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1.
Nature ; 606(7915): 791-796, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35322234

RESUMEN

Immune checkpoint blockade has revolutionized the field of oncology, inducing durable anti-tumour immunity in solid tumours. In patients with advanced prostate cancer, immunotherapy treatments have largely failed1-5. Androgen deprivation therapy is classically administered in these patients to inhibit tumour cell growth, and we postulated that this therapy also affects tumour-associated T cells. Here we demonstrate that androgen receptor (AR) blockade sensitizes tumour-bearing hosts to effective checkpoint blockade by directly enhancing CD8 T cell function. Inhibition of AR activity in CD8 T cells prevented T cell exhaustion and improved responsiveness to PD-1 targeted therapy via increased IFNγ expression. AR bound directly to Ifng and eviction of AR with a small molecule significantly increased cytokine production in CD8 T cells. Together, our findings establish that T cell intrinsic AR activity represses IFNγ expression and represents a novel mechanism of immunotherapy resistance.


Asunto(s)
Linfocitos T CD8-positivos , Inmunoterapia , Neoplasias de la Próstata , Receptores Androgénicos , Antagonistas de Andrógenos/farmacología , Antagonistas de Andrógenos/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Interferón gamma , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Insuficiencia del Tratamiento
2.
J Immunol ; 210(4): 496-503, 2023 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-36548468

RESUMEN

The thymus is a hormone-sensitive organ, which involutes with age in response to production of sex steroids. Thymic involution leads to a decrease in the generation of recent thymic emigrants (RTEs), resulting in a reduced response to immune challenges such as cancer. Interestingly, the standard of care for prostate cancer patients is androgen deprivation therapy (ADT), which leads to thymic regeneration and an increase in thymic output. It remains unknown whether these newly produced T cells can contribute to the antitumor immune response. This study defines the kinetics of thymic regeneration in response to ADT in mice, determining that thymic epithelial cell proliferation is critical for the increase in RTE output. Using a mouse model to track RTE in vivo, we demonstrate that these newly generated RTEs can traffic to tumors, where they become activated and produce effector cytokines at levels similar to more mature T cells. Collectively, these data suggest that RTEs produced from ADT-induced thymic regeneration could be harnessed for the antitumor immune response.


Asunto(s)
Neoplasias de la Próstata , Timo , Humanos , Masculino , Andrógenos , Antagonistas de Andrógenos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Linfocitos T
3.
Eur J Immunol ; 51(6): 1473-1481, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33684223

RESUMEN

Therapeutic antibodies blocking PD-1-/PD-L1 interaction have achieved remarkable clinical success in cancer. In addition to blocking a target molecule, some isotypes of antibodies can activate complement, NK cells or phagocytes, resulting in death of the cell expressing the antibody's target. Human anti-PD-1 therapeutics use antibody isotypes designed to minimize such antibody-dependent lysis. In contrast, anti-PD-1 reagents used in mice are derived from multiple species, with different isotypes, and are not engineered to reduce target cell death: few studies analyze or discuss how antibody species and isotype may impact data interpretation. We demonstrate here that anti-PD-1 therapy to promote activation and proliferation of murine PD-1-expressing CD8 T cells sometimes led instead to a loss of antigen specific cells. This phenomenon was seen in two tumor models and a model of virus infection, and varied with the clone of anti-PD-1 antibody. Additionally, we compared competition among anti-PD-1 clones to find a combination that allows detection of PD-1-expressing cells despite the presence of blocking anti-PD1 antibodies in vivo. These data bring attention to the possibility of unintended target cell depletion with some commonly used anti-mouse PD-1 clones, and should provide a valuable resource for the design and interpretation of anti-PD-1 studies in mice.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Infecciones por Herpesviridae/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Muromegalovirus/fisiología , Sarcoma/inmunología , Neoplasias Cutáneas/inmunología , Animales , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/trasplante , Muerte Celular , Línea Celular Tumoral , Cricetinae , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Infecciones por Herpesviridae/terapia , Humanos , Inmunoglobulina G/metabolismo , Isotipos de Inmunoglobulinas/metabolismo , Metilcolantreno , Ratones , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Ratas , Sarcoma/terapia , Neoplasias Cutáneas/terapia
4.
J Immunol ; 203(7): 2011-2019, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31434709

RESUMEN

OX40 is a costimulatory molecule from the TNFR family. In mice, it is expressed on Foxp3+ regulatory T cells (Tregs) constitutively and on conventional CD4 (Tconv) and CD8 T cells after Ag encounter. OX40 agonists are in clinical development to enhance antitumor immune responses, and one proposed mechanism of action is loss of Treg suppressive function. Studies have postulated that agonist OX40 therapy can impair Treg suppressive function. Using tools developed since the initial studies were published, we evaluated a direct effect of OX40 agonism on Treg function. We conclude that OX40 agonist Abs do not intrinsically impair Treg function but rather enhance Tconv cell IL-2 production, increasing Treg and Tconv cell proliferation. OX40-stimulated Tregs retain suppressive function, but also gain IFN-γ, TNF-α, and granzyme B expression. These data help resolve mechanistic questions regarding OX40 agonist immunotherapy and thus are relevant to developing combination therapies that target distinct T cell functions.


Asunto(s)
Anticuerpos Antineoplásicos/farmacología , Linfocitos T CD8-positivos/inmunología , Inmunoterapia , Proteínas de Neoplasias , Neoplasias , Receptores OX40 , Linfocitos T Reguladores/inmunología , Animales , Anticuerpos Antineoplásicos/inmunología , Linfocitos T CD8-positivos/patología , Línea Celular Tumoral , Citocinas/genética , Citocinas/inmunología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/inmunología , Ratones , Ratones Transgénicos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Receptores OX40/antagonistas & inhibidores , Receptores OX40/genética , Receptores OX40/inmunología , Linfocitos T Reguladores/patología
5.
Oncology (Williston Park) ; 34(3)2020 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-32212131

RESUMEN

Indications for checkpoint inhibitors (CPIs) are growing rapidly within the field of oncology; however, they continue to have heterogeneous outcomes in different cancers. Other than mismatch repair deficiency, there are no consistent tests to determine a tumor's susceptibility. By exploring factors beyond the cancer cell, researchers have learned that the efficacy of CPIs may be governed by a myriad of variable host factors, including the tumor microenvironment (TME) and gut microbiome (GMB). The GMB serves as one of the primary organs of immune defense and has well-established local and systemic effects on the host immune system. Recent investigations suggest that the GMB also affects the TME. This review article discusses the concepts of a TME and a GMB and their effects on responses to CPIs. It also reviews recent research investigating these 3 topics, and how it can be applied to using CPIs in prostate cancer. By highlighting this important pathophysiologic process, we hope to provide insight into a possible explanation for differences in interindividual response to CPIs, discuss a potential method for transferring treatment efficacy between patients, and propose a method for expanding the use of CPIs to prostate cancer.


Asunto(s)
Microbioma Gastrointestinal , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias de la Próstata/microbiología , Neoplasias de la Próstata/terapia , Ensayos Clínicos Fase III como Asunto , Humanos , Masculino , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Microambiente Tumoral/inmunología
6.
J Immunol ; 201(7): 1889-1898, 2018 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-30150283

RESUMEN

Arthritis in a genetically susceptible SKG strain of mice models a theoretical paradigm wherein autoimmune arthritis arises because of interplay between preexisting autoreactive T cells and environmental stimuli. SKG mice have a point mutation in ZAP-70 that results in attenuated TCR signaling, altered thymic selection, and spontaneous production of autoreactive T cells that cause arthritis following exposure to microbial ß-glucans. In this study, we identify Nod2, an innate immune receptor, as a critical suppressor of arthritis in SKG mice. SKG mice deficient in Nod2 (Nod2-/-SKG) developed a dramatically exacerbated form of arthritis, which was independent of sex and microbiota, but required the skg mutation in T cells. Worsened arthritis in Nod2-/-SKG mice was accompanied by expansion of Th17 cells, which to some measure coproduced TNF, GM-CSF, and IL-22, along with elevated IL-17A levels within joint synovial fluid. Importantly, neutralization of IL-17A mitigated arthritis in Nod2-/-SKG mice, indicating that Nod2-mediated protection occurs through suppression of the Th17 response. Nod2 deficiency did not alter regulatory T cell development or function. Instead, Nod2 deficiency resulted in an enhanced fundamental ability of SKG CD4+ T cells (from naive mice) to produce increased levels of IL-17 and to passively transfer arthritis to lymphopenic recipients on a single-cell level. These data reveal a previously unconsidered role for T cell-intrinsic Nod2 as an endogenous negative regulator of Th17 responses and arthritogenic T cells. Based on our findings, future studies aimed at understanding a negative regulatory function of Nod2 within autoreactive T cells could provide novel therapeutic strategies for treatment of patients with arthritis.


Asunto(s)
Artritis/inmunología , Enfermedades Autoinmunes/inmunología , Proteína Adaptadora de Señalización NOD2/metabolismo , Células Th17/inmunología , Animales , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Tolerancia Inmunológica , Inmunidad Innata , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Mutantes , Mutación/genética , Proteína Adaptadora de Señalización NOD2/genética , Proteína Tirosina Quinasa ZAP-70/genética , beta-Glucanos/inmunología
7.
J Immunol ; 197(6): 2509-21, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27503208

RESUMEN

Cancer cells harbor high-affinity tumor-associated Ags capable of eliciting potent antitumor T cell responses, yet detecting these polyclonal T cells is challenging. Therefore, surrogate markers of T cell activation such as CD69, CD44, and programmed death-1 (PD-1) have been used. We report in this study that in mice, expression of activation markers including PD-1 is insufficient in the tumor microenvironment to identify tumor Ag-specific T cells. Using the Nur77GFP T cell affinity reporter mouse, we highlight that PD-1 expression can be induced independent of TCR ligation within the tumor. Given this, we characterized the utility of the Nur77GFP model system in elucidating mechanisms of action of immunotherapies independent of PD-1 expression. Coexpression of Nur77GFP and OX40 identifies a polyclonal population of high-affinity tumor-associated Ag-specific CD8(+) T cells, which produce more IFN-γ in situ than OX40 negative and doubles in quantity with anti-OX40 and anti-CTLA4 mAb therapy but not with anti-PD-1 or programmed death ligand-1. Moreover, expansion of these high-affinity CD8 T cells prolongs survival of tumor-bearing animals. Upon chronic stimulation in tumors and after adoptive cell therapy, CD8 TCR signaling and Nur77GFP induction is impaired, and tumors progress. However, this can be reversed and overall survival significantly enhanced after adoptive cell therapy with agonist OX40 immunotherapy. Therefore, we propose that OX40 agonist immunotherapy can maintain functional TCR signaling of chronically stimulated tumor-resident CD8 T cells, thereby increasing the frequency of cytotoxic, high-affinity, tumor-associated Ag-specific cells.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunoterapia Adoptiva/métodos , Linfocitos Infiltrantes de Tumor/inmunología , Receptor de Muerte Celular Programada 1/genética , Linfocitos T Citotóxicos/inmunología , Animales , Linfocitos T CD8-positivos/fisiología , Antígeno CTLA-4/inmunología , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor/fisiología , Ratones , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Receptor de Muerte Celular Programada 1/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores OX40/agonistas , Receptores OX40/genética , Subgrupos de Linfocitos T/inmunología , Microambiente Tumoral
9.
Int Immunol ; 25(4): 259-69, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23334952

RESUMEN

The duration of signaling through the MAP kinase (or ERK pathway) cascade has been implicated in thymic development, particularly positive and negative selection. In T cells, two isoforms of the MAP kinase kinase kinase Raf function to transmit signals from the T-cell receptor to ERK: C-Raf and B-Raf. In this study, we conditionally ablated B-Raf expression within thymocytes to assess the effects on ERK activation and thymocyte development. The complete loss of B-Raf is accompanied by a dramatic loss of ERK activation in both the double positive (DP) and single positive (SP) thymocytes, as well as peripheral splenocytes. There was a significant decrease in the cellularity of KO thymi, largely due to a loss of pre-selected DP cells, a decrease in DP cells undergoing positive selection, and a defect in SP maturation. B-Raf plays significant roles in survival of DP thymocytes and function of SP cells in the periphery. Surprisingly, we saw no effect of B-Raf deficiency on negative selection of autoreactive SP thymocytes, despite the greatly reduced ERK activation in these cells.


Asunto(s)
Proteínas Proto-Oncogénicas B-raf/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Timo/inmunología , Animales , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Diferenciación Celular/genética , Supervivencia Celular/genética , Células Cultivadas , Supresión Clonal/genética , Activación Enzimática/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Sistema de Señalización de MAP Quinasas/genética , Sistema de Señalización de MAP Quinasas/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/inmunología
10.
Immunohorizons ; 8(3): 281-294, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38551395

RESUMEN

Inhibitory proteins, such as programmed cell death protein 1 (PD-1), have been studied extensively in peripheral T cell responses to foreign Ags, self-Ags, and neoantigens. Notably, these proteins are first expressed during T cell development in the thymus. Reports suggest that PD-1 limits regulatory T cell (Treg) development, but the mechanism by which PD-1 exerts this function remains unknown. The present study expands the evaluation of murine PD-1 and its ligands in the thymus, demonstrating that some of the highest expressers of PD-1 and programmed death-ligand 1 are agonist selected cells. Surprisingly, we reveal a selective role for PD-1 in regulating the developmental niche only for Tregs because other agonist selected cell populations, such as NK T cells, remain unchanged. We also ruled out PD-1 as a regulator of proliferation or cell death of agonist selected Tregs and further demonstrated that PD-1-deficient Tregs have reduced TCR signaling. Unexpectedly, the data suggest that PD-1-deficient thymocytes produce elevated levels of IL-2, a Treg niche-limiting cytokine. Collectively, these data suggest a novel role for PD-1 in regulating IL-2 production and the concurrent agonist selection of murine thymic Tregs. This observation has implications for the use of checkpoint blockade in the context of cancer and infection.


Asunto(s)
Interleucina-2 , Receptor de Muerte Celular Programada 1 , Linfocitos T Reguladores , Timo , Animales , Ratones , Citocinas/metabolismo , Interleucina-2/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T Reguladores/inmunología , Timo/citología , Timo/inmunología
11.
bioRxiv ; 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38798471

RESUMEN

There is now increasing recognition of the important role of androgen receptor (AR) in modulating immune function. To gain a comprehensive understanding of the effects of AR activity on cancer immunity, we employed a computational approach to profile AR activity in 33 human tumor types using RNA-Seq datasets from The Cancer Genome Atlas. Our pan-cancer analysis revealed that the genes most negatively correlated with AR activity across cancers are involved in active immune system processes. Importantly, we observed a significant negative correlation between AR activity and IFNγ pathway activity at the pan-cancer level. Indeed, using a matched biopsy dataset from subjects with prostate cancer before and after AR-targeted treatment, we verified that inhibiting AR enriches immune cell abundances and is associated with higher IFNγ pathway activity. Furthermore, by analyzing immunotherapy datasets in multiple cancers, our results demonstrate that low AR activity was significantly associated with a favorable response to immunotherapy. Together, our data provide a comprehensive assessment of the relationship between AR signaling and tumor immunity.

12.
Trends Cancer ; 9(8): 666-678, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37173189

RESUMEN

The thymus is responsible for generating a diverse T cell repertoire that is tolerant to self, but capable of responding to various immunologic insults, including cancer. Checkpoint blockade has changed the face of cancer treatment by targeting inhibitory molecules, which are known to regulate peripheral T cell responses. However, these inhibitory molecules and their ligands are expressed during T cell development in the thymus. In this review, we describe the underappreciated role of checkpoint molecule expression during the formation of the T cell repertoire and detail the importance of inhibitory molecules in regulating T cell lineage commitment. Understanding how these molecules function in the thymus may inform therapeutic strategies for better patient outcomes.


Asunto(s)
Proteínas de Punto de Control Inmunitario , Neoplasias , Humanos , Proteínas de Punto de Control Inmunitario/metabolismo , Linfocitos T , Neoplasias/genética , Neoplasias/terapia , Activación de Linfocitos , Inmunoterapia
13.
Immunology ; 135(4): 261-7, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22182461

RESUMEN

Understanding the thymic processes that support the generation of functionally competent and self-tolerant lymphocytes requires dissection of the T-cell receptor (TCR) response to ligands of different affinities. In spatially segregated regions of the thymus, with unique expression of proteases and cytokines, TCR affinity guides a number of cell fate decisions. Yet affinity alone does not explain the selection paradox. Increasing evidence suggests that the 'altered peptide' model of the 1980s together with the affinity model might best explain how the thymus supports conventional and regulatory T-cell development. Development of new tools to study the strength of TCR signals perceived by T cells, novel regulatory T-cell transgenic mice, and tetramer enrichment strategies have provided an insight into the nature of TCR signals perceived during thymocyte development. These topics are discussed and support for the prevailing hypotheses is presented.


Asunto(s)
Diferenciación Celular , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/citología , Timo/citología , Animales , Humanos , Ratones , Ratones Transgénicos , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Timo/inmunología
14.
Neoplasia ; 32: 100822, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35908379

RESUMEN

Recent studies in cancer patients and animal models demonstrate that intestinal microbiota influence the therapeutic efficacy of cancer treatments, including immune checkpoint inhibition. However, no studies to-date have investigated relationships between gastrointestinal microbiota composition and response to checkpoint inhibition in advanced metastatic castrate resistant prostate cancer (mCRPC). We performed 16S rRNA gene sequencing of fecal DNA from 23 individuals with mCRPC progressing on enzalutamide and just prior to treatment with anti-PD-1 (pembrolizumab) to determine whether certain features of the microbiome are associated with treatment response (defined as serum PSA decrease >50% at any time on treatment or radiographic response per RECIST V.1.1). Global bacterial composition was similar between responders and non-responders, as assessed by multiple alpha and beta diversity metrics. However, certain bacterial taxa identified by sequencing across multiple 16S rRNA hypervariable regions were consistently associated with response, including the archetypal oral bacterium Streptococcus salivarius. Quantitative PCR (qPCR) of DNA extracts from fecal samples confirmed increased Streptococcus salivarius fecal levels in responders, whereas qPCR of oral swish DNA extracts showed no relationship between oral Streptococcus salivarius levels and response status. Contrary to previous reports in other cancer types, Akkermansia muciniphila levels were reduced in responder samples as assessed by both 16S rRNA sequencing and qPCR. We further analyzed our data in the context of a previously published "integrated index" describing bacteria associated with response and non-response to checkpoint inhibition. We found that the index was not reflective of response status in our cohort. Lastly, we demonstrate little change in the microbiome over time, and with pembrolizumab treatment. Our results suggest that the association between fecal microbiota and treatment response to immunotherapy may be unique to cancer type and/or previous treatment history.


Asunto(s)
Microbioma Gastrointestinal , Neoplasias de la Próstata Resistentes a la Castración , Animales , Anticuerpos Monoclonales Humanizados , Benzamidas , Humanos , Masculino , Nitrilos , Feniltiohidantoína , ARN Ribosómico 16S
15.
Nat Biotechnol ; 40(4): 527-538, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34764492

RESUMEN

Single-cell RNA sequencing (scRNA-seq) distinguishes cell types, states and lineages within the context of heterogeneous tissues. However, current single-cell data cannot directly link cell clusters with specific phenotypes. Here we present Scissor, a method that identifies cell subpopulations from single-cell data that are associated with a given phenotype. Scissor integrates phenotype-associated bulk expression data and single-cell data by first quantifying the similarity between each single cell and each bulk sample. It then optimizes a regression model on the correlation matrix with the sample phenotype to identify relevant subpopulations. Applied to a lung cancer scRNA-seq dataset, Scissor identified subsets of cells associated with worse survival and with TP53 mutations. In melanoma, Scissor discerned a T cell subpopulation with low PDCD1/CTLA4 and high TCF7 expression associated with an immunotherapy response. Beyond cancer, Scissor was effective in interpreting facioscapulohumeral muscular dystrophy and Alzheimer's disease datasets. Scissor identifies biologically and clinically relevant cell subpopulations from single-cell assays by leveraging phenotype and bulk-omics datasets.


Asunto(s)
Melanoma , Análisis de la Célula Individual , Perfilación de la Expresión Génica , Humanos , Melanoma/genética , Fenotipo , Análisis de Secuencia de ARN
16.
Cancer Immunol Res ; 9(11): 1245-1251, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34544686

RESUMEN

Recent success in the use of immunotherapy for a broad range of cancers has propelled the field of cancer immunology to the forefront of cancer research. As more and more young investigators join the community of cancer immunologists, the Arthur L. Irving Family Foundation Cancer Immunology Symposium provided a platform to bring this expanding and vibrant community together and support the development of the future leaders in the field. This commentary outlines the lessons that emerged from the inaugural symposium highlighting the areas of scientific and career development that are essential for professional growth in the field of cancer immunology and beyond. Leading scientists and clinicians in the field provided their experience on the topics of scientific trajectory, career trajectory, publishing, fundraising, leadership, mentoring, and collaboration. Herein, we provide a conceptual and practical framework for career development to the broader scientific community.


Asunto(s)
Alergia e Inmunología/educación , Investigación Biomédica/métodos , Neoplasias/epidemiología , Médicos/organización & administración , Humanos , Liderazgo
17.
Front Oncol ; 10: 1381, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32850444

RESUMEN

Background: Phase 3 studies of immune checkpoint inhibitors have not shown a survival benefit in prostate cancer, but some patients have a profound anticancer response. Patients and Methods: We evaluated the efficacy of the CTLA-4 targeted agent, ipilimumab, in metastatic prostate cancer patients who had an incomplete biochemical response to initial androgen deprivation therapy (ADT) alone. Ten patients were enrolled, each treated with ipilimumab 10 mg/kg (every 3 weeks for up to 4 doses) with maintenance ipilimumab every 12 weeks for non-progressing patients. The primary endpoint was proportion of patients with an undetectable PSA. The total sample size was 30 patients, but there was an interim analysis planned at 10 for futility. If none of the 10 patients achieved an undetectable PSA, the study would be halted. Results: The study was halted at the interim analysis as none of the 10 patients achieved the primary endpoint, but 30% of patients demonstrated a >50% reduction in PSA, with one patient achieving a >90% reduction in PSA. Peripheral blood mononuclear cells (PBMC) examined by mass cytometry showed that patients with clinical responses had an increase in effector memory T-cell subsets as well as an increase in T-cell expression of T-bet, suggesting induction of a Th1 response. Conclusions: This study provides further evidence that ipilimumab has activity in some patients with prostate cancer and provides further rationale for the development of future studies aimed at identifying a subset of patients with CPRC that are more likely to derive a benefit from treatment with ipilimumab. Implications for Practice: There is insufficient evidence to use ipilimumab in prostate cancer in routine practice. Trial Registration: ClinicalTrials.gov, NCT01498978. Registered 26 December 2011. https://www.clinicaltrials.gov/ct2/show/NCT01498978?term=julie+graff&rank=3.

18.
J Immunother Cancer ; 8(2)2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32616555

RESUMEN

BACKGROUND: Checkpoint inhibitors can induce profound anticancer responses, but programmed cell death protein-1 (PD-1) inhibition monotherapy has shown minimal activity in prostate cancer. A published report showed that men with prostate cancer who were resistant to the second-generation androgen receptor inhibitor enzalutamide had increased programmed death-ligand 1 (PD-L1) expression on circulating antigen-presenting cells. We hypothesized that the addition of PD-1 inhibition in these patients could induce a meaningful cancer response. METHODS: We evaluated enzalutamide plus the PD-1 inhibitor pembrolizumab in a single-arm phase II study of 28 men with metastatic castration-resistant prostate cancer (mprogressing on enzalutamide alone. Pembrolizumab 200 mg intravenous was given every 3 weeks for four doses with enzalutamide. The primary endpoint was prostate-specific antigen (PSA) decline of ≥50%. Secondary endpoints were objective response, PSA progression-free survival (PFS), time to subsequent treatment, and time to death. Baseline tumor biopsies were obtained when feasible, and samples were sequenced and evaluated for the expression of PD-L1, microsatellite instability (MSI), mutational and neoepitope burdens. RESULTS: Five (18%) of 28 patients had a PSA decline of ≥50%. Three (25%) of 12 patients with measurable disease at baseline achieved an objective response. Of the five responders, two continue with PSA and radiographic response after 39.3 and 37.8 months. For the entire cohort, median follow-up was 37 months, and median PSA PFS time was 3.8 months (95% CI: 2.8 to 9.9 months). Time to subsequent treatment was 7.21 months (95% CI: 5.1 to 11.1 months). Median overall survival for all patients was 21.9 months (95% CI: 14.7 to 28 .4 months), versus 41.7 months (95% CI: 22.16 to not reached (NR)) in the responders. Of the three responders with baseline biopsies, one had MSI high disease with mutations consistent with DNA-repair defects. None had detectable PD-L1 expression. CONCLUSIONS: Pembrolizumab has activity in mCRPC when added to enzalutamide. Responses were deep and durable and did not require tumor PD-L1 expression or DNA-repair defects. TRIAL REGISTRATION NUMBER: clinicaltrials.gov (NCT02312557).


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/uso terapéutico , Nitrilos/uso terapéutico , Feniltiohidantoína/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Benzamidas/farmacología , Humanos , Masculino , Persona de Mediana Edad , Nitrilos/farmacología , Feniltiohidantoína/farmacología
19.
Cancer Immunol Res ; 7(2): 269-281, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30563828

RESUMEN

The protective capability of tumor antigen-specific T cells is regulated by costimulatory and inhibitory signals. Current approaches in cancer immunotherapy seek to restore the function of unresponsive T cells by blocking inhibitory pathways. In contrast, providing exogenous costimulatory signals to T cells also enhances antitumor functionality. By combining these two clinical approaches, we demonstrate the synergy of targeting PD-L1 together with the costimulatory molecule OX40, to enhance antitumor immunity. Concurrently blocking PD-L1 and providing a costimulatory agonist to OX40 increased the presence and functionality of tumor antigen-specific CD8+ T cells with simultaneous enhancement of T-helper type 1 (Th1)-skewed CD4+ T cells. This shift was functionally supported by increased glucose metabolism of antigen-specific CD8+ T cells and the acquisition of granzyme B by regulatory T cells. Together, this mechanism promoted tumor regression of late-stage tumors beyond that achieved by either blockade as monotherapy. These findings indicate that targeting both T-cell intrinsic (OX40) and extrinsic (PD-L1) regulatory molecules increases the bioenergetic potential of T cells, thereby expanding functional and tumor antigen-specific T cells.


Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Neoplasias/inmunología , Neoplasias/metabolismo , Receptores OX40/agonistas , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Cancer Res ; 66(12): 6432-8, 2006 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-16778222

RESUMEN

Selective cyclooxygenase-2 (COX-2) inhibitors are widely prescribed for severe arthritis and are currently under study in human chemoprevention trials. Recently, long-term use of these agents has come under scrutiny due to reports of treatment-associated cardiovascular toxicity. On short-term administration, the selective COX-2 inhibitor celecoxib inhibits adenoma growth in animal tumor models, including the C57BL/6J-Min/+ (Min/+) mouse. With uninterrupted long-term celecoxib administration, intestinal tumors in Min/+ mice initially regressed and then recurred to levels comparable with untreated controls. Celecoxib treatment initially suppressed COX-2 and prostaglandin E2 (PGE2) expression, but long-term use produced significantly higher levels of these molecules and reactivated PGE2-associated growth factor signaling pathways in tumor and normal tissues. These results indicate that COX-2 is an important chemoprevention target and that inhibition of this enzyme alters a paracrine enterocyte regulatory pathway. Chronic uninterrupted celecoxib treatment, however, induces untoward effects that enhance early progression events in intestinal tumorigenesis and may contribute to treatment toxicity.


Asunto(s)
Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Neoplasias Intestinales/tratamiento farmacológico , Pirazoles/administración & dosificación , Sulfonamidas/administración & dosificación , Adenoma/tratamiento farmacológico , Adenoma/enzimología , Adenoma/metabolismo , Animales , Celecoxib , Dinoprostona/metabolismo , Esquema de Medicación , Neoplasias Intestinales/enzimología , Neoplasias Intestinales/metabolismo , Lipooxigenasa/biosíntesis , Ratones , Ratones Endogámicos C57BL , Receptores de Prostaglandina/biosíntesis , Transducción de Señal/efectos de los fármacos
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