187-2017

capecitabine (XELOX) and are generally treated for 6 months following surgical resection. Treatment with this combination regimen reduces the recurrence rate after surgery by 35% and clearly improves overall patient survival compared with surgery alone.

Significant advances have been made over the past 10 years with respect to treatment of metastatic CRC. Five active cytotoxic agents have been approved during this time period—5-FU, the oral fluoropyrimidine analogs capecitabine and TAS-102, oxaliplatin, and irinotecan. In addition, 5 novel biologic agents and one small molecule inhibitor have been approved, including the anti-VEGF antibody bevacizumab; the recombinant fusion protein ziv-aflibercept, which targets VEGF-A, VEGF-B, and PlGF; the anti-VEGF-R2 antibody ramucirumab, which inhibits binding of the VEGF ligands VEGF-A, VEGF-C, and VEGF-D; the two anti-EGFR antibodies cetuximab and panitumumab; and the small molecule TKI inhibitor regorafenib. In general, a fluoropy- rimidine—either intravenous 5-FU or oral capecitabine—serves as the main foundation of cytotoxic chemotherapy regimens. Recent clinical studies have shown that in tumors with wild-type KRAS and NRAS, FOLFOX/FOLFIRI regimens in combination with the anti-VEGF antibody bevacizumab or with the antiEGFR antibody cetuximab or panitumumab result in significantly improved clinical efficacy with no worsening of the toxicities normally observed with chemotherapy. In order for patients to derive maximal benefit, they should be treated with each of these active agents in a continuum of care approach. Regorafenib and TAS102 are approved for the chemo-refractory disease setting, but unfortunately, each drug is associated with significant toxicities and only limited clinical efficacy with very low overall response rates; median progression-free survival is about 2-months. Given all of the available treatment regimens, median overall survival for metastatic CRC is now in the 28to 30-month range and, in some cases, approaches or even exceeds 3 years.

The incidence of gastric cancer, esophageal cancer, and pancreatic cancer is much lower than for CRC, but these malignancies tend to be more aggressive and result in greater tumor-related symptoms. In most cases, they cannot be completely resected surgically, as most patients present with either locally advanced or metastatic disease at the time of their initial diagnosis. 5-FU-based chemotherapy, using either intravenous 5-FU or oral capecitabine, is generally considered the main backbone for regimens targeting gastroesophageal cancers. In addition, cisplatin-based regimens in combination with either irinotecan or one of the taxanes (paclitaxel or docetaxel) also exhibit clinical activity. Response rates in the 40–50% range are now being reported. The addition of the biologic agent trastuzumab to cisplatin-containing chemotherapy regimens provides significant clinical benefit in metastatic gastric cancer patients whose tumors overexpress the HER-2/neu receptor. At present, the optimal fluoropyrimidine backbone has not been established, and either infused 5-FU or oral capecitabine can be combined with cisplatin plus trastuzumab. For secondline therapy, the combination of ramucirumab plus paclitaxel is recommended for patients with a good performance status and favorable comorbidity profile. In patients who are unable to tolerate more intensive therapy, single-agent ramucirumab or paclitaxel monotherapy are more appropriate treatment options.

Although gemcitabine is approved for use as a single agent in metastatic pancreatic cancer, the overall response rate is low at less than 10%, with complete responses being exceedingly rare. Intense efforts have focused on incorporating gemcitabine into various combination regimens, and currently, the most commonly used regimen for the first-line treatment of metastatic pancreatic cancer is gemcitabine plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel [Abraxane]). In patients who are able to tolerate a more aggressive approach, the FOLFIRINOX regimen, which includes intravenous 5-FU, irinotecan, and oxaliplatin, has become a widely used therapy. Single-agent irinotecan or liposomal irinotecan in combination with intravenous 5-FU are appropriate treatment options in the second-line setting. In patients with early-stage pancreatic cancer who have undergone successful surgical resection, adjuvant chemotherapy with either single-agent gemcitabine or 5-FU/leucovorin is recommended.

Hepatocellular cancer (HCC) has been a relatively difficult tumor to treat as it frequently occurs in the context of chronic liver disease and cirrhosis. It is usually diagnosed late in the course of chronic liver disease, and a large majority of patients have underlying poor liver function and only limited hepatic reserve. In general, HCC is considered to be a chemotherapy-resistant disease, and palliative chemotherapy is usually not recommended as first-line therapy in patients with unresectable or advanced HCC. Single-agent sorafenib therapy is currently approved for advanced or unresectable HCC, and in patients who have progressed on front-line sorafenib therapy, the small molecule tyrosine kinase inhibitor regorafenib is recommended.

LUNG CANCERS

Lung cancer is divided into two main histopathologic subtypes, non-small cell and small cell. Non-small cell lung cancer (NSCLC) makes up about 75–80% of all cases of lung cancer, and this group includes adenocarcinoma, squamous cell cancer, and large cell cancer, while small cell lung cancer (SCLC) makes up the remaining 20–25%. When NSCLC is diagnosed in an advanced stage with metastatic disease, the prognosis is extremely poor, with a median survival of about 8 months. It is clear that prevention (primarily through avoidance of cigarette smoking) and early detection remain the most important means of control. When diagnosed at an early stage, surgical resection results in patient cure. Moreover, recent studies have shown that adjuvant platinum-based chemotherapy provides a survival benefit in patients with pathologic stage IB, II, and IIIA disease. However, in most cases, distant metastases have occurred at the time of diagnosis. In certain instances, radiation therapy can be offered for palliation of pain, airway obstruction, or bleeding and to treat patients whose performance status would not allow for more aggressive treatments.

In patients with advanced disease, systemic chemotherapy is generally recommended. Combination regimens that include a platinum agent (“platinum doublets”) appear superior to non-platinum doublets, and either cisplatin or carboplatin are appropriate platinum agents for such regimens. For the second drug, paclitaxel and vinorelbine appear to have activity

independent of histology, while the antifolate pemetrexed should be used for non-squamous cell cancer, and gemcitabine for squamous cell cancer. For patients with good performance status and those with non-squamous histology, the combination of the antiVEGF antibody bevacizumab with carboplatin and paclitaxel is a standard treatment option. In patients deemed not to be appropriate candidates for bevacizumab therapy and those with squamous cell histology, a platinum-based chemotherapy regimen in combination with the anti-EGFR antibody cetuximab is a reasonable treatment strategy. Maintenance chemotherapy with pemetrexed is now used in patients with non-squamous NSCLC whose disease has remained stable after four cycles of platinum-based first-line chemotherapy.

Patients with advanced NSCLC should have molecular testing of their tumor. Patients whose tumors contain an actionable mutation should then receive a targeted therapy. For example, first-line therapy with erlotinib significantly improves outcomes in advanced NSCLC patients with sensitizing EGFR mutations, which include exon 19 deletions or exon 21 (L858R) substitution mutations. Afatinib is a small molecule inhibitor of EGFR, HER2, and HER4, and it is approved for the first-line treatment of metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 mutations. Osimertinib is approved for the treatment of metastatic EGFR T790M-mutant NSCLC following progression on or after EGFR TKI therapy. This small molecule is important as it is able to overcome the resistance that arises from the emergence of the T790M gatekeeper mutation either de novo or following previous EGFR TKI therapy. In NSCLC that is ALK-positive, three new small molecules have been developed: crizotinib, ceritinib, and alectinib. Crizotinib is the first-generation ALK inhibitor, while ceritinib and alectinib have clinical efficacy in patients whose disease has progressed on or who have become intolerant to crizotinib.

Squamous cell NSCLC makes up approximately 30% of NSCLC. This form of NSCLC is responsive to platinum-based chemotherapy with either cisplatin or carboplatin in combination with gemcitabine. Recent studies have shown superior clinical activity when cisplatin and gemcitabine are combined with the anti-EGFR antibody necitumumab when compared to the cisplatin-gemcitabine combination in the first-line treatment of metastatic disease. In 2015, the immune checkpoint inhibitor nivolumab was approved to treat metastatic squamous cell NSCLC whose cancer has progressed during or after standard platinum-based chemotherapy. This agent binds to the PD-1 receptor and inhibits the PD-1 immune signaling pathway, which then leads to activation and proliferation of T cells as well as inhibition of T-regulatory cells.

Small cell lung cancer is the most aggressive form of lung cancer. It is usually exquisitely sensitive, at least initially, to platinumbased combination regimens, including cisplatin and etoposide or cisplatin and irinotecan. Unfortunately, drug resistance eventually develops in nearly all patients with extensive disease. When diagnosed at an early stage, this disease is potentially curable using combined chemotherapy and radiation therapy. Topotecan is used as second-line monotherapy in patients who have failed a platinum-based regimen.

OVARIAN CANCER

In the majority of patients, ovarian cancer remains occult and becomes symptomatic only after it has already metastasized to the peritoneal cavity. At this stage, it usually presents with malignant ascites. It is important to accurately stage this cancer with laparoscopy, ultrasound, and CT scanning. Patients with stage I disease appear to benefit from whole-abdomen radiotherapy and may receive additional benefit from combination chemotherapy with cisplatin and cyclophosphamide.

Combination chemotherapy is the standard approach to stage III and stage IV disease. Randomized clinical studies have shown that the combination of paclitaxel and cisplatin provides survival benefit compared with the previous standard combination of cisplatin plus cyclophosphamide. More recently, carboplatin plus paclitaxel has become the treatment of choice. In patients who present with recurrent disease, topotecan, altretamine, or liposomal doxorubicin are used as single-agent monotherapy.

TESTICULAR CANCER

The introduction of platinum-based combination chemotherapy has made an impressive change in the treatment of patients with advanced testicular cancer. Presently, chemotherapy is recommended for patients with stage IIC or stage III seminomas and nonseminomatous disease. Over 90% of patients respond to chemotherapy and, depending upon the extent and severity of disease, complete remissions are observed in 70–80% of patients. More than 50% of patients achieving complete remission are cured with chemotherapy. In patients with good risk features, three cycles of cisplatin, etoposide, and bleomycin (PEB protocol) or four cycles of cisplatin and etoposide yield virtually identical results. In patients with high-risk disease, the combination of cisplatin, etoposide, and ifosfamide can be used as well as etoposide and bleomycin with high-dose cisplatin.

MALIGNANT MELANOMA

Malignant melanoma is curable with surgical resection when it presents locally (see also Chapter 61). However, once metastasis has occurred, it is one of the most difficult cancers to treat because of drug resistance. While dacarbazine, temozolomide, and cisplatin are the most active cytotoxic agents for this disease, the overall response rates to these agents remain low. Biologic agents, including IFN-α and interleukin 2 (IL-2), have greater activity than traditional cytotoxic agents, and treatment with high-dose IL-2 has led to cures, albeit in a relatively small subset of patients. Ipilimumab binds to cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), which is expressed on the surface of activated CD4 and CD8 T-cells. CTLA-4 normally acts as a brake on T-cell antitumor activity. Binding of ipilimumab results in inhibition of the interaction between CTLA-4 and its target ligands CD80/CD86 and thus enhances T-cell immune responses, which include T-cell activation and proliferation. This agent is approved for the treatment of metastatic melanoma. More recently, ipilimumab is recommended as adjuvant therapy for cutaneous melanoma following complete surgical resection, with treatment for up to 3 years.

Nivolumab and pembrolizumab are IgG4 antibodies that bind to the programmed death (PD)-1 receptor, which is expressed on T cells, and they inhibit the interaction between the programmed death ligand 1 (PD-L1) and ligand 2 (PD-L2) and the PD-1 receptor. The PD-1 signaling pathway mediates an immune escape mechanism, and inhibition of this pathway enhances T-cell immune response, leading to T cell activation and proliferation. Each of these agents is approved for unresectable or metastatic melanoma as monotherapy. In addition, nivolumab is also approved in combination with ipilimumab for BRAF V600 mutation–positive unresectable or metastatic melanoma.

The BRAF V600E mutation has been identified in the large majority of melanomas. This mutation results in constitutive activation of BRAF kinase, which then leads to activation of downstream signaling pathways involved in cell growth and proliferation. Two oral and highly selective small molecule inhibitors of BRAF V600E are approved for metastatic melanoma: vemurafenib and dabrafenib. Studies are ongoing to determine their activity in combination with other cytotoxic and biologic agents for metastatic melanoma as well as their potential role in the adjuvant and neoadjuvant therapy of early stage melanoma.

Trametinib and cobimetinib are reversible inhibitors of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and kinase 2 (MEK2), and in combination with a BRAF inhibitor molecule, they are approved for patients with metastatic melanoma whose tumors express the BRAF V600E or V600K mutation. While these agents have clinical activity as monotherapies, clinical studies suggest that the most promising clinical activity is seen when they are used in combination with a BRAF inhibitor.

BRAIN CANCER

In general, chemotherapy has had only limited efficacy in the treatment of malignant gliomas. Because of their ability to cross the blood-brain barrier, the nitrosoureas have historically been the most active agents in this disease. Carmustine (BCNU) has been used as a single agent, or lomustine (CCNU) can be used in

combination with procarbazine and vincristine (PCV regimen). In addition, the alkylating agent temozolomide is active when combined with radiotherapy and is also used in patients with newly diagnosed glioblastoma multiforme (GBM) as well as in those with recurrent disease. The histopathologic subtype oligodendroglioma has been shown to be especially chemosensitive, and the PCV combination regimen is the treatment of choice for this disease. It is now well-established that the anti-VEGF antibody bevacizumab alone or in combination with chemotherapy has documented clinical activity in adult GBM. Bevacizumab is presently approved as a single agent for adult GBM in the setting of progressive disease following first-line chemotherapy.

SECONDARY MALIGNANCIES & CANCER CHEMOTHERAPY

The development of secondary malignancies is a late complication of the alkylating agents and the epipodophyllotoxin etoposide. For both drug classes, the most frequent secondary malignancy is acute myelogenous leukemia (AML). AML develops in up to 15% of patients with Hodgkin’s lymphoma who have received radiotherapy plus MOPP chemotherapy and in patients with multiple myeloma, ovarian carcinoma, or breast carcinoma treated with melphalan. The increased risk of AML is observed as early as 2–4 years after the initiation of chemotherapy and typically peaks at 5 and 9 years. With improvements in the clinical efficacy of various combination chemotherapy regimens resulting in prolonged survival and in some cases actual cure of cancer, the issue of how second cancers may affect long-term survival assumes greater importance. Certain alkylating agents (eg, cyclophosphamide) may be less carcinogenic than others (eg, melphalan). In addition to AML, other secondary malignancies have been well-described, including non-Hodgkin’s lymphoma and bladder cancer, the latter most typically associated with cyclophosphamide therapy. Etoposide can give rise to an 11:23 translocation, which has been associated with the development of the M4 and M5 AML histologic subtypes.

REFERENCES

Books &Monographs

Abeloff MD et al: Clinical Oncology, 5th ed. Elsevier, 2014.

Barakat RR et al: Principles and Practice of Gynecologic Oncology, 5th ed. Lippincott Williams & Wilkins, 2009.

Chabner BA, Longo DL: Cancer Chemotherapy and Biotherapy: Principles and Practice, 5th ed. Lippincott Williams & Wilkins, 2011.

Chu E, DeVita VT Jr: Cancer Chemotherapy Drug Manual 2017, 17th ed. Jones & Bartlett.

DeVita VT Jr, Hellman S, Rosenberg SA: Cancer: Principles and Practice of Oncology, 10th ed. Lippincott Williams & Wilkins, 2015.

Harris JR et al: Diseases of the Breast, 4th ed. Lippincott Williams & Wilkins, 2009. Hoppe R et al: Textbook of Radiation Oncology, 3rd ed. Elsevier, 2010.

Kantoff PW et al: Prostate Cancer: Principles and Practice. Lippincott Williams & Wilkins, 2001.

Kelsen DP et al: Gastrointestinal Oncology: Principles and Practices, 2nd ed. Lippincott Williams & Wilkins, 2007.

Kufe D et al: Cancer Medicine, 7th ed. BC Decker, 2006.

Mendelsohn J et al: The Molecular Basis of Cancer, 3rd ed. Saunders, 2008.

Pass HI et al: Principles and Practice of Lung Cancer: The Official Reference Text of the International Association for the Study of Lung Cancer (IASLC), 4th ed. Lippincott Williams & Wilkins, 2010.

Pizzo PA, Poplack AG: Principles and Practice of Pediatric Oncology, 6th ed. Lippincott Williams & Wilkins, 2010.

Weinberg RA: Biology of Cancer, 2nd ed. Taylor & Francis, 2013.

Articles& Reviews

DeVita VT, Chu E:The history of cancer chemotherapy. Cancer Res 2008;68:8643.

Redmond KM et al: Resistance mechanisms to cancer chemotherapy. Front Biosci 2008;13:5138.

C A S E S T U D Y A N S W E R

The 5-year survival rate for patients with high-risk stage III CRC is on the order of 25–30%. Because the patient has no symptoms after surgery and has no comorbid illnesses, he would be an appropriate candidate to receive aggressive adjuvant chemotherapy. Adjuvant chemotherapy is usually begun 4–6 weeks after surgery to allow sufficient time for the surgical wound to heal. The usual recommendation would be to administer 6 months of oxaliplatin-based chemotherapy using either intravenous 5-FU or oral capecitabine as the fluoropyrimidine base in combination with oxaliplatin.

Patients with partial or complete deficiency in the enzyme dihydropyrimidine dehydrogenase (DPD) experience an increased incidence of severe toxicity to fluoropyrimidines in the form of myelosuppression, gastrointestinal

toxicity in the form of mucositis and diarrhea, and neurotoxicity. This is an autosomal recessive pharmacogenetic syndrome that is present in up to 10% of the North American population (see Chapter 5). Although mutations in DPD can be identified in peripheral blood mononuclear cells, nearly 50% of patients who exhibit severe 5-FU toxicity do not have a defined mutation in the DPDgene. In addition, such mutations may not result in reduced expression of the DPD protein or in altered enzymatic activity. For this reason, genetic testing is not recommended at this time as part of routine clinical practice. There is now an immunoassay that can measure 5-FU drug levels in the peripheral blood that can help guide 5-FU dosing even in patients with DPD deficiency.

C A S E S T U D Y

A 45-year-old man with high-risk acute myelogenous leukemia undergoes high-dose chemotherapy followed by an allogeneic stem cell transplant from an unrelated donor. He receives tacrolimus and low-dose methotrexate as prophylaxis for graft-vs-host disease. One month after blood count

Agents that suppress the immune system play an important role in preventing the rejection of organ or tissue grafts and in the treatment of certain diseases that arise from dysregulation of the immune response. While precise details of the mechanisms of action of a number of these agents are still obscure, knowledge of the elements of the immune system is useful in understanding their effects. Agents that augment the immune response or selectively alter the balance of various components of the immune system are also becoming important in the management of certain diseases such as cancer, AIDS, and autoimmune or inflammatory diseases. A growing number of other conditions (infections, cardiovascular diseases, organ transplantation) are also areas for immune manipulation.

■ ELEMENTS OF THE IMMUNE SYSTEM

NORMAL IMMUNE RESPONSES

The immune system has evolved to protect the host from invading pathogens and to eliminate disease. When functioning at its best, the immune system is exquisitely responsive to invading pathogens while retaining the capacity to recognize self tissues and antigens to which it is tolerant. Protection from infection and disease is provided by the collaborative efforts of the innate and adaptive immune systems.

recovery, he develops a skin rash despite ongoing tacrolimus therapy. A skin biopsy confirms grade II acute graft-vs-host disease. How should this case be pharmacologically managed at this point?

The Innate Immune System

The innate immune system is the first line of defense against invading pathogens (eg, bacteria, viruses, fungi, parasites) and consists of mechanical, biochemical, and cellular components. Mechanical components include skin/epidermis and mucus; biochemical components include antimicrobial peptides and proteins (eg, defensins), complement, enzymes (eg, lysozyme, acid hydrolases), interferons, acidic pH, and free radicals (eg, hydrogen peroxide, superoxide anions); cellular components include neutrophils, monocytes, macrophages, natural killer (NK) cells, and natural killer-T (NKT) cells. Unlike adaptive immunity, the innate immune response exists prior to infection, is not enhanced by repeated infection, and is generally not antigen-specific. An intact skin or mucosa is the first barrier to infection. When this barrier is breached, an immediate innate immune response, referred to as “inflammation,” is provoked and ultimately leads to destruction of the pathogen. The process of pathogen destruction can be accomplished, for example, by biochemical components such as lysozyme (which breaks down bacterial peptidoglycan cell walls) and complement activation. Complement components (Figure 55–1) enhance macrophage and neutrophil phagocytosis by acting as opsonins (C3b) and chemoattractants (C3a, C5a), which recruit immune cells from the bloodstream to the site of infection. The activation of complement eventually leads to pathogen lysis via the generation of a membrane attack complex that creates holes in the pathogen membrane, killing it. Although the complement cascade helps

eliminate invading pathogens from the host, in some individuals with complement inhibitor deficiency, complement may lyse host red blood cells and cause a disease called paroxysmal nocturnal hemoglobinuria (PNH). These patients can be treated with a monoclonal antibody (Mab) that binds the C5 component of complement (see Mab section below), disrupting the lytic cascade. Patients taking a C5 inhibitor are at risk of life-threatening meningococcal infections.

During the inflammatory response triggered by infection, neutrophils and monocytes enter the tissue sites from the peripheral circulation. This cellular influx is mediated by the action of chemoattractant cytokines (chemokines) (eg, inter- leukin-8 [IL-8; CXCL8], macrophage chemotactic protein-1 [MCP-1; CCL2], and macrophage inflammatory protein-1α [MIP-1α; CCL3]) released from activated endothelial cells and immune cells (mostly tissue macrophages) at the inflammatory site. Egress of the immune cells from blood vessels into the inflammatory site is mediated by adhesive interactions between cell surface receptors (eg, -selectin, integrins) on the immune cells and ligands (eg, sialyl-Lewis x, intercellular

adhesion molecule-1 [ICAM-1]) on the activated endothelial cell surface. The tissue macrophages as well as dendritic cells express pattern recognition receptors (PRRs) that include Toll-like receptors (TLRs), nucleotide-binding oligomerization domain-like receptors (NLRs), scavenger receptors, mannose receptors, and lipopolysaccharide (LPS)-binding protein, which recognize key evolutionarily conserved pathogen components referred to as pathogen-associated molecular patterns (PAMPs). Examples of PAMPs include microbe-derived unmethylated CpG DNA, flagellin, double-stranded RNA, peptidoglycan, and LPS. The PRRs recognize PAMPs in various components of pathogens and stimulate the release of proinflammatory cytokines, chemokines, and interferons. If the innate immune response is successfully executed, the invading pathogen is ingested, degraded, and eliminated, and disease is either prevented or is of short duration.

In addition to monocytes and neutrophils, natural killer (NK), natural killer-T (NKT), and gamma-delta T (fc T) cells recruited to the inflammatory site contribute to the innate response by secreting interferon-gamma (IFN-γ) and

A C R O N Y M S

interleukin-17 (IL-17), which activate resident tissue macrophages and dendritic cells and recruit neutrophils, respectively, to successfully eliminate invading pathogens. NK cells are so called because they are able to recognize and destroy virus-infected normal cells as well as tumor cells without prior stimulation. This activity is regulated by “killer cell immunoglobulin-like receptors” (KIRs) on the NK cell surface that are specific for major histocompatibility complex (MHC) class I molecules. When NK cells bind self MHC class I proteins (expressed on all nucleated cells), these receptors deliver inhibitory signals, preventing them from killing normal host cells. Tumor cells or virus-infected cells that have downregulated MHC class I expression do not engage these KIRs, resulting in activation of NK cells and subsequent destruction of the target cell. NK cells kill target cells by releasing cytotoxic granules such as perforins and granzymes that induce programmed cell death.

NKT cells express T-cell receptors as well as receptors commonly found on NK cells. NKT cells recognize microbial lipid antigens presented by a unique class of MHC-like molecules

Interferons and interleukins are cytokines, which are discussed later in this chapter.

known as CD1 and have been implicated in host defense against microbial agents, autoimmune diseases, and tumors.

The Adaptive Immune System

The adaptive immune system is mobilized by cues from the innate response when the innate processes are incapable of coping with an infection. The adaptive immune system has a number of characteristics that contribute to its success in eliminating pathogens. These include the ability to (1) respond to a variety of antigens, each in a specific manner; (2) discriminate between foreign (“nonself”) antigens (pathogens) and self antigens of the host; and

(3) respond to a previously encountered antigen in a learned way by initiating a vigorous memory response. This adaptive response culminates in the production of antibodies, which are the effectors of humoral immunity; and the activation of T lymphocytes, which are the effectors of cell-mediated immunity.

The induction of specific adaptive immunity requires the participation of professional antigen-presenting cells (APCs), which include dendritic cells (DCs), macrophages, and B lymphocytes. These cells play pivotal roles in the induction of an adaptive immune response because of their capacity to phagocytize particulate antigens (eg, pathogens) or endocytose protein antigens, and enzymatically digest them to generate peptides, which are then loaded onto class I or class II MHC proteins and “presented” to the cell surface T-cell receptor (TCR) (Figure 55–2). CD8 T cells recognize class I–MHC peptide complexes while CD4 T cells recognize class II–MHC peptide complexes. At least two signals are necessary for the activation of T cells. The first signal is delivered following engagement of the TCR with peptide-bound MHC molecules. In the absence of a second signal, the T cells become

FIGURE 55 2 T-cell activation by an antigen-presenting cell requires engagement of the T-cell receptor by the MHC-peptide complex (signal 1) and binding of the costimulatory molecules (CD80, CD86) on the dendritic cell to CD28 on the T cell (signal 2). The activation signals are strengthened by CD40/CD40L and ICAM-1/ LFA-1 interactions. In a normal immune response, T-cell activation is regulated by T-cell–derived CTLA-4 and PD-1. CTLA-4 binds to CD80 or CD86 with higher affinity than CD28 and sends inhibitory signals to the nucleus of the T cell, while ligation of PD-1 by PD-L1 or -L2 also inhibits T cell proliferation.

unresponsive (anergic) or undergo apoptosis. The second signal involves binding of costimulatory molecules (CD40, CD80 [also known as B7-1], and CD86 [also known as B7-2]) on the APC to their respective ligands (CD40L for CD40, CD28 for CD80 or CD86). Activation of T cells is regulated via a negative feedback loop involving another molecule known as T-lymphocyte– associated antigen 4 (CTLA-4). Following engagement of CD28 with CD80 or CD86, CTLA-4 in the cytoplasm is mobilized to the cell surface where, because of its higher affinity of binding to CD80 and CD86, it outcompetes or displaces CD28 resulting in suppression of T-cell activation and proliferation. This property of CTLA-4 has been exploited as a strategy for sustaining a desirable immune response such as that directed against cancer. A recombinant humanized antibody (ipilimumab) that binds CTLA-4 prevents its association with CD80/CD86. In so doing, the activated state of T cells is sustained. Programmed cell death protein-1 (PD-1) is another negative regulator of T cells. Ligation of PD-1 with its ligands (PD-L1 or PD-L2) suppresses T-cell activity. Like CTLA-4, Mabs have been developed to block the interaction of PD-1 with PD-L1, having the effect of sustained T cell activation. Mabs to CTLA-4 and PD-1/PD-L1 are immune checkpoint inhibitors. They have been associated in some patients with the development of autoimmune toxicity that subsides upon discontinuation of Mab therapy.

T lymphocytes develop and learn to recognize self and non-self antigens in the thymus; those T cells that bind with high affinity to self antigens in the thymus undergo apoptosis (negative selection), while those that are capable of recognizing foreign antigens in the presence of self MHC molecules are retained and expanded (positive selection) for export to the periphery (lymph nodes, spleen, mucosa-associated lymphoid tissue, peripheral blood), where they become activated after encountering MHC-presented peptides (Figures 55–2 and 55–3).

Studies using murine T-cell clones have demonstrated the presence of two subsets of T helper lymphocytes (T 1 and T 2) based on the cytokines they secrete after activation. The T 1 subset characteristically produces IFN-γ, IL-2, and IL-12 and induces cell-mediated immunity by activation of macrophages, cytotoxic T cells (CTLs), and NK cells. The T 2 subset produces IL-4, IL-5, IL-6, and IL-10 (and sometimes IL-13), which induce B-cell proliferation and differentiation into antibody-secreting plasma cells. IL-10 produced by T 2 cells inhibits cytokine production by T 1 cells via the downregulation of MHC expression by APCs. Conversely, IFN-γ produced by T 1 cells inhibits the proliferation of T 2 cells (Figure 55–3). Although these subsets have been well described in vitro, the nature of the antigenic challenge that elicits a T 1 or T 2 phenotype is less clear. Extracellular bacteria typically cause the elaboration of T 2 cytokines, culminating in the production of neutralizing or opsonic antibodies. In contrast, intracellular organisms (eg, mycobacteria) elicit the production of T 1 cytokines, which lead to the activation of effector cells such as macrophages.

Another subset of CD4 T cells that secrete IL-17 (T 17) is important in leukocyte recruitment to sites of bacterial and fungal pathogens. T 17 cells also contribute to the pathogenesis of autoimmune diseases such as psoriasis, inflammatory bowel

disease, rheumatoid arthritis, and multiple sclerosis. In fact, new Mabs for some of these diseases that neutralize IL-17 by binding to the cytokine itself or to its receptor (see Mab section below) have recently been FDA-approved.

Regulatory T (Treg) cells constitute a population of CD4 T cells that is essential for preventing autoimmunity and allergy as well as maintaining homeostasis and tolerance to self antigens. This cell population exists as natural Treg (nTreg), derived directly from the thymus, and induced (adaptive) Treg (iTreg), generated from naïve CD4 T cells in the periphery. Both populations have also been shown to inhibit antitumor immune responses and are implicated in fostering tumor growth and progression. Recent attempts to distinguish both populations have resulted in the discovery of a transcription factor, Helios, in nTreg but not in iTreg cells.

CD8 T lymphocytes recognize endogenously processed peptides presented by virus-infected cells or tumor cells. These peptides are usually nine-amino-acid fragments derived from virus or protein tumor antigens in the cytoplasm and are loaded onto MHC class I molecules (Figure 55–2) in the endoplasmic reticulum. In contrast, class II MHC molecules present peptides (usually 11–22 amino acids) derived from extracellular (exogenous) pathogens to CD4 T helper cells. In some instances, exogenous antigens, upon ingestion by APCs, can be presented on class I MHC molecules to CD8 T cells. This phenomenon, referred to as “cross-presentation,” involves retro-translocation of antigens from the endosome to the cytosol for peptide generation in the proteosome and is thought to be useful in generating effective immune responses against infected host cells that are incapable of priming T lymphocytes. Upon activation, CD8 T cells induce target cell death via lytic granule enzymes (“granzymes”), perforin, and the Fas-Fas ligand (Fas-FasL) apoptosis pathways.

B lymphocytes undergo selection in the bone marrow, during which self-reactive B lymphocytes are clonally deleted while B-cell clones specific for foreign antigens are retained and expanded. The repertoire of antigen specificities by T cells is genetically determined and arises from T-cell receptor gene rearrangement while the specificities of B cells arise from immunoglobulin gene rearrangement; for both types of cells, these determinations occur prior to encounters with antigen. Upon an encounter with antigen, a mature B cell binds the antigen, internalizes and processes it, and presents its peptide—bound to class II MHC—to CD4 helper cells, which in turn secrete IL-4 and IL-5. These interleukins stimulate B-cell proliferation and differentiation into memory B cells and antibody-secreting plasma cells. The primary antibody response consists mostly of IgM-class immunoglobulins. Subsequent antigenic stimulation results in a vigorous “booster” response accompanied by class (isotype) switching to produce IgG, IgA, and IgE antibodies with diverse effector functions (Figure 55–3). These antibodies also undergo affinity maturation, which allows them to bind more efficiently to the antigen. With the passage of time, this results in accelerated elimination of microorganisms in subsequent infections. Antibodies mediate their functions by acting as opsonins to enhance phagocytosis and cellular cytotoxicity and by activating complement to elicit an inflammatory response and induce bacterial lysis (Figure 55–4).

ABNORMAL IMMUNE RESPONSES

Whereas the normally functioning immune response can successfully neutralize toxins, inactivate viruses, destroy transformed cells, and eliminate pathogens, inappropriate responses can lead to extensive tissue damage (hypersensitivity) or reactivity against self antigens (autoimmunity); conversely, impaired reactivity to appropriate targets (immunodeficiency) may occur and abrogate essential defense mechanisms.

Hypersensitivity

Hypersensitivity can be classified as antibody-mediated or cellmediated. Three types of hypersensitivity are antibody-mediated (types I–III), while the fourth is cell-mediated (type IV). Hypersensitivity occurs in two phases: the sensitization phase and the effector phase. Sensitization occurs upon initial encounter with an antigen; the effector phase involves immunologic memory and results in tissue pathology upon a subsequent encounter with that antigen.

Epitope

Macrophage

Complement activation

Bacterial lysis

1.Type I—Immediate, or type I, hypersensitivity is IgE-mediated, with symptoms usually occurring within minutes following the patient’s reencounter with antigen. Type I hypersensitivity results from cross-linking of membrane-bound IgE on blood basophils or tissue mast cells by antigen. This cross-linking causes cells to degranulate, releasing substances such as histamine, leukotrienes, and eosinophil chemotactic factor, which induce anaphylaxis, asthma, hay fever, or urticaria (hives) in affected individuals (Figure 55–5). A severe type I hypersensitivity reaction such as systemic anaphylaxis (eg, from insect envenomation, ingestion of certain foods, or drug hypersensitivity) requires immediate medical intervention.

2.Type II—Type II hypersensitivity results from the formation of antigen-antibody complexes between foreign antigen and IgM or

IgG immunoglobulins. One example of this type of hypersensitivity is a blood transfusion reaction that can occur if blood is not cross-matched properly. Preformed antibodies bind to red blood cell membrane antigens that activate the complement cascade, generating a membrane attack complex that lyses the transfused red blood cells. In hemolytic disease of the newborn, anti-Rh IgG antibodies produced by an Rh-negative mother cross the placenta, bind to red blood cells of an Rh-positive fetus, and damage them. The disease is prevented in subsequent pregnancies by the administration of anti-Rh antibodies to the mother 24–48 hours after delivery (see Immunosuppressive Antibodies, below). Type II hypersensitivity can also be drug-induced and may occur during the administration of penicillin (for example) to allergic patients. In these patients, penicillin binds to red blood cells or other host