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May2010 Immunotherapy of Malignant Gliomas Using Autologous And Anti-Cancer Agents in Medicinal Chemistry, 2010, 10, 000-000 1 Immunotherapy of Malignant Gliomas Using Autologous and Allogeneic Tissue Cells F.M. Hofman1,*, A. Stathopoulos2, C.A. Kruse3, T.C. Chen4 and V.E.J.C. Schijns5,* 1Departments of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, California, USA; 2Dept. of Neurosurgery, Arlon Hospital, Arlon, Belgium; 3Sanford-Burnham Medical Research Institute, Joan S. Holmes Memorial Biothera- peutics Research Laboratory, La Jolla, CA 92037, USA; 4Department of Neurosurgery, University of Southern California, Keck School of Medicine, Los Angeles, California, USA; and 5Cell Biology & Immunology Group, Wageningen University, PO Box 338, 6700 AH Wageningen, The Netherlands Abstract: Immunotherapy of brain tumors is rapidly emerging as a potential clinical option [1-3]. The quality and magnitude of immune responses evoked by the new generation anti-tumor vaccines is in general highly dependent on the source or choice of peptide antigens, and as well, a suitable immunopotentiator. Poorly immunogenic antigens, such as those present in tumor cell lysates, may not reliably provide stimulation like recombinant or DNA-encoded protein antigens might be expected to. In addition, the efficacy of the vaccine may depend on inherent counteracting measures of the tumor which dampen immune surveillance and immune effector activity triggered by immunization [4]. Our body has many means of limiting an immune response to our own (self) proteins. In particular, patients with glio- mas exhibit a broad suppression of cell-mediated immunity [5-8]. Unfortunately, for most tumor vaccines the induction of local or sys- temic immune effector cells does not necessarily translate into objective clinical responses or increased survival [9]. Here we review im- munotherapeutic approaches against gliomas and recent pre-clinical and clinical initiatives based on cellular or active immunization of the patient’s immune system using autologous and allogeneic tissues or cultured cells. Available evidence shows that single modality cancer therapies likely remain suboptimal. Combination regimens targeting the immune system at multiple coordinated levels must be developed, and possibly combined with strategies to inhibit immune suppressive factors if significant clinical benefit is to be achieved. Keywords: Astrocytoma, allogeneic, biotherapy, brain tumor, CTL, glioma, immunotherapy, immunization. INTRODUCTION THE LONG ROAD TO CURRENT GLIOMA THERAPEU- Glioblastoma multiforme (GBM) is the most common and TIC VACCINE APPROACHES malignant of all gliomas, with 75% of patients dying within 18 The first report on cancer therapy dates from the Edwin Smith months of diagnosis. Brain tumors are graded according to their Papyrus, 1600 B.C., the oldest known historical text on surgery. It likely rate of growth, from grade I (benign) to grade IV (most ma- mentions primitive surgical excision of a tumor using a knife. It has lignant), with grades III and IV considered high-grade gliomas. only been for the past two hundred years that surgical excision be- Grade IV glioma is also known as glioblastoma multiforme (GBM). came established as the preferred option for treating solid tumors. The prognosis for patients with this tumor is very poor. Glioblas- Radiation therapy was introduced shortly after 1895, when Roent- toma overall survival rates are less than 3.3% at 5 years [10]. In the gen first reported the use of x-rays for diagnostic medical purposes, United States alone over 18,000 primary brain tumors are estimated and remained a primary treatment option of certain tumors, espe- to occur each year. Of these 18,000, over 60% are diagnosed cially solid tumors. Today radiation therapy can be tailored to the gliomas. The median survival time of untreated GBM tumors is 3 irregular shape of the tumor, allowing a reduction of intensity. Dur- months, with death most commonly due to cerebral edema or ing World War I, exposure of soldiers to nitrogen mustard gases increased intracranial pressure. Even with the best available current resulted in pancytopenia. This observation triggered interest for therapy, which includes surgery, radiation, and chemotherapy, the chemotherapeutic therapy, especially in patients with hematologic median survival time is 14.6 months [11]. Due to their highly malignancies. Today chemotherapy is a well documented treatment infiltrative nature complete surgical resection is difficult. These option. For glioblastomas, the alkylating agent temozolomide has tumors are, therefore, inevitably recurrent either locally, usually become a well-appreciated option [12]. within 2 cm of the original tumor, or at distant sites. Treatment of About one hundred years ago William B. Coley, an early 20th these recurrent lesions by a second surgery and further century New York City surgeon, observed that some of his patients chemotherapy may increase the symptom free interval, but the 5- with sarcoma would undergo spontaneous regression of their tumor year survival remains 10%. The present review discusses various and that this regression was associated with antecedent bacterial typical immunotherapeutic strategies in a comprehensive way, with infection (erysipelas, or streptococcus pyogenes in the first patient) a focus on active therapeutic immune intervention. All these which eliminated malignant cells [13, 14]. He intentionally injected therapies will serve as additions to, rather than a replacement of cancer patients with a mixture of killed bacterial lysates, later current medical practice. Due to many examples it is impossible to called Coley's Toxins, to stimulate a cytokine storm. William Coley cover all preclinical approaches and past or ongoing clinical trials. thus became the godfather of cancer immunotherapy [15]. He was We will, therefore, address only the most promising or remarkable the first to recognize the potential role of the immune system in strategies, but omission from or inclusion into this review should cancer treatment. Activation of the patient’s immune system to not be interpreted as rejection or support of a particular approach; better recognize the tumor and to eliminate invasive tumor cells that they are examples. We propose that immune adjuvant therapies are not adequately removed by surgery will be discussed in greater need to be explored to improve median or overall survival. detail. This area in cancer therapy is based on knowledge accumu- lated in the vaccine and immunology fields. *Address correspondence to these authors at the Departments of Pathology, Immunization attempts for glioma patients date back to the University of Southern California, Keck School of Medicine, Los Angeles, early 1960s [16]. Two investigative teams hypothesized that brain California, USA; Tel: 323-442-1153; E-mail: [email protected] and Cell tumors were hidden from the immune system because of location in Biology & Immunology Group, Wageningen University, PO Box 338, 6700 the central nervous system. To ensure that immune cells located AH Wageningen, The Netherlands; Tel: +31(0)317-483922; systemically could “see” the tumor, they placed autologous glioma E-mail: [email protected] cells into the thighs of patients. The vaccines given into the thighs 1871-5206/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd. 2 Anti-Cancer Agents in Medicinal Chemistry, 2010, Vol. 10, No. 6 Hofman et al. actually started growing there and metastasized to regional nodes that were not consistently encouraging [26]. A further variant of [16, 17]. Ten years later, Bloom and colleagues administered irradi- this approach included genetic manipulation of such ex vivo isolated ated, whole autologous tumor cell vaccines. Again, there was no cells by the introduction of immunostimulatory transgenes [27]. effect, but the results may well have been different had they used an Tumor Associated Antigens (TAAs) adjuvant, such as that used by Trouillas and Lapras [18] who im- munized 20 patients with autologous tumor and Freund’s complete One important step in producing a therapeutic vaccine is the adjuvant. These early attempts at active immunotherapy had obsta- identification of appropriate glioma-associated antigens. Limited cles consisting of potentially radiation resistant cells, and the ab- knowledge of molecularly defined antigens explains why initial sences of, or inappropriate, immune adjuvant. Degrees of sophisti- approaches used tumor lysates derived from autologous irradiated cation in vaccine development have occurred in the past 50 years; glioma cells as the source of tumor antigens. This approach war- and at last the benefits of active immunotherapy are finally docu- rants specific activation of the immune response against a broad set mented. of potential tumor associated antigens, which may enhance immune therapy but may also result in immune reactions against unwanted KEY CONSIDERATIONS FOR DEVELOPMENT OF IM- antigens [28]. Glioma associated, rather than glioma specific, ap- MUNOTHERAPY APPROACHES pears to be the more correct terminology since the antigens appear Tumor Directed Immune Responses to be present at very low levels on normal brain cells, but overex- Distinct from classical preventive vaccines, which mostly re- pressed on glioma cells. Importantly, for the majority of studies no quire the generation of antibodies, the goal of most therapeutic evidence of adverse autoimmunity was noted after such immuniza- GBM vaccines is to stimulate tumor-specific cytotoxic T cells tions. The premise was
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