Director, Pediatric Hereditary Cancer Predisposition Program
Associate professor of Pediatrics, University of Pennsylvania School of Medicine
- Department: Pediatrics
- Division: Oncology
- Primary Address:
Children's Hospital of Philadelphia
Division of Oncology
Colket Translational Research Building, Rm 3012
3501 Civic Center Boulevard
Philadelphia, PA 19104
- (267) 425-3000
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.
Our laboratory is interested in the study of immune cells and their roles in maintaining health and mediating disease. In particular, we are interested in the targeting of invariant natural killer T (iNKT) cells to tumors and in inducing their anti-tumor activity. We use tissue culture systems and murine models for our investigations. Our studies are relevant to the understanding of normal immune responses as well as the development of novel cancer treatments.
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-?, 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
- Associate Professor of Pediatrics at the Children's Hospital of Philadelphia (2007 – present)
- Assistant Professor of Pediatrics at the Children's Hospital of Philadelphia (1999 – 2007)
- M.D., Medicine, Duke University School of Medicine (1989)
- B.A., Biology, Dartmouth College (1984)
I'm director of the Pediatric Hereditary Cancer Predisposition Program at The Children's Hospital of Philadelphia. Our program was established in 2005 and is one of the few in the nation to provide specialty oncology care and genetic counseling to children with a predisposition to cancer. The program also houses the Beckwith-Wiedemann syndrome (BWS)/isolated hemihypertrophy team. This sub-group within the program works with families of children with BWS and isolated hemihypertrophy, diseases that genetically predispose children to cancer.
In the clinic, we help identify families and children at increased risk to develop neoplasms, educate and monitor for the development of certain cancers, and provide treatment. Since these conditions require specialized management, we work closely with clinical genetics, as well as orthopedics, gastroenterology, surgery, immunology and bone marrow transplantation to provide optimized and comprehensive care for our patients.
Having established a clinical framework in pediatric cancer predisposition, we are now developing research protocols to collect blood and other tissues from patients for use in future studies aiming to identify novel genetic causes of pediatric cancer. We are also working to establish the proper combination of surveillance measures to most effectively monitor children affected by specific conditions and are evaluating the psychological issues related to cancer genetic testing in children.
In the laboratory, my research focuses on identifying and understanding how specific genes protect against the development of cancers and infections. Individuals with defects in their immune system are more likely to get certain kinds of cancer, such as lymphoma. As we expand our knowledge of the genes involved in predisposition to lymphoma and virus infections, we will be able to identify and develop new therapies for these conditions.
My interest in immune and genetic issues is long standing. As a post doctoral fellow, I worked on identifying the gene for X-linked lymphoproliferative (XLP) syndrome. This extremely rare inherited immunodeficiency disorder is caused by a defect in the SH2D1A gene. XLP is associated with increased susceptibility to infection with Epstein-Barr virus (EBV), as well as development of non-Hodgkin's B-cell lymphomas and immune system abnormalities, such as lowered production of antibodies. When individuals with XLP are exposed to EBV, many develop an overactive, yet dysfunctional immune response that results in a life-threatening condition known as hemophagocytic lymphohistiocytosis. Because of the poor prognosis, an early diagnosis to patients and families is critical.
The SH2D1A gene produces a protein known as SAP that is expressed in and controls the functions of cancer- and virus-fighting types of white blood cells known as T lymphocytes and natural killer (NK) cells. Most recently, we observed that SAP is critical for promoting the development of natural killer T (NKT) cells, a rare lymphocyte lineage that protects from infections, cancers and prevents autoimmune diseases.
Our current research is focused on understanding how SAP regulates NKT cell development and establishing whether SAP plays a role in mature NKT cell activation. We are also interested in determining whether NKT cells contribute to the control of EBV infection in normal individuals and assessing if the lack of NKT cells contributes to the development of disease manifestations in patients with XLP. While our research is directed primarily at XLP, it is also relevant to the understanding and treatment of an emerging group of genetic disorders known as familial HLH, which shares many clinical and laboratory features with XLP.
As a result of our clinical and research efforts, the Hereditary Cancer Predisposition Program and my laboratory research group is poised to advance our understanding of the genetic basis of diseases that predispose to cancer and immunodeficiency.
- 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. Vol in press. 2013 November.
- 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. Vol in press. 2013 November.
- Chaigne-Delalande Benjamin, Li Feng-Yen, O'Connor Geraldine M, Lukacs Marshall J, Jiang Ping, Zheng Lixin, Shatzer Amber, Biancalana Matthew, Pittaluga Stefania, Matthews Helen F, Jancel Timothy J, Bleesing Jack J, Marsh Rebecca A, Kuijpers Taco W, Nichols Kim E, Lucas Carrie L, Nagpal Sunil, Mehmet Huseyin, Su Helen C, Cohen Jeffrey I, Uzel Gulbu, Lenardo Michael J. Mg2+ Regulates Cytotoxic Functions of NK and CD8 T Cells in Chronic EBV Infection Through NKG2D. Science. Vol 341(6142) . 2013 Jul:186-191.
- Kalish Jennifer M, Conlin Laura K, Bhatti Tricia R, Dubbs Holly A, Harris Mary Catherine, Izumi Kosuke, Mostoufi-Moab Sogol, Mulchandani Surabhi, Saitta Sulagna, States Lisa J, Swarr Daniel T, Wilkens Alisha B, Zackai Elaine H, Zelley Kristin, Bartolomei Marisa S, Nichols Kim E, Palladino Andrew A, Spinner Nancy B, Deardorff Matthew A. Clinical features of three girls with mosaic genome-wide paternal uniparental isodisomy. American Journal of Medical Genetics. 2013 Jun.
- Teachey David T, Rheingold Susan R, Maude Shannon L, Zugmaier Gerhard, Barrett David M, Seif Alix E, Nichols Kim E, Suppa Erica K, Kalos Michael, Berg Robert A, Fitzgerald Julie C, Aplenc Richard, Gore Lia, Grupp Stephan A. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy.. Blood. Vol 121(26) . 2013 Jun:5154-7.
- Chellapandian Deepakbabu, Das Rupali, Zelley Kristin, Wiener Susan J, Zhao Huaqing, Teachey David T, Nichols Kim E. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. British Journal of Haematology. Vol 162(3) . 2013 May:376-82.
- 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. 2013 March.
- Das Rupali, Bassiri Hamid, Guan Peng, Wiener Susan, Banerjee Pinaki P, Zhong Ming-Chao, Veillette André, Orange Jordan S, Nichols Kim E. The adaptor molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation. Blood. 2013 Feb.
- May Rebecca M, Okumura Mariko, Hsu Chin-Jung, Bassiri Hamid, Yang Enjun, Rak Gregory, Mace Emily M, Philip Naomi H, Zhang Weiguo, Baumgart Tobias, Orange Jordan S, Nichols Kim E, Kambayashi Taku. Murine natural killer immunoreceptors use distinct proximal signaling complexes to direct cell function. Blood. 2013 Feb.
- 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. Vol 120(17) . 2012 Oct:3615-24.