Marc S Ernstoff

Dartmouth College, Hanover, New Hampshire, United States

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Publications (193)1160.87 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: High-dose aldesleukin (HD IL-2) received FDA approval for the treatment of mRCC in 1992, producing a 14% objective response rate (ORR) and durable remissions. Retrospective studies suggested that clinical and pathologic features could predict for benefit. The Cytokine Working Group conducted this prospective trial to validate proposed predictive markers of response to HD IL-2. Experimental Design: Standard HD IL-2 was administered to prospectively evaluate whether the ORR of mRCC patients with "good" predictive pathologic features based on an "integrated selection" model (ISM) (e.g. clear-cell histology sub-classification and carbonic anhydrase-9 (CA-9) IHC staining) was significantly higher than the ORR of a historical, unselected population. Archived tumor was collected for pathologic analysis including tumor programmed death-ligand 1 (PD-L1) expression. Results: 120 eligible patients enrolled between 11/06 and 7/09; 70% were MSKCC intermediate risk, 96% had clear cell RCC and 99% had prior nephrectomy. The independently assessed ORR was 25% (30/120, 95% CI = 17.5%-33.7%, p=0.0014) (3 CR, 27 PR) and was higher than a historical ORR. Thirteen patients (11%) remained progression-free at 3 years and the median OS was 42.8 months. ORR was not statistically different by ISM classification ("good-risk" 23% vs. "poor-risk" 30%, (p=0.39)). ORR was positively associated with tumor PD-L1 expression (p=0.01) by IHC. Conclusions: In this prospective, biomarker validation study, HD IL-2 produced durable remissions and prolonged survival in both "good" and "poor-risk" patients. The proposed ISM was unable to improve the selection criteria. Novel markers (e.g. tumor PD-L1expression) appeared useful, but require independent validation. Copyright © 2014, American Association for Cancer Research.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 11/2014;
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    ABSTRACT: A growing body of evidence suggests that BRAF-inhibitors, in addition to their acute tumor growth-inhibitory effects, can also promote immune responses to melanoma. The present studies aimed to define the immunological basis of BRAF-inhibitor therapy using the Braf/Pten model of inducible, autochthonous melanoma on a pure C57BL/6 background. In the tumor microenvironment, PLX4720 functioned by on-target mechanisms to selectively decrease both the proportions and absolute numbers of CD4+Foxp3+ regulatory T cells (Treg) and CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs), while preserving numbers of CD8+ effector T cells. In PLX4720-treated mice, intratumoral Treg populations were quantitatively lost, demonstrating enhanced apopotosis. CD11b+ myeloid cells taken from PLX4720-treated tumors also exhibited decreased immunosuppressive function on a per-cell basis. In accordance with a reversion of tumor immune suppression, tumors that had been treated with PLX4720 grew with reduced kinetics after treatment was discontinued, and this growth delay was dependent on CD8 T cells. These findings demonstrate that BRAF inhibition selectively reverses two major mechanisms of immunosuppression in melanoma, and liberates host adaptive anti-tumor immunity.
    Cancer immunology research. 09/2014;
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    ABSTRACT: V-domain Ig suppressor of T cell activation (VISTA) is a potent negative regulator of T-cell function that is expressed on hematopoietic cells. VISTA levels are heightened within the tumor microenvironment, in which its blockade can enhance antitumor immune responses in mice. In humans, blockade of the related programmed cell death 1 (PD-1) pathway has shown great potential in clinical immunotherapy trials. Here, we report the structure of human VISTA and examine its function in lymphocyte negative regulation in cancer. VISTA is expressed predominantly within the hematopoietic compartment with highest expression within the myeloid lineage. VISTA-Ig suppressed proliferation of T cells but not B cells and blunted the production of T-cell cytokines and activation markers. Our results establish VISTA as a negative checkpoint regulator that suppresses T-cell activation, induces Foxp3 expression, and is highly expressed within the tumor microenvironment. By analogy to PD-1 and PD-L1 blockade, VISTA blockade may offer an immunotherapeutic strategy for human cancer. Cancer Res; 74(7); 1924-32. ©2013 AACR.
    Cancer Research 04/2014; 74(7):1924-32. · 9.28 Impact Factor
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    ABSTRACT: Electron paramagnetic resonance (EPR) spectroscopy has been well established as a viable technique for measurement of free radicals and oxygen in biological systems, from in vitro cellular systems to in vivo small animal models of disease. However, the use of EPR in human subjects in the clinical setting, although attractive for a variety of important applications such as oxygen measurement, is challenged with several factors including the need for instrumentation customized for human subjects, probe, and regulatory constraints. This article describes the rationale and development of the first clinical EPR systems for two important clinical applications, namely, measurement of tissue oxygen (oximetry) and radiation dose (dosimetry) in humans. The clinical spectrometers operate at 1.2 GHz frequency and use surface-loop resonators capable of providing topical measurements up to 1 cm depth in tissues. Tissue pO2 measurements can be carried out noninvasively and repeatedly after placement of an oxygen-sensitive paramagnetic material (currently India ink) at the site of interest. Our EPR dosimetry system is capable of measuring radiation-induced free radicals in the tooth of irradiated human subjects to determine the exposure dose. These developments offer potential opportunities for clinical dosimetry and oximetry, which include guiding therapy for individual patients with tumors or vascular disease by monitoring of tissue oxygenation. Further work is in progress to translate this unique technology to routine clinical practice.
    Academic radiology 02/2014; 21(2):197-206. · 2.09 Impact Factor
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    ABSTRACT: The BRAF(V600E) mutation, which approaches 50% in human melanomas, constitutively activates pERK and contributes to disease progression. The BRAF(V600E) inhibitor, Vemurafenib (PLX4032), shows promising clinical responses, but resistance to PLX4032 usually develops within a year. Transgenic mouse models allow the study of BRaf(V600E) melanoma in vivo, however in vitro models are necessary to better understand the molecular mechanism underlying disease progression and resistance. We established melanoma cell lines (D4M cells) from the conditional mouse model of metastatic melanoma: Tyr::CreER;Braf(CA) ;Pten(lox/lox) , which recapitulates human disease. Cultured D4M cells express high constitutive pERK. PLX4032 abrogates ERK phosphorylation, inhibits D4M proliferation, and increases expression of the melanoma associated antigen, pmel, in vitro, consistent with human BRAF(V600E) melanoma cell lines. D4M cells are transplantable in either immune-compromised or syngeneic B6 mice. Thus, D4M cell lines allow correlation of in vitro studies on molecular mechanisms of melanoma with in vivo investigations on pathology and immunology. This article is protected by copyright. All rights reserved.
    Pigment Cell & Melanoma Research 01/2014; · 5.84 Impact Factor
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    ABSTRACT: The NKG2D receptor, one of the natural killer (NK) cell-activating receptors, is expressed on the surface of CD3+CD8+ T cells, γδ+ T cells, NK cells, NKT cells, and a few CD4+ T cells. We show, for the first time, a critical role for the NKG2D receptor on CD3+CD8+ T cells isolated from myeloma patients, in identifying and killing autologous myeloma cells isolated from the same patients' marrow. We also show that blocking NKG2D using anti-NKG2D reverses the cytotoxicity while blocking HLA-I using antibodies does not have the same effect, showing that the autologous cytotoxicity is NKG2D dependent and major histocompatibility complex (MHC)-I independent. We further confirmed the NKG2D specificity by small interfering RNA (siRNA) down regulation of NKG2D receptor. Using ex vivo expansion methods that enrich for NKG2D+CD3+CD8+ T cells, we investigated whether these ex vivo expanded NKG2D+CD3+CD8+ T cells would recognize and lyse autologous and allogeneic myeloma cells, independent of T-cell receptor or MHC-I expression. Myeloma cell lysis by the NKG2D+CD3+CD8+ T cells correlated with the amount of NKG2D ligand expression. With receptor-ligand interaction, interferon-γ and tumor necrosis factor-α were released. Blocking the NKG2D receptor by using either monoclonal antibodies or siRNAs inhibited the receptor's function and prevented myeloma cell lysis. Clinical trials are ongoing to determine a correlation with the number and function of NKG2D+CD3+CD8+ T cells and clinical outcomes in transplanted myeloma patients, including lymphocyte recovery following transplant and overall survival.
    Transfusion 01/2014; · 3.53 Impact Factor
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    Journal for immunotherapy of cancer. 01/2014; 2:22.
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    ABSTRACT: Despite the positive impact of targeted therapies on metastatic renal cell carcinoma (mRCC), durable responses are infrequent and an unmet need exists for novel therapies with distinct mechanisms of action. We investigated the combination of recombinant Interleukin 21 (IL-21), a cytokine with unique immunostimulatory properties, plus sorafenib, a VEGFR tyrosine kinase inhibitor. In this phase 1/2 study, 52 mRCC patients received outpatient treatment with oral sorafenib 400 mg twice daily plus intravenous IL-21 (10-50 mcg/kg) on days 1-5 and 15-19 of each 7-week treatment course. The safety, antitumor activity, pharmacokinetic and pharmacodynamic effects of the combination were evaluated. In phase 1 (n = 19), the maximum tolerated dose for IL-21 with the standard dose of sorafenib was determined to be 30 mcg/kg/day; grade 3 skin rash was the only dose-limiting toxicity. In phase 2, 33 previously-treated patients tolerated the combination therapy well with appropriate dose reductions; toxicities were mostly grade 1 or 2. The objective response rate was 21% and disease control rate was 82%. Two patients have durable responses that are ongoing, despite cessation of both IL-21 and sorafenib, at 41+ and 30+ months, respectively. The median progression-free survival in phase 2 was 5.6 months. The pharmacokinetic and pharmacodynamic properties of IL-21 appeared to be preserved in the presence of sorafenib. IL-21 plus sorafenib has antitumor activity and acceptable safety in previously treated mRCC patients. IL-21 may represent a suitable immunotherapy in further exploration of combination strategies in mRCC. Identifier: NCT00389285.
    Journal for immunotherapy of cancer. 01/2014; 2:2.
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    ABSTRACT: Vemurafenib is an orally bioavailable BRAF inhibitor approved for the treatment of BRAF(V600) -mutant metastatic melanoma. It is important to understand the effects of a high-fat meal on the pharmacokinetics (PK) of vemurafenib in humans because it is a Biopharmaceutics Classification System Class IV drug and its PK can be altered by food. An open-label, multicenter, randomized, 2-period crossover study was performed to evaluate the effect of food (high-fat meal) on the PK of a single oral dose of vemurafenib. Secondary objectives were safety and tolerability, efficacy with best overall response rate, and overall survival during the treatment period. The concomitant intake of food (high-fat meal) increased mean Cmax 3.5 to 7.5 µg/mL and mean AUC0-∞ 119 to 360 µg · h/mL after a single 960 mg dose of vemurafenib (N = 13-15 patients). An effect of food on single-dose exposure is suggested by point estimates and 90% CI of geometric mean ratios for vemurafenib plasma AUC0-∞ (4.7) and Cmax (2.5). Toxicity and response rate of vemurafenib in this study were consistent with prior experience in patients with BRAF(V600) -mutant metastatic melanoma. A high-fat meal increased the exposure to vemurafenib without altering the mean terminal half-life.
    The Journal of Clinical Pharmacology 12/2013; · 2.84 Impact Factor
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    ABSTRACT: Polo-like kinases (Plks) control multiple steps during the cell cycle, and Plk1 is overexpressed in urothelial cancer (UC). Volasertib (BI 6727), a Plk inhibitor, has demonstrated antitumor activity in several malignancies, including UC. In this phase 2 trial, the authors investigated volasertib as a second-line treatment in advanced/metastatic UC. Patients who progressed within 2 years of 1 prior chemotherapy regimen received 300 mg volasertib on day 1 every 3 weeks. The dose was escalated to 350 mg in cycle 2 if volasertib was tolerated in cycle 1. The primary endpoint was tumor response, which was assessed every 6 weeks; secondary endpoints were progression-free survival, overall survival, duration of response, safety, and pharmacokinetics. Fifty patients were enrolled, and the median patient age was 68.5 years (range, 52-83 years). All patients had received prior platinum, 94% of patients had relapsed ≤2 years after prior therapy, 36% had liver metastases, and 54% had lung metastases. The median number of treatment cycles was 2 (range, 1-27 treatment cycles), and 23 patients were dose escalated at cycle 2. Seven patients (14%) had a partial response, 13 (26%) had stable disease, and 30 (60%) progressed within 6 weeks. The median response duration was 41 weeks (range, 29.1-77.3 weeks). The median progression-free survival was 1.4 months, and the median overall survival was 8.5 months. The most frequent grade 3 and 4 adverse events were neutropenia (28%), thrombocytopenia (20%), and anemia (16%). No cumulative toxicity was observed. Volasertib as second-line treatment for advanced/metastatic UC had an acceptable safety profile but demonstrated insufficient antitumor activity for further evaluation as a monotherapy. Cancer 2013. © 2013 American Cancer Society.
    Cancer 12/2013; · 5.20 Impact Factor
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    ABSTRACT: The Merkel cell polyomavirus (MCV) is involved in the development of up to 100% of Merkel cell cancer (MCC) cases. Early studies have reported that the virus was infrequently detected in other small cell or neuroendocrine lung carcinomas, which share histological features with MCC. The present study investigated the presence of MCV in cases of extrapulmonary small cell carcinoma (ESCC), which also shares histological features with MCC. A total of 25 cases of ESCC that were diagnosed between 2004 and 2009 were identified at The Dartmouth Hitchcock Medical Center. Archived tissue was available for testing in 16 of these cases. A total of 11 tissue specimens of MCC were used as positive controls. DNA that was extracted from the archived tissue was subjected to five separate quantitative (q)PCR assays for the detection of four MCV genomic targets. MCV DNA was detected in 3/16 (19%) of the ESCCs and in all 11 MCCs. In the three MCV-positive ESCCs, the viral target was only detected by either one or two of the PCR assays. In 8/11 MCV-positive MCCs, the DNA tested positive by either three or all four assays and the remaining three MCCs tested positive by either one or two assays. The β-globin endogenous control was detected in all the samples that were tested. Although MCC and ESCC share numerous histological features, MCV is detected at a lower frequency in ESCC. The possible role for MCV in the etiology of ESCC remains uncertain and may account for the rare cases of ESCC with no other identifiable etiology. The failure of other assays to detect MCV may be due to sequence variability in the MCV genome.
    Oncology letters 10/2013; 6(4):1049-1052. · 0.24 Impact Factor
  • Daniel G Coit, Marc S Ernstoff, Klaus J Busam
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    ABSTRACT: Pediatric melanoma is a rare disease about which there is little agreement as to the accurate diagnosis of borderline lesions or early lymph node metastases. A better understanding of the natural history of this condition will require large centralized registries, consistent histopathologic and cytogenetic review, and long term clinical follow‐up.
    Cancer 09/2013; · 5.20 Impact Factor
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    ABSTRACT: Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts-including physicians, nurses, and patient advocates-to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-α2b, pegylated-interferon-α2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted.
    Nature Reviews Clinical Oncology 08/2013; · 15.03 Impact Factor
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    ABSTRACT: SUMMARY Glioblastoma remains the most lethal human brain tumor, despite the advent of multimodal treatment approaches. Because immune tolerance plays an important role in tumor progression, adding immunotherapy has become an attractive and innovative treatment approach for these aggressive tumors. Several early-phase clinical trials have demonstrated that vaccine-based immunotherapies, including dendritic cell therapy, peptide-based vaccines and vaccines containing autologous tumor lysates, are feasible and well tolerated. These trials have revealed promising trends in overall survival and progression-free survival for patients with glioblastoma, and have paved the way for ongoing randomized controlled trials.
    CNS oncology. 07/2013; 2(4):331-349.
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    ABSTRACT: Temozolomide (TMZ) is an oral alkylating agent used in the treatment of central nervous system neoplasms and metastatic melanoma. Preclinical and clinical data suggested that combining TMZ with interferon alpha-2b (IFN-alpha-2b) may result in increased anti-tumour efficacy. This was a phase I, dose-escalation study to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of cyclical oral TMZ (days 1-7 and 15-21) in combination with pegylated IFN-alpha-2b (PEG-IFN-alpha-2b) in patients with advanced solid tumours. We treated 19 patients (10 female and nine male), median age 58 years (range: 41-79 years). Ten patients tolerated TMZ at 100 mg/m(2) on days 1-7 and 15-21 plus PEG-IFN-alpha-2b at 1.5 mcg/kg/week on 28-day cycles which was the MTD of the combination. The pharmacokinetic parameters of PEG-IFN-alpha-2b were not altered by TMZ, at the MTD.
    Journal of chemotherapy (Florence, Italy) 06/2013; · 0.83 Impact Factor
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    ABSTRACT: PURPOSEAmplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities. PATIENTS AND METHODS We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations. Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatment-related toxicities. Additional oncogene mutation screening was performed by mass spectroscopy.ResultsTwenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months (range, 3.7 to 27.1 months). Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only). There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated v 18% amplified). Four patients harbored pretreatment NRAS mutations, and one patient acquired increased KIT amplification after treatment. CONCLUSION Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.
    Journal of Clinical Oncology 06/2013; · 18.04 Impact Factor
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    ABSTRACT: To evaluate long-term follow-up of a phase II trial of chemohormonal therapy in 62 men with prostate cancer biochemical relapse (BR). Treatment was 4 cycles of docetaxel (70 mg/m) every 3 weeks and estramustine 280 mg three times a day (days 1-5) followed by 15 months of goserelin acetate/bicalutamide. The primary endpoint was the proportion with prostate-specific antigen (PSA) <0.1 with recovered testosterone 5 years after completion of therapy. Secondary endpoints included time to progression (TTP), time to reinitiate androgen deprivation therapy (ADT), the proportion with castration-resistant prostate cancer (CRPC), and overall survival (OS). Median follow-up was 8.6 years (range 1.3-11.1 years). At 5 year follow-up, 7 patients (11%) had PSA <0.1 (5 undetectable); 8 (13%) had PSA >0.1 but without reinitiation of ADT (median PSA 0.37). Of the 15 (24%) men without reinitiation of ADT, and 14 have recovered testosterone to normal range. Median TTP for the complete cohort was 35.0 months (95% confidence interval [CI] 31.7-39.2). Baseline PSA <3.0 ng/dL, no prior ADT, and prostatectomy (vs radiation) were associated with longer TTP (P = .0001, P = .0055, and P = .0398, respectively). At the time of analysis, 42 men (68%) had restarted ADT, 23 men had CRPC (37%), and 11 (18%) had chemotherapy. Median time to reinitiation of ADT was 32.6 months (range 0-107.6 months). Median OS has not been reached; there were 15 deaths. Chemotherapy plus ADT for BR resulted in durable (>5 years) complete responses (<0.1 ng/mL) in 7 men (11%). Twenty-four percent of men have not re-initiated ADT 5 years from completion of protocol therapy.
    Urology 03/2013; 81(3):611-6. · 2.42 Impact Factor
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    ABSTRACT: Purpose Preclinical studies in human melanoma cell lines and murine xenograft tumor models suggest that the proteasome inhibitor bortezomib enhances the activity of the cytotoxic agent dacarbazine. We performed a phase I trial of bortezomib and dacarbazine in melanoma, soft tissue sarcoma, and amine precursor uptake and decarboxylation tumors. The primary objective was to identify recommended phase II doses for the combination. Experimental design Bortezomib and dacarbazine were both administered intravenously once weekly. All patients received prophylactic antiemetics. Dose escalation proceeded using a standard 3 + 3 design. Response was assessed according to NCI RECIST v1.0. Results Twenty eight patients were enrolled to six dose levels. Bortezomib 1.6 mg/m(2) and dacarbazine 580 mg/m(2) are the recommended phase II weekly doses. The combination was generally well tolerated. Among 15 patients with melanoma there was one durable complete response in a patient with an exon-11 cKIT mutation, and one partial response. Among 12 patients with soft tissue sarcoma there was one partial response. Conclusions Bortezomib 1.6 mg/m(2) and dacarbazine 580 mg/m(2) administered intravenously once weekly is well tolerated and has at least minimal activity in melanoma and soft tissue sarcoma.
    Investigational New Drugs 01/2013; · 3.50 Impact Factor
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    ABSTRACT: Among the dendritic cell (DC) subsets, plasmacytoid DC's (pDC) are thought to be important in the generation of both antiviral and antitumor responses. While pDC may be useful in developing dendritic cell-based tumor vaccines, the low frequency of these cells in the peripheral blood has hampered attempts to understand their biology. To provide better insight into the biology of pDC, we isolated these unperturbed cells from the peripheral blood of healthy donors in order to further characterize their gene expression. Using gene array technology we compared the genetic profiles of these cells to those of CD14+ monocytes isolated from the same donors and found several immune related genes upregulated in this cell population. This is the first description, to our knowledge, of gene expression in this subset of DCs obtained from the peripheral blood of adult human donors without exposure in vitro to cytokine or growth factors. Understanding the natural genetic profiles of this dendritic cell subtype as well as others such as the BDCA-1 expressing myeloid DCs may enable us to manipulate these cells ex-vivo to generate enhanced DC-based tumor vaccines inducing more robust antitumor responses.
    Experimental Hematology and Oncology. 01/2013; 2(8).
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    ABSTRACT: The number of circulating lymphocytes on day 15 after transplantation correlates with improved survival in patients with myeloma, but the lymphocyte subset responsible is unknown. NKG2D is a natural killer (NK) cell activating receptor that mediates non-MHC restricted and TCR-independent cell lysis. Our preliminary results indicate that CD3(+)CD8(+) T cells expressing NKG2D may be a critical lymphocyte population. A phase II trial examined the feasibility of infusing ex vivo-expanded cells enriched for NKG2D(+)CD3(+)CD8(+) T cells at weeks 1, 2, 4, and 8 after an autologous transplantation. In addition, low-dose IL-2 (6 × 10(5) IU/m(2)/day) was administered for 4 weeks, beginning on the day of transplantation. Twenty-three patients were accrued and 19 patients are evaluable. There were no treatment-related deaths. All patients completed their course of IL-2 and demonstrated normal engraftment. When compared with patients with myeloma who underwent transplantation not receiving posttransplantation immune therapy, the treated patients demonstrated an increase in the number of circulating NKG2D(+)CD3(+)CD8(+) T cells/μL (P < .004), CD3(+)CD8(+) T cells/μL (P < .04), CD3(+)CD8(+)CD56(+) T cells/μL (P < .004), and NKG2D(+)CD3(-)CD56(+) T cells/μL (P < .003). Myeloma cell-directed cytotoxicity by the circulating mononuclear cells increased after transplantation (P < .002). When compared to posttransplantation IL-2 therapy alone in this patient population, the addition of cells enriched for NKG2D(+)CD3(+)CD8(+) T cells increased tumor-specific immunity, as demonstrated by enhanced lysis of autologous myeloma cells (P = .02). We postulate that this regimen that increased the number and function of the NKG2D(+)CD3(+)CD8(+) T cells after transplantation may improve clinical outcomes by eliminating residual malignant cells in vivo.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2012; · 3.15 Impact Factor

Publication Stats

5k Citations
1,160.87 Total Impact Points


  • 2001–2014
    • Dartmouth College
      • • Department of Medicine
      • • Department of Community and Family Medicine
      Hanover, New Hampshire, United States
  • 1993–2014
    • Geisel School of Medicine at Dartmouth
      • • Department of Medicine
      • • Department of Microbiology and Immunology
      • • Department of Community and Family Medicine
      Hanover, New Hampshire, United States
  • 2013
    • Rush University Medical Center
      Chicago, Illinois, United States
  • 1996–2013
    • Dartmouth–Hitchcock Medical Center
      • Department of Surgery
      Lebanon, New Hampshire, United States
  • 2008
    • Vanderbilt University
      • Vanderbilt-Ingram Cancer Center (VICC)
      Nashville, MI, United States
    • Boston University
      • Department of Medicine
      Boston, MA, United States
  • 2007
    • Loyola University Chicago
      • Cardinal Bernardin Cancer Center
      Chicago, IL, United States
  • 2005
    • Beth Israel Deaconess Medical Center
      • Division of Hematology/Oncology
      Boston, MA, United States
  • 2003
    • Emory University
      • Winship Cancer Institute
      Atlanta, GA, United States
  • 1999
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
    • Hannover Medical School
      Hanover, Lower Saxony, Germany
  • 1992–1999
    • University of Pittsburgh
      • School of Medicine
      Pittsburgh, PA, United States
    • Harvard Medical School
      • Department of Dermatology
      Boston, MA, United States
    • Pittsburg State University
      Kansas, United States
  • 1998
    • University of the Sciences in Philadelphia
      Philadelphia, Pennsylvania, United States
  • 1991–1992
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 1985–1992
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 1990
    • Hospital of the University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 1986
    • Yale University
      New Haven, Connecticut, United States