Targeting of Innate and Adaptive Immunity Against Human Glioma via Dendritic Cells

Kavita Dhodapkar, M.D.

Rockefeller University

Funded in September, 2003: $300000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . SELECTED PUBLICATIONS .

LAY SUMMARY

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Can Innate and Adaptive Immune Responses Be Elicited Against Brain Tumors?

This laboratory study will examine whether immune system cells of patients with deadly brain tumors, called gliomas, can be enhanced in the laboratory to attack the tumor cells. If so, this could lead to development of a new therapeutic approach to this currently untreatable brain cancer.

Gliomas are particularly virulent brain tumors that are not detected by the patient's immune system. This is because dendritic cells, immune system sentries that ordinarily spot invaders and organize an attack by immune T cells, are not present in the brain. Moreover, only immune T cells that already have been taught to attack a specific antigen (pathogen) are granted entry into the brain by its gatekeeper, the blood-brain-barrier. Further complicating the situation, gloimas are highly heterogeneous. Their many antigens require a coordinated immune response. The Rockefeller researchers hypothesize, however, that dendritic cells can be experimentally induced to activate a coordinated attack by the body's two types of immune cells: innate immune cells (which usually mount a short, generalized attack) and adaptive immune cells (which mount a highly directed and sustained attack against a specific invader).

This hypothesis is based on the researchers' recent finding that certain innate immune cells, called "Natural Killer" (NK) T cells, are present and functioning in the blood of glioma patients. In laboratory studies, these innate NKT cells can destroy certain glioma molecules that are present both in the tumors and in the blood vessels that supply them. Now the investigators want to determine whether they can modify dendritic cells in the laboratory to stimulate both the innate NKT cells and the adaptive immune system's T cells to attack these glioma molecules.

First, the investigators will obtain blood samples from glioma patients and determine whether their NKT cells are able to be expanded in the laboratory to respond to this specific glioma molecule. Then the investigators will conduct laboratory studies to determine how best to acquaint dendritic cells with glioma antigens, so that the dendritic cells can instruct immune T cells to recognize and attack the antigens. Finally, the researchers will undertake preliminary laboratory experiments to test whether the combined presence of innate NKT cells and instructed T cells leads to enhanced killing of tumor cells. If so, this will pave the way for future efforts to see if patients' immune cells, once enhanced in the laboratory, can be re-introduced into their bodies to mount a strong, coordinated attack against glioma.

ABSTRACT

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Targeting of Innate and Adaptive Immunity Against Human Glioma via Dendritic Cells

The prognosis for patients with brain tumors remains poor with current modalities of treatment. Brain tumors are the leading cause of cancer related mortality and morbidity in children. Newer approaches for therapy of these tumors are urgently needed. Dendritic cells (DCs), nature's adjuvant, are potent antigen presenting cells. DCs are central to initiating and regulating both the innate and the adaptive immunity. In prior studies, we have shown that DCs can efficiently activate both T and natural killer T (NKT cells) in culture.

Our hypothesis is that recruiting both innate and adaptive lymphocytes is essential for optimal immunity to brain tumors in patients. In Specific Aim 1, we will characterize the nature of spontaneous NKT cell responses in patients with glioma using a panel of functional assays, including expression of cytokines in response to antigenic stimulation. We will also examine the ability of NKT cells to infiltrate tumor tissue, and correlate this with the expression of chemokine receptors. Specific Aim 2 of the proposal builds upon our prior studies targeting tumor antigens via Fc receptors on DCs. We will focus on optimizing antigen presentation by antigen loaded DCs using either antibody coated dying glioma cells or tumor derived RNA.

Finally, in Specific Aim 3, we will merge these approaches and test the synergy between tumor specific T and NKT cells to mediate anti-glioma effects. Our long term goal is to identify optimal approaches to recruit the host immune system to resist these tumors.

INVESTIGATOR BIOGRAPHIES

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Kavita Dhodapkar, M.D.

Kavita Dhodapkar, M.D. ,is currently a Clinical Scholar at the Rockefeller University in New York City. She also has a joint faculty appointment in Pediatric Hematology-Oncology at the New York University. She received her medical degree from Seth G.S. Medical College in Bombay, India, followed by a pediatric residency at the Mayo Clinic. She completed her oncology fellowship training at St. Jude Children's Hospital and the New York University, before joining Rockefeller.

Her research is focused on studying the interactions between immune cells and brain tumors and developing novel approaches to boost immunity to these tumors in patients.

SELECTED PUBLICATIONS

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Dhodapkar K.M., Banerjee D., Connolly J., Kukreja A., Matayeva E., Veri M.C., Ravetch J.V., Steinman R.M., and Dhodapkar M.V.  Selective blockade of the inhibitory Fcgamma receptor (FcgammaRIIB) in human dendritic cells and monocytes induces a type I interferon response program.   J Exp Med. 2007 Jun 11;204(6):1359-69.

Banerjee D., Matthews P., Matayeva E., Kaufman J.L., Steinman R.M., and Dhodapkar K.M.   Enhanced T-cell responses to glioma cells coated with the anti-EGF receptor antibody and targeted to activating FcgammaRs on human dendritic cells.  J Immunother. 2008 Feb-Mar;31(2):113-20.