Chapter 16. Immunotherapy
Philip J. Bergman
The term immunity is derived from the Latin word immunitas , which refers to the legal protection afforded to Roman senators holding office. Although the immune system is normally thought of as providing protection against infectious disease, the immune system’s ability to recognize and eliminate cancer is the fundamental rationale for the immunotherapy of cancer. Multiple lines of evidence support a role for the immune system in managing cancer, including: (1) spontaneous remissions in cancer patients without treatment, (2) the presence of tumor-specific cytotoxic T-cells within tumor or draining lymph nodes, (3) the presence of monocytic, lymphocytic, and plasmacytic cellular infiltrates in tumors, (4) the increased incidence of some types of cancer in immunosuppressed patients, and (5) documentation of cancer remissions with the use of immunomodulators. 1 With the tools of molecular biology and a greater understanding of mechanisms to harness the immune system, effective tumor immunotherapy is becoming a reality. This new class of therapeutics offers a more targeted and therefore precise approach to the treatment of cancer. It is extremely likely that immunotherapy will have a place alongside the classic cancer treatment triad components of surgery, radiation therapy, and chemotherapy within the next 5 to 10 years.
TUMOR IMMUNOLOGY
Cellular Components
The immune system is generally divided into two primary components: the innate immune response , and the highly specific, but more slowly developing adaptive or acquired immune response ( Figure 16-1 , A ). Innate immunity is rapidly acting but typically not very specific and includes physico-chemical barriers (e.g., skin and mucosa); blood proteins such as complement, phagocytic cells (macrophages, neutrophils, dendritic cells [DCs], and natural killer [NK] cells); and cytokines that coordinate and regulate the cells involved in innate immunity. Adaptive immunity is thought of as the acquired arm of immunity that allows for exquisite specificity, an ability to remember the previous existence of the pathogen and differentiate self from non-self, and importantly the ability to respond more vigorously upon repeat exposure to the pathogen. Adaptive immunity consists of T and B cells. The T cells are further divided into CD8 (cluster of differentiation) and MHC (major histocompatibility complex) Class I cytotoxic T lymphocytes (CTL) and helper T cells (CD4 and MHC class II), NK cells, and regulatory T cells. B cells produce antibodies (humoral system) that may activate complement, enhance phagocytosis of opsonized target cells, and induce antibody dependent cellular cytotoxicity (ADCC). B-cell responses to tumors are thought by many investigators to be less important than the development of T-cell mediated immunity, but there is little evidence to fully support this notion. 2 The innate and adaptive arms of immunity are not mutually exclusive; they are linked by (1) the innate response’s ability to stimulate and influence the nature of the adaptive response, and (2) the sharing of effector mechanisms between innate and adaptive immune responses.
Immune responses can be further separated by whether they are induced by exposure to a foreign antigen (an “active” response) or if they are transferred through serum or lymphocytes from an immunized individual (a “passive” response). Although both approaches have the ability to be extremely specific for an antigen of interest, one important difference is the inability of passive approaches to confer memory. The principal components of the active/adaptive immune system are lymphocytes, antigen-presenting cells, and effector cells. Furthermore, responses can be subdivided by whether they are specific for a certain antigen, or a non-specific response whereby immunity is attempted to be conferred by up-regulating the immune system without a specific target. These definitions are helpful because they allow methodologies to be more completely characterized, such as active-specific, active-nonspecific, passive-nonspecific, etc.
Immune Surveillance
The idea that the immune system may actively prevent the development of neoplasia is termed cancer immunosurveillance . Sound scientific evidence supports some aspects of this hypothesis, 3,4 including: (1) IFN-γ protects mice against the growth of tumors, (2) mice lacking IFN-γ receptor were more sensitive to chemically induced sarcomas than normal mice and were more likely to spontaneously develop tumors, (3) mice lacking major components of the adaptive immune response (T and B cells) have a high rate of spontaneous tumors, and (4) mice that lack IFN-γ and B or T cells develop tumors, especially at a young age.
Immune Evasion by Tumors
There are significant barriers to the generation of effective anti-tumor immunity by the host. Many tumors evade surveillance mechanisms and grow in immunocompetent hosts as is easily illustrated by the overwhelming numbers of people and animals succumbing to cancer. There are multiple ways in which tumors evade the immune response including those noted in Box 16-1 .
BOX 16-1
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METHODS BY WHICH TUMORS MAY EVADE THE IMMUNE RESPONSE
1. Immunosuppressive cytokine production
• Examples: TGF-β and IL-10 5,6
2. Impaired DC function
• Via inactivation (“anergy”)
• Via poor DC maturation through changes in IL-6/IL-10/VEGF/GM-CSF 7
3. Induction of cells called regulatory T cells (Treg)
• Treg cells were initially called suppressor T cells and are CD4/CD25/CTLA-4/GITR/Foxp3-positive cells that can suppress tumor-specific CD4/CD8+ T cells 8
4. MHC I loss
• Structural defect in MHC I
• Changes in B2-microglobulin synthesis
• Defects in transporter-associated antigen processing
• Actual MHC I gene loss (i.e., allelic or locus loss)
5. MHC I antigen presentation loss through B7-1 attenuation
• B7-1 is an important co-stimulatory molecule for CD28-mediated T-cell receptor and MHC engagement when the MHC system in no. 4 remains intact.
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