Publications by authors named "Herbert Kim Lyerly"

32 Publications

Changes in Peripheral Blood Regulatory T Cells and IL-6 and IL-10 Levels Predict Response of Pediatric Medulloblastoma and Germ Cell Tumors With Residual or Disseminated Disease to Craniospinal Irradiation.

Int J Radiat Oncol Biol Phys 2021 May 8. Epub 2021 May 8.

Department of Surgery, Duke University Medical Center, Durham, North Carolina. Electronic address:

Purpose: Radiation therapy (RT) modulates immune cells and cytokines, resulting in both clinically beneficial and detrimental effects. The changes in peripheral blood T lymphocyte subsets and cytokines during RT for pediatric brain tumors and the association of these changes with therapeutic outcomes have not been well described.

Methods And Materials: The study population consisted of children (n = 83, aged 3~18) with primary brain tumors (medulloblastoma, glioma, germ cell tumors (GCT), and central nervous system embryonal tumor-not otherwise specified), with or without residual or disseminated (R/D) diseases who were starting standard postoperative focal or craniospinal irradiation (CSI). Peripheral blood T lymphocyte subsets collected before and 4 weeks after RT were enumerated by flow cytometry. Plasma levels of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-α, interferon-γ, and IL-17A were measured by cytometric bead array.

Results: Patients with R/D lesions receiving CSI (n = 32) had a post-RT increase in the frequency of CD3+T and CD8+T cells, a decrease in CD4+T cells, and an increase in regulatory T cells (Tregs) and CD8+CD28- suppressor cells, which was more predominantly seen in these patients than in other groups. In the CSI group with such R/D lesions, consisting of patients with medulloblastoma and germ cell tumors, 19 experienced a complete response (CR) and 13 experienced a partial response (PR) on imaging at 4 weeks after RT. The post/pre-RT ratio of Tregs (P = .0493), IL-6 (P = .0111), and IL-10 (P = .0070) was lower in the CR group than in the PR group. Multivariate analysis revealed that the post/pre-RT ratios of Treg, IL-6, and IL-10 were independent predictors of CR (P < .0001, P = .018, P < .0001, respectively). The areas under the receiver operating curves and confidence intervals were 0.7652 (0.5831-0.8964), 0.7794 (0.5980-0.9067), and 0.7085 (0.5223-0.8552) for IL-6, IL-10, and Treg, respectively. The sensitivities of IL-6, IL-10, and Treg to predict radiotherapeutic responses were 100%, 92.3%, and 61.5%, and specificity was 52.6%, 57.9%, and 84.2%, respectively.

Conclusions: CSI treatment to those with R/D lesions predominantly exerted an effect on antitumor immune response compared with both R/D lesion-free but exposed to focal or CSI RT and with R/D lesions and exposed to focal RT. Such CSI with R/D lesions group experiencing CR is more likely to have a decrease in immunoinhibitory molecules and cells than patients who only achieve PR. Measuring peripheral blood Treg, IL-6, and IL-10 levels could be valuable for predicting radiotherapeutic responses of pediatric brain tumors with R/D lesions to CSI for medulloblastoma and intracranial germ cell tumors.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.041DOI Listing
May 2021

Serial assessment of circulating T lymphocyte phenotype and receptor repertoire during treatment of non-muscle invasive bladder cancer with adoptive T cell immunotherapy.

Am J Cancer Res 2021 15;11(4):1709-1718. Epub 2021 Apr 15.

Department of Surgery, Duke University Medical Center Durham, NC 27710, USA.

Recurrence and progression of non-muscle-invasive bladder cancer (NMIBC), frequent despite the availability of multiple treatment modalities, may be partly explained by the presence of immunosuppressive cell populations. We hypothesized that progression of disease could be prevented by the administration of an activated T cell immunotherapy (ACT) at time points when immunosuppressive populations increased in peripheral blood. In an N-of-1 study, a patient with multiple primary bladder high grade urothelial carcinomas, previously treated with standard local resection and chemotherapy but with evidence of progression, received ACT consisting of dendritic cells mixed with cytokine induced killer cells (DC/CIK), intravenously 18 times over a 6 year period at indicated time of observed increases in peripheral blood immunosuppressive CD8/CD28 cells. Peripheral blood was analyzed for T cell phenotype by flow cytometry, T cell receptor (TCR) repertoire, and circulating tumor DNA (ctDNA) by next generation sequencing (NGS) at the time of each infusion. Cystoscopy and pelvic CT scans were performed at routine intervals to assess clinical status of disease. There has been no recurrence or metastasis of urothelial carcinoma. Peripheral blood cytotoxic T cells and unique TCR clones increased and suppressive T cell populations decreased after DC/CIK infusions evidenced by the two more proof-of concept cases. ctDNA analysis detected mutations in six genes (ARID1B, MYCN, CDH23, SETD2, NOTCH4 and FAT1) which appeared at different times, but all of them disappeared after the DC-CIK infusions. These data suggest that DC/CIK infusions may be associated with beneficial changes in T cell phenotype, TCR repertoire, decreases in circulating tumor DNA and sustained recurrence-free survival.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085852PMC
April 2021

Infiltration of metastatic lymph nodes with PD-1 T cells is associated with improved disease-free and overall survival in resected N NSCLC.

Am J Cancer Res 2020 1;10(12):4435-4449. Epub 2020 Dec 1.

Department of Surgery, Duke University Medical Center Durham, NC 27710, USA.

Tumor metastases to regional lymph nodes are associated with worse outcome for patients with resected non-small cell lung cancer (NSCLC), but there is a wide variation in survival. We hypothesized that infiltration of tumor-involved lymph nodes with activated effector T cells would impact subsequent outcome. A total of 54 lymph nodes (27 N and 15 N collected from 12 patients with Stage IIB (TNM) and 12 N lymph nodes collected from 10 patients with Stage IIA (TNM) who underwent lymphadenectomy during surgical management of their NSCLC) were analyzed for effector T cells expressing activation markers PD-1 and TIM-3 using the -multiple immunofluorescence assay. The frequency of CD3CD8 (P=0.0001), CD3CD8TIM-3 (P<0.0001), and CD3CD8TIM-3Ki-67 (P<0.0001) T cells was greater in lymph nodes of IIA patients compared with IIB patients; however the frequency of CD3CD8PD-1 (P=0.0086), CD3CD8TIM-3 (P=0.0129), CD3CD8PD-1Ki-67 (P<0.0001) and CD3CD8TIM-3Ki-67 (P=0.0001) T cells was greater among the tumor involved (N) nodes of N1 patients compared with the tumor-uninvolved (N) nodes. The frequency of intranodal CD3CD8, CD3CD8PD-1 and CD3CD8PD-1Ki-67 T cells in N nodes was associated with prolonged progression-free (PFS) and overall survival (OS). These data suggest that CD3CD8TIM-3 T cells may suppress tumor spread to regional lymph nodes but once tumor cells metastasize to lymph nodes, CD3/CD8/PD-1/Ki67 T cells localizing to N nodes may prevent further tumor spread, resulting in prolonged survival.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783752PMC
December 2020

Long-term survival of patients with stage III colon cancer treated with VRP-CEA(6D), an alphavirus vector that increases the CD8+ effector memory T cell to Treg ratio.

J Immunother Cancer 2020 11;8(2)

Surgery, Duke University School of Medicine, Durham, North Carolina, USA

Background: There remains a significant need to eliminate the risk of recurrence of resected cancers. Cancer vaccines are well tolerated and activate tumor-specific immune effectors and lead to long-term survival in some patients. We hypothesized that vaccination with alphaviral replicon particles encoding tumor associated antigens would generate clinically significant antitumor immunity to enable prolonged overall survival (OS) in patients with both metastatic and resected cancer.

Methods: OS was monitored for patients with stage IV cancer treated in a phase I study of virus-like replicon particle (VRP)-carcinoembryonic antigen (CEA), an alphaviral replicon particle encoding a modified CEA. An expansion cohort of patients (n=12) with resected stage III colorectal cancer who had completed their standard postoperative adjuvant chemotherapy was administered VRP-CEA every 3 weeks for a total of 4 immunizations. OS and relapse-free survival (RFS) were determined, as well as preimmunization and postimmunization cellular and humoral immunity.

Results: Among the patients with stage IV cancer, median follow-up was 10.9 years and 5-year survival was 17%, (95% CI 6% to 33%). Among the patients with stage III cancer, the 5-year RFS was 75%, (95%CI 40% to 91%); no deaths were observed. At a median follow-up of 5.8 years (range: 3.9-7.0 years) all patients were still alive. All patients demonstrated CEA-specific humoral immunity. Patients with stage III cancer had an increase in CD8 +T (in 10/12) and decrease in FOXP3 +Tregs (in 10/12) following vaccination. Further, CEA-specific, IFNγ-producing CD8+granzyme B+T cells were increased.

Conclusions: VRP-CEA induces antigen-specific effector T cells while decreasing Tregs, suggesting favorable immune modulation. Long-term survivors were identified in both cohorts, suggesting the OS may be prolonged.
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http://dx.doi.org/10.1136/jitc-2020-001662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661359PMC
November 2020

Clinical efficacy of intra-cavitary infusions of autologous dendritic cell/cytokine-induced killer cell products for the treatment of refractory malignant pleural effusions and ascites.

Am J Transl Res 2020 15;12(7):3940-3952. Epub 2020 Jul 15.

Department of Surgery, Duke University Medical Center Durham, NC 27710, USA.

To explore the safety and efficacy of intra-cavitary infusions of autologous mixed dendritic cell (DC)-cytokine-induced killer (CIK) cell products in advanced cancer patients with malignant pleural effusions or ascites. DC-CIKs were expanded ex vivo (mean yield of 1.36×10 cells (range, 0.74~4.98×10)) from peripheral blood mononuclear cells obtained by repeated venipuncture or apheresis. Patients received at least 1 cycle of 3 infusions of the DC-CIKs administered by indwelling catheter into the pleural or peritoneal cavity every other day. The volume of malignant effusions was assessed radiologically. Peripheral blood lymphocyte populations were enumerated by flow cytometry. Quality of life (QoL) during the DC-CIK infusions was assessed by the EORTC QLQ-30 instrument. ctDNA sequencing was performed to analyze gene clonal load and molecular tumor burden during the infusion treatment. Thirty-seven patients with breast, lung and other malignancies were enrolled. The results showed that intra-cavitary DC-CIK infusions (16 intrapleural and 21 intraperitoneal) were well-tolerated with no grade 3/4 adverse events. There was one complete response with effusion disappearance (CR) (3%), 13 partial responses (PR) (35%), 12 with stable disease (SD) (32%) and 11 with progressive disease (PD) (30%), resulting in a clinical effusion control rate (CCR) of 70% (26/37). The total number of infused CIKs and the CD3+/CD8+ and CD8+/CD28+ T cell frequencies within the CIKs were associated with effusion control (P=0.013). Moreover, increased peripheral blood CD3+/CD8+ (P=0.035) and decreased CD4+/CD25+ T cell frequencies (P=0.041) following the DC-CIK infusions were associated with malignant effusion and ascites control. Reductions in ctDNA correlated with clinical benefit. In conclusion, intra-cavitary autologous cellular immunotherapy is an alternative method to effectively control malignant pleural effusions and ascites. The overall effusion control rate was associated with higher peripheral blood effector T cell frequencies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407744PMC
July 2020

Novel Therapeutic Interventions Early in the Disease Trajectory: Drug Development Beyond the Refractory Setting.

Clin Cancer Res 2020 09 22;26(18):4743-4747. Epub 2020 Jun 22.

Yale Cancer Center, New Haven, Connecticut.

The 2019 Accelerating Anticancer Agent Development Workshop assembled a panel of experts for an in-depth discussion session to present "novel therapeutic interventions early in the disease trajectory." The panel reviewed the limitations of evaluating investigational cancer therapeutics solely in advanced metastatic and relapsed/refractory disease settings, and recommended strategies for drug evaluation earlier in the disease course, including in the first line in combination with standard chemotherapy, and in the maintenance and neoadjuvant disease settings. Advantages of earlier drug evaluation were discussed, including expanding the population of evaluable patients, earlier response assessment via surrogate endpoints, earlier clinical benefit in the disease course, tailoring of therapies based on response, and furthering our understanding of biomarker-driven therapies.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-4035DOI Listing
September 2020

An age-independent gene signature for monitoring acute rejection in kidney transplantation.

Theranostics 2020 25;10(15):6977-6986. Epub 2020 May 25.

Department of Surgery, Duke University Medical Center, Durham, United States.

Acute rejection (AR) remains a significant problem that negatively impacts long-term renal allograft survival. Numerous therapies are used to prevent AR that differ by center and recipient age. This variability confounds diagnostic methods. : To develop an age-independent gene signature for AR effective across a broad array of immunosuppressive regimens, we compiled kidney transplant biopsy (n=1091) and peripheral blood (n=392) gene expression profiles from 12 independent public datasets. After removing genes differentially expressed in pediatric and adult patients, we compared gene expression profiles from biopsy and peripheral blood samples of patients with AR to those who were stable (STA), using Mann-Whitney U Tests with validation in independent testing datasets. We confirmed this signature in pediatric and adult patients (42 AR and 47 STA) from our institutional biorepository. : We identified a novel age-independent gene network that identified AR from both kidney and blood samples. We developed a 90-probe set signature targeting 76 genes that differentiated AR from STA and found an 8 gene subset (DIP2C, ENOSF1, FBXO21, KCTD6, PDXDC1, REXO2, HLA-E, and RAB31) that was associated with AR. : We used publicly available datasets to create a gene signature of AR that identified AR irrespective of immunosuppression regimen or recipient age. This study highlights a novel model to screen and validate biomarkers across multiple treatment regimens.
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http://dx.doi.org/10.7150/thno.42110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295062PMC
May 2021

HER2-LAMP vaccines effectively traffic to endolysosomal compartments and generate enhanced polyfunctional T cell responses that induce complete tumor regression.

J Immunother Cancer 2020 06;8(1)

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

Background: The advent of immune checkpoint blockade antibodies has demonstrated that effective mobilization of T cell responses can cause tumor regression of metastatic cancers, although these responses are heterogeneous and restricted to certain histologic types of cancer. To enhance these responses, there has been renewed emphasis in developing effective cancer-specific vaccines to stimulate and direct T cell immunity to important oncologic targets, such as the oncogene human epidermal growth factor receptor 2 (HER2), expressed in ~20% of breast cancers (BCs).

Methods: In our study, we explored the use of alternative antigen trafficking through use of a lysosome-associated membrane protein 1 (LAMP) domain to enhance vaccine efficacy against HER2 and other model antigens in both and studies.

Results: We found that inclusion of this domain in plasmid vaccines effectively trafficked antigens to endolysosomal compartments, resulting in enhanced major histocompatibility complex (MHC) class I and II presentation. Additionally, this augmented the expansion/activation of antigen-specific CD4+ and CD8+ T cells and also led to elevated levels of antigen-specific polyfunctional CD8+ T cells. Significantly, vaccination with HER2-LAMP produced tumor regression in ~30% of vaccinated mice with established tumors in an endogenous model of metastatic HER2+ BC, compared with 0% of HER2-WT vaccinated mice. This therapeutic benefit is associated with enhanced tumor infiltration of activated CD4+ and CD8+ T cells.

Conclusions: These data demonstrate the potential of using LAMP-based endolysosomal trafficking as a means to augment the generation of polyfunctional, antigen-specific T cells in order to improve antitumor therapeutic responses using cancer antigen vaccines.
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http://dx.doi.org/10.1136/jitc-2019-000258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295440PMC
June 2020

IL26, a Noncanonical Mediator of DNA Inflammatory Stimulation, Promotes TNBC Engraftment and Progression in Association with Neutrophils.

Cancer Res 2020 08 4;80(15):3088-3100. Epub 2020 May 4.

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

IL26 is a unique amphipathic member of the IL10 family of cytokines that participates in inflammatory signaling through a canonical receptor pathway. It also directly binds DNA to facilitate cellular transduction and intracellular inflammatory signaling. Although IL26 has almost no described role in cancer, our screen of inflammatory and cytokine pathway genes revealed IL26 to be one of the most significant inflammatory mediators of mammary engraftment and lung metastatic growth in triple-negative breast cancer (TNBC). Examination of human breast cancers demonstrated elevated IL26 transcripts in TNBC specimens, specifically in tumor cells as well as in Th17 CD4 T cells within clinical TNBC specimens. IL26 did not have an autocrine effect on human TNBC cells, but rather its effect on engraftment and growth required neutrophils. IL26 enhanced mouse-derived DNA induction of inflammatory cytokines, which were collectively important for mammary and metastatic lung engraftment. To neutralize this effect, we developed a novel IL26 vaccine to stimulate antibody production and suppress IL26-enhanced engraftment , suggesting that targeting this inflammatory amplifier could be a unique means to control cancer-promoting inflammation in TNBC and other autoimmune diseases. Thus, we identified IL26 as a novel key modulator of TNBC metastasis and a potential therapeutic target in TNBC as well as other diseases reliant upon IL26-mediated inflammatory stimulation. SIGNIFICANCE: These findings identify IL26 as a unique, clinically relevant, inflammatory amplifier that enhances TNBC engraftment and dissemination in association with neutrophils, which has potential as a therapeutic target. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/15/3088/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415539PMC
August 2020

DC-CIK as a widely applicable cancer immunotherapy.

Expert Opin Biol Ther 2020 06 13;20(6):601-607. Epub 2020 Feb 13.

Department of Medical Oncology, Beijing Key Laboratory for Therapeutic Cancer Vaccines, Capital Medical University Cancer Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.

: Immunotherapy is now a standard treatment for many malignancies. Although immune checkpoint inhibition has demonstrated substantial efficacy by enhancing T cell activation and function in the tumor microenvironment, adoptive transfer of T and NK cell products promises to provide activated cells capable of immediate and direct tumor destruction. A widely applicable, non-MHC dependent, cellular therapy, consisting of generated dendritic cells (DC) combined with cytokine-induced killer cells (CIK), is highly efficient to produce from individual patients and has demonstrated safety and efficacy alone or with chemotherapy.: We summarize the clinical data from studies of DC-CIK and discuss future research directions.: Patients with a wide variety of tumor types who have received DC-CIK therapy may experience clinical responses. This versatile therapy synergizes with other anti-cancer therapies including chemotherapy and immunotherapy.
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http://dx.doi.org/10.1080/14712598.2020.1728250DOI Listing
June 2020

Immune correlates of clinical benefit in a phase I study of hyperthermia with adoptive T cell immunotherapy in patients with solid tumors.

Int J Hyperthermia 2019 11;36(sup1):74-82

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

To characterize the T cell receptor (TCR) repertoire, serum cytokine levels, peripheral blood T lymphocyte populations, safety, and clinical efficacy of hyperthermia (HT) combined with autologous adoptive cell therapy (ACT) and either salvage chemotherapy (CT) or anti-PD-1 antibody in patients with previously treated advanced solid tumors. Thirty-three (33) patients with ovarian, pancreatic, gastric, colorectal, cervical, or endometrial cancer were recruited into the following therapeutic groups: HT + ACT ( = 10), HT + ACT + anti-PD-1 inhibitor (pembrolizumab) ( = 11) and HT + ACT + CT ( = 12). Peripheral blood was collected to analyze TCR repertoire, measurements of cytokines levels and lymphocyte sub-populations before and after treatment. The objective response rate (ORR) was 30% (10/33), including three complete responses (CR) (9.1%) and seven partial responses (PR) (21.2%) and a disease control rate (DCR = CR + PR + SD) of 66.7% (22 of 33). The most common adverse reactions, blistering, subcutaneous fat induration, local heat-related pain, vomiting and sinus tachycardia, were observed in association with HT. IL-2, IL-4, TNF-α, and IFN-γ levels in peripheral blood were significantly increased among the clinical responders ( < 0.05) while IL-6 and IL-10 were elevated among those with progressive disease ( < 0.05). Peripheral blood CD8/CD28 T cells increased ( = 0.002), while the CD4/CD25/CD127Treg cells decreased after therapy ( = 0.012). TCR diversity was substantially increased among the clinical responders. Combining HT with ACT plus either CT or anti-PD-1 antibody was safe, generated clinical responses in previously treated advanced cancers, and promoted TCR repertoire diversity and favorable changes in serum IL-2, IL-4, TNF-α, and IFN-γ levels in clinical responders.
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http://dx.doi.org/10.1080/02656736.2019.1647350DOI Listing
November 2019

Miniaturized Intracavitary Forward-Looking Ultrasound Transducer for Tissue Ablation.

IEEE Trans Biomed Eng 2020 07 22;67(7):2084-2093. Epub 2019 Nov 22.

Objective: This paper aims to develop a miniaturized forward-looking ultrasound transducer for intracavitary tissue ablation, which can be used through an endoscopic device. The internal ultrasound (US) delivery is capable of directly interacting with the target tumor, resolving adverse issues of currently available US devices, such as unintended tissue damage and insufficient delivery of acoustic power.

Methods: To transmit a high acoustic pressure from a small aperture (<3 mm), a double layer transducer (1.3 MHz) was designed and fabricated based on numerical simulations. The electric impedance and the acoustic pressure of the actual device was characterized with an impedance analyzer and a hydrophone. Ex vivo tissue ablation tests and temperature monitoring were then conducted with porcine livers.

Results: The acoustic intensity of the transducer was 37.1 W/cm under 250 V and 20% duty cycle. The tissue temperature was elevated to 51.8 °C with a 67 Hz pulse-repetition frequency. The temperature profile in the tissue indicated that ultrasound energy was effectively absorbed inside the tissue. During a 5-min sonification, an approximate tissue volume of 2.5 × 2.5 × 1.0 mm was ablated, resulting in an irreversible lesion.

Conclusion: This miniaturized US transducer is a promising medical option for the precise tissue ablation, which can reduce the risk of unintended tissue damage found in noninvasive US treatments.

Significance: Having a small aperture (2 mm), the intracavitary device is capable of ablating a bio tissue in 5 min with a relatively low electric power (<17 W).
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http://dx.doi.org/10.1109/TBME.2019.2954524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269183PMC
July 2020

CD47 blockade augmentation of trastuzumab antitumor efficacy dependent on antibody-dependent cellular phagocytosis.

JCI Insight 2019 12 19;4(24). Epub 2019 Dec 19.

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

The HER2-specific monoclonal antibody (mAb), trastuzumab, has been the mainstay of therapy for HER2+ breast cancer (BC) for approximately 20 years. However, its therapeutic mechanism of action (MOA) remains unclear, with antitumor responses to trastuzumab remaining heterogeneous and metastatic HER2+ BC remaining incurable. Consequently, understanding its MOA could enable rational strategies to enhance its efficacy. Using both murine and human versions of trastuzumab, we found its antitumor activity dependent on Fcγ receptor stimulation of tumor-associated macrophages (TAMs) and antibody-dependent cellular phagocytosis (ADCP), but not cellular cytotoxicity (ADCC). Trastuzumab also stimulated TAM activation and expansion, but did not require adaptive immunity, natural killer cells, and/or neutrophils. Moreover, inhibition of the innate immune ADCP checkpoint, CD47, significantly enhanced trastuzumab-mediated ADCP and TAM expansion and activation, resulting in the emergence of a unique hyperphagocytic macrophage population, improved antitumor responses, and prolonged survival. In addition, we found that tumor-associated CD47 expression was inversely associated with survival in HER2+ BC patients and that human HER2+ BC xenografts treated with trastuzumab plus CD47 inhibition underwent complete tumor regression. Collectively, our study identifies trastuzumab-mediated ADCP as an important antitumor MOA that may be clinically enabled by CD47 blockade to augment therapeutic efficacy.
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http://dx.doi.org/10.1172/jci.insight.131882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975273PMC
December 2019

Adoptive immunotherapy with autologous T-cell infusions reduces opioid requirements in advanced cancer patients.

Pain 2020 01;161(1):127-134

Department of Surgery, Duke University Medical Center, Durham, United States.

Relief of cancer-related pain remains challenging despite the availability of a range of opioid and nonopioid medications. Animal models demonstrate that T lymphocytes may mediate analgesia by producing endogenous opioids, but definitive clinical data are limited. Transfer of ex vivo adoptive cellular therapy (ACT) is being tested as an anticancer therapy. We retrospectively reviewed the medical charts of 357 patients with various malignancies who received 3 intravenous infusions of autologous cytokine-activated T-cell-enriched products. Among these were 55 patients who required opioids for moderate or severe cancer-related pain. Opioid dosage and cancer pain score were recorded daily for 2 consecutive weeks before and 2 weeks after the ACT infusions. The average oral morphine equivalent doses and cancer pain scores were significantly decreased after the ACT infusions. The proportion of patients with breakthrough pain also declined. Moreover, higher frequencies of expanded CD3, CD3/CD4, and CD3/CD8 T cells within the ACT product were associated with favorable analgesic effects. Transient elevations in CD3 and CD3/CD8T-cell subpopulations and decreases in CD4CD25 Treg were observed in patients' blood after the ACT. In conclusion, ACT was capable of reducing cancer pain severity and opioid consumption and favorably modulating peripheral blood T-cell populations.
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http://dx.doi.org/10.1097/j.pain.0000000000001702DOI Listing
January 2020

T-Scan: A Genome-wide Method for the Systematic Discovery of T Cell Epitopes.

Cell 2019 08;178(4):1016-1028.e13

Division of Genetics, Department of Medicine, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard University Medical School, Boston, MA, USA. Electronic address:

T cell recognition of specific antigens mediates protection from pathogens and controls neoplasias, but can also cause autoimmunity. Our knowledge of T cell antigens and their implications for human health is limited by the technical limitations of T cell profiling technologies. Here, we present T-Scan, a high-throughput platform for identification of antigens productively recognized by T cells. T-Scan uses lentiviral delivery of antigen libraries into cells for endogenous processing and presentation on major histocompatibility complex (MHC) molecules. Target cells functionally recognized by T cells are isolated using a reporter for granzyme B activity, and the antigens mediating recognition are identified by next-generation sequencing. We show T-Scan correctly identifies cognate antigens of T cell receptors (TCRs) from viral and human genome-wide libraries. We apply T-Scan to discover new viral antigens, perform high-resolution mapping of TCR specificity, and characterize the reactivity of a tumor-derived TCR. T-Scan is a powerful approach for studying T cell responses.
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http://dx.doi.org/10.1016/j.cell.2019.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939866PMC
August 2019

Impact of synchronized anti-PD-1 with Ad-CEA vaccination on inhibition of colon cancer growth.

Immunotherapy 2019 08 13;11(11):953-966. Epub 2019 Jun 13.

Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.

The purpose of this study was to determine whether addition of anti-PD-1 antibody increased the immunogenicity and anti-tumor activity of Ad-CEA vaccination in a murine model of colon cancer. Ad-CEA was administered prior to implantation of MC-38-CEA cells followed by administration of anti-PD-1 antibody. CEA-specific T-cell responses were measured by flow cytometry and ELISPOT. Dynamic co-culture of splenocytes with tumor cells was conducted to analyze anti-tumor activities. Tumor infiltration by lymphocytes was measured by IHC. Tumor volume and overall survival were also recorded. Ad-CEA combined with anti-PD-1 antibody showed greater anti-tumor activity compared with either alone. The combination also increased T-cell infiltration but decreased Tregs. Combining Ad-CEA vaccination with anti-PD-1 antibody enhanced anti-tumor activity and immune responses.
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http://dx.doi.org/10.2217/imt-2019-0055DOI Listing
August 2019

Functional CD3CD8PD1 T Cell Accumulation and PD-L1 Expression Increases During Tumor Invasion in DCIS of the Breast.

Clin Breast Cancer 2019 10 16;19(5):e617-e623. Epub 2019 Apr 16.

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

Background: The changes in T cell subsets and programmed death ligand 1 (PD-L1) expression during the transition from ductal carcinoma in situ (DCIS) to early invasive breast cancer had not been well studied.

Patients And Methods: A total of 85 DCIS patients were classified into 49 DCIS (clinical stage: Tis, noninvasive) and 36 with a minimally infiltrating lesion (MIL; < 5 mm; clinical stage: T1a). We explored the quantitative alterations of T-cell markers and PD-L1 in these groups using the Opal multi-immunohistochemistry technique.

Results: We observed increased infiltration of CD3-positive (CD3)CD8 programmed death 1 (PD1)-negative T cells and higher PD-L1 expression in DCIS with MIL. Elevated PD1 expression correlated with PD-L1 expression in MIL and DCIS.

Conclusion: We conclude that during the transition from DCIS to an invasive lesion, the host cytolytic T cells begin interacting with the tumor and destroy the tumor tissue, leading to an adaptive upregulation of PD-L1 and tumor protection against immune destruction.
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http://dx.doi.org/10.1016/j.clbc.2019.04.001DOI Listing
October 2019

Prospective randomized comparative study on rivaroxaban and LMWH for prophylaxis of post-apheresis thrombosis in adoptive T cell immunotherapy cancer patients.

J Thromb Thrombolysis 2019 May;47(4):505-511

Department of Surgery, Duke University Medical Center, 203 Research Drive, Suite 433, Box 2606, Durham, NC, 27710, USA.

Autologous adoptive T cell immunotherapy has been recognized as an effective treatment for cancer patients. The initial qualified lymphocytes is the core element determining the immunotherapeutic outcomes clinically. Cell separator based apheresis procedure is an optimal procedure to collect adequate mono-nucleated lymphocytes to generate efficient ex vivo T cell expansions; however, potential catheter-associated femoral vein thrombosis at post-apheresis might rise an additional deteriorated morbidity for cancer patients. The emerging prophylactic medications are required at such circumstances. Therefore this study was designed to compare the prophylactic effects of rivaroxaban versus low molecular weight heparin (LMWH) in patients who had exposed during the femoral vein catheterization for apheresis. 74 Patients were randomized 1:1:1 into three groups: subcutaneous injection of LMWH, Fraxiparine (n = 23) (0.4 ml, 3800 IU/day) for 2 days, oral rivaroxaban 10 mg/d (n = 26), and oral rivaroxaban 20 mg/d (n = 25) for consecutive 2 days. The primary endpoint was to compare the venous thromboembolism (VTE) occurrence cases in one month post catheterization. There were 4 cases confirmed VTE occurrence in LMWH group with contrast to 1 case in rivaroxaban 10 mg administration group. None was seen in rivaroxaban 20 mg group (P = 0.02 as the comparison with LMWH). Meantime there was no bleeding events occurrence afterwards. Oral rivaroxaban 20 mg/day was recommendable to be considered which superior to LMWH. Although these limited data and patient volume reached the statistical difference which was able to provide the evidence proofed to compare the potency of those two anticoagulants, it could be regarded as the preliminary data provide the clinical results for cancer patients who were placed in the condition of apheresis and subsequently undergone adoptive T cell immunotherapy.Trial registration ClinicalTrials.gov identifier, NCT03282643. Registered 16 February 2016, http://www.ClinicalTrials.gov/ NCT03282643.
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http://dx.doi.org/10.1007/s11239-019-01844-7DOI Listing
May 2019

Niclosamide-induced Wnt signaling inhibition in colorectal cancer is mediated by autophagy.

Biochem J 2019 02 8;476(3):535-546. Epub 2019 Feb 8.

Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A.

The Wnt signaling pathway, known for regulating genes critical to normal embryonic development and tissue homeostasis, is dysregulated in many types of cancer. Previously, we identified that the anthelmintic drug niclosamide inhibited Wnt signaling by promoting internalization of Wnt receptor Frizzled 1 and degradation of Wnt signaling pathway proteins, Dishevelled 2 and β-catenin, contributing to suppression of colorectal cancer growth and Here, we provide evidence that niclosamide-mediated inhibition of Wnt signaling is mediated through autophagosomes induced by niclosamide. Specifically, niclosamide promotes the co-localization of Frizzled 1 or β-catenin with LC3, an autophagosome marker. Niclosamide inhibition of Wnt signaling is attenuated in autophagosome-deficient ATG5 MEF cells or cells expressing shRNA targeting Beclin1, a critical constituent of autophagosome. Treatment with the autophagosome inhibitor 3MA blocks niclosamide-mediated Frizzled 1 degradation. The sensitivity of colorectal cancer cells to growth inhibition by niclosamide is correlated with autophagosome formation induced by niclosamide. Niclosamide inhibits mTORC1 and ULK1 activities and induces LC3B expression in niclosamide-sensitive cell lines, but not in the niclosamide-resistant cell lines tested. Interestingly, niclosamide is a less effective inhibitor of Wnt-responsive genes (β-catenin, c-Myc, and Survivin) in the niclosamide-resistant cells than in the niclosamide-sensitive cells, suggesting that deficient autophagy induction by niclosamide compromises the effect of niclosamide on Wnt signaling. Our findings provide a mechanistic understanding of the role of autophagosomes in the inhibition of Wnt signaling by niclosamide and may provide biomarkers to assist selection of patients whose tumors are likely to respond to niclosamide.
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http://dx.doi.org/10.1042/BCJ20180385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643999PMC
February 2019

Autologous Dendritic Cell-Cytokine Induced Killer Cell Immunotherapy Combined with S-1 Plus Cisplatin in Patients with Advanced Gastric Cancer: A Prospective Study.

Clin Cancer Res 2019 03 4;25(5):1494-1504. Epub 2018 Dec 4.

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

Purpose: We have assessed the combination of DC-CIK with S-1 plus cisplatin chemotherapy in advanced gastric cancer (AGC) and the role of mutational analysis of circulating tumor DNA (ctDNA) and T-cell receptor (TCR) repertoire in predicting clinical outcomes.

Patients And Methods: Consecutive patients ( = 63) with AGC were allocated to treatment with S-1 alone, S-1 plus cisplatin, DC-CIK combined with S-1 or DC-CIK combined with S-1 plus cisplatin. The primary endpoints were progression-free survival (PFS) and overall survival (OS) at 1 year; the secondary endpoints were disease control rate and analysis of ctDNA and TCR repertoire.

Results: The DC-CIK infusions were well tolerated with no serious adverse events. The disease control rates (CRPRSD) were 5.6%, 33.3%, 47.1%, and 76.9% in the S-1 alone, the S-1 plus cisplatin, DC-CIK combined with S-1 and DC-CIK combined with the S-1 plus cisplatin groups, respectively ( = 0.001). After adjusting for competing risk factors, treatment with DC-CIK combined with S-1 plus cisplatin was confirmed to be an independent predictor of PFS and OS ( = 0.001). A decrease in the frequency and number of mutations in ctDNA was observed in 19 patients (63.3%) following the DC-CIK infusions. Decreased ctDNA mutational frequency and restored TCR repertoire were associated with improved PFS and OS ( = 0.001).

Conclusions: DC-CIK combined with S-1 plus cisplatin provided a favorable PFS and OS in patients with AGC and the combination therapy was safe with tolerable toxicities. Clinical efficacy correlated with decreases in ctDNA mutational profiles and restored TCR repertoire.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2360DOI Listing
March 2019

White paper on microbial anti-cancer therapy and prevention.

J Immunother Cancer 2018 08 6;6(1):78. Epub 2018 Aug 6.

0000 0001 2151 2636grid.215654.1Center for Immunotherapy, Vaccines and Virotherapy , Biodesign InstituteArizona State University 727 E Tyler Street, Room A330E 85281 Tempe AZ USA

In this White Paper, we discuss the current state of microbial cancer therapy. This paper resulted from a meeting ('Microbial Based Cancer Therapy') at the US National Cancer Institute in the summer of 2017. Here, we define 'Microbial Therapy' to include both oncolytic viral therapy and bacterial anticancer therapy. Both of these fields exploit tumor-specific infectious microbes to treat cancer, have similar mechanisms of action, and are facing similar challenges to commercialization. We designed this paper to nucleate this growing field of microbial therapeutics and increase interactions between researchers in it and related fields. The authors of this paper include many primary researchers in this field. In this paper, we discuss the potential, status and opportunities for microbial therapy as well as strategies attempted to date and important questions that need to be addressed. The main areas that we think will have the greatest impact are immune stimulation, control of efficacy, control of delivery, and safety. There is much excitement about the potential of this field to treat currently intractable cancer. Much of the potential exists because these therapies utilize unique mechanisms of action, difficult to achieve with other biological or small molecule drugs. By better understanding and controlling these mechanisms, we will create new therapies that will become integral components of cancer care.
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http://dx.doi.org/10.1186/s40425-018-0381-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091193PMC
August 2018

Circulating CD8CD28 suppressor T cells tied to poorer prognosis among metastatic breast cancer patients receiving adoptive T-cell therapy: A cohort study.

Cytotherapy 2018 01 4;20(1):126-133. Epub 2017 Oct 4.

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

Background Aims: This study aimed to determine the prognostic value of circulating CD8CD28 T lymphocytes among breast cancer patients treated with adoptive T-lymphocyte immunotherapy after chemotherapy.

Methods: Two hundred and thirty-two breast cancer patients underwent adoptive T-cell immunotherapy. Circulating CD8CD28 proportion was measured by flow cytometry. Median proportion of CD8CD28 was 24.2% and set as the categorical cutoff value for further analysis. The median survival was estimated by Kaplan-Meier curve, with difference detection and hazard ratio estimation by log-rank test and Cox hazard proportion regression model.

Results: With adoptive T-cell therapy, patients with higher CD8CD28 levels experienced median progression-free and overall survival of 7.1 months and 26.9 months, respectively-significantly shorter than patients with lower levels (11.8 and 36.2 months). CD8CD28 proportion >24.2% demonstrated a hazard ratio (HR) of 2.06 (95% confidence interval [CI] 1.31-3.12) for progression and an HR of 1.97 (95% CI 1.06-3.67) for death. Among patients who had received previous first-line chemotherapy, CD8CD28 proportion >24.2% demonstrated an HR of 2.66 (95% CI 1.45-4.88) for progression. Among patients exposed to previous second-line or higher chemotherapy, CD8CD28 proportion >24.2% demonstrated a 486% higher risk for death (HR = 5.86, 95% CI 1.77-19.39). A 1% increase in suppressive T cells was associated with a 5% increased risk of death.

Discussion: Elevated peripheral blood CD8CD28 was associated with poorer prognosis for metastatic breast cancer, especially for higher risk of progression among patients with first-line chemotherapy and higher risk of death among patients with more than second-line chemotherapy.
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http://dx.doi.org/10.1016/j.jcyt.2017.08.018DOI Listing
January 2018

The prognostic value of peripheral CD4+CD25+ T lymphocytes among early stage and triple negative breast cancer patients receiving dendritic cells-cytokine induced killer cells infusion.

Oncotarget 2015 Dec;6(38):41350-9

Department of Surgery, Duke University Medical Center, Durham, NC 27710, United States of America.

Objective: This study aimed to assess the prognostic value of CD4+CD25+ T lymphocyte in peripheral blood among breast cancer patients treated with adoptive T lymphocytes immunotherapy.

Methods: 217 patients participated in the follow-up study. CD4+CD25+ proportion was measured by flow cytometry in peripheral T cells. The median survival was estimated by Kaplan-Meier curve, Log-rank test and Cox hazard proportion regression model, between groups of CD4+CD25+ proportion more than 5% and less than or equal to 5% in peripheral T cells.

Results: Peripheral CD4+CD25+ T lymphocytes had not a relationship with progression-free survival. It was featured that above 5% peripheral CD4+CD25+ proportion of T cells was related with the median overall survival by a shorten of 51 months (p < 0.05) with the HR 1.65 (95%CI 1.04, 2.62). Above 5% CD4+CD25+proportion of T cells produced the HR to be 1.76 (95%CI 1.07, 2.87) In stage 0-II patients, and 3.59 (95%CI 1.05, 12.29) in triple negative breast cancer patients.

Conclusions: Cellular immunity restoration recovered by adoptive T cell infusions which resulted in less proportion of peripheral CD4+CD25+T lymphocytes could be a potential prognostic indicator among early stage and triple negative patients.
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http://dx.doi.org/10.18632/oncotarget.5534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747410PMC
December 2015

Transformation of alkylating regimen of thiotepa into tepa determines the disease progression through GSTP1 gene polymorphism for metastatic breast cancer patients receiving thiotepa containing salvage chemotherapy.

Int J Clin Pharmacol Ther 2015 Nov;53(11):914-22

Background: The shifts to second-line chemotherapy for metastatic breast cancer (MBC) were widely required based on pharmaceutical molecular profiles to reach out precision medicine. The emerging precise treatment of cancer requires the implementation of clarified pharmacogenetic profiles which are capable of elucidating the predictive responses to cancer chemotherapy. Therefore we were interested in the analysis of the roles of single nucleotide polymorphism (SNP) of GSTP1 (glutathione S-transferase pi 1 gene) alleles to identify pharmacological links with predictors of clinical responses and toxicities.

Methods: 93 MBC patients receiving thiotepa plus docetaxel chemotherapy were enrolled in this study. Optimized CYP3A5, CYP2B6, and GSTP1 were predominantly selected as candidate genes and their three SNPs (CYP2B6 G516T, CYP3A5 A6986G, and GSTP1 A313G) were genotyped by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry. Progression-free survival (PFS), disease control rate, and chemo-related toxicities were recorded.

Results: GSTP1 A313G (rs1695) was identified to be related with disease progression. In particular, patients harboring AG/GG genotype demonstrated a statistically longer PFS than those with AA. Multivariate analysis confirmed that AG/GG genotype was associated with both clinical responses and liver-localized metastatic lesions. No correlation was found between these three SNPs and chemotherapy-induced toxicity.

Conclusions: These results suggest that the GSTP1 polymorphism is a novel prognostic marker for clinical response to thiotepa-containing chemotherapy regimens. Such evidence could provide insight into the role of pharmacogenetics to deprive of biases in shifting regimens solely by empirical choices.
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http://dx.doi.org/10.5414/CP202391DOI Listing
November 2015

Breast Cancer Challenges and Screening in China: Lessons From Current Registry Data and Population Screening Studies.

Oncologist 2015 Jul 22;20(7):773-9. Epub 2015 May 22.

Beijing Key Laboratory of Therapeutic Cancer Vaccine, Capital Medical University Cancer Center, Beijing Shijitan Hospital, Beijing, People's Republic of China; Duke University Medical Center, Durham, North Carolina, USA

Background: As one of its responses to the increasing global burden of breast cancer (BC), China has deployed a national registration and BC screening campaign. The present report describes these programs and the initial results of these national BC control strategies, highlighting the challenges to be considered.

Materials And Methods: The primary BC incidence and prevalence data were obtained from the Chinese National Central Cancer Registry. MapInfo software was used to map the geographic distribution and variation. The time trends were estimated by the annual percentage of change from 2003 to 2009. The description of the screening plans and preliminary results were provided by the Ministry of Health.

Results: Chinese cancer registries were primarily developed and activated in the East and Coastal regions of China, with only 12.5% of the registries located in West China. Geographic variation was noted, with the incidence of BC higher in North China than in South China and in urban areas compared with rural areas. Of great interest, these registries reported that the overall BC incidence has been increasing in China, with an earlier age of onset compared with Western countries and a peak incidence rate at age 50. In response to this increasing incidence and early age of onset, BC screening programs assessed 1.46 million women aged 35-59 years, using clinical breast examinations and ultrasound as primary screening tools between 2009 and 2011. The diagnostic rate for this screening program was only 48.0/10(5) with 440 cases of early stage BC. Early stage BC was detected in nearly 70% of screened patients. Subsequently, a second-generation screening program was conducted that included older women aged 35-64 years and an additional 6 million women were screened.

Conclusion: The cancer registration system in China has been uneven, with a greater focus on East rather than West China. The data from these registries demonstrate regional variation, an increasing BC incidence, and an early age of onset. The 2009 to 2011 BC screening program targeting women aged 35-59 years had a low detection rate that resulted in a second-generation screening program that extended the cohort size and ages screened to 35-64 years.

Implications For Practice: Cancer registration has been active in China for decades; however, a national survey of registries has not been routinely reported. This study used MapInfo to describe the reported data and found asymmetric registration activities, geographic variations in breast cancer (BC) burdens, and an increasing incidence with a peak at age 50. The initial Chinese BC screening programs focused on a relatively young population of women aged 35-59 years and had a low detection rate, but 69.7% of patients had early stage BC. Older women were included in the second-generation screening programs, and an additional 6 million women were screened. Consideration of regional variations and age is necessary to optimize the efficiency and utility of BC screening in China, with the ultimate goal to reduce BC mortality.
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http://dx.doi.org/10.1634/theoncologist.2014-0351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492227PMC
July 2015

Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth.

Breast Cancer Res 2015 Feb 15;17:20. Epub 2015 Feb 15.

Introduction: Human epidermal growth factor receptor HER3 has been implicated in promoting the aggressiveness and metastatic potential of breast cancer. Upregulation of HER3 has been found to be a major mechanism underlying drug resistance to EGFR and HER2 tyrosine kinase inhibitors and to endocrine therapy in the treatment of breast cancer. Thus, agents that reduce HER3 expression at the plasma membrane may synergize with current therapies and offer a novel therapeutic strategy to improve treatment.

Methods: We devised an image-based screening platform using membrane localized HER3-YFP to identify small molecules that promote HER3 internalization and degradation. In vitro and in vivo tumor models were used to characterize the signaling effects of perhexiline, an anti-anginal drug, identified by the screening platform.

Results: We found perhexiline, an anti-anginal drug, selectively internalized HER3, decreased HER3 expression, and subsequently inhibited signaling downstream of HER3. Consistent with these results, perhexiline inhibited breast cancer cell proliferation in vitro and tumor growth in vivo.

Conclusions: This is the first demonstration that HER3 can be targeted with small molecules by eliminating it from the cell membrane. The novel approach used here led to the discovery that perhexiline ablates HER3 expression, and offers an opportunity to identify HER3 ablation modulators as innovative therapeutics to improve survival in breast cancer patients.
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http://dx.doi.org/10.1186/s13058-015-0528-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358700PMC
February 2015

Continuous DC-CIK infusions restore CD8+ cellular immunity, physical activity and improve clinical efficacy in advanced cancer patients unresponsive to conventional treatments.

Asian Pac J Cancer Prev 2015 ;16(6):2419-23

Cancer Center, Beijing Shijitan Hospital, Capital Medical University, Beijing Key Lab of Therapeutic Cancer Vaccines, Beijing, China E-mail :

Background: There are few choices for treatment of advanced cancer patients who do not respond to or tolerate conventional anti-cancer treatments. Therefore this study aimed to deploy the benefits and clinical efficacy of continuous dendritic cell-cytokine induced killer cell infusions in such patients.

Materials And Methods: A total of 381 infusions (from 67 advanced cases recruited) were included in this study. All patients underwent peripheral blood mononuclear cell apheresis for the following cellular therapy and dendritic cells-cytokine induced killer cells were expanded in vitro. Peripheral blood T lymphocyte subsets were quantified through flow cytometry to address the cellular immunity status. Clinical efficacy and physical activities were evaluated by RECIST criteria and Eastern Cooperative Oncology Group scores respectively. Logistic regression model was used to estimate the association between cellular infusions and clinical benefits.

Results: An average of 5.7±2.94x10(9) induced cells were infused each time and patients were exposed to 6 infusions. Cellular immunity was improved in that cytotoxic CD8+CD28+T lymphocytes were increased by 74% and suppressive CD8+CD28-T lymphocytes were elevated by 16% (p<0.05). Continuous infusion of dendritic cells-cytokine induced killer cells was associated with improvement of both patient status and cellular immunity. A median of six infusions were capable of reducing risk of progression by 70% (95%CI 0.10-0.91). Every elevation of one ECOG score corresponded to a 3.90-fold higher progression risk (p<0.05) and 1% increase of CD8+CD28- T cell proportion reflecting a 5% higher risk of progression (p<0.05).

Conclusions: In advanced cancer patients, continuous dendritic cell-cytokine induced killer cell infusions are capable of recovering cellular immunity, improving patient status and quality of life in those who are unresponsive to conventional cancer treatment.
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http://dx.doi.org/10.7314/apjcp.2015.16.6.2419DOI Listing
February 2016

Elevated level of peripheral CD8(+)CD28(-) T lymphocytes are an independent predictor of progression-free survival in patients with metastatic breast cancer during the course of chemotherapy.

Cancer Immunol Immunother 2013 Jun 21;62(6):1123-30. Epub 2013 Apr 21.

Department of Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, 52 Fucheng Rd, Beijing 100142, China.

Purpose: Suppression of cellular immunity resulting from tumorigenesis and/or therapy might promote cancer cells' growth, progression and invasion. Here, we explored whether T lymphocyte subtypes from peripheral blood of metastatic breast cancer (MBC) female patients could be used as alternative surrogate markers for cancer progress. Additionally, plasma levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IFN-γ, and transforming growth factor-β1 were quantitated from MBC and healthy volunteers.

Experimental Design: This study included 89 female MBC patients during the post-salvage chemotherapy follow-up and 50 age- and sex-matched healthy volunteers as control. The percentages of T lymphocyte subpopulations from peripheral blood and plasma levels of cytokines were measured.

Results: Both CD8(+)CD28(-) and CD4(+)CD25(+) were elevated in MBC patients compared to the control cohort (P < 0.05). In contrast, CD3(+) and CD8(+)CD28(+)cells were significantly lower in MBC patients (P < 0.0001, P = 0.045, respectively). MBC patients had elevated levels of immunosuppressive cytokines IL-6 and IL-10. Patients with elevated CD8(+)CD28(-) and CD4(+)CD25(+) cells showed increased levels of IL-6, and only patients with elevated CD8(+)CD28(-) had decreased interferon-γ. Univariate analysis indicated increased CD3(+)CD4(+) or CD8(+)CD28(+)correlated with prolonged progression-free survival (PFS), while elevated CD8(+)CD28(-)associated with shorten PFS. The percent of CD8(+)CD28(-) T lymphocytes is an independent predictor for PFS through multivariate analysis.

Conclusions: This study suggests that progressive elevated levels of CD8(+)CD28(-) suppressor T lymphocytes represent a novel independent predictor of PFS during post-chemotherapy follow-up.
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http://dx.doi.org/10.1007/s00262-013-1424-8DOI Listing
June 2013

Selections of appropriate regimen of high-dose chemotherapy combined with adoptive cellular therapy with dendritic and cytokine-induced killer cells improved progression-free and overall survival in patients with metastatic breast cancer: reargument of such contentious therapeutic preferences.

Clin Transl Oncol 2013 Oct 29;15(10):780-8. Epub 2013 Jan 29.

Department of Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, 52 Fucheng Rd, Beijing, 100142, China,

Background: We hypothesized that combination of dendritic cell (DC) with autologous cytokine-induced killer (CIK) immunotherapy in setting of high-dose chemotherapy (HDC) would be effective for selected metastatic breast cancer (MBC) patients.

Patients And Methods: Our previous work showed thiotepa could eradicate breast cancer stem cells. From 2004 to 2009, 79 patients received standard dose chemotherapy (SDC) of 75 mg/m(2) docetaxel and 75 mg/m(2) thiotepa versus 87 patients of HDC + DC/CIK: 120 mg/m(2) docetaxel to mobilize peripheral CD34(+) progenitor cells, a sequence of HDC (120 mg/m(2) docetaxel, plus 175 mg/m(2) thiotepa) + DC/CIK, with or without 400 mg/m(2) carboplatin depending upon bone marrow function. The endpoints were response rates (RR), progression-free survival (PFS), and overall survival (OS).

Results: Compared with SDC, PFS and OS were improved in HDC + DC/CIK (median PFS 10.2 vs. 3.7 months, P < 0.001; median OS 33.1 vs. 15.2 months, P < 0.001). Patients of pre-menopausal, HDC as first-line treatment after metastasis, or with visceral metastasis showed prolonged PFS and OS. SDC group also achieved the similar response as previous reports.

Conclusion: Our study demonstrated the novel combination of HDC with DC/CIK to be an effective choice for the selected MBC population, in which choosing appropriate chemo regimens played important roles, and also specific HDC regimen plus DC/CIK immunotherapy showed the clinical benefits compared with chemotherapy alone.
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http://dx.doi.org/10.1007/s12094-013-1001-9DOI Listing
October 2013

Specific genetic polymorphisms of IL10-592 AA and IL10-819 TT genotypes lead to the key role for inducing docetaxel-induced liver injury in breast cancer patients.

Clin Transl Oncol 2013 Apr 10;15(4):331-4. Epub 2012 Nov 10.

Department of Medical Oncology, Peking University Cancer Hospital and Institute, Beijing, China.

Aim: This study was designed to explore the genetic polymorphism of IL-10 (-1082A/G, -592A/C, -819T/C), TNF-α (-308G/A) with susceptibility to docetaxel-induced liver injury (DILI) in Chinese breast cancer patients.

Methods: The targeted genetic polymorphisms of IL10-1082G/A, IL10-592A/C, IL10-819T/C, TNF-308G/A from 40 patients with DILI were assayed by matrix-assisted laser desorption/ionization-time of flight of Sequenom.

Results: AA genotype of IL10-592 and TT of IL10-819 significantly increased incidence of DILI (P = 0.005, OR = 3.137). No differences of TNF gene polymorphism between the two groups were seen.

Conclusion: The genetic polymorphism of the IL10-592A/C AA genotype and IL10-819T/C TT genotype was predominantly conferred to the incidence of docetaxel-induced liver injury.
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http://dx.doi.org/10.1007/s12094-012-0936-6DOI Listing
April 2013