Publications by authors named "Brent A Hanks"

29 Publications

  • Page 1 of 1

The State of Melanoma: Emergent Challenges and Opportunities.

Clin Cancer Res 2021 Jan 7. Epub 2021 Jan 7.

Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute

Five years ago, the Melanoma Research Foundation (MRF) conducted an assessment of the challenges and opportunities facing the melanoma research community and patients with melanoma. Since then, remarkable progress has been made on both the basic and clinical research fronts. However, the incidence, recurrence and death rates for melanoma remain unacceptably high and significant challenges remain. Hence, the MRF Scientific Advisory Council and Breakthrough Consortium, a group that includes clinicians and scientists, reconvened to facilitate intensive discussions on thematic areas essential to melanoma researchers and patients alike - prevention, detection, diagnosis, metastatic dormancy and progression, response and resistance to targeted and immune-based therapy, and the clinical consequences of COVID-19 for melanoma patients and providers. These extensive discussions helped to crystalize our understanding of the challenges and opportunities facing the broader melanoma community today. In this report, we discuss the progress made since the last MRF assessment, comment on what remains to be overcome and offer recommendations for the best path forward.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4092DOI Listing
January 2021

SITC cancer immunotherapy resource document: a compass in the land of biomarker discovery.

J Immunother Cancer 2020 12;8(2)

Stanford University Medical Center, Stanford, California, USA

Since the publication of the Society for Immunotherapy of Cancer's (SITC) original cancer immunotherapy biomarkers resource document, there have been remarkable breakthroughs in cancer immunotherapy, in particular the development and approval of immune checkpoint inhibitors, engineered cellular therapies, and tumor vaccines to unleash antitumor immune activity. The most notable feature of these breakthroughs is the achievement of durable clinical responses in some patients, enabling long-term survival. These durable responses have been noted in tumor types that were not previously considered immunotherapy-sensitive, suggesting that all patients with cancer may have the potential to benefit from immunotherapy. However, a persistent challenge in the field is the fact that only a minority of patients respond to immunotherapy, especially those therapies that rely on endogenous immune activation such as checkpoint inhibitors and vaccination due to the complex and heterogeneous immune escape mechanisms which can develop in each patient. Therefore, the development of robust biomarkers for each immunotherapy strategy, enabling rational patient selection and the design of precise combination therapies, is key for the continued success and improvement of immunotherapy. In this document, we summarize and update established biomarkers, guidelines, and regulatory considerations for clinical immune biomarker development, discuss well-known and novel technologies for biomarker discovery and validation, and provide tools and resources that can be used by the biomarker research community to facilitate the continued development of immuno-oncology and aid in the goal of durable responses in all patients.
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http://dx.doi.org/10.1136/jitc-2020-000705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713206PMC
December 2020

Tumor Mutational Burden as a Predictor of Immunotherapy Response: Is More Always Better?

Clin Cancer Res 2021 Mar 16;27(5):1236-1241. Epub 2020 Nov 16.

Duke Cancer Institute, Duke University, Durham, North Carolina.

Immune checkpoint inhibitors, including antibodies that block programmed cell death protein-1 (PD-1) and PD-L1, have transformed the management of many cancers. However, the majority of patients have primary or acquired resistance to these immunotherapies. There is a significant unmet need for predictive biomarkers that can reliably identify patients who derive a clinically meaningful response from PD-1/PD-L1 blockade. High tumor mutational burden (TMB-H) has shown promise as a biomarker in lung cancer, but the broad applicability of TMB-H as a biomarker of response across all solid tumors is unclear. The FDA has approved the PD-1 inhibitor, pembrolizumab, as a therapy for all solid tumors with TMB equal to or greater than 10 mutations/megabase as measured by the FoundationOne CDx assay. This approval was based on an exploratory analysis of the KEYNOTE-158 study, which was a single-arm, phase II multi-cohort study of pembrolizumab for select, previously treated advanced solid tumors. Here, we elucidate the caveats of using TMB as a biomarker with a universal threshold across all solid tumors. While we recognize the importance of this and other FDA pan-cancer approvals, several questions about TMB as a predictive biomarker remain unanswered. In this perspective, we discuss clinical trial evidence in this area. We review the relationship between TMB and the tumor immune microenvironment. We highlight the risks of extrapolating evidence from a limited number of tumor histologies to all solid tumors, and we propose avenues for future research.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3054DOI Listing
March 2021

Ipilimumab and Radiation in Patients with High-risk Resected or Regionally Advanced Melanoma.

Clin Cancer Res 2021 Mar 10;27(5):1287-1295. Epub 2020 Nov 10.

Department of Radiation Oncology, Duke University, Durham, North Carolina.

Purpose: In this prospective trial, we sought to assess the feasibility of concurrent administration of ipilimumab and radiation as adjuvant, neoadjuvant, or definitive therapy in patients with regionally advanced melanoma.

Patients And Methods: Twenty-four patients in two cohorts were enrolled and received ipilimumab at 3 mg/kg every 3 weeks for four doses in conjunction with radiation; median dose was 4,000 cGy (interquartile range, 3,550-4,800 cGy). Patients in cohort 1 were treated adjuvantly; patients in cohort 2 were treated either neoadjuvantly or as definitive therapy.

Results: Adverse event profiles were consistent with those previously reported with checkpoint inhibition and radiation. For the neoadjuvant/definitive cohort, the objective response rate was 64% (80% confidence interval, 40%-83%), with 4 of 10 evaluable patients achieving a radiographic complete response. An additional 3 patients in this cohort had a partial response and went on to surgical resection. With 2 years of follow-up, the 6-, 12-, and 24-month relapse-free survival for the adjuvant cohort was 85%, 69%, and 62%, respectively. At 2 years, all patients in the neoadjuvant/definitive cohort and 10/13 patients in the adjuvant cohort were still alive. Correlative studies suggested that response in some patients were associated with specific CD4 T-cell subsets.

Conclusions: Overall, concurrent administration of ipilimumab and radiation was feasible, and resulted in a high response rate, converting some patients with unresectable disease into surgical candidates. Additional studies to investigate the combination of radiation and checkpoint inhibitor therapy are warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2452DOI Listing
March 2021

The utility of initial staging PET-CT as a baseline scan for surveillance imaging in stage II and III melanoma.

Surg Oncol 2020 Dec 2;35:533-539. Epub 2020 Nov 2.

Department of Surgery, Duke University Medical Center, Durham, NC, USA. Electronic address:

Background: This study evaluates the utility of whole-body PET-CT for the initial staging and subsequent surveillance imaging of patients with completely resected stage II and stage III melanoma.

Methods: A single-center, retrospective review of patients who received perioperative whole-body PET-CT from January 1, 2005 to December 1, 2019 within three months of initial melanoma diagnosis was performed.

Results: Of 258 total patients with completely resected melanoma who had a PET-CT within 3 months after their melanoma diagnosis, 113 had stage II and 145 had stage III melanoma. PET-CT detected distant metastasis in 3 (2.7%) of 113 stage II patients and 7 (4.8%) of 145 stage III patients. 179 of 258 patients had adequate follow-up time to determine whether they received surveillance cross-sectional imaging and whether they had a melanoma recurrence. 143 (79.9%) received subsequent surveillance imaging, 74 of whom developed a recurrence. In 64 (86.5%) of 74 cases, recurrence was detected by routine surveillance. 26 (34.2%) of 76 stage II and 65 (63.1%) of 103 stage III patients developed a recurrence. The median time to recurrence among the 179 patients for stage II and III was 16.3 and 13.0 months, respectively.

Conclusions: These findings indicate that baseline staging with whole-body PET-CT rarely provides information that changes initial management. Rather, the value of the initial PET-CT is as a baseline for subsequent surveillance scans. Therefore, it may be premature to discourage cross-sectional imaging for patients with stage II and III melanoma without supportive evidence or a reliable biomarker of recurrent disease.
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http://dx.doi.org/10.1016/j.suronc.2020.10.018DOI Listing
December 2020

Higher BMI, But Not Sarcopenia, Is Associated With Pembrolizumab-related Toxicity in Patients With Advanced Melanoma.

Anticancer Res 2020 Sep;40(9):5245-5254

Department of Surgery, Duke University Medical Center, Durham, NC, U.S.A.

Background/aim: To determine whether BMI and sarcopenia were related to treatment-limiting toxicity or efficacy of pembrolizumab treatment in melanoma patients.

Patients And Methods: Medical records for melanoma patients undergoing pembrolizumab treatment at Duke University from January 2014 to September 2018 were reviewed. Pre-treatment measurements such as BMI were collected. Pre-treatment CT imaging was used to determine psoas muscle index (PMI). Patients in the lowest sex-specific tertile of PMI were sarcopenic. Logistic regression measured associations with treatment toxicity and response. Kaplan-Meier analysis assessed progression-free survival (PFS) and overall survival (OS).

Results: Among 156 patients, the overall objective response rate was 46.2% and 29 patients (18.6%) experienced treatment-limiting toxicity. Sarcopenia was not significantly associated with toxicity, response, or survival. However, obese patients (BMI >30) experienced higher rates of toxicity (p=0.0007).

Conclusion: Sarcopenia did not appear to predict clinically relevant outcomes. Obesity, however, represents a readily available predictor of pembrolizumab toxicity.
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http://dx.doi.org/10.21873/anticanres.14528DOI Listing
September 2020

Dissecting the immune landscape of tumor draining lymph nodes in melanoma with high-plex spatially resolved protein detection.

Cancer Immunol Immunother 2021 Feb 19;70(2):475-483. Epub 2020 Aug 19.

Department of Surgery, Duke University, DUMC Box 3118, Durham, NC, 27710, USA.

Background: In melanoma patients, microscopic tumor in the sentinel lymph-node biopsy (SLN) increases the risk of distant metastases, but the transition from tumor in the SLN to metastatic disease remains poorly understood.

Methods: Fluorescent staining for CD3, CD20, CD11c, and DNA was performed on SLN tissue and matching primary tumors. Regions of interest (ROI) were then chosen geometrically (e.g., tumor) or by fluorescent cell subset markers (e.g., CD11c). Each ROI was further analyzed using NanoString Digital Spatial Profiling high-resolution multiplex profiling. Digital counts for 59-panel immune-related proteins were collected and normalized to account for system variation and ROI area.

Results: Tumor regions of SLNs had variable infiltration of CD3 cells among patients. The patient with overall survival (OS) > 8 years had the most CD11c- and CD3-expressing cells infiltrating the SLN tumor region. All patients had CD11c (dendritic cell, DC) infiltration into the SLN tumor region. Selecting ROI by specific cell subtype, we compared protein expression of CD11c cells between tumor and non-tumor/normal tissue SLN regions. Known markers of DC activation such as CD86, HLA-DR, and OX40L were lowest on CD11c cells within SLN tumor for the patient with OS < 1 year and highest on the patient with OS > 8 years.

Conclusion: We demonstrate the feasibility of profiling the protein expression of CD11c cells within the SLN tumor. Identifying early regulators of melanoma control when the disease is microscopically detected in the SLN is beneficial and requires follow-up studies in a larger cohort of patients.
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http://dx.doi.org/10.1007/s00262-020-02698-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892641PMC
February 2021

Role of dendritic cell metabolic reprogramming in tumor immune evasion.

Int Immunol 2020 06;32(7):485-491

The dendritic cell (DC) is recognized as a vital mediator of anti-tumor immunity. More recent studies have also demonstrated the important role of DCs in the generation of effective responses to checkpoint inhibitor immunotherapy. Metabolic programming of DCs dictates their functionality and can determine which DCs become immunostimulatory versus those that develop a tolerized phenotype capable of actively suppressing effector T-cell responses to cancers. As a result, there is great interest in understanding what mechanisms have evolved in cancers to alter these metabolic pathways, thereby allowing for their continued progression and metastasis. The therapeutic strategies developed to reverse these processes of DC tolerization in the tumor microenvironment represent promising candidates for future testing in combination immunotherapy clinical trials.
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http://dx.doi.org/10.1093/intimm/dxaa036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318778PMC
June 2020

A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy.

J Clin Invest 2020 05;130(5):2570-2586

Division of Medical Oncology and.

An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8+ T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain-containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti-PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti-PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.
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http://dx.doi.org/10.1172/JCI133055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190922PMC
May 2020

Role of Tumor-Mediated Dendritic Cell Tolerization in Immune Evasion.

Front Immunol 2019 10;10:2876. Epub 2019 Dec 10.

Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Durham, NC, United States.

The vast majority of cancer-related deaths are due to metastasis, a process that requires evasion of the host immune system. In addition, a significant percentage of cancer patients do not benefit from our current immunotherapy arsenal due to either primary or secondary immunotherapy resistance. Importantly, select subsets of dendritic cells (DCs) have been shown to be indispensable for generating responses to checkpoint inhibitor immunotherapy. These observations are consistent with the critical role of DCs in antigen cross-presentation and the generation of effective anti-tumor immunity. Therefore, the evolution of efficient tumor-extrinsic mechanisms to modulate DCs is expected to be a potent strategy to escape immunosurveillance and various immunotherapy strategies. Despite this critical role, little is known regarding the methods by which cancers subvert DC function. Herein, we focus on those select mechanisms utilized by developing cancers to co-opt and tolerize local DC populations. We discuss the reported mechanisms utilized by cancers to induce DC tolerization in the tumor microenvironment, describing various parallels between the evolution of these mechanisms and the process of mesenchymal transformation involved in tumorigenesis and metastasis, and we highlight strategies to reverse these mechanisms in order to enhance the efficacy of the currently available checkpoint inhibitor immunotherapies.
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http://dx.doi.org/10.3389/fimmu.2019.02876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914818PMC
November 2020

Retrospective analysis of safety and efficacy of anti-PD-1 therapy and radiation therapy in advanced melanoma: A bi-institutional study.

Radiother Oncol 2019 09 25;138:114-120. Epub 2019 Jun 25.

Department of Medicine, Duke University Medical Center, Durham, United States. Electronic address:

Background And Purpose: Antibodies against programmed cell death protein 1 (PD-1) are standard treatments for advanced melanoma. Palliative radiation therapy (RT) is commonly administered for this disease. Safety and optimal timing for this combination for melanoma has not been established.

Materials And Methods: In this retrospective cohort study, records for melanoma patients who received anti-PD-1 therapy at Duke University or Emory University (1/1/2013-12/30/2015) were reviewed. Patients were categorized by receipt of RT and RT timing relative to anti-PD-1.

Results: 151 patients received anti-PD-1 therapy. Median follow-up was 12.9 months. Patients receiving RT (n = 85) had worse baseline prognostic factors than patients without RT (n = 66). One-year overall survival (OS) was lower for RT patients than patients without RT (66%, 95% CI: 55-77% vs 83%, 95% CI: 73-92%). One-year OS was 61% for patients receiving RT before anti-PD-1 (95% CI: 46-76%), 78% for RT during anti-PD-1 (95% CI: 60-95%), and 58% for RT after anti-PD-1 (95% CI: 26-89%). On Cox regression, OS for patients without RT did not differ significantly from patients receiving RT during anti-PD-1 (HR 1.07, 95% CI: 0.41-2.84) or RT before anti-PD-1 (HR 0.56, 95% CI: 0.21-1.45). RT and anti-PD-1 therapy administered within 6 weeks of each other was well tolerated.

Conclusion: RT can be safely administered with anti-PD-1 therapy. Despite worse baseline prognostic characteristics for patients receiving RT, OS was similar for patients receiving concurrent RT with anti-PD-1 therapy compared to patients receiving anti-PD-1 therapy alone.
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http://dx.doi.org/10.1016/j.radonc.2019.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566286PMC
September 2019

Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma.

J Immunother Cancer 2019 03 20;7(1):80. Epub 2019 Mar 20.

Donald A. Adam Melanoma and Skin Cancer Research Center of Excellence, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, USA.

Background: Epacadostat is a potent inhibitor of the immunosuppressive indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. We present phase 1 results from a phase 1/2 clinical study of epacadostat in combination with ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 antibody, in advanced melanoma (NCT01604889).

Methods: Only the phase 1, open-label portion of the study was conducted, per the sponsor's decision to terminate the study early based on the changing melanoma treatment landscape favoring exploration of programmed cell death protein 1 (PD-1)/PD-ligand 1 inhibitor-based combination strategies. Such decision was not related to the safety of epacadostat plus ipilimumab. Patients received oral epacadostat (25, 50, 100, or 300 mg twice daily [BID]; 75 mg daily [50 mg AM, 25 mg PM]; or 50 mg BID intermittent [2 weeks on/1 week off]) plus intravenous ipilimumab 3 mg/kg every 3 weeks.

Results: Fifty patients received ≥1 dose of epacadostat. As of January 20, 2017, 2 patients completed treatment and 48 discontinued, primarily because of adverse events (AEs) and disease progression (n = 20 each). Dose-limiting toxicities occurred in 11 patients (n = 1 each with epacadostat 25 mg BID, 50 mg BID intermittent, 75 mg daily; n = 4 each with epacadostat 50 mg BID, 300 mg BID). The most common immune-related treatment-emergent AEs included rash (50%), alanine aminotransferase elevation (28%), pruritus (28%), aspartate aminotransferase elevation (24%), and hypothyroidism (10%). Among immunotherapy-naive patients (n = 39), the objective response rate was 26% by immune-related response criteria and 23% by Response Evaluation Criteria in Solid Tumors version 1.1. No objective response was seen in the 11 patients who received prior immunotherapy. Epacadostat exposure was dose proportional, with clinically significant IDO1 inhibition at doses ≥25 mg BID.

Conclusions: When combined with ipilimumab, epacadostat ≤50 mg BID demonstrated clinical and pharmacologic activity and was generally well tolerated in patients with advanced melanoma.

Trial Registration: ClinicalTrials.gov identifier, NCT01604889 . Registration date, May 9, 2012, retrospectively registered.
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http://dx.doi.org/10.1186/s40425-019-0562-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425606PMC
March 2019

Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy.

J Clin Oncol 2019 03 6;37(9):693-702. Epub 2019 Feb 6.

2 Johns Hopkins Kimmel Cancer Center and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD.

Purpose: Merkel cell carcinoma (MCC) is an aggressive skin cancer often caused by the Merkel cell polyomavirus. Clinical trials of programmed cell death-1 pathway inhibitors for advanced MCC (aMCC) demonstrate increased progression-free survival (PFS) compared with historical chemotherapy data. However, response durability and overall survival (OS) data are limited.

Patients And Methods: In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017), 50 adults naïve to systemic therapy for aMCC received pembrolizumab (2 mg/kg every 3 weeks) for up to 2 years. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Results: Among 50 patients, the median age was 70.5 years, and 64% had Merkel cell polyomavirus-positive tumors. The objective response rate (ORR) to pembrolizumab was 56% (complete response [24%] plus partial response [32%]; 95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors. Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+ months). The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6 months to not estimable). The 24-month OS rate was 68.7%, and median OS time was not reached. Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend toward improved PFS and OS in patients with programmed death ligand-1-positive tumors. Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients and led to treatment discontinuation in seven (14%) of 50 patients, including one treatment-related death.

Conclusion: Here, we present the longest observation to date of patients with aMCC receiving first-line anti-programmed cell death-1 therapy. Pembrolizumab demonstrated durable tumor control, a generally manageable safety profile, and favorable OS compared with historical data from patients treated with first-line chemotherapy.
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http://dx.doi.org/10.1200/JCO.18.01896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424137PMC
March 2019

Updates in adjuvant systemic therapy for melanoma.

J Surg Oncol 2019 Jan 27;119(2):222-231. Epub 2018 Nov 27.

Department of Surgery, Duke University, Durham, North Carolina.

There has been a rapid increase in adjuvant therapies approved for treatment following surgical resection of stages III/IV melanoma. We review current indications for adjuvant therapy, which currently includes a heterogenous group of stages III and IV patients with melanoma. We describe several pivotal clinical trials of systemic immune therapies, targeted immune therapies, and adjuvant vaccine strategies. Finally, we discuss the evidence for selecting the most appropriate treatment regimen(s) for the individual patient.
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http://dx.doi.org/10.1002/jso.25298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330126PMC
January 2019

Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma.

Cancer Immunol Res 2018 12 12;6(12):1459-1471. Epub 2018 Sep 12.

Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.

Although anti-PD-1 therapy has improved clinical outcomes for select patients with advanced cancer, many patients exhibit either primary or adaptive resistance to checkpoint inhibitor immunotherapy. The role of the tumor stroma in the development of these mechanisms of resistance to checkpoint inhibitors remains unclear. We demonstrated that pharmacologic inhibition of the TGFβ signaling pathway synergistically enhanced the efficacy of anti-CTLA-4 immunotherapy but failed to augment anti-PD-1/PD-L1 responses in an autochthonous model of BRAF melanoma. Additional mechanistic studies revealed that TGFβ pathway inhibition promoted the proliferative expansion of stromal fibroblasts, thereby facilitating MMP-9-dependent cleavage of PD-L1 surface expression, leading to anti-PD-1 resistance in this model. Further work demonstrated that melanomas escaping anti-PD-1 therapy exhibited a mesenchymal phenotype associated with enhanced TGFβ signaling activity. Delayed TGFβ inhibitor therapy, following anti-PD-1 escape, better served to control further disease progression and was superior to a continuous combination of anti-PD-1 and TGFβ inhibition. This work illustrates that formulating immunotherapy combination regimens to enhance the efficacy of checkpoint blockade requires an in-depth understanding of the impact of these agents on the tumor microenvironment. These data indicated that stromal fibroblast MMP-9 may desensitize tumors to anti-PD-1 and suggests that TGFβ inhibition may generate greater immunologic efficacy when administered following the development of acquired anti-PD-1 resistance..
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279598PMC
December 2018

Paracrine Wnt5a-β-Catenin Signaling Triggers a Metabolic Program that Drives Dendritic Cell Tolerization.

Immunity 2018 01;48(1):147-160.e7

Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Durham, NC 27710, USA. Electronic address:

Despite recent advances, many cancers remain refractory to available immunotherapeutic strategies. Emerging evidence indicates that the tolerization of local dendritic cells (DCs) within the tumor microenvironment promotes immune evasion. Here, we have described a mechanism by which melanomas establish a site of immune privilege via a paracrine Wnt5a-β-catenin-peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling pathway that drives fatty acid oxidation (FAO) in DCs by upregulating the expression of the carnitine palmitoyltransferase-1A (CPT1A) fatty acid transporter. This FAO shift increased the protoporphyrin IX prosthetic group of indoleamine 2,3-dioxgenase-1 (IDO) while suppressing interleukin(IL)-6 and IL-12 cytokine expression, culminating in enhanced IDO activity and the generation of regulatory T cells. We demonstrated that blockade of this pathway augmented anti-melanoma immunity, enhanced the activity of anti-PD-1 antibody immunotherapy, and suppressed disease progression in a transgenic melanoma model. This work implicates a role for tumor-mediated metabolic reprogramming of local DCs in immune evasion and immunotherapy resistance.
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http://dx.doi.org/10.1016/j.immuni.2017.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777287PMC
January 2018

Identifying baseline immune-related biomarkers to predict clinical outcome of immunotherapy.

J Immunother Cancer 2017 16;5:44. Epub 2017 May 16.

Department of Medicine, Surgery and Immunology, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213 USA.

As cancer strikes, individuals vary not only in terms of factors that contribute to its occurrence and development, but as importantly, in their capacity to respond to treatment. While exciting new therapeutic options that mobilize the immune system against cancer have led to breakthroughs for a variety of malignancies, success is limited to a subset of patients. Pre-existing immunological features of both the host and the tumor may contribute to how patients will eventually fare with immunotherapy. A broad understanding of baseline immunity, both in the periphery and in the tumor microenvironment, is needed in order to fully realize the potential of cancer immunotherapy. Such interrogation of the tumor, blood, and host immune parameters prior to treatment is expected to identify biomarkers predictive of clinical outcome as well as to elucidate why some patients fail to respond to immunotherapy. To approach these opportunities for progress, the Society for Immunotherapy of Cancer (SITC) reconvened the Immune Biomarkers Task Force. Comprised of an international multidisciplinary panel of experts, Working Group 4 sought to make recommendations that focus on the complexity of the tumor microenvironment, with its diversity of immune genes, proteins, cells, and pathways naturally present at baseline and in circulation, and novel tools to aid in such broad analyses.
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http://dx.doi.org/10.1186/s40425-017-0243-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432988PMC
January 2018

Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy.

J Immunother Cancer 2016 20;4:89. Epub 2016 Dec 20.

Department of Medicine, Division of Medical Oncology, Melanoma Program, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710 USA.

Background: Checkpoint inhibitor immunotherapy is becoming an effective treatment modality for an increasing number of malignancies. As a result, autoinflammatory side-effects are also being observed more commonly in the clinic. We are currently unable to predict which patients will develop more severe toxicities associated with these treatment regimens.

Case Presentation: We present a patient with stage IV melanoma that developed rapid onset autoimmune type 1 diabetes (T1D) in response to combination ipilimumab and nivolumab immunotherapy. At the time of the patient's presentation with diabetes ketoacidosis, a confirmed anti-GAD antibody seroconversion was noted. Longer-term follow-up of this patient has demonstrated a durable complete response based on PET CT imaging along with a persistently undetectable C-peptide level. Single nucleotide polymorphism gene sequencing and HLA risk allele analysis has revealed the patient to lack any established genetic predisposition to the development of autoimmune T1D.

Conclusions: While larger studies are necessary to better understand the role of genetic risk factors for the development of autoimmune toxicities in those patients undergoing checkpoint inhibitor immunotherapy, these results suggest that pre-screening patients for known T1D risk alleles may not be indicated. Additional investigation is needed to determine whether an approach such as T cell receptor clonotypic analysis to identify the presence of autoreactive T cell clones may be an effective approach for predicting which patients are at risk for the development of autoinflammatory toxicities while undergoing checkpoint inhibitor immunotherapy.
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http://dx.doi.org/10.1186/s40425-016-0196-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5170902PMC
December 2016

Safety and Efficacy of Radiation Therapy in Advanced Melanoma Patients Treated With Ipilimumab.

Int J Radiat Oncol Biol Phys 2016 09 21;96(1):72-7. Epub 2016 Apr 21.

Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina. Electronic address:

Purpose: Ipilimumab and radiation therapy (RT) are standard treatments for advanced melanoma; preclinical models suggest the potential for synergy. However, limited clinical information exists regarding safety and optimal timing of the combination.

Methods And Materials: We reviewed the records of consecutive patients with unresectable stage 3 or 4 melanoma treated with ipilimumab. Patients were categorized as having received RT or not. Differences were estimated between these 2 cohorts.

Results: We identified 88 patients treated with ipilimumab. At baseline, the ipilimumab-plus-RT group (n=44) had more unfavorable characteristics. Despite this, overall survival, progression-free survival, and both immune-related and non-immune-related toxicity were not statistically different (P=.67). Patients who received ipilimumab before RT had an increased duration of irradiated tumor response compared with patients receiving ipilimumab after RT (74.7% vs 44.8% at 12 months; P=.01, log-rank test). In addition, patients receiving ablative RT had non-statistically significantly improved median overall survival (19.6 vs 10.2 months), as well as 6-month (95.1% vs 72.7%) and 12-month (79.7% vs 48.5%) survival rates, compared with those treated with conventionally fractionated RT.

Conclusions: We found that both ablative and conventionally fractionated RT can be safely administered with ipilimumab without a clinically apparent increase in toxicity. Patients who received ipilimumab before RT had an increased duration of irradiated tumor response.
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http://dx.doi.org/10.1016/j.ijrobp.2016.04.017DOI Listing
September 2016

Immune evasion pathways and the design of dendritic cell-based cancer vaccines.

Authors:
Brent A Hanks

Discov Med 2016 Feb;21(114):135-42

Department of Medicine Division of Medical Oncology, Duke University Medical Center, Durham, NC 27710, USA.

Emerging data is suggesting that the process of dendritic cell (DC) tolerization is an important step in tumorigenesis. Our understanding of the networks within the tumor microenvironment that functionally tolerize DC function is evolving while methods for genetically manipulating DC populations in situ continue to develop. A more intimate understanding of the paracrine signaling pathways which mediate immune evasion by subverting DC function promises to provide novel strategies for improving the clinical efficacy of DC-based cancer vaccines. This will likely require a better understanding of both the antigen expression profile and the immune evasion network of the tumor and its associated stromal tissues.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4934601PMC
February 2016

Isolated recto-sigmoid colitis: a new imaging pattern of ipilimumab-associated colitis.

Abdom Radiol (NY) 2016 Feb;41(2):207-14

Department of Radiology, Duke University Medical Center, Box 3808, Durham, NC, 27710, USA.

Purpose: The purpose of this study is to describe typical CT findings and distinct imaging patterns of ipilimumab-associated colitis in immunotherapeutic treatment of melanoma.

Materials And Methods: This HIPAA-compliant retrospective study included 86 patients with melanoma imaged with CT or PET/CT of the abdomen and pelvis during or shortly after administration of ipilimumab. Twelve of 86 patients (14%) developed symptoms of colitis and underwent CT imaging of the abdomen and pelvis while symptomatic. Two radiologists reviewed CT images to evaluate for the presence of CT findings of colitis including mesenteric vessel engorgement, pericolonic inflammatory change, hyperenhancement of colonic mucosa, colonic wall thickening, fluid-filled colonic distension, pneumoperitoneum, pneumatosis, and diverticulosis in the inflamed segment of colon. One nuclear medicine radiologist reviewed PET images for abnormally increased FDG uptake in the colon. The diagnosis of ipilimumab-associated colitis was made based on clinical presentation, imaging findings, and laboratory data.

Results: Common CT findings of ipilimumab-associated colitis included colonic mucosal hyperenhancement (10/12 [83%]), mesenteric vessel engorgement (9/12 [75.0%]), colonic wall thickening (9/12 [75%]), and pericolonic fat stranding (2/12 [16%]). No patient developed pneumatosis or pneumoperitoneum. Diffuse colitis was present in 4/12 (33%) patients. Segmental colitis with associated diverticulosis (was present in 2/12 (17%) patients). A third pattern, isolated recto-sigmoid colitis without diverticulosis, was observed in 6/12 (50%) patients. All patients with colitis demonstrated recto-sigmoid involvement.

Conclusions: A third radiologic pattern of ipilimumab-associated colitis was observed in this study: isolated recto-sigmoid colitis without diverticulosis. All patterns of ipilimumab-associated colitis include recto-sigmoid involvement.
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http://dx.doi.org/10.1007/s00261-015-0560-3DOI Listing
February 2016

Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy.

Cancer Immunol Res 2015 Sep 3;3(9):1082-95. Epub 2015 Jun 3.

Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina.

The β-catenin signaling pathway has been demonstrated to promote the development of a tolerogenic dendritic cell (DC) population capable of driving regulatory T-cell (Treg) differentiation. Further studies have implicated tolerogenic DCs in promoting carcinogenesis in preclinical models. The molecular mechanisms underlying the establishment of immune tolerance by this DC population are poorly understood, and the methods by which developing cancers can co-opt this pathway to subvert immune surveillance are currently unknown. This work demonstrates that melanoma-derived Wnt5a ligand upregulates the durable expression and activity of the indoleamine 2,3-dioxygenase-1 (IDO) enzyme by local DCs in a manner that depends upon the β-catenin signaling pathway. These data indicate that Wnt5a-conditioned DCs promote the differentiation of Tregs in an IDO-dependent manner, and that this process serves to suppress melanoma immune surveillance. We further show that the genetic silencing of the PORCN membrane-bound O-acyl transferase, which is necessary for melanoma Wnt ligand secretion, enhances antitumor T-cell immunity, and that the pharmacologic inhibition of this enzyme synergistically suppresses melanoma progression when combined with anti-CTLA-4 antibody therapy. Finally, our data suggest that β-catenin signaling activity, based on a target gene expression profile that includes IDO in human sentinel lymph node-derived DCs, is associated with melanoma disease burden and diminished progression-free survival. This work implicates the Wnt-β-catenin signaling pathway as a novel therapeutic target in the melanoma immune microenvironment and demonstrates the potential impact of manipulating DC function as a strategy for optimizing tumor immunotherapy.
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http://dx.doi.org/10.1158/2326-6066.CIR-14-0167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927300PMC
September 2015

Rapid complete response of metastatic melanoma in a patient undergoing ipilimumab immunotherapy in the setting of active ulcerative colitis.

J Immunother Cancer 2015 19;3:19. Epub 2015 May 19.

Melanoma Program, Division of Medical Oncology, Department of Internal Medicine, Duke University Medical Center, 203 Research Drive, MSRB1, Room 397, Box 2639, Durham, NC 27710 USA.

While blockade of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) T cell regulatory receptor has become a commonly utilized strategy in the management of advanced melanoma, many questions remain regarding the use of this agent in patient populations with autoimmune disease. We present a case involving the treatment of a patient with stage IV melanoma and ulcerative colitis (UC) with anti-CTLA-4 antibody immunotherapy. Upon initial treatment, the patient developed grade III colitis requiring tumor necrosis factor-alpha (TNF-α) blocking antibody therapy, however re-treatment with anti-CTLA-4 antibody following a total colectomy resulted in a rapid complete response accompanied by the development of a tracheobronchitis, a previously described extra-intestinal manifestation of UC. This case contributes to the evolving literature on the use of checkpoint inhibitors in patients also suffering from autoimmune disease, supports future clinical trials investigating the use of these agents in patients with autoimmune diseases, and suggests that an understanding of the specific molecular pathways involved in a patient's autoimmune pathology may provide insight into the development of more effective novel combinatorial immunotherapeutic strategies.
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http://dx.doi.org/10.1186/s40425-015-0064-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437559PMC
May 2015

Early Carcinogenesis Involves the Establishment of Immune Privilege via Intrinsic and Extrinsic Regulation of Indoleamine 2,3-dioxygenase-1: Translational Implications in Cancer Immunotherapy.

Front Immunol 2014 6;5:438. Epub 2014 Oct 6.

Division of Medical Oncology, Department of Medicine, Duke University Medical Center , Durham, NC , USA.

Although prolonged genetic pressure has been conjectured to be necessary for the eventual development of tumor immune evasion mechanisms, recent work is demonstrating that early genetic mutations are capable of moonlighting as both intrinsic and extrinsic modulators of the tumor immune microenvironment. The indoleamine 2,3-dioxygenase-1 (IDO) immunoregulatory enzyme is emerging as a key player in tumor-mediated immune tolerance. While loss of the tumor suppressor, BIN-1, and the over-expression of cyclooxygenase-2 have been implicated in intrinsic regulation of IDO, recent findings have demonstrated the loss of TβRIII and the upregulation of Wnt5a by developing cancers to play a role in the extrinsic control of IDO activity by local dendritic cell populations residing within tumor and tumor-draining lymph node tissues. Together, these genetic changes are capable of modulating paracrine signaling pathways in the early stages of carcinogenesis to establish a site of immune privilege by promoting the differentiation and activation of local regulatory T cells. Additional investigation of these immune evasion pathways promises to provide opportunities for the development of novel strategies to synergistically enhance the efficacy of the evolving class of T cell-targeted "checkpoint" inhibitors.
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http://dx.doi.org/10.3389/fimmu.2014.00438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186479PMC
October 2014

Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment.

J Clin Invest 2013 09 8;123(9):3925-40. Epub 2013 Aug 8.

Department of Medicine, Duke University Medical Center, Durham, North Carolina 27708, USA.

Cancers subvert the host immune system to facilitate disease progression. These evolved immunosuppressive mechanisms are also implicated in circumventing immunotherapeutic strategies. Emerging data indicate that local tumor-associated DC populations exhibit tolerogenic features by promoting Treg development; however, the mechanisms by which tumors manipulate DC and Treg function in the tumor microenvironment remain unclear. Type III TGF-β receptor (TGFBR3) and its shed extracellular domain (sTGFBR3) regulate TGF-β signaling and maintain epithelial homeostasis, with loss of TGFBR3 expression promoting progression early in breast cancer development. Using murine models of breast cancer and melanoma, we elucidated a tumor immunoevasion mechanism whereby loss of tumor-expressed TGFBR3/sTGFBR3 enhanced TGF-β signaling within locoregional DC populations and upregulated both the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in plasmacytoid DCs and the CCL22 chemokine in myeloid DCs. Alterations in these DC populations mediated Treg infiltration and the suppression of antitumor immunity. Our findings provide mechanistic support for using TGF-β inhibitors to enhance the efficacy of tumor immunotherapy, indicate that sTGFBR3 levels could serve as a predictive immunotherapy biomarker, and expand the mechanisms by which TGFBR3 suppresses cancer progression to include effects on the tumor immune microenvironment.
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http://dx.doi.org/10.1172/JCI65745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754240PMC
September 2013

Improved time to progression for transarterial chemoembolization compared with transarterial embolization for patients with unresectable hepatocellular carcinoma.

Clin Colorectal Cancer 2012 Sep 26;11(3):185-90. Epub 2012 Jan 26.

Duke University Medical Center, Durham, NC, USA.

Background: Embolizing branches of the hepatic artery lengthens survival for patients with unresectable hepatocellular carcinoma (HCC), but the benefit of combining chemotherapy with the embolizing particles remains controversial.

Methods: A retrospective review was undertaken of sequential patients with advanced HCC undergoing embolization in the past 10 years at 2 neighboring institutions and with 2 years of follow-up data. TACE was generally performed with doxorubicin plus mitomycin C.

Results: One hundred twenty-four patients were included; 77 received TACE and 47 received TAE. On multivariable analysis stratified by institution, type of embolization and CLIP score significantly predicted PFS and time to progression (TTP), whereas CLIP score and AFP independently predicted overall survival (OS). TACE significantly prolonged PFS and TTP (P = .0004 and P = .001, respectively), but not OS (P = .83).

Conclusions: The addition of chemotherapy to TAE prolongs PFS and TTP. Future efforts should focus on adjunctive therapies after the embolization to increase survival.
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http://dx.doi.org/10.1016/j.clcc.2011.11.003DOI Listing
September 2012

Pharmacological inhibition of TGFβ as a strategy to augment the antitumor immune response.

Curr Opin Investig Drugs 2010 Dec;11(12):1342-53

Department of Internal Medicine, Division of Hematology and Oncology, Duke University Medical Center, 450 Research Drive, Durham, NC 27708, USA.

There is considerable evidence suggesting that a variety of malignancies utilize the TGFβ cytokine to evade immune surveillance mechanisms to facilitate tumor growth and metastatic progression. The recently developed large- and small-molecule TGFβ inhibitors have demonstrated antitumor efficacy in several preclinical tumor models. Further investigation has revealed these agents to be critically dependent upon the host's immune system, suggesting that the inhibition of TGFβ may overcome the immunosuppressive tumor microenvironment and, ultimately, augment the antitumor immune response. These findings strongly support combining this strategy with other immunotherapeutic approaches for the treatment of metastatic cancer. This review discusses the immunoregulatory and antitumor properties of these pharmacological inhibitors of TGFβ signaling as either independent agents or in combination with various immunotherapeutic strategies, their potential side effects, as well as additional avenues of research that may be necessary for their eventual clinical application.
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December 2010

Enhanced activation of human dendritic cells by inducible CD40 and Toll-like receptor-4 ligation.

Cancer Res 2007 Nov;67(21):10528-37

Scott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA.

Despite the potency of dendritic cells (DC) as antigen-presenting cells for priming adaptive immunity, DC-based cancer vaccines have been largely insufficient to effectively reduce tumor burden or prevent tumor progression in most patients. To enhance DC-based vaccines, we used the combination of a synthetic ligand-inducible CD40 receptor (iCD40) along with Toll-like receptor-4 (TLR-4) ligation in human monocyte-derived DCs. The iCD40 receptor permits targeted, reversible activation of CD40 in vivo, potentially bypassing the essential role of CD4(+) T cells for activation of DCs. As a rigorous preclinical study of this approach, we evaluated key parameters of DC activation and function. Whereas neither iCD40 nor TLR-4 signaling alone led to high levels of interleukin (IL)-12p70 and IL-6, using iCD40 in combination with lipopolysaccharide (LPS) or monophosphoryl lipid A led to strongly synergistic production of both. Furthermore, this approach led to high expression of DC maturation markers, epitope-specific CTL and T helper 1 responses, as well as DC migration in vitro and in vivo. Moreover, use of iCD40-modified and LPS-stimulated DCs led to targeted expansion of autologous T cells against tumor-associated antigens, including prostate-specific membrane antigen, and elimination of preestablished tumors, supporting this technology as a potent strategy for DC-based cancer immunotherapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-0833DOI Listing
November 2007

Re-engineered CD40 receptor enables potent pharmacological activation of dendritic-cell cancer vaccines in vivo.

Nat Med 2005 Feb 23;11(2):130-7. Epub 2005 Jan 23.

Department of Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.

Modest clinical outcomes of dendritic-cell (DC) vaccine trials call for the refinement of DC vaccine design. Although many potential antigens have been identified, development of methods to enhance antigen presentation by DCs has lagged. We have engineered a potent, drug-inducible CD40 (iCD40) receptor that permits temporally controlled, lymphoid-localized, DC-specific activation. iCD40 is comprised of a membrane-localized cytoplasmic domain of CD40 fused to drug-binding domains. This allows it to respond to a lipid-permeable, high-affinity dimerizer drug while circumventing ectodomain-dependent negative-feedback mechanisms. These modifications permit prolonged activation of iCD40-expressing DCs in vivo, resulting in more potent CD8(+) T-cell effector responses, including the eradication of previously established solid tumors, relative to activation of DCs ex vivo (P < 0.01), typical of most clinical DC protocols. In addition, iCD40-mediated DC activation exceeded that achieved by stimulating the full-length, endogenous CD40 receptor both in vitro and in vivo. Because iCD40 is insulated from the extracellular environment and can be activated within the context of an immunological synapse, iCD40-expressing DCs have a prolonged lifespan and should lead to more potent vaccines, perhaps even in immune-compromised patients.
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http://dx.doi.org/10.1038/nm1183DOI Listing
February 2005