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Author

Marie Andrée Forget

Other affiliations: Université de Montréal
Bio: Marie Andrée Forget is an academic researcher from University of Texas MD Anderson Cancer Center. The author has contributed to research in topics: Immunotherapy & Tumor-infiltrating lymphocytes. The author has an hindex of 25, co-authored 39 publications receiving 2494 citations. Previous affiliations of Marie Andrée Forget include Université de Montréal.

Papers
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Journal ArticleDOI
01 Nov 2018-Cell
TL;DR: A resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion is identified, and this study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance.

794 citations

Journal ArticleDOI
TL;DR: CD19-specific CAR T cells generated with Sleeping Beauty transposon/transposase platforms were safe, and may provide additional cancer control as planned infusions after HSCT, and support further clinical development of this nonviral gene therapy approach.
Abstract: BACKGROUND. T cells expressing antigen-specific chimeric antigen receptors (CARs) improve outcomes for CD19-expressing B cell malignancies. We evaluated a human application of T cells that were genetically modified using the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR. METHODS. T cells were genetically modified using DNA plasmids from the SB platform to stably express a second-generation CD19-specific CAR and selectively propagated ex vivo with activating and propagating cells (AaPCs) and cytokines. Twenty-six patients with advanced non-Hodgkin lymphoma and acute lymphoblastic leukemia safely underwent hematopoietic stem cell transplantation (HSCT) and infusion of CAR T cells as adjuvant therapy in the autologous (n = 7) or allogeneic settings (n = 19). RESULTS. SB-mediated genetic transposition and stimulation resulted in 2,200- to 2,500-fold ex vivo expansion of genetically modified T cells, with 84% CAR expression, and without integration hotspots. Following autologous HSCT, the 30-month progression-free and overall survivals were 83% and 100%, respectively. After allogeneic HSCT, the respective 12-month rates were 53% and 63%. No acute or late toxicities and no exacerbation of graft-versus-host disease were observed. Despite a low antigen burden and unsupportive recipient cytokine environment, CAR T cells persisted for an average of 201 days for autologous recipients and 51 days for allogeneic recipients. CONCLUSIONS. CD19-specific CAR T cells generated with SB and AaPC platforms were safe, and may provide additional cancer control as planned infusions after HSCT. These results support further clinical development of this nonviral gene therapy approach. TRIAL REGISTRATION. Autologous, {"type":"clinical-trial","attrs":{"text":"NCT00968760","term_id":"NCT00968760"}}NCT00968760; allogeneic, {"type":"clinical-trial","attrs":{"text":"NCT01497184","term_id":"NCT01497184"}}NCT01497184; long-term follow-up, {"type":"clinical-trial","attrs":{"text":"NCT01492036","term_id":"NCT01492036"}}NCT01492036. FUNDING. National Cancer Institute, private foundations, and institutional funds. Please see Acknowledgments for details.

386 citations

Journal ArticleDOI
TL;DR: Results demonstrate that CAR+ T cells can develop long-term persistence with a memory stem-cell phenotype sustained by signaling through mbIL15, and may contribute to improving the safety and therapeutic efficacy of CAR-based immunotherapies of patients with advanced cancer.
Abstract: Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. T-memory stem cells (TSCM) retain superior potential for long-lived persistence, but challenges exist in manufacturing this T-cell subset because they are rare among circulating lymphocytes. We report a clinically relevant approach to generating CAR+ T cells with preserved TSCM potential using the Sleeping Beauty platform. Because IL-15 is fundamental to T-cell memory, we incorporated its costimulatory properties by coexpressing CAR with a membrane-bound chimeric IL-15 (mbIL15). The mbIL15-CAR T cells signaled through signal transducer and activator of transcription 5 to yield improved T-cell persistence independent of CAR signaling, without apparent autonomous growth or transformation, and achieved potent rejection of CD19+ leukemia. Long-lived T cells were CD45ROnegCCR7+CD95+, phenotypically most similar to TSCM, and possessed a memory-like transcriptional profile. Overall, these results demonstrate that CAR+ T cells can develop long-term persistence with a memory stem-cell phenotype sustained by signaling through mbIL15. This observation warrants evaluation in clinical trials.

311 citations

Journal ArticleDOI
TL;DR: A model in which both effector-memory and more differentiated effector T cells ultimately may need to cooperate to mediate long-term tumor control in responding patients is presented, predicting that TILs will indeed emerge to become an approved treatment in the upcoming years through pivotal clinical trials.
Abstract: Immunotherapy using autologous T cells has emerged to be a powerful treatment option for patients with metastatic melanoma. These include the adoptive transfer of autologous tumor-infiltrating lymphocytes (TILs), T cells transduced with high-affinity T cell receptors against major tumor antigens, and T cells transduced with chimeric antigen receptors composed of hybrid immunoglobulin light chains with endodomains of T-cell signaling molecules. Among these and other options for T-cell therapy, TILs together with high-dose interleukin 2 have had the longest clinical history with multiple clinical trials in centers across the world consistently demonstrating durable clinical response rates near 50% or more. A distinct advantage of TIL therapy making it still the T-cell therapy of choice is the broad nature of the T-cell recognition against both defined and undefined tumors antigens against all possible major histocompatibility complex, rather than the single specificity and limited major histocompatibility complex coverage of the newer T cell receptors and chimeric antigen receptor transduction technologies. In the past decade, significant inroads have been made in defining the phenotypes of T cells in TIL-mediating tumor regression. CD8+ T cells are emerging to be critical, although the exact subset of CD8+ T cells exhibiting the highest clinical activity in terms of memory and effector markers is still controversial. We present a model in which both effector-memory and more differentiated effector T cells ultimately may need to cooperate to mediate long-term tumor control in responding patients. Although TIL therapy has shown great potential to treat metastatic melanoma, a number of issues have emerged that need to be addressed to bring it more into the mainstream of melanoma care. First, we have a reached the point where a pivotal phase II or phase III trial is needed in an attempt to gain regulatory approval of TILs as standard of care. Second, improvements in how we expand TILs for therapy are needed that minimize the time the T cells are in culture and improve the memory and effector characteristics of the T cells for longer persistence and enhanced anti-tumor activity in vivo. Third, there is a critical need to identify surrogate and predictive biomarkers to better select suitable patients for TIL therapy to improve response rate and duration. Overall, the outlook for TIL therapy for melanoma is very bright. We predict that TILs will indeed emerge to become an approved treatment in the upcoming years through pivotal clinical trials. Moreover, new approaches combining TILs with targeted signaling pathway drugs, such as mutant B-RAF inhibitors, and synergistic immunomodulatory interventions enhancing T-cell costimulation and preventing negative regulation should further increase therapeutic efficacy and durable complete response rates.

215 citations

Journal ArticleDOI
TL;DR: This mIF methodology can be an invaluable tool for tumor tissue immune-profiling to allow multiple targets in the same tissue section and it is provided that is accurate and reproducible method when is performed carefully under pathologist supervision.
Abstract: Immune-profiling is becoming an important tool to identify predictive markers for the response to immunotherapy. Our goal was to validate multiplex immunofluorescence (mIF) panels to apply to formalin-fixed and paraffin-embedded tissues using a set of immune marker antibodies, with the Opal™ 7 color Kit (PerkinElmer) in the same tissue section. We validated and we described two panels aiming to characterize the expression of PD-L1, PD-1, and subsets of tumor associated immune cells. Panel 1 included pancytokeratin (AE1/AE3), PD-L1, CD4, CD8, CD3, CD68, and DAPI, and Panel 2 included pancytokeratin, PD-1, CD45RO, granzyme B, CD57, FOXP3, and DAPI. After all primary antibodies were tested in positive and negative controls by immunohistochemistry and uniplex IF, panels were developed and simultaneous marker expressions were quantified using the Vectra 3.0™ multispectral microscopy and image analysis InForm™ 2.2.1 software (PerkinElmer).These two mIF panels demonstrated specific co-localization in different cells that can identify the expression of PD-L1 in malignant cells and macrophages, and different T-cell subpopulations. This mIF methodology can be an invaluable tool for tumor tissue immune-profiling to allow multiple targets in the same tissue section and we provide that is accurate and reproducible method when is performed carefully under pathologist supervision.

190 citations


Cited by
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Journal ArticleDOI
09 Feb 2017-Cell
TL;DR: As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.

3,131 citations

Journal ArticleDOI
Robert M. Samstein1, Chung-Han Lee2, Chung-Han Lee1, Alexander N. Shoushtari2, Alexander N. Shoushtari1, Matthew D. Hellmann2, Matthew D. Hellmann1, Ronglai Shen1, Yelena Y. Janjigian2, Yelena Y. Janjigian1, David Barron1, Ahmet Zehir1, Emmet Jordan1, Antonio Omuro1, Thomas Kaley1, Sviatoslav M. Kendall1, Robert J. Motzer1, Robert J. Motzer2, A. Ari Hakimi1, Martin H. Voss1, Martin H. Voss2, Paul Russo1, Jonathan E. Rosenberg1, Jonathan E. Rosenberg2, Gopa Iyer1, Gopa Iyer2, Bernard H. Bochner1, Dean F. Bajorin2, Dean F. Bajorin1, Hikmat Al-Ahmadie1, Jamie E. Chaft1, Jamie E. Chaft2, Charles M. Rudin1, Charles M. Rudin2, Gregory J. Riely2, Gregory J. Riely1, Shrujal S. Baxi2, Shrujal S. Baxi1, Alan L. Ho2, Alan L. Ho1, Richard J. Wong1, David G. Pfister2, David G. Pfister1, Jedd D. Wolchok2, Jedd D. Wolchok1, Christopher A. Barker1, Philip H. Gutin1, Cameron Brennan1, Viviane Tabar1, Ingo K. Mellinghoff1, Lisa M. DeAngelis1, Charlotte E. Ariyan1, Nancy Y. Lee1, William D. Tap2, William D. Tap1, Mrinal M. Gounder1, Mrinal M. Gounder2, Sandra P. D'Angelo2, Sandra P. D'Angelo1, Leonard B. Saltz2, Leonard B. Saltz1, Zsofia K. Stadler2, Zsofia K. Stadler1, Howard I. Scher2, Howard I. Scher1, José Baselga1, José Baselga2, Pedram Razavi1, Pedram Razavi2, Christopher A. Klebanoff2, Christopher A. Klebanoff1, Rona Yaeger1, Rona Yaeger2, Neil H. Segal2, Neil H. Segal1, Geoffrey Y. Ku2, Geoffrey Y. Ku1, Ronald P. DeMatteo1, Marc Ladanyi1, Naiyer A. Rizvi3, Michael F. Berger1, Nadeem Riaz1, David B. Solit1, Timothy A. Chan1, Luc G. T. Morris1 
TL;DR: Analysis of advanced cancer patients treated with immune-checkpoint inhibitors shows that tumor mutational burden, as assessed by targeted next-generation sequencing, predicts survival after immunotherapy across multiple cancer types.
Abstract: Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.

2,343 citations

Journal ArticleDOI
16 Jul 2019-Immunity
TL;DR: How tumor-promoting inflammation closely resembles inflammatory processes typically found during development, immunity, maintenance of tissue homeostasis, or tissue repair is discussed and the distinctions between tissue-protective and pro-tumorigenic inflammation are illuminated.

1,563 citations

Journal ArticleDOI
TL;DR: The multidisciplinary approach adopted at institutions is described, and recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR-T-cell therapy are provided.
Abstract: Immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) is rapidly emerging as a promising new treatment for haematological and non-haematological malignancies. CAR-T-cell therapy can induce rapid and durable clinical responses, but is associated with unique acute toxicities, which can be severe or even fatal. Cytokine-release syndrome (CRS), the most commonly observed toxicity, can range in severity from low-grade constitutional symptoms to a high-grade syndrome associated with life-threatening multiorgan dysfunction; rarely, severe CRS can evolve into fulminant haemophagocytic lymphohistiocytosis (HLH). Neurotoxicity, termed CAR-T-cell-related encephalopathy syndrome (CRES), is the second most-common adverse event, and can occur concurrently with or after CRS. Intensive monitoring and prompt management of toxicities is essential to minimize the morbidity and mortality associated with this potentially curative therapeutic approach; however, algorithms for accurate and consistent grading and management of the toxicities are lacking. To address this unmet need, we formed a CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising investigators from multiple institutions and medical disciplines who have experience in treating patients with various CAR-T-cell therapy products. Herein, we describe the multidisciplinary approach adopted at our institutions, and provide recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR-T-cell therapy.

1,492 citations