- Email: [email protected]
Immunotherapy of brain tumors
Handbook of Clinical Neurology, Vol. 104 (3rd series) Neuro-oncology W. Grisold and R. Soffietti, Editors # 2012 Elsevier B.V. All rights reserved
Chapter 20
Immunotherapy of brain tumors DEANA MARSHALL,1 DUANE A. MITCHELL,2 MICHAEL W. GRANER,3* AND DARELL D. BIGNER3 1 North Carolina State University, Raleigh, NC, USA 2
Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC, USA 3
Department of Pathology, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA
CELLULAR IMMUNOTHERAPY IN THE TREATMENT OF MALIGNANT GLIOMA The appeal of immunotherapy for the treatment of malignant disease is conceptually entrenched with the immune system’s ability to recognize and eradicate target cells with both specificity and efficiency without modification of normal cells. The body is sophisticated enough to not only recognize foreign pathogens such as viruses, but also to respond with a sufficient amount of humoral and cellular effectors to manage the infection and eliminate a majority of the infected cells from the body. Tumor immunologists have hoped to exploit this stunning cytotoxic capacity for use against malignant cancer cells. Despite aggressive multimodality therapy, including surgery, chemotherapy, and radiation therapy, patients diagnosed with glioblastoma multiforme (GBM), the most aggressive and unfortunately most common type of adult brain tumor, have a median survival of less than 1 year (Davis and McCarthy, 2000). Added to the burden of this poor prognosis for patients diagnosed with high-grade brain tumors are the debilitating cognitive and motor deficits that the patients often experience while receiving the standard treatments for this disease. The development of more effective and specific therapies, such as immunotherapy, for the treatment of brain tumors is a high priority for clinicians and patients who deal with this fatal disease. Complicating this effort, however, is that high-grade malignant brain tumors, unlike other malignant diseases, receive assistance from the central nervous system (CNS). Further,
there are concerns about autoimmunity, which presents a distinctive challenge in tumor immunotherapy. The focus of research in tumor immunotherapy has moved beyond a debate as to whether tumors expose antigens that can be recognized and targeted by the immune system. It is no longer questionable whether the immune system is capable of effectively eradicating malignant tumor cells, at least in experimental cancer models. Classic transplantation models were first used to examine the issue of whether the immune system was capable of responding against tumor antigens. These models demonstrated that chemically induced tumors contain antigens that can initiate the specific recognition and rejection of tumors in immunocompetent mice (Foley, 1953; Baldwin, 1955). Although chemically induced tumor cell lines demonstrated the capacity of the immune system to mediate tumor rejection, their strong immunogenic properties did not closely parallel the rather nonimmunogenic nature of most human tumors. It was later shown, in more relevant tumor models, that even the less immunogenic or nonimmunogenic tumor cell lines expressed antigens that could be recognized by the immune system (van der Bruggen et al., 1991; Wu et al., 1991). The first human tumor antigens were discovered in malignant melanoma through the notable efforts of van der Bruggen et al. (1991) and Boon and colleagues (1994). Beyond this moment, the identification of tumor antigens and the developmental approaches to the immunological treatment of cancer quickly transpired. The goals of current research are to continue to identify new antigens in tumors, to understand how tumors
*Correspondence to: Michael W. Graner, PhD, Department of Pathology, Box 3156, 177 MSRB1, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710 USA. Tel: 919-684-4187, Fax: 919-681-8337, E-mail: michael. [email protected]
Chapter 20
Immunotherapy of brain tumors DEANA MARSHALL,1 DUANE A. MITCHELL,2 MICHAEL W. GRANER,3* AND DARELL D. BIGNER3 1 North Carolina State University, Raleigh, NC, USA 2
Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC, USA 3
Department of Pathology, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA
CELLULAR IMMUNOTHERAPY IN THE TREATMENT OF MALIGNANT GLIOMA The appeal of immunotherapy for the treatment of malignant disease is conceptually entrenched with the immune system’s ability to recognize and eradicate target cells with both specificity and efficiency without modification of normal cells. The body is sophisticated enough to not only recognize foreign pathogens such as viruses, but also to respond with a sufficient amount of humoral and cellular effectors to manage the infection and eliminate a majority of the infected cells from the body. Tumor immunologists have hoped to exploit this stunning cytotoxic capacity for use against malignant cancer cells. Despite aggressive multimodality therapy, including surgery, chemotherapy, and radiation therapy, patients diagnosed with glioblastoma multiforme (GBM), the most aggressive and unfortunately most common type of adult brain tumor, have a median survival of less than 1 year (Davis and McCarthy, 2000). Added to the burden of this poor prognosis for patients diagnosed with high-grade brain tumors are the debilitating cognitive and motor deficits that the patients often experience while receiving the standard treatments for this disease. The development of more effective and specific therapies, such as immunotherapy, for the treatment of brain tumors is a high priority for clinicians and patients who deal with this fatal disease. Complicating this effort, however, is that high-grade malignant brain tumors, unlike other malignant diseases, receive assistance from the central nervous system (CNS). Further,
there are concerns about autoimmunity, which presents a distinctive challenge in tumor immunotherapy. The focus of research in tumor immunotherapy has moved beyond a debate as to whether tumors expose antigens that can be recognized and targeted by the immune system. It is no longer questionable whether the immune system is capable of effectively eradicating malignant tumor cells, at least in experimental cancer models. Classic transplantation models were first used to examine the issue of whether the immune system was capable of responding against tumor antigens. These models demonstrated that chemically induced tumors contain antigens that can initiate the specific recognition and rejection of tumors in immunocompetent mice (Foley, 1953; Baldwin, 1955). Although chemically induced tumor cell lines demonstrated the capacity of the immune system to mediate tumor rejection, their strong immunogenic properties did not closely parallel the rather nonimmunogenic nature of most human tumors. It was later shown, in more relevant tumor models, that even the less immunogenic or nonimmunogenic tumor cell lines expressed antigens that could be recognized by the immune system (van der Bruggen et al., 1991; Wu et al., 1991). The first human tumor antigens were discovered in malignant melanoma through the notable efforts of van der Bruggen et al. (1991) and Boon and colleagues (1994). Beyond this moment, the identification of tumor antigens and the developmental approaches to the immunological treatment of cancer quickly transpired. The goals of current research are to continue to identify new antigens in tumors, to understand how tumors
*Correspondence to: Michael W. Graner, PhD, Department of Pathology, Box 3156, 177 MSRB1, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710 USA. Tel: 919-684-4187, Fax: 919-681-8337, E-mail: michael. [email protected]