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In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.
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Neoplasias dos Ductos Biliares , Neoplasias do Sistema Biliar , Colangiocarcinoma , Neoplasias da Vesícula Biliar , Neoplasias Hepáticas , Humanos , Neoplasias do Sistema Biliar/diagnóstico , Neoplasias do Sistema Biliar/terapia , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/terapia , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/terapia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Ductos Biliares Intra-HepáticosRESUMO
Glioblastoma (GBM) is the most common malignant brain tumor in adults with a median survival of 14.6months. A contributing factor to GBM aggressiveness is the intratumoral expression of the potently immunosuppressive enzyme, indoleamine 2,3 dioxygenase 1 (IDO1). The enzymatic activity of IDO1 is associated with the conversion of tryptophan into downstream kynurenine (Kyn), which has previously been hypothesized to contribute toward the suppression of tumor immunity. Utilizing the syngeneic, immunocompetent, intracranial GL261 cell GBM model, we previously demonstrated that tumor cell, but not non-tumor cell IDO1, suppresses T cell-mediated brain tumor regression in mice. Paradoxically, we also showed that the survival advantage mediated by immune checkpoint blockade is abrogated by non-tumor cell IDO1 deficiency. Here, we have built on our past observations and confirm the maladaptive role of tumor cell IDO1 in a novel mouse GBM model. We also demonstrate that, non-tumor cells, rather than mouse GBM cells, are the dominant contributor to IDO1-mediated enzyme activity. Finally, we show the novel associations between maximally-effective immune-checkpoint blockade-mediated survival, non-tumor cell IDO1 and intra-GBM Kyn levels. These data suggest for the first time that, GBM cell-mediated immunosuppression is IDO1 enzyme independent, while the survival benefits of immune checkpoint blockade require non-tumor cell IDO1 enzyme activity. Given that current clinical inhibitors vary in their mechanism of action, in terms of targeting IDO1 enzyme activity versus enzyme-independent effects, this work suggests that choosing an appropriate IDO1 pharmacologic will maximize the effectiveness of future immune checkpoint blockade approaches.
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Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Glioblastoma/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Animais , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Modelos Animais de Doenças , Glioblastoma/patologia , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Camundongos , Camundongos KnockoutRESUMO
Myeloid-derived CD11b(+)Gr1(+) suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are considered a major obstacle for effective adoptive T cell therapy. Myeloid cells suppress naive T cell proliferation ex vivo and can prevent the generation of T cell responses in vivo. We find, however, that adoptively transferred immune T cells eradicate well-established tumors in the presence of MDSCs and TAMs, which are strongly immunosuppressive ex vivo. These MDSCs and TAMs were comparable in numbers and immunosuppressive capacity among different tumor models. Longitudinal microscopy of tumors in vivo revealed that after T cell transfer, tumor vasculature and cancer cells disappeared simultaneously. During T cell-mediated tumor destruction, the tumor stroma contained abundant myeloid cells (mainly TAMs) that retained their suppressive properties. Preimmunized but not naive mice resisted immune suppression caused by an unrelated tumor burden, supporting the idea that in vivo, myeloid immunosuppressive cells can suppress naive but not memory T cell responses.
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Imunoterapia Adotiva , Macrófagos/imunologia , Células Mieloides/imunologia , Neoplasias Experimentais/terapia , Subpopulações de Linfócitos T/transplante , Evasão Tumoral/imunologia , Animais , Antígeno CD11b/análise , Vacinas Anticâncer/imunologia , Proteínas de Ligação a DNA/deficiência , Proteínas de Homeodomínio/genética , Imunização , Memória Imunológica , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Modelos Biológicos , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neovascularização Patológica/imunologia , Neovascularização Patológica/terapia , Receptores de Quimiocinas/análise , Técnica de Janela Cutânea , Subpopulações de Linfócitos T/imunologia , Carga TumoralRESUMO
Physicians and other healthcare professionals are often the end users of medical innovation; however, they are rarely involved in the beginning design stages. This often results in ineffective healthcare solutions with poor adoption rates. At the early design stage, innovation would benefit from input from healthcare professionals. This report describes the first-ever rehabilitation hackathon-an interdisciplinary and competitive team event aimed at accelerating and improving healthcare solutions and providing an educational experience for participants. Hackathons are gaining traction as a way to accelerate innovation by bringing together a diverse group of interdisciplinary professionals from different industries who work collaboratively in teams and learn from each other, focus on a specific problem ("pain point"), develop a solution using design thinking techniques, pitch the solution to participants, gather fast feedback and quickly alter the prototype design ("pivoting"). 102 hackers including 19 (18.6 %) physicians and other professionals participated, and over the course of 2 days worked in teams, pitched ideas and developed design prototypes. Three awards were given for prototypes that may improve function in persons with disabilities. 43 hackers were women (42.2 %) and 59 men (57.8 %); they ranged in age from 16 to 79 years old; and, of the 75 hackers who reported their age, 63 (84 %) were less than 40 years old and 12 (16 %) were 40 years or older. This report contributes to the emerging literature on healthcare hackathons as a means of providing interdisciplinary education and training and supporting innovation.
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Pessoal de Saúde/educação , Sistemas de Informação/organização & administração , Capacitação em Serviço/organização & administração , Equipe de Assistência ao Paciente/organização & administração , Design de Software , Adolescente , Adulto , Idoso , Segurança Computacional , Confidencialidade , Comportamento Cooperativo , Feminino , Humanos , Sistemas de Informação/normas , Comunicação Interdisciplinar , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: Dynamic contrast-enhanced MRI (DCE-MRI) has become a standard component of multiparametric protocols for MRI examination of the prostate, and its use is incorporated into current guidelines for prostate MRI examination. Analysis of DCE-MRI data for the prostate is usually based on the distribution of gadolinium-based agents, such as gadodiamide, into two well-mixed compartments, and it assumes that gadodiamide does not enter into the glandular lumen. However, this assumption has not been directly tested. The purpose of this study was to use x-ray fluorescence microscopy (XFM) imaging in situ to measure the concentration of gadodiamide in the epithelia and lumens of the prostate of healthy mice after IV injection of the contrast agent. MATERIALS AND METHODS: Six C57Bl6 male mice (age, 28 weeks) were sacrificed 10 minutes after IV injection of gadodiamide (0.13 mmol/kg), and three mice were sacrificed after saline injection. Prostate tissue samples obtained from each mouse were harvested and frozen; 7-µm-thick slices were sectioned for XFM imaging, and adjacent 5-µm-thick slices were sectioned for H and E staining. Elemental concentrations were determined from XFM images. RESULTS: A mean (± SD) baseline concentration of gadolinium of 0.01 ± 0.01 mM was determined from XFM measurements of prostatic tissue samples when no gadodiamide was administered, and it was used to determine the measurement error. When gadodiamide was added, the mean concentrations of gadolinium in the epithelia and lumens in 32 prostatic glands from six mice were 1.00 ± 0.13 and 0.36 ± 0.09 mM, respectively. CONCLUSION: Our data suggest that IV administration of gadodiamide results in uptake of contrast agent by the glandular lumens of the mouse prostate. We were able to quantitatively determine gadodiamide distributions in mouse prostatic epithelia and lumens.
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Meios de Contraste/farmacocinética , Gadolínio DTPA/farmacocinética , Próstata/diagnóstico por imagem , Próstata/metabolismo , Animais , Meios de Contraste/administração & dosagem , Epitélio/diagnóstico por imagem , Epitélio/metabolismo , Gadolínio DTPA/administração & dosagem , Injeções Intravenosas , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Modelos Animais , RadiografiaRESUMO
ABSTRACT: The oligometastatic disease state, defined as a cancer with 5 or fewer sites of metastasis, is a therapeutic opportunity to improve oncologic outcomes. Colorectal cancer (CRC) was among the first for which oligometastatic treatment was used in routine clinical practice, and recent studies have shown potential for improved overall survival with metastasis-directed therapies. As CRC is the third most common cause of cancer death in men and women, improving oncologic outcomes in this population is of paramount importance. The relatively recent identification of this treatment paradigm and paucity of high-quality data have led to heterogeneity in clinical practice. This review will explore perspectives of a panel of surgical and radiation oncologists for complex or controversial cases of metastatic CRC.
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Neoplasias Colorretais , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Feminino , Masculino , Metástase Neoplásica , Pessoa de Meia-Idade , Idoso , Terapia Combinada/métodos , Resultado do TratamentoRESUMO
OBJECTIVE: Chronic pain is multidimensional, requiring expanded interventions for optimal management. Pain education, mindfulness training, and virtual reality (VR) are showing promise, but barriers remain for implementation by clinicians. The purpose of this study was to explore the experiences with a pain education and mindfulness intervention for patients with chronic low back pain and their treating clinicians. METHODS: This was a prospectively designed exploratory trial registered at ClinicalTrials.gov: NCT04777877. Patients were identified by study staff and consented. Baseline and follow-up questionnaires and surveys were collected with quantitative and qualitative data. Patients viewed five videos explaining key pain concepts and guided imagery nature videos using a VR headset. RESULTS: Twenty patients consented, and 15 patients completed the intervention. Patients and clinicians rated their experiences with the program as excellent; however, concerns were raised related to logistical challenges around use of the VR headset in busy clinic settings. Percentage changes in patient pain knowledge occurred in the desired direction in 8 out of 9 key concepts. CONCLUSIONS: Delivering educational and mindfulness content with a VR headset to patients with chronic low back pain was feasible and acceptable to patients and clinicians. Concerns remain regarding the increased time burden with use of this technology in a busy clinic setting weighed against potential benefits. Alternative delivery methods are needed to reduce logistical challenges and increase patient access to content outside of the clinic setting.
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Chronic pain is a major public health problem. There is a need to develop novel treatment strategies to address this growing issue. Virtual reality is emerging as an alternative approach to help people suffering from chronic pain. The purpose of this work was to explore the feasibility, acceptability, and impact of a brief virtual reality relaxation video on peri-procedural pain and anxiety in chronic low back pain patients receiving spinal injections. The intervention was delivered in the context of a busy fluoroscopy injection clinic. Upon arrival to the clinic, consented patients were randomized into one of three groups: (1) Audiovisual monitor-flat screen (AV) (2) Virtual Reality headset (VR) and (3) Control-no intervention. The main questions we set out to answer were: (1) Is it feasible to deliver the intervention in the context of clinical care? (2) Was the intervention acceptable to patients? and (3) Did the intervention impact pain and anxiety surrounding the injection procedure? Viewing a brief relaxation nature video in AV or VR format was not associated with statistically lower pain scores following an injection procedure compared to controls. However, the intervention was associated with lower anxiety scores recorded prior to the injection compared to controls. Importantly, the virtual reality intervention was acceptable and feasible to integrate into a clinic setting, however, to maximize effectiveness, the content delivered to this population should be targeted and delivered over a longer duration. In addition, alternative outcomes and settings beyond peri-procedural pain surrounding an injection should be explored.
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BACKGROUND: Radioresistance represents a major problem in the treatment of head and neck cancer (HNC) patients. To improve response, understanding tumor microenvironmental factors that contribute to radiation resistance is important. Regulatory T cells (Tregs) are enriched in numerous cancers and can dampen the response to radiation by creating an immune-inhibitory microenvironment. The purpose of this study was to investigate mechanisms of Treg modulation by radiation in HNC. METHODS: We utilized an orthotopic mouse model of HNC. Anti-CD25 was used for Treg depletion. Image-guided radiation was delivered to a dose of 10 Gy. Flow cytometry was used to analyze abundance and function of intratumoral immune cells. Enzyme-linked immunosorbent assay was performed to assess secreted factors. For immune-modulating therapies, anti-PD-L1, anti-CTLA-4, and STAT3 antisense oligonucleotide (ASO) were used. All statistical tests were two-sided. RESULTS: Treatment with anti-CD25 and radiation led to tumor eradication (57.1%, n = 4 of 7 mice), enhanced T-cell cytotoxicity compared with RT alone (CD4 effector T cells [Teff]: RT group mean = 5.37 [ 0.58] vs RT + αCD25 group mean =10.71 [0.67], P = .005; CD8 Teff: RT group mean = 9.98 [0.81] vs RT + αCD25 group mean =16.88 [2.49], P = .01) and induced tumor antigen-specific memory response (100.0%, n = 4 mice). In contrast, radiation alone or when combined with anti-CTLA4 did not lead to durable tumor control (0.0%, n = 7 mice). STAT3 inhibition in combination with radiation, but not as a single agent, improved tumor growth delay, decreased Tregs, myeloid-derived suppressor cells, and M2 macrophages and enhanced effector T cells and M1 macrophages. Experiments in nude mice inhibited the benefit of STAT3 ASO and radiation. CONCLUSION: We propose that STAT3 inhibition is a viable and potent therapeutic target against Tregs. Our data support the design of clinical trials integrating STAT3 ASO in the standard of care for cancer patients receiving radiation.
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Neoplasias de Cabeça e Pescoço/radioterapia , Depleção Linfocítica , Radioimunoterapia/métodos , Fator de Transcrição STAT3/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Linfócitos T Reguladores/efeitos da radiação , Análise de Variância , Animais , Citotoxicidade Imunológica , Feminino , Fatores de Transcrição Forkhead/genética , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Memória Imunológica , Subunidade alfa de Receptor de Interleucina-2/genética , Depleção Linfocítica/métodos , Macrófagos/efeitos da radiação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Células Supressoras Mieloides/efeitos da radiação , Tolerância a Radiação , Radioterapia Guiada por Imagem , Fator de Transcrição STAT3/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta1/genética , Microambiente TumoralRESUMO
Preclinical modeling and gene expression analyses have yielded distinct observations for the role of immune checkpoint, IDO1, in glioblastoma (GBM). Accordingly, our recent work differs with Garg et al. (2017) with respect to IDO1 among preclinical and bioinformatic GBM datasets. Here, we discuss the methodological differences that affected study interpretation, and potentially, future clinical decision-making for IDO1-targeting approaches against GBM.
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Glioblastoma , Biomarcadores , Glioblastoma/tratamento farmacológico , Humanos , Indolamina-Pirrol 2,3,-DioxigenaseRESUMO
Purpose: Radiotherapy (RT) can transform the immune landscape and render poorly immunogenic tumors sensitive to PD-L1 inhibition. Here, we established that the response to combined RT and PD-L1 inhibition is transient and investigated mechanisms of resistance.Experimental Design: Mechanisms of resistance to RT and PD-L1 blockade were investigated in orthotopic murine head and neck squamous cell carcinoma (HNSCC) tumors using mass cytometry and whole-genome sequencing. Mice were treated with anti-PD-L1 or anti-TIM-3 alone and in combination with and without RT. Tumor growth and survival were assessed. Flow cytometry was used to assess phenotypic and functional changes in intratumoral T-cell populations. Depletion of regulatory T cells (Treg) was performed using anti-CD25 antibody.Results: We show that the immune checkpoint receptor, TIM-3, is upregulated on CD8 T cells and Tregs in tumors treated with RT and PD-L1 blockade. Treatment with anti-TIM-3 concurrently with anti-PD-L1 and RT led to significant tumor growth delay, enhanced T-cell cytotoxicity, decreased Tregs, and improved survival in orthotopic models of HNSCC. Despite this treatment combination, the response was not durable, and analysis of relapsed tumors revealed resurgence of Tregs. Targeted Treg depletion, however, restored antitumor immunity in mice treated with RT and dual immune checkpoint blockade and resulted in tumor rejection and induction of immunologic memory.Conclusions: These data reveal multiple layers of immune regulation that can promote tumorigenesis and the therapeutic potential of sequential targeting to overcome tumor resistance mechanisms. We propose that targeted Treg inhibitors may be critical for achieving durable tumor response with combined radiotherapy and immunotherapy. Clin Cancer Res; 24(21); 5368-80. ©2018 AACR.
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Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Tolerância a Radiação , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Linhagem Celular Tumoral , Terapia Combinada , Citotoxicidade Imunológica , Modelos Animais de Doenças , Humanos , Imunomodulação/efeitos dos fármacos , Imunomodulação/genética , Camundongos , Radioterapia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Purpose: Glioblastoma is the most aggressive primary brain tumor in adults with a median survival of 15-20 months. Numerous approaches and novel therapeutics for treating glioblastoma have been investigated in the setting of phase III clinical trials, including a recent analysis of the immune checkpoint inhibitor, nivolumab (anti-PD-1), which failed to improve recurrent glioblastoma patient survival. However, rather than abandoning immune checkpoint inhibitor treatment for glioblastoma, which has shown promise in other types of cancer, ongoing studies are currently evaluating this therapeutic class when combined with other agents.Experimental Design: Here, we investigated immunocompetent orthotopic mouse models of glioblastoma treated with the potent CNS-penetrating IDO1 enzyme inhibitor, BGB-5777, combined with anti-PD1 mAb, as well as radiotherapy, based on our recent observation that tumor-infiltrating T cells directly increase immunosuppressive IDO1 levels in human glioblastoma, the previously described reinvigoration of immune cell functions after PD-1 blockade, as well as the proinflammatory effects of radiation.Results: Our results demonstrate a durable survival benefit from this novel three-agent treatment, but not for any single- or dual-agent combination. Unexpectedly, treatment efficacy required IDO1 enzyme inhibition in non-glioblastoma cells, rather than tumor cells. Timing of effector T-cell infiltration, animal subject age, and usage of systemic chemotherapy, all directly impacted therapy-mediated survival benefit.Conclusions: These data highlight a novel and clinically relevant immunotherapeutic approach with associated mechanistic considerations that have formed the basis of a newly initiated phase I/II trial for glioblastoma patients. Clin Cancer Res; 24(11); 2559-73. ©2018 AACR.
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Antineoplásicos Imunológicos/farmacologia , Inibidores Enzimáticos/farmacologia , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Radiação Ionizante , Animais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacocinética , Linhagem Celular Tumoral , Terapia Combinada , Modelos Animais de Doenças , Sinergismo Farmacológico , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/efeitos da radiação , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Camundongos , Camundongos Knockout , Metástase Neoplásica , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/metabolismo , Análise de Sobrevida , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Salmonella Typhimurium, engineered to express flagellin B, recently demonstrated unprecedented tumor control through a TLR-dependent mechanism. Here, we review new observations that support the potential of utilizing modified bacteria to enhance antitumor immunity. We also discuss the implications of these findings for clinical applications, including immune checkpoint blockade therapies.
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Flagelina/imunologia , Flagelina/uso terapêutico , Imunoterapia/métodos , Neoplasias/terapia , Salmonella typhimurium/imunologia , Animais , Flagelina/genética , Humanos , Neoplasias/imunologia , Salmonella typhimurium/genética , Receptores Toll-Like/genética , Receptores Toll-Like/imunologiaRESUMO
BACKGROUND: Patients with melanoma brain metastases (MBM) have been excluded from trials evaluating immunotherapy in melanoma. As such, immunotherapy's role in MBM is poorly understood, particularly in combination with radiotherapy. METHODS: The National Cancer Database was queried for patients with MBM receiving brain radiotherapy. They were classified according to immunotherapy receipt. Multivariate Cox regression was performed to identify factors associated with survival. RESULTS: Among 1287 patients, 185 received immunotherapy. Factors associated with improved survival included younger age, academic facility, lower extracranial disease burden, stereotactic radiotherapy, chemotherapy, and immunotherapy. CONCLUSIONS: Adding immunotherapy to radiotherapy for MBM is associated with improved survival.
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Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Irradiação Craniana/métodos , Imunoterapia/métodos , Melanoma/patologia , Adulto , Distribuição por Idade , Idoso , Neoplasias Encefálicas/mortalidade , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-IdadeRESUMO
Purpose: Indoleamine 2,3 dioxygenase 1 (IDO1) mediates potent immunosuppression in multiple preclinical models of cancer. However, the basis for elevated IDO1 expression in human cancer, including the most common primary malignant brain tumor in adults, glioblastoma (GBM), is poorly understood. The major objective of this study is to address this gap in our understanding of how IDO1 expression contributes to the biology of GBM, and whether its level of expression is a determinant of GBM patient outcome.Experimental Design: Patient-resected GBM, The Cancer Genome Atlas, human T-cell:GBM cocultures, as well as nu/nu, NOD-scid, and humanized (NSG-SGM3-BLT) mice-engrafted human GBM form the basis of our investigation.Results:In situ hybridization for IDO1 revealed transcript expression throughout patient-resected GBM, whereas immunohistochemical IDO1 positivity was highly variable. Multivariate statistical analysis revealed that higher levels of IDO1 transcript predict a poor patient prognosis (P = 0.0076). GBM IDO1 mRNA levels positively correlated with increased gene expression for markers of cytolytic and regulatory T cells, in addition to decreased patient survival. Humanized mice intracranially engrafted human GBM revealed an IFNγ-associated T-cell-mediated increase of intratumoral IDO1Conclusions: Our data demonstrate that high intratumoral IDO1 mRNA levels correlate with a poor GBM patient prognosis. It also confirms the positive correlation between increased GBM IDO1 levels and human-infiltrating T cells. Collectively, this study suggests that future efforts aimed at increasing T-cell-mediated effects against GBM should consider combinatorial approaches that coinhibit potential T-cell-mediated IDO1 enhancement during therapy. Clin Cancer Res; 23(21); 6650-60. ©2017 AACR.
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Glioblastoma/genética , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Linfócitos do Interstício Tumoral/metabolismo , Prognóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Técnicas de Cocultura , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Humanos , Linfócitos do Interstício Tumoral/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , RNA Mensageiro/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Immunotherapy clinical trials targeting the programmed-death ligand axis (PD-1/PD-L1) show that most head and neck squamous cell carcinoma (HNSCC) patients are resistant to PD-1/PD-L1 inhibition. We investigated whether local radiation to the tumor can transform the immune landscape and render poorly immunogenic HNSCC tumors sensitive to PD-L1 inhibition. We used the first novel orthotopic model of HNSCC with genetically distinct murine cell lines. Tumors were resistant to PD-L1 checkpoint blockade, harbored minimal PD-L1 expression and tumor infiltrating lymphocytes at baseline, and were resistant to radiotherapy. The combination of radiation and PD-L1 inhibition significantly enhanced tumor control and improved survival. This was mediated in part through upregulation of PD-L1 on tumor cells and increased T-cell infiltration after RT, resulting in a highly inflamed tumor. Depletion of both CD4 and CD8 T-cells completely abrogated the effect of anti PD-L1 with radiation on tumor growth. Our findings provide evidence that radiation to the tumor can induce sensitivity to PD-L1 checkpoint blockade in orthotopic models of HNSCC. These findings have direct relevance to high risk HNSCC patients with poorly immunogenic tumors and who may benefit from combined radiation and checkpoint blockade.
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Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and still remains incurable. Although immunotherapeutic vaccination against GBM has demonstrated immune-stimulating activity with some promising survival benefits, tumor relapse is common, highlighting the need for additional and/or combinatorial approaches. Recently, antibodies targeting immune checkpoints were demonstrated to generate impressive clinical responses against advanced melanoma and other malignancies, in addition to showing potential for enhancing vaccination and radiotherapy (RT). Here, we summarize the current knowledge of central nervous system (CNS) immunosuppression, evaluate past and current immunotherapeutic trials and discuss promising future immunotherapeutic directions to treat CNS-localized malignancies.
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We recently reported that therapeutic vaccination with live tumor antigen-producing Salmonella typhimurium rescues dysfunctional endogenous T cell responses and eradicates long-established tumors refractory to αCTLA-4 and αPD-L1 checkpoint inhibitor blockade. Here, we show that live intravenously injected or heat-killed (HK) intratumorally injected Salmonella typhimurium, even when not producing tumor antigen, synergize with adoptive T cell therapy to eradicate tumors. These data demonstrate that the combination of adoptive T cell transfer with the injection of live or dead Salmonella typhimurium is a promising approach for cancer treatment.
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The effective treatment of adult and pediatric malignant glioma is a significant clinical challenge. In adults, glioblastoma (GBM) accounts for the majority of malignant glioma diagnoses with a median survival of 14.6 mo. In children, malignant glioma accounts for 20% of primary CNS tumors with a median survival of less than 1 y. Here, we discuss vaccine treatment for children diagnosed with malignant glioma, through targeting EphA2, IL-13Rα2 and/or histone H3 K27M, while in adults, treatments with RINTEGA, Prophage Series G-100 and dendritic cells are explored. We conclude by proposing new strategies that are built on current vaccine technologies and improved upon with novel combinatorial approaches.
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Combining radiation and immune checkpoint blockade provides synergistic antitumor responses in animal models and a small subset of patients. New preclinical data have provided mechanistic insight into this treatment interaction and identification of therapeutic targets to optimize this approach.