challenge current criteria for TIL and tertiary lymphoid structure assessment in breast cancer and recommend that how pathologists evaluate immune infiltrates be reexamined for future studies.
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Tumor Infiltrating Lymphocyte composition organization and pd 1 pd l1 expression are linked in breast cancer
OncoImmunology, 2017Co-Authors: Laurence Buisseret, Soizic Garaud, Alexandre De Wind, Celine Naveaux, Anaïs Boisson, Cinzia Solinas, Gert Van Den Eynden, Chunyan Gutrantien, Jeannicolas Lodewyckx, Hugues DuvillierAbstract:ABSTRACTThe clinical relevance of Tumor-Infiltrating Lymphocytes (TIL) in breast cancer (BC) has been clearly established by their demonstrated correlation with long-term positive outcomes. Nevertheless, the relationship between protective immunity, observed in some patients, and critical features of the infiltrate remains unresolved. This study examined TIL density, composition and organization together with PD-1 and PD-L1 expression in freshly collected and paraffin-embedded tissues from 125 patients with invasive primary BC. Tumor and normal breast tissues were analyzed using both flow cytometry and immunohistochemistry. TIL density distribution is a continuum with 25% of Tumors identified as TIL-negative at a TIL density equivalent to normal breast tissues. TIL-positive Tumors (75%) were equally divided into TIL-intermediate and TIL-high. Tumors had higher mean frequencies of CD4+ T cells and CD19+ B cells and a lower mean frequency of CD8+ T cells compare with normal tissues, increasing the CD4+/CD8+...
