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Kim E. Nichols, MD

Kim E. Nichols, MD

faculty photo
Associate Professor of Pediatrics at the Children's Hospital of Philadelphia
Department: Pediatrics
Graduate Group Affiliations

Contact information
Children's Hospital of Philadelphia
Division of Oncology
Colket Translational Research Building, Rm 3012
3501 Civic Center Boulevard

nicholsk@email.chop.edu
Philadelphia, PA 19104
Office: (267) 425-3000
Fax: (215) 590-3770
Lab: (267) 425-3001
Education:
B.A. (Biology)
Dartmouth College, 1984.
M.D. (Medicine)
Duke University School of Medicine, 1989.
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Description of Research Expertise

I am a pediatric oncologist with clinical and basic research interests focusing on the genetic mechanisms that protect against specific virus infections and cancer. I would like to understand how defects in these mechanisms contribute to human disease and use this information to increase awareness, facilitate diagnosis and improve the treatment of patients at increased genetic risk for infection and cancer.

1) Defining the pathogenesis and improving the treatment for patients with X-linked lymphoproliferative disease (XLP): As a post-doctoral fellow, I used positional cloning to identify SH2D1A, the gene responsible for XLP, a rare primary immunodeficiency associated with development of Epstein-Barr-virus (EBV)-induced hemophagocytic lymphohistiocytosis (HLH) and B cell lymphomas. Currently, my laboratory is working to understand how the XLP gene product SAP controls immune cell development and function. In 2005, we reported that SAP is a critical molecule required for the ontogeny of invariant natural killer T (iNKT) cells, innate-type T lymphocytes with important roles in host immunity. Currently, we are trying to understand how SAP and its signaling partners control iNKT cell development and determine whether they also regulate mature iNKT cell functions. From a clinical perspective, we are working to identify novel and more effective therapies for patients with XLP and HLH who are experiencing overwhelming EBV infection. In this regard, we have recently published that chemo-immunotherapeutic regiments containing the B cell depleting antibody rituximab significantly reduce viral load and diminish inflammation in patients with EBV-HLH.

2) Development of iNKT-cell based cancer therapies: iNKT cells are lipid reactive T lymphocytes that potently kill tumor cells and promote the tumor-directed functions of dendritic, NK, T and B cells. Because they stimulate innate and adaptive immune responses to tumors, iNKT cells warrant serious consideration for inclusion in cell-based therapies for cancer. In most cases, optimal iNKT cell recognition of tumors is T cell receptor (TCR)-dependent, requires tumor cell expression of the antigen-presenting molecule CD1d and the pre-loading of tumor cells with lipids that engage the invariant TCR and induce iNKT cell activation. However, tumors down-regulate CD1d and thus become invisible to iNKT cell attack. To circumvent this issue, it is important to understand how to effectively target iNKT cells to and activate them at the site of tumors. Furthermore, it is imperative to identify the tumors against which iNKT cells have the greatest impact. Recently, we cloned and purified a novel soluble fusion protein that induces iNKT cell activation and promotes iNKT cell lysis of CD1d-negative B leukemia cells in vitro. We are now investigating whether the fusion induces tumor clearance in leukemia-bearing mice. Soluble proteins serve as an attractive means to target effector cells to tumors as their administration does not rely on the genetic manipulation of immune cells and one can titrate the dose and schedule to produce desired effects while minimizing toxicity. We believe that this approach represents an innovative and potentially more effective means to induce the antitumor effects of iNKTs in situ.

3) Studies into the pathogenesis and treatment of other genetic forms of HLH: Current therapies for HLH, including steroids and etoposide, are effective in only a proportion of patients and unfortunately up to 50% of patients die due to the disease. As a result, newer and more effective treatments are desperately needed. In HLH, activated T cells and macrophages secrete high levels of pro-inflammatory cytokines, such as interleukins (IL)-2, 6, 12 and interferon-γ, which drive immune cell activation and promote an often-fatal sepsis-like syndrome typified by profound hypotension and vascular leak. In the laboratory, we are using novel therapeutic approaches to down-modulate cytokine receptor signaling using murine models of HLH. It is our expectation that this maneuver will minimize inflammation and potentially improve outcome. If effective in the pre-clinical models, we plan to test the effects of these drugs in a prospective clinical trial. To optimize the treatment of patients with HLH at CHOP, we have created a formal HLH Treatment team consisting of members of the divisions of oncology, rheumatology, immunology, neurology, critical care and pharmacy. This team meets monthly to discuss patient management, review and refine diagnostic guidelines, generate educational materials and initiate clinical and basic research projects in HLH.

The current lab personnel are:

Rupali Das, PhD
Peng Guan, BS
Sarah Thornton, MS
Nishant Patel, MD
Les Sprague, BS, MS

Description of Clinical Expertise

Dr. Nichols is a pediatric oncologist with clinical interests in cancer genetics and the treatment of children with lymphoma, EBV-related lymphoproliferative disorders, Langerhans cell histiocytosis and the hemophagocytic lymphohistiocytoses.

Selected Publications

Menard L, Chamberlain N, Cantaert T, Tangye SG, Riminton S, Church JA, Klion A, Cunninham-Rundles C, Nichols KE, Meffre E: Signaling Lymphocytic Activation Moledule (SLAM)-associated protein (SAP) regulates human B cell tolerance. Journal of Allergy and Clinical Immunology in press, November 2013.

Bassiri H, Das R, Guan P, Barrett DM, Brennan PJ, Banerjee PP, Wiener SJ, Orange JS, Brenner MB, Grupp SA, and Nichols KE: iNKT cell cytotoxic responses control T-lymphoma growth in vitro and in vivo Cancer Immunology Research in press, November 2013.

Chaigne-Delalande B, Li FY, O'Connor GM, Lukacs MJ, JP, Zheng L, Shatzer A, Biancalana M, Pittaluga S, Matthews HF, Jancel TJ, Bleesing JJ, Marsh RA, Kuijpers TW, Nichols KE, Lucas CL, Nagpal S, Mehmet H, Su HC, Cohen JI, Uzel G, Lenardo MJ: Mg2+ Regulates Cytotoxic Functions of NK and CD8 T Cells in Chronic EBV Infection Through NKG2D. Science 341(6142): 186-191, Jul 2013.

Kalish JM, Conlin LK, Bhatti TR, Dubbs HA, Harris MC, Izumi K, Mostoufi-Moab S, Mulchandani S, Saitta S, States LJ, Swarr DT, Wilkens AB, Zackai EH, Zelley K, Bartolomei MS, Nichols KE, Palladino AA, Spinner NB, Deardorff MA: Clinical features of three girls with mosaic genome-wide paternal uniparental isodisomy. American Journal of Medical Genetics Jun 2013.

Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, Seif AE, Nichols KE, Suppa EK, Kalos M, Berg RA, Fitzgerald JC, Aplenc R, Gore L, Grupp SA: Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood 121(26): 5154-7, Jun 2013.

Chellapandian D, Das R, Zelley K, Wiener SJ, Zhao H, Teachey DT, Nichols KE: Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. British Journal of Haematology 162(3): 376-82, May 2013.

Kalish JM, Conlin LK, Mostoufi-Moab S, Wilkens AB, Mulchandani S, Zelley K, Kowalski M, Bhatti TR, Russo P, Mattei P, Mackenzie WG, LiVolsi V, Nichols KE, Biegel JA, Spinner NB, and Deardorff MA. : Hemihyperplasia, Bilateral Pheochromocytomas, and Subtle Somatic Mosaicism: The Importance of Detecting Low-level Uniparental Disomy. American Journal of Human Genetics March 2013.

Das R, Bassiri H, Guan P, Wiener S, Banerjee PP, Zhong MC, Veillette A, Orange JS, Nichols KE: The adaptor molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation. Blood Feb 2013.

May RM, Okumura M, Hsu CJ, Bassiri H, Yang E, RG, Mace EM, Philip NH, Zhang W, Baumgart T, Orange JS, Nichols KE, Kambayashi T: Murine natural killer immunoreceptors use distinct proximal signaling complexes to direct cell function. Blood Feb 2013.

Hassan A, Booth C, Brightwell A, Allwood Z, Veys P, Rao K, Honig M, Friedrich W, Gennery A, Slatter M, Bredius R, Finocchi A, Cancrini C, Aiuti A, Porta F, Ridella M, Steward C, Filipovich A, Marsh R, Bordon V, Al-Muhsen S, Al-Mousa H, Alsum Z, Al-Dhekri H, Al Ghonaium A, Speckmann C, Fischer F, Mahlaoui N, Nichols KE, Grunebaum E, Al Zaharani D, Roifman CM, Boelens J, Davies EJ, Cavazzana-Calvo M, Notarangelo L and Gaspar HB.: Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency. Blood 120(17): 3615-24, Oct 2012.

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Last updated: 02/10/2014
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