Bio

Bio


Adrienne Long, MD, PhD is a fellow in the Division of Pediatric Hematology and Oncology at the Lucile Packard Children's Hospital Stanford. Dr. Long attend Northwestern University, where she earned both a BS in biomedical engineering and her MD. Driven by a clinical interest in pediatric oncology and the recognized need for novel treatment approaches, she chose to pursue a PhD studying CAR T cells at the National Institutes of Health (NIH) with Dr. Crystal Mackall. Her thesis work was the first to identify T cell exhaustion as a critical factor limiting efficacy of CAR T cell therapies (Long et al., Nature Medicine, 2015). She also worked on novel methods to enhance CAR T cell therapies for pediatric solid tumors (Long/Highfill et al., Cancer Immunology Research, 2016). Dr. Long went on to complete her pediatrics residency training at Boston Children?s Hospital, where she continued her research in cancer immunology with Dr. Nicholas Haining ? this time focusing on strategies to enhance antigen presentation to augment PD1 blockade (Long et al. presented at the Keystone Symposium on Cancer Immunotherapy, 2019). She remains dedicated to a career as a physician-scientist focused on developing novel immunotherapies for children with cancer.

Clinical Focus


  • Fellow
  • Pediatric Hematology and Oncology
  • Cancer Immunology and Immunotherapy

Honors & Awards


  • Fredrick H. Lovejoy, Jr. Award, Boston Children's Hospital (2019)
  • Member, Alpha Omega Alpha Honor Medical Society (2015)
  • Scholar-in-Training Award, American Association for Cancer Research (2015)
  • Women in Cancer Research Award, American Association for Cancer Research (2014)
  • Fellows Award for Research Excellence, National Institutes of Health (2013)
  • Cloister Research Scholar, Howard Hughes Medical Institute - National Institutes of Health (2011)

Professional Education


  • Residency, Pediatrics, Boston Children's Hospital (2019)
  • MD, Northwestern University, The Feinberg School of Medicine (2016)
  • PhD, Cancer Immunology, National Institutes of Health (2015)
  • BS, Biomedical Engineering, Northwestern University (2008)

Publications

All Publications


  • 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors NATURE MEDICINE Long, A. H., Haso, W. M., Shern, J. F., Wanhainen, K. M., Murgai, M., Ingaramo, M., Smith, J. P., Walker, A. J., Kohler, M. E., Venkateshwara, V. R., Kaplan, R. N., Patterson, G. H., Fry, T. J., Orentas, R. J., Mackall, C. L. 2015; 21 (6): 581-590

    Abstract

    Chimeric antigen receptors (CARs) targeting CD19 have mediated dramatic antitumor responses in hematologic malignancies, but tumor regression has rarely occurred using CARs targeting other antigens. It remains unknown whether the impressive effects of CD19 CARs relate to greater susceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CAR itself. We show that tonic CAR CD3-? phosphorylation, triggered by antigen-independent clustering of CAR single-chain variable fragments, can induce early exhaustion of CAR T cells that limits antitumor efficacy. Such activation is present to varying degrees in all CARs studied, except the highly effective CD19 CAR. We further determine that CD28 costimulation augments, whereas 4-1BB costimulation reduces, exhaustion induced by persistent CAR signaling. Our results provide biological explanations for the antitumor effects of CD19 CARs and for the observations that CD19 CAR T cells incorporating the 4-1BB costimulatory domain are more persistent than those incorporating CD28 in clinical trials.

    View details for DOI 10.1038/nm.3838

    View details for Web of Science ID 000355778300014

    View details for PubMedID 25939063

    View details for PubMedCentralID PMC4458184

  • Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature Ishizuka, J. J., Manguso, R. T., Cheruiyot, C. K., Bi, K., Panda, A., Iracheta-Vellve, A., Miller, B. C., Du, P. P., Yates, K. B., Dubrot, J., Buchumenski, I., Comstock, D. E., Brown, F. D., Ayer, A., Kohnle, I. C., Pope, H. W., Zimmer, M. D., Sen, D. R., Lane-Reticker, S. K., Robitschek, E. J., Griffin, G. K., Collins, N. B., Long, A. H., Doench, J. G., Kozono, D., Levanon, E. Y., Haining, W. N. 2019; 565 (7737): 43?48

    Abstract

    Most patients with cancer either do not respond to immune checkpoint blockade or develop resistance to it, often because of acquired mutations that impair antigen presentation. Here we show that loss of function of the RNA-editing enzyme ADAR1 in tumour cells profoundly sensitizes tumours to immunotherapy and overcomes resistance to checkpoint blockade. In the absence of ADAR1, A-to-I editing of interferon-inducible RNA species is reduced, leading to double-stranded RNA ligand sensing by PKR and MDA5; this results in growth inhibition and tumour inflammation, respectively. Loss of ADAR1 overcomes resistance to PD-1 checkpoint blockade caused by inactivation of antigen presentation by tumour cells. Thus, effective anti-tumour immunity is constrained by inhibitory checkpoints such as ADAR1 that limit the sensing of innate ligands. The induction of sufficient inflammation in tumours that are sensitized to interferon can bypass the therapeutic requirement for CD8+ T cell recognition of cancer cells and may provide a general strategy to overcome immunotherapy resistance.

    View details for DOI 10.1038/s41586-018-0768-9

    View details for PubMedID 30559380

  • Hypotonia and Lethargy in a Two-Day-Old Male Infant. Pediatrics Long, A. H., Fiore, J. G., Gillani, R., Douglass, L. M., Fujii, A. M., Hoffman, J. D. 2019; 144 (1)

    Abstract

    A 2-day old term male infant was found to be hypotonic and minimally reactive during routine nursing care in the newborn nursery. At 40 hours of life, he was hypoglycemic and had intermittent desaturations to 70%. His mother had an unremarkable pregnancy and spontaneous vaginal delivery. The mother's prenatal serology results were negative for infectious risk factors. Apgar scores were 9 at 1 and 5 minutes of life. On day 1 of life, he fed, stooled, and voided well. Our expert panel discusses the differential diagnosis of hypotonia in a neonate, offers diagnostic and management recommendations, and discusses the final diagnosis.

    View details for DOI 10.1542/peds.2018-0788

    View details for PubMedID 31227563

  • Tumor Antigen and Receptor Densities Regulate Efficacy of a Chimeric Antigen Receptor Targeting Anaplastic Lymphoma Kinase. Molecular therapy : the journal of the American Society of Gene Therapy Walker, A. J., Majzner, R. G., Zhang, L., Wanhainen, K., Long, A. H., Nguyen, S. M., Lopomo, P., Vigny, M., Fry, T. J., Orentas, R. J., Mackall, C. L. 2017

    Abstract

    We explored the utility of targeting anaplastic lymphoma kinase (ALK), a cell surface receptor overexpressed on pediatric solid tumors, using chimeric antigen receptor (CAR)-based immunotherapy. Tácells expressing a CAR incorporating the single-chain variable fragment sequence of the ALK48 mAb linked to a 4-1BB-CD3? signaling domain lysed ALK-expressing tumor lines and produced interferon-gamma upon antigen stimulation but had limited anti-tumor efficacy in two xenograft models of human neuroblastoma. Further exploration demonstrated that cytokine production was highly dependent upon ALK target density and that target density of ALK on neuroblastoma cell lines was insufficient for maximal activation of CAR Tácells. In addition, ALK CAR Tácells demonstrated rapid and complete antigen-induced loss of receptor from the Tácell surface via internalization. Using a model that simultaneously modulated antigen density and CAR expression, we demonstrated that CAR functionality is regulated by target antigen and CAR density and that low expression of either contributes to limited anti-tumor efficacy of the ALK CAR. These data suggest that stoichiometric relationships between CAR receptors and target antigens may significantly impact the anti-tumor efficacy of CAR Tácells and that manipulation of these parameters could allow precise tuning of CAR Tácell activity.

    View details for PubMedID 28676342

  • Reduction of MDSCs with All-trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas CANCER IMMUNOLOGY RESEARCH Long, A. H., Highfill, S. L., Cui, Y., Smith, J. P., Walker, A. J., Ramakrishna, S., El-Etriby, R., Galli, S., Tsokos, M. G., Orentas, R. J., Mackall, C. L. 2016; 4 (10): 869-880

    Abstract

    Genetically engineered T cells expressing CD19-specific chimeric antigen receptors (CAR) have shown impressive activity against B-cell malignancies, and preliminary results suggest that T cells expressing a first-generation disialoganglioside (GD2)-specific CAR can also provide clinical benefit in patients with neuroblastoma. We sought to assess the potential of GD2-CAR therapies to treat pediatric sarcomas. We observed that 18 of 18 (100%) of osteosarcomas, 2 of 15 (13%) of rhabdomyosarcomas, and 7 of 35 (20%) of Ewing sarcomas expressed GD2. T cells engineered to express a third-generation GD2-CAR incorporating the 14g2a-scFv with the CD28, OX40, and CD3? signaling domains (14g2a.CD28.OX40.?) mediated efficient and comparable lysis of both GD2(+) sarcoma and neuroblastoma cell lines in vitro However, in xenograft models, GD2-CAR T cells had no antitumor effect against GD2(+) sarcoma, despite effectively controlling GD2(+) neuroblastoma. We observed that pediatric sarcoma xenografts, but not neuroblastoma xenografts, induced large populations of monocytic and granulocytic murine myeloid-derived suppressor cells (MDSC) that inhibited human CAR T-cell responses in vitro Treatment of sarcoma-bearing mice with all-trans retinoic acid (ATRA) largely eradicated monocytic MDSCs and diminished the suppressive capacity of granulocytic MDSCs. Combined therapy using GD2-CAR T cells plus ATRA significantly improved antitumor efficacy against sarcoma xenografts. We conclude that retinoids provide a clinically accessible class of agents capable of diminishing the suppressive effects of MDSCs, and that co-administration of retinoids may enhance the efficacy of CAR therapies targeting solid tumors. Cancer Immunol Res; 4(10); 869-80. ę2016 AACR.

    View details for DOI 10.1158/2326-6066.CIR-15-0230

    View details for Web of Science ID 000385632900007

    View details for PubMedID 27549124

    View details for PubMedCentralID PMC5050151

  • Comparison against 186 canid whole-genome sequences reveals survival strategies of an ancient clonally transmissible canine tumor GENOME RESEARCH Decker, B., Davis, B. W., Rimbault, M., Long, A. H., Karlins, E., Jagannathan, V., Reiman, R., Parker, H. G., Droegemueller, C., Corneveaux, J. J., Chapman, E. S., Trent, J. M., Leeb, T., Huentelman, M. J., Wayne, R. K., Karyadi, D. M., Ostranderl, E. A. 2015; 25 (11): 1646?55

    Abstract

    Canine transmissible venereal tumor (CTVT) is a parasitic cancer clone that has propagated for thousands of years via sexual transfer of malignant cells. Little is understood about the mechanisms that converted an ancient tumor into the world's oldest known continuously propagating somatic cell lineage. We created the largest existing catalog of canine genome-wide variation and compared it against two CTVT genome sequences, thereby separating alleles derived from the founder's genome from somatic mutations that must drive clonal transmissibility. We show that CTVT has undergone continuous adaptation to its transmissible allograft niche, with overlapping mutations at every step of immunosurveillance, particularly self-antigen presentation and apoptosis. We also identified chronologically early somatic mutations in oncogenesis- and immune-related genes that may represent key initiators of clonal transmissibility. Thus, we provide the first insights into the specific genomic aberrations that underlie CTVT's dogged perseverance in canids around the world.

    View details for DOI 10.1101/gr.190314.115

    View details for Web of Science ID 000364355600006

    View details for PubMedID 26232412

    View details for PubMedCentralID PMC4617961

  • 4-1BB costimulation ameliorates exhaustion and prolongs in vivo persistence of chimeric antigen receptor (CAR) expressing T cells Long, A. H., Haso, W. M., Smith, J. P., Walker, A. J., Fry, T. J., Orentas, R. J., Mackall, C. L. AMER ASSOC CANCER RESEARCH. 2015
  • 14g2a-based GD2-specific chimeric antigen receptors (CARs) constitutively signal, leading to rapidly induced T-cell exhaustion and poor antitumor efficacy in vivo Long, A., Orentas, R. J., Mackall, C. L. AMER ASSOC CANCER RESEARCH. 2014
  • Synthetic Chimeric Antigen Receptors (CARs) Rapidly Induce Exhaustion and Augmented Glycolytic Metabolism In Human T Cells and Implicate Persistent CD28 Signaling As a Driver Of Exhaustion In Human T Cells Long, A. H., Orentas, R. J., Mackall, C. L. AMER SOC HEMATOLOGY. 2013
  • Evaluating the susceptibility of solid tumors to chimeric antigen receptor modified T cell therapies Long, A. H., Highfill, S. L., Haso, W. M., Orentas, R. J., Mackall, C. L. AMER ASSOC CANCER RESEARCH. 2013
  • Lessons learned from a highly-active CD22-specific chimeric antigen receptor. Oncoimmunology Long, A. H., Haso, W. M., Orentas, R. J. 2013; 2 (4): e23621

    Abstract

    CD22 is an attractive target for the development of immunotherapeutic approaches for the therapy of B-cell malignancies. In particular, an m971 antibody-derived, second generation chimeric antigen receptor (CAR) that targets CD22 holds significant therapeutic promise. The key aspect for the development of such a highly-active CAR was its ability to target a membrane-proximal epitope of CD22.

    View details for DOI 10.4161/onci.23621

    View details for PubMedID 23734316

    View details for PubMedCentralID PMC3654586

  • Evaluating the Susceptibility of Solid Tumors to Chimeric Antigen Receptor Modified T Cell Therapies Long, A. H., Haso, W., Lee, D., Highfill, S., Orentas, R., Mackall, C. LIPPINCOTT WILLIAMS & WILKINS. 2012: 726
  • Triggered release of therapeutic antibodies from nanodiamond complexes NANOSCALE Smith, A. H., Robinson, E. M., Zhang, X., Chow, E. K., Lin, Y., Osawa, E., Xi, J., Ho, D. 2011; 3 (7): 2844?48

    Abstract

    Recent reports have revealed that detonation nanodiamonds (NDs) can serve as efficient, biocompatible, and versatile drug delivery platforms. Consequently, further investigations exploring additional therapeutic applications are warranted. Current limitations associated with the non-specific nature of intravenous drugs limit the potential of certain pharmacological agents. One such treatment that could benefit from a stable delivery platform is antibody (Ab) therapy. Determination of Ab adsorption and desorption to a ND surface was subsequently examined using the transforming growth factor ? (TGF-?) antibody as a model therapeutic. ND-Ab complexes were found to be stable in water through enzyme-linked immunosorbent assays (ELISAs), UV-vis spectroscopy and TEM, with no Ab released after ten days. Released Abs were detected in extreme pH solutions (3.5), DMEM (+) serum with pH levels ranging from 4 to 10.5, and inorganic saline solutions. Preserved activity of Abs released in DMEM (+) serum was confirmed using an ELISA. These results suggest ND-Ab complexes are synthesized and stabilized in water and are triggered to release active Abs upon exposure to physiological conditions.

    View details for DOI 10.1039/c1nr10278h

    View details for Web of Science ID 000292776300019

    View details for PubMedID 21617824

  • Improved methods and standards for telomerase detection: quantitative histopathology using antibody staining BIOTECHNIC & HISTOCHEMISTRY Jakupciak, J. P., Gallant, N. D., Smith, A. H., Becker, M. L., Tona, A., Atha, D. H. 2009; 84 (5): 195?206

    Abstract

    Evaluation of telomerase as an early detection biomarker for cancer has been hindered by a lack of reliable methods and standards for in situ histochemical measurement. Improved histochemical methods for measuring telomerase could expedite the acceptance of telomerase as a biomarker for use in diagnostic and clinical applications. The lack of a crystal structure for telomerase coupled with high variability in the antibodies available for immunohistochemical analysis has led to confusion in the literature regarding the binding specificity of these antibodies. We have developed an automated fluorescence microscopy protocol to assess the specificity of three fluorescently labeled telomerase antibodies and to quantify telomerase in cultured human tumor cells and in human fibroblast cells as a control. Significant differences in staining intensity and distribution were observed. Fluorescence measurements in these cell lines were compared to telomerase measured by the telomerase repeat amplification protocol, reverse transcription-polymerase chain reaction, and flow cytometry. This combination of measurements ensured a more complete quantitation of telomerase levels in each of the cell lines and could also be used as a model for validation of other biomarkers for clinical use.

    View details for DOI 10.1080/10520290903039060

    View details for Web of Science ID 000271236900002

    View details for PubMedID 19886756

  • Properties of ceramics in the system ZrB2-Ta5Si3 JOURNAL OF MATERIALS RESEARCH Talmy, I. G., Zaykoski, J. A., Opeka, M. M., Smith, A. H. 2006; 21 (10): 2593?99

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