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Dive into the research topics where Beata Berent-Maoz is active.

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Featured researches published by Beata Berent-Maoz.


The New England Journal of Medicine | 2016

Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma

Jesse M. Zaretsky; Angel Garcia-Diaz; Daniel S. Shin; Helena Escuin-Ordinas; Willy Hugo; Siwen Hu-Lieskovan; Davis Y. Torrejon; Gabriel Abril-Rodriguez; Salemiz Sandoval; Lucas Barthly; Justin Saco; Blanca Homet Moreno; Riccardo Mezzadra; Bartosz Chmielowski; Kathleen Ruchalski; I. Peter Shintaku; Phillip J. Sanchez; Cristina Puig-Saus; Grace Cherry; Elizabeth Seja; Xiangju Kong; Jia Pang; Beata Berent-Maoz; Begoña Comin-Anduix; Thomas G. Graeber; Paul C. Tumeh; Ton N. M. Schumacher; Roger S. Lo; Antoni Ribas

BACKGROUND Approximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown. METHODS We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti-PD-1 therapy (pembrolizumab) followed by disease progression months to years later. RESULTS Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I. CONCLUSIONS In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.).


Cell | 2016

Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma

Willy Hugo; Jesse M. Zaretsky; Lu Sun; Chunying Song; Blanca Homet Moreno; Siwen Hu-Lieskovan; Beata Berent-Maoz; Jia Pang; Bartosz Chmielowski; Grace Cherry; Elizabeth Seja; Shirley Lomeli; Xiangju Kong; Mark C. Kelley; Jeffrey A. Sosman; Douglas B. Johnson; Antoni Ribas; Roger S. Lo

PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that overall high mutational loads associate with improved survival, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES, or innate anti-PD-1 resistance), indicating concurrent up-expression of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPK inhibitor resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD-1 response in melanoma and other cancer types.PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that overall high mutational loads associate with improved survival, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES, or innate anti-PD-1 resistance), indicating concurrent up-expression of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPK inhibitor resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD-1 response in melanoma and other cancer types.


Cancer Discovery | 2017

Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations

Daniel Sanghoon Shin; Jesse M. Zaretsky; Helena Escuin-Ordinas; Angel Garcia-Diaz; Siwen Hu-Lieskovan; Anusha Kalbasi; Catherine S. Grasso; Willy Hugo; Salemiz Sandoval; Davis Y. Torrejon; Nicolaos Palaskas; Rodriguez Ga; Giulia Parisi; Azhdam A; Bartosz Chmielowski; Grace Cherry; Elizabeth Seja; Beata Berent-Maoz; Shintaku Ip; Le Dt; Pardoll Dm; Diaz La; Paul C. Tumeh; Thomas G. Graeber; Roger S. Lo; Begonya Comin-Anduix; Antoni Ribas

Loss-of-function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned that they may also be involved in primary resistance to anti-PD-1 therapy. JAK1/2-inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair-deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK1/2 mutations, which led to a lack of PD-L1 expression upon interferon gamma exposure mediated by an inability to signal through the interferon gamma receptor pathway. JAK1/2 loss-of-function alterations in The Cancer Genome Atlas confer adverse outcomes in patients. We propose that JAK1/2 loss-of-function mutations are a genetic mechanism of lack of reactive PD-L1 expression and response to interferon gamma, leading to primary resistance to PD-1 blockade therapy. SIGNIFICANCE A key functional result from somatic JAK1/2 mutations in a cancer cell is the inability to respond to interferon gamma by expressing PD-L1 and many other interferon-stimulated genes. These mutations result in a genetic mechanism for the absence of reactive PD-L1 expression, and patients harboring such tumors would be unlikely to respond to PD-1 blockade therapy. Cancer Discov; 7(2); 188-201. ©2016 AACR.See related commentary by Marabelle et al., p. 128This article is highlighted in the In This Issue feature, p. 115.


Journal of Clinical Investigation | 2013

Causes, consequences, and reversal of immune system aging

Encarnacion Montecino-Rodriguez; Beata Berent-Maoz; Kenneth Dorshkind

The effects of aging on the immune system are manifest at multiple levels that include reduced production of B and T cells in bone marrow and thymus and diminished function of mature lymphocytes in secondary lymphoid tissues. As a result, elderly individuals do not respond to immune challenge as robustly as the young. An important goal of aging research is to define the cellular changes that occur in the immune system and the molecular events that underlie them. Considerable progress has been made in this regard, and this information has provided the rationale for clinical trials to rejuvenate the aging immune system.


Blood | 2012

Fibroblast growth factor-7 partially reverses murine thymocyte progenitor aging by repression of Ink4a

Beata Berent-Maoz; Encarnacion Montecino-Rodriguez; Robert A.J. Signer; Kenneth Dorshkind

Involution of the thymus results in reduced production of naive T cells, and this in turn is thought to contribute to impaired immunity in the elderly. Early T-cell progenitors (ETPs), the most immature intrathymic T-cell precursors, harvested from the involuted thymus exhibit a diminished proliferative potential and increased rate of apoptosis and as a result their number is significantly reduced. In the present study, we show that these age-induced alterations result in part from increased expression of the Ink4a tumor-suppressor gene in ETPs. We also show that repression of Ink4a in aged ETPs results in their partial rejuvenation and that this can be accomplished by in vivo fibroblast growth factor 7 administration. These results define a genetic basis for thymocyte progenitor aging and demonstrate that the senescence-associated gene Ink4a can be pharmacologically repressed in ETPs to partially reverse the effects of aging.


Seminars in Immunology | 2012

Genetic regulation of thymocyte progenitor aging.

Beata Berent-Maoz; Encarnacion Montecino-Rodriguez; Kenneth Dorshkind

The number of T cell progenitors is significantly reduced in the involuted thymus, and the growth and developmental potential of the few cells that are present is severely attenuated. This review provides an overview of how aging affects T cell precursors before and following entry into the thymus and discusses the age-related genetic changes that may occur in them. Finally, interventions that rejuvenate thymopoiesis in the elderly by targeting T cell progenitors are discussed.


Journal for ImmunoTherapy of Cancer | 2015

Innate resistance of PD-1 blockade through loss of function mutations in JAK resulting in inability to express PD-L1 upon interferon exposure

Daniel Shin; Angel Garcia-Diaz; Jesse M. Zaretsky; Helena Escuin-Ordinas; Siwen Hu-Lieskovan; Nicolaos Palaskas; Willy Hugo; Marie Sara Komenan; Bartosz Chmielowski; Grace Cherry; Beata Berent-Maoz; Thomas G. Graeber; Roger S. Lo; Begonya Comin-Anduix; Antoni Ribas

PD-L1-negative tumors assessed by immunohistochemistry often still respond to PD-1 blockade. PD-L1 is inducible by interferon, therefore, absolute negative tumors are the ones unable to up-regulate PD-L1 in response to interferons. Genetic mutations in the interferon receptor signaling pathway leading to loss of PD-L1 up-regulation were hypothesized to exhibit innate resistance to PD-1 blockade.


PLOS ONE | 2015

The expansion of thymopoiesis in neonatal mice is dependent on expression of high mobility group a 2 protein (Hmga2).

Beata Berent-Maoz; Encarnacion Montecino-Rodriguez; Michael Fice; David Casero; Christopher Seet; William E. Lowry; Kenneth Dorshkind

Cell number in the mouse thymus increases steadily during the first two weeks after birth. It then plateaus and begins to decline by seven weeks after birth. The factors governing these dramatic changes in cell production are not well understood. The data herein correlate levels of High mobility group A 2 protein (Hmga2) expression with these temporal changes in thymopoiesis. Hmga2 is expressed at high levels in murine fetal and neonatal early T cell progenitors (ETP), which are the most immature intrathymic precursors, and becomes almost undetectable in these progenitors after 5 weeks of age. Hmga2 expression is critical for the initial, exponential expansion of thymopoiesis, as Hmga2 deficient mice have a deficit of ETPs within days after birth, and total thymocyte number is repressed compared to wild type littermates. Finally, our data raise the possibility that similar events occur in humans, because Hmga2 expression is high in human fetal thymic progenitors and falls in these cells during early infancy.


Cancer Discovery | 2018

Immunotherapy Resistance by Inflammation-Induced Dedifferentiation

Arnav Mehta; Yeon Joo Kim; Lidia Robert; Jennifer Tsoi; Begoña Comin-Anduix; Beata Berent-Maoz; Alistair J. Cochran; James S. Economou; Paul C. Tumeh; Cristina Puig-Saus; Antoni Ribas

A promising arsenal of targeted and immunotherapy treatments for metastatic melanoma has emerged over the last decade. With these therapies, we now face new mechanisms of tumor-acquired resistance. We report here a patient whose metastatic melanoma underwent dedifferentiation as a resistance mechanism to adoptive T-cell transfer therapy (ACT) to the MART1 antigen, a phenomenon that had been observed only in mouse studies to date. After an initial period of tumor regression, the patient presented in relapse with tumors lacking melanocytic antigens (MART1, gp100) and expressing an inflammation-induced neural crest marker (NGFR). We demonstrate using human melanoma cell lines that this resistance phenotype can be induced in vitro by treatment with MART1 T cell receptor-expressing T cells or with TNFα, and that the phenotype is reversible with withdrawal of inflammatory stimuli. This supports the hypothesis that acquired resistance to cancer immunotherapy can be mediated by inflammation-induced cancer dedifferentiation.Significance: We report a patient whose metastatic melanoma underwent inflammation-induced dedifferentiation as a resistance mechanism to ACT to the MART1 antigen. Our results suggest that future melanoma ACT protocols may benefit from the simultaneous targeting of multiple tumor antigens, modulating the inflammatory response, and inhibition of inflammatory dedifferentiation-inducing signals. Cancer Discov; 8(8); 935-43. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 899.


Cancer Research | 2017

Abstract 3765: IND-Enabling GLP study to support a clinical trial of dual adoptive cell therapy combining stem cells and T cells engineered with an NY-ESO-1 TCR

Cristina Puig-Saus; Giulia Parisi; Paige Krystofinski; Angel Garcia-Diaz; Salemiz Sandoval; James McCabe; Ruixue Zhang; Gardenia Cheung-Lau; Nhat Truong; Justin Saco; Sara Marie D. Komenan; Agustin Vega-Crespo; Mignonette Macabali; Begoña Comin-Anduix; Beata Berent-Maoz; Donald B. Kohn; Paula Kaplan-Lefko; Antoni Ribas

T cell receptor (TCR) engineered adoptive T cell transfer (ACT) has shown remarkable antitumor efficacy in several clinical trials. However, low persistence of modified cells limits long-term clinical responses. To overcome this hurdle, we propose a clinical trial co-administering genetically modified T cells and stem cells both expressing an NY-ESO-1 TCR such that the engrafted stem cells generate a source for constant renewal of modified T cells. Here we report a pre-clinical IND-enabling study performed at UCLA under Good Laboratory Practice (GLP) compliance to assess whether co-administration impacts (I) safety; (II) engraftment and cell lineage differentiation of gene modified stem cells; and (III) persistence of adoptively transferred T cells and stem cell-derived progeny. We performed 12 optimization studies to define the optimal conditions for TCR gene modified ACT and TCR gene modified hematopoietic stem cell (HSC) bone marrow transplantation (BMT). Sixty-four HLA-A2/kb transgenic mice were myelodepleted and received syngeneic BMT with Lineage depleted bone marrow (Lin-) cells transduced with the LV-NYESO-1 TCR/sr39TK and ACT with T cells transduced with the RV-NYESO-1 TCR. Control groups were as follows: untreated mice, mice receiving mock transduced Lin- cells and T cells, mice receiving transduced Lin- cells and mock transduced T cells, and mice receiving mock transduced Lin- cells and transduced T cells (n = 16 per group). Overall survival at 3 months was 87.5%; no significant differences in survival were observed among cohorts. After BMT we observed a decrease in body weight, elevation in creatinine kinase and transaminases, and gonadal germ cell ablation in all cohorts. Three months after BMT, all blood cell lineages were reconstituted in surviving mice. Using digital droplet PCR and flow cytometry, we confirmed that transduced stem cells engrafted and their progeny persisted long term. In the bone marrow, NY-ESO-1 TCR was expressed intracellularly among progenitor cells (Lin-, LSK and HSC) as well as all hematopoietic cell lineages within the spleen (CD8+ T cells, CD4+ T cells, NKT cells, B cells and granulocytes). Co-administration with gene modified T cells and stem cells did not affect engraftment, cell lineage differentiation or persistence of the gene modified stem cells. Moreover, co-administration with stem cells did not affect persistence of adoptively transferred T cells. These data demonstrate that 1) NY-ESO-1 TCR genetically modified stem cells engraft and differentiate into all hematopoietic cell lineage progeny, which persists at 3 months; 2) adoptively transferred NY-ESO-1 TCR T cells persist at 3 months; 3) co-administration of stem cells and T cells genetically modified to express an NY-ESO-1 TCR is safe and does not negatively impact stem cell engraftment, lineage differentiation and progeny persistence or T cell persistence. Citation Format: Cristina Puig-Saus, Giulia Parisi, Paige Krystofinski, Angel Garcia-Diaz, Salemiz Sandoval, James McCabe, Ruixue Zhang, Gardenia Cheung-Lau, Nhat Truong, Justin Saco, Sara Komenan, Agustin Vega-Crespo, Mignonette H Macabali, Begona Comin-Anduix, Beata Berent-Maoz, Donald Kohn, Paula Kaplan-Lefko, Antoni Ribas. IND-Enabling GLP study to support a clinical trial of dual adoptive cell therapy combining stem cells and T cells engineered with an NY-ESO-1 TCR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3765. doi:10.1158/1538-7445.AM2017-3765

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Antoni Ribas

University of California

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Grace Cherry

University of California

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Roger S. Lo

University of California

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Willy Hugo

University of California

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