Immunotherapy, Tumor Immunology & Complementary Therapy: Prahlad Parajuli, PhD
Dr. Parajuli's Neuro-oncology/Immunology laboratory focuses on developing novel adjuvant therapeutic strategies by combining immunotherapy and complementary/alternative approaches for the treatment of malignant gliomas.
Malignant gliomas are one of the most aggressive and lethal solid tumors with a high rate of invasion into normal brain tissue. Each year, more than 18,000 people are diagnosed with this deadly disease in the USA. The median survival rate remains a dismal 12 months, in spite of aggressive surgical and chemotherapeutic interventions.
Immunotherapy using tumor-antigen loaded dendritic cells (DC) has the potential to specifically target and eradicate the invasive tumor cells without affecting the surrounding normal brain tissue. Studies on immunotherapy mostly focus on activation of cytolytic T lymphocytes (CTL) for targeting tumor cells bearing specific antigens with MHC class I molecules.
However, malignant tumors often circumvent an immune attack by both passive and active mechanisms. One of the ways malignant tumors evade immune attack is by lowering the expression of MHC class I molecules. Novel DC-based vaccine strategies for activation of natural killer-T (NK-T) cells along with CTLs are being developed in order to effectively target all tumor cells irrespective of the level of MHC class I expression. In this context, studies on elucidation of molecular mechanisms of NK-T cell activation and tumor cytolysis are also being pursued. The laboratory is also actively collaborating with Dr. Sandeep Mittal and Dr. Lawrence Lum in developing a Phase I/II clinical immunotherapeutic strategy using bi-specific antibodies.
Most malignant gliomas maintain constitutively high TGF-Î² activity, which is pivotal in modulating cell-mediated immune response either by directly inhibiting DC and CTL activities, or via generation and/or expansion of regulatory T (Treg) cells. Studies are being conducted to combine immunotherapy with administration of a novel herbal product derived from a traditional medicinal plant Scutellaria sp, which significantly inhibits the secretion of TGF-Î² in malignant gliomas. The phytochemical composition of the herbal product and their molecular mechanisms of anti-glioma/anti-TGF-Î² activity are being studied. Potential adjuvant therapy of gliomas with the herbal product in combination with the alkylating agent temozolomide is also being explored.
|Mechanisms of immune suppression by malignant tumors |
Malignant tumors can directly induce Treg cell or T-DC activity via elaboration of several membrane-bound or secreted cytokines/factors. Treg cells and T-DC can also modulate each other via similar cytokine interactions. These suppressor cells or mediators, in turn, inhibit cytolytic functions of effector T cells (CTLs) or NK cells. TGF-Î², which is expressed in both membrane-bound and soluble forms, can be very critical in most of these interactions.
CTL: Cytotoxic T lymphocyte; DC: Dendritic cell; NK: Natural killer; PGE2: Prostaglandin E2; T-DC: Tolerogenic/suppressor DC; TGF: Transforming growth factor; Treg: Regulatory T cells.
Parajuli P, Mathupala SM, Mittal S, Sloan, AE. Dendritic cell-based active specific immunotherapy for malignant glioma. Expert Opinion on Biological Therapy, 7:439-48, 2007.
Resident/Research Associate/Student participants:
The following students have participated in various aspects of the research projects in the lab for partial fulfillment of their residency/graduate/undergraduate school requirements:
- Vaninder Chabra, M.D., Neurosurgery Resident (2004-2005)
- Pingyang Yu, M.D., Research Associate (2004-2006)
- Sean Quinlan-Davidson, Medical Student (2003 summer)
- Mavis Twum, Medical Student (2009 summer)
- Snigdha Hota (2006-2007)
- John Purakal (2007-2008)
- Marco P. Centi (2008-2009)
- Khari Wilson (2003 summer)
- Jeffery Kallas (2005-2007, part-time)
- Johnny Fells (2008 summer)
- Linford Williams (2009 summer)
- Vasuki Nittoor (2009 summer)
- Ajay Gopalakrishna (2009-2010, part time)
- Paras Patel (2009-2010, part time)
- Mouli Mandalaparty (2009-2010, part time)
- Sandeep Mittal, M.D., Professor and Chair, Department of Neurosurgery, Wayne State University School of Medicine, and Chief, Neuro-oncology, Karmanos Cancer Institute, Detroit, MI.
- Sree Chinni, Ph.D., Assistant Professor, Departments of Urology and Pathology, Wayne State University School of Medicine, Detroit, MI.
- Nirmal Joshee, Ph.D., Assistant Professor, Fort Valley State University, Fort Valley, GA.
- Anand K. Yadav, Ph.D., Professor, Fort Valley State University, Fort Valley, GA.
- Agnes Rimando, Ph.D., Natural Products Utilization Research Unit, USDA, University, MS.
- Andrew, E. Sloan, M.D., Associate Professor, Department of Neurosurgery, Case Western Reserve University Medical School, Cleveland, OH.
- Judith Abrams, Director, Integrated Biostatistics Unit, Wayne State University School of Medicine, Detroit, MI.
- Laboratory for Education Research and Learning in Neurosciences (LEARN) Foundation of Michigan, (Role: PI) 2002-2004.
- USDA-CRES (Role: Collaborator, PI on sub-contract), 2003-2007
- Fund for Medical Research and Education (FMRE), Wayne State University School of Medicine (Role PI) 2004-2008
- USDA-CRES (Role: Co-PI), 2008-2011