Monoclonal Antibodies Are Effective in Treating Some Tumors

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Monoclonal antibodies have been used in various ways as experimental immunotherapeutic agents for cancer. For example, anti-idiotype monoclonal antibodies have been used with some success in treating human B-cell lymphomas and T-cell leukemias. In one remarkable study, R. Levy and his colleagues successfully treated a 64-year-old man with terminal B-cell lymphoma. At the time of treatment, the lymphoma had metastasized to the liver, spleen, bone marrow, and peripheral blood. Because this was a B-cell cancer, the membrane-bound antibody on all the cancerous cells had the same idiotype. By the procedure outlined in Figure 22-14, these researchers produced mouse monoclonal antibody specific for the B-lymphoma idiotype. When this mouse monoclonal anti-idiotype antibody was injected into the patient, it bound specifically to the B-lymphoma cells, because these cells expressed that particular idiotype. Since B-lymphoma cells are susceptible to complement-mediated lysis, the monoclonal antibody activated the complement system and lysed the lymphoma cells without harming other cells. After four injections with this anti-idiotype monoclonal antibody, the tumors began to shrink, and this patient entered an unusually long period of complete remission.

However, this approach requires that a custom monoclonal antibody be raised for each lymphoma patient. This is prohibitively expensive and cannot be used as a general therapeutic approach for the thousands of patients diagnosed each year with B lymphoma. Recently, Levy and his colleagues have used direct immunization to recruit the immune systems of patients to an attack against their B lymphoma. In a clinical trial with 41 B-cell lymphoma patients, the genes encoding the rearranged immunoglobulin genes of the lymphomas of each patient were isolated and used to encode the synthesis of recombinant immunoglobulin that bore the idiotype typical of the patient's tumor. Each of these Igs was coupled to keyhole limpet hemocyanin (KLH), a mollusk protein that is often used as a carrier protein because of its efficient recruitment of T-cell help. The patients were immunized with their own tumor-specific antigens, the idiotypically unique immuno-globulins produced by their own lymphomas. About 50% of the patients developed anti-idiotype antibodies against their tumors. Significantly, improved clinical outcomes were seen in the 20 patients with anti-idiotype responses, but not in the others. In fact, 2 of these 20 experienced complete remission.

Despite its promise, the anti-idiotypic approach is by its very nature patient-specific. A more general monoclonal-antibody therapy for B-cell lymphoma is based on the fact that most B cells, whether normal or cancerous, bear lineage-distinctive antigens. One such determinant, CD20, has been the target of intensive efforts; a monoclonal antibody to it, raised in mice and engineered to contain mostly human sequences, has been useful in the treatment of B-cell lymphoma (see Clinical Focus, Chapter 5). Aside from CD20, a number of tumor-associated antigens (Table 22-4) are being tested in clinical trials for their suitability as targets for antibody-mediated anti-tumor therapy.

A variety of tumors express significantly increased levels of growth-factor receptors, which are promising targets for anti-tumor monoclonal antibodies. For example, in 25 to 30 percent of women with metastatic breast cancer, a genetic alteration of the tumor cells results in the increased expression of HER2, an epidermal-growth-factor-like receptor. An anti-HER2 monoclonal antibody was raised in mice and the genes encoding it were isolated. Except for the sequences encoding the antibody's CDRs, the mouse Ig sequences were replaced with human Ig counterparts. This prevents the generation of human anti-mouse antibodies (HAMAs) and allows the patient to receive repeated doses of the "humanized" anti-HER2 in large amounts (100 milligrams or more). Preparations of this antibody, called Herceptin, are now commercially available for the treatment of HER2-receptor-bearing breast cancers (see Clinical Focus, Chapter 5). Monoclonal antibodies also have been used to prepare tumor-

Humanized Anti Her2 Antibody

B-lymphoma cells Human myeloma cell

Inject anti-idiotype Ab-2 into patient

B-lymphoma Ab +

B-lymphoma Ab +

B-lymphoma cells Human myeloma cell

Fuse and select for hybridoma secreting B-lymphoma Ab

Fuse and select for hybridoma secreting B-lymphoma Ab

Inject anti-idiotype Ab-2 into patient

B-lymphoma monoclonal Ab (Ab-1)

Spleen cells + Mouse myeloma cells Fuse SteP ©

Secreted Ab-2 to Ab -1 idiotype

Anti-idiotype hybridomas

B-lymphoma monoclonal Ab (Ab-1)

Anti-idiotype hybridomas

Secreted Ab to Ab-1 isotype Anti-isotype hybridomas

Selection: binds to Normal human Ig +

Monoclonal Ab-1 +

FIGURE 22-14

Treatment of B-cell lymphoma with monoclonal antibody specific for idiotypic determinants on the cancer cells. Because all the lymphoma cells are derived from a single transformed B cell, they all express membrane-bound antibody (Ab-1) with the same idiotype (i.e., the same antigenic specificity). In the procedure illustrated, monoclonal anti-idiotype antibody (Ab-2) against the B-lymphoma membrane-bound antibody was produced (steps 1-4). When this anti-idiotype antibody was injected into the patient (step 5), it bound selectively to B-lymphoma cells, which then were susceptible to complement-plus-antibody lysis.

specific anti-tumor agents. In this approach, antibodies to tumor-specific or tumor-associated antigens are coupled with radioactive isotopes, chemotherapy drugs, or potent toxins of biological origin. In such "guided missile" therapies, the toxic agents are delivered specifically to tumor cells. This focuses the toxic effects on the tumor and spares normal tissues. Reagents known as immunotoxins have been constructed by coupling the inhibitor chain of a toxin (e.g., diphtheria toxin) to an antibody against a tumor-specific or tumor-associated antigen (see Figure 4-23). In vitro studies have demonstrated that these "magic bullets" can kill tumor cells without harming normal cells. Immunotoxins specific for tumor antigens in a variety of cancers (e.g., melanoma, col-orectal carcinoma, metastatic breast carcinoma, and various lymphomas and leukemias) have been evaluated in phase I or phase II clinical trials. In a number of trials, significant numbers of leukemia and lymphoma patients exhibited partial or complete remission. However in a number of cases, the clinical responses in patients with larger tumor masses were disap-

pointing. In some of these patients, the sheer size of the tumor may render most of its cells inaccessible to the immunotoxin.

SUMMARY

■ Tumor cells differ from normal cells in numerous ways. In particular, changes in the regulation of growth of tumor cells allow them to proliferate indefinitely, then invade the underlying tissue, and eventually metastasize to other tissues (see Figure 22-1). Normal cells can be transformed in vitro by chemical and physical carcinogens and by transforming viruses. Transformed cells exhibit altered growth properties and are sometimes capable of inducing cancer when they are injected into animals.

■ Proto-oncogenes encode proteins involved in control of normal cellular growth. The conversion of proto-oncogenes to oncogenes is one of the key steps in the induction of most human cancer. This conversion may result from mutation in

TABLE 22-4

Some tumor-associated antigens under examination as potential targets for monoclonal-antibody therapy

TABLE 22-4

Some tumor-associated antigens under examination as potential targets for monoclonal-antibody therapy

Tumor antigen

Tumor type

Target antigen

LYMPHOID CELL-SURFACE MARKERS

T-cell marker

T-cell leukemia/lymphoma

CD5

B-cell marker

B-cell lymphoma

CD20

Hematopoietic-cell marker

Acute myeloblastic leukemia

CD45

Anti-idiotype

B-cell lymphoma

Immunoglobulin

NONLYMPHOID TISSUE MARKERS

Cell-surface antigens

Carcinoembryonic antigen (CEA)

Colon cancer (some others)

Glycoprotein

MUC1

Breast cancer

Glycoprotein

Gangliosides such as GD2 and GD3

Neuroectodermal tumors

Glycolipids associated with neural tissue

Growth-factor receptors

Epidermal growth-factor receptor (EGFR)

Some lung, head, neck, and breast tumors

EGF-binding cell surface protein

HER2 (and EFG-like receptor)

Breast and ovarian tumors

Cell-surface EGF-binding protein

with homology to EGFR

SOURCE: Adapted from Scott and Welt, 1997, Curr. Opin. Immunol. 9:717.

an oncogene, its translocation, or its amplification (see Figure 22-2).

■ A number of B- and T-cell leukemias and lymphomas are associated with translocated proto-oncogenes. In its new site, the translocated gene may come under the influence of enhancers or promoters that cause its transcription at higher levels than usual (see Figure 22-5).

■ Tumor cells display tumor-specific antigens and the more common tumor-associated antigens. Among the latter are oncofetal antigens, (see Table 22-3) and increased levels of normal oncogene products (see Figure 22-6). In contrast to tumor antigens induced by chemicals or radiation, virally encoded tumor antigens are shared by all tumors induced by the same virus.

■ The tumor antigens recognized by T cells fall into one of four major categories: antigens encoded by genes with tumor-specific expression; antigens encoded by variant forms of normal genes that have been altered by mutation; certain antigens normally expressed only at certain stages of differentiation or differentiation lineages; antigens that are overexpressed in particular tumors.

■ The use of a variety of genetic, biochemical, and immuno-logical approaches has allowed the identification of several tumor-associated antigens (see Table 22-4). In many cases the antigen is expressed on more than one type of tumor.

Common tumor antigens offer hope for the design of better therapies, detection, and monitoring, and have important implications for the possibility of anti-tumor immunization.

■ The immune response to tumors includes CTL-mediated lysis, NK-cell activity, macrophage-mediated tumor destruction, and destruction mediated by ADCC. Several cytotoxic factors, including TNF-a and TNF-p, help to mediate tumor-cell killing. Tumors may evade the immune response by modulating their tumor antigens, by reducing their expression of class I MHC molecules, and by antibody-mediated or immune complex-mediated inhibition of CTL activity.

■ Experimental cancer immunotherapy is exploring a variety of approaches. Some of these are the enhancement of the co-stimulatory signal required for T-cell activation (see Figure 22-11a), genetically engineering tumor cells to secrete cytokines that may increase the intensity of the immune response against them (see Figure 22-11b), the therapeutic use of cytokines (see Figure 22-12), and ways of increasing the activity of antigen-presenting cells.

■ A number of encouraging clinical results have been obtained with therapy using monoclonal antibodies against tumor-associated and (in a few cases) tumor-specific antigens (see Figure 22-14). Coupling of antibodies against

Tumor-associated and tumor-specific antigen peptides recognized by human T cells

Human tumor

Protein

Peptide

Many melanomas, esophageal carcinomas, non small-cell lung carcinomas and hepatocellular carcinomas Melanoma

Colon cancer

Breast and ovarian cancer

Head and neck squamous-cell carcinoma

Chronic myeloid leukemia

Prostatic cancer

MAGE-1

Tyrosinase

Carcinoembryonic antigen (CEA)

HER2/NEU

Caspase 8

bcr-abl fusion protein (product of a fusion of an Ig gene with the ablgene)

EADPTGHSY and SAYGEPRKL

MLLAVLYCL, YMNGTMSQV, YMDGTMSQV, and others YLSGANLNL KIFGSLAFL FPSDSWCYF ATGFKQSSKALQRPVAS

FLTPKKKLQCV and VISNDVCAQV

SOURCE: Adapted from B. Van Den Eynde and P. van der Bruggen, 1996, Curr. Opin. Immunol. 9:684.

tumor antigens with toxins, chemotherapeutic agents, or radioactive elements is being examined. The expectation is that such strategies will focus the toxic effects of these agents on the tumor and spare normal cells their deleterious effects.

■ Key elements in the design of strategies for vaccination against cancer are the identification of significant tumor antigens by genetic or biochemical approaches; the development of strategies for the effective presentation of tumor antigens; and the generation of activated populations of helper or cytotoxic T cells.

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