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4 Personalized Cancer Vaccines Florentina Teofilovici and Kerry Wentworth Antigenics Inc., Lexington, Massachusetts, U.S.A. THERAPEUTIC CANCER VACCINES VS. TRADITIONAL CANCER TREATMENT Traditional cancer drugs are cytotoxic agents, meaning that they kill cells. Although most chemotherapeutics preferentially affect rapidly dividing cells (i.e., cancer cells), they cannot differentiate between malignant and normal cells. The unavoidable toxicity to normal cells often results in treatment-related toxicities such as increased susceptibility to bleeding and infection, mucositis, nausea and vomiting, hair loss, etc. This nonspecific approach to cancer treatment makes it more suitable for use in disease settings in which the tumor burden is high, such as advanced or metastatic disease. Therapeutic cancer vaccines belong to a newer class of targeted cancer therapies. Like innovative treatments such as Gleevec 1 (imatinib mesylate; Novartis, New Jersey, U.S.) and Herceptin 1 (trastuzumab; Genentech, California, U.S.), most cancer vaccines in development are designed to attack only malignant cells. By targeting tumor cells with high specificity, this new class of treatments tends to be associated with fewer toxicities compared with traditional cancer drugs. The discovery that cancer regression can be achieved when antigens (substances capable of triggering immune response) on malignant cells are recognized by the immune system means that, theoretically, malignant cells can be eradicated without toxicity to normal, healthy tissues. 69
70 Teofilovici and Wentworth In 1908, Paul Ehrlich and Ilya Mechnikov were awarded the Nobel Prize for their hypothesis of the immune surveillance theory of cancer, which suggested that the immune system continually “removes” tumors that arise spontaneously (1). Their theories lay largely dormant until it was noticed a half century later that Kaposi’s sarcoma occurred in kidney transplant recipients whose immune systems were pharmacologically suppressed to allow their transplanted organ to “take.” Once immunosuppression was stopped, the tumors regressed (2–5). At this time, Klein et al. demonstrated the phenomenon that one could immunize against tumors in the same manner as was being performed with remarkable success against polio and smallpox viruses (6,7). It was known that although tumors are of self-origin (in contrast with viruses), they are still capable of triggering an immune response. From this observation, researchers correctly predicted that tumors must express tumor-specific antigens that are responsible for triggering this response. Burnett also suggested that transplantation antigens expressed on tumor cells could stimulate the immune system, leading to the generation of “protective” immunity that prevented against tumor development (8,9). Recently, use of a new generation of mice with deficient immune systems has solidified the crucial role of the immune system in protecting against spontaneous tumors (10). The increased risk of cancers in patients with medically induced primary or acquired immunosuppression has firmly established a role for the immune system in the control of cancer (11). The tumors observed in medically immunosuppressed organ transplant patients are similar to cancers seen in individuals infected with human immunodeficiency virus (HIV). HIV patients have a 10,000-fold increased risk of developing blood cancers as well as a significantly higher incidence of other cancers (11,12). However, similar to immunosuppression-induced cancers in transplant recipients, cancers often regress when an HIV patient’s immune system is restored using highly active antiretroviral therapy (13–15). The clear demonstration of a relationship between the immune system and cancer has led to the development of many therapeutic cancer vaccines. PERSONALIZED CANCER VACCINES Despite the varied approaches employed by the many therapeutic cancer vaccines in development, they all share one fundamental goal: to program a patient’s immune system to attack the patient’s cancer. Some vaccines utilize antigens (any substance capable of stimulating an immune response) that are known to be associated with certain types of tumors. In recent years, there was an increased interest on so-called unique antigens that are products of random mutations arising in the course of tumor cells’ uncontrolled cell divisions. This led researchers’ interest and work on personalized (autologous) cancer vaccines that use the patients’ own tumor cells to generate immune response specific to the
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Translational Medicine Series 6 Can
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TRANSLATIONAL MEDICINE SERIES 1. Pr
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Informa Healthcare USA, Inc. 52 Van
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Preface Throughout the last 20 year
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Preface vii Table 1 A Diverse Techn
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Preface . . . . v Contributors . .
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Contributors Pedro Alves Ludwig Ins
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1 Factoring in Antigen Processing i
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7 Multimodality Immunization Approa
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Multimodality Immunization Approach
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Figure 8.5 A schematic representati
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8 Bidirectional Bedside Lab Bench P
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Development of Novel Immunotherapeu
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Diagnostic Approaches to Maximize T
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206 Index Antigenic peptides degrad
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208 Index Chromogens, enzymatic act
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210 Index Freund’s adjuvants. See
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212 Index Langerhans cells, 133, 13
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214 Index [Peptide vaccines] invest
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216 Index TCRL. See TCR-like immuno
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Oncology and Immunology about the b
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