Tumour immunology

The transformation of a cell to the cancerous state is normally associated with increased surface expression of antigens recognized as foreign by the host immune system. These surface antigens, often termed tumour antigens or tumour surface antigens, are either not expressed at all by the untransformed cell or are expressed at such low levels that they fail to induce immunological tolerance.

The presence of tumour-specific antigens implies that the immune system should be capable of recognizing and destroying transformed cells. This concept, known as immunosurveillance, probably does function to some extent in the body. The immune system does respond to the presence of some tumours, causing their partial or complete regression. The major anti-tumour immune elements include:

• T-lymphocytes, which are capable of recognizing and lysing malignant cells.

• NK cells, which, like some T-cells, can induce lysis of tumour cells. The tumouricidal activity of NK cells is potentiated by various cytokines (e.g. IL-2 and TNF).

• Macrophages can destroy tumour cells, largely by releasing damaging lysosomal enzymes and reactive oxygen metabolites at the tumour cell surface. Macrophages also produce TNF, which can kill tumour cells by (a) binding to high-affinity TNF cell surface receptors (which is directly toxic to the cells) and (b) promoting synthesis of additional cytokines (which can, indirectly, lead to tumour destruction via activation of other elements of immunity).

Table 13.2 Monoclonal/engineered antibodies thus far approved for medical use. The sponsoring companies and therapeutic indications are also listed

Product

Company

Indication

CEA-Scan (Arcitumomab, murine Mab fragment (Fab), directed against human CEA)

MyoScint (Imiciromab-Pentetate, murine Mab fragment directed against human cardiac myosin)

OncoScint CR/OV (Satumomab Pendetide, murine Mab directed against TAG-72, a high molecular weight tumour associated glycoprotein) Orthoclone OKT3 (Muromomab CD3, murine Mab directed against the T-lymphocyte surface antigen CD3) ProstaScint (Capromab Pentetate murine Mab directed against the tumour surface antigen PSMA)

ReoPro (Abciximab, Fab fragments derived from a chimaeric Mab, directed against the platelet surface receptor GPIIb/IIIa) Rituxan (Rituximab chimaeric Mab directed against CD20 antigen found on the surface of B-lymphocytes) Verluma (Nofetumomab murine Mab fragments (Fab) directed against carcinoma-associated antigen) Zenapax (Daclizumab, humanized Mab directed against the a chain of the IL-2 receptor)

Simulect (Basiliximab, chimaeric Mab directed against the a chain of the IL-2 receptor)

Remicade (Infliximab, chimaeric Mab directed against TNF-a) Synagis (Palivizumab, humanized Mab directed against an epitope on the surface of respiratory syncytial virus)

Herceptin (Trastuzumab, humanized antibody directed against HER2, i.e. human epidermal growth factor receptor 2) Indimacis 125 (Igovomab, Murine Mab fragment (Fab2) directed against the tumour-associated antigen CA 125) Tecnemab KI (murine Mab fragments (Fab/ Fab2 mix) directed against HMW-MAA, i.e. high molecular weight melanoma-associated antigen)

Immunomedics

Centocor

Cytogen

Ortho Biotech

Cytogen

Centocor

Genentech/IDEC Pharmaceuticals

Boehringer Ingelheim/ NeoRx

Hoffman La Roche

Novartis

Centocor

MedImmune (USA) Abbott (EU)

Genentech (USA) Roche Registration

Sorin

Detection of recurrent/metastatic colorectal cancer

Myocardial infarction imaging agent

Detection/staging/follow up of colorectal and ovarian cancers

Reversal of acute kidney transplant rejection

Detection/staging/follow up of prostate adenocarcinoma

Prevention of blood clots

Non-Hodgkin's lymphoma

Detection of small cell lung cancer

Prevention of acute kidney transplant rejection

Prophylaxis of acute organ rejection in allogeneic renal transplantation

Treatment of Crohn's disease

Prophylaxis of lower respiratory tract disease caused by respiratory syncytial virus in paediatric patients

Treatment of metastatic breast cancer if tumour overexpresses HER2 protein

Diagnosis of ovarian adenocarcinoma

Diagnosis of cutaneous melanoma lesions

Table 13.2 (Continued)

Product

Company

Indication

LeukoScan (Sulesomab, murine Mab fragment (Fab) directed against NCA 90, a surface granulocyte non-specific cross-reacting antigen)

Humaspect (Votumumab, human Mab directed against cytokeratin tumour-associated antigen)

Mabthera (Rituximab, chimaeric Mab directed against CD 20 surface antigen of B-lymphocytes)

Mabcampath (EU) or Campath (USA); alemtuzumab; a humanized monoclonal antibody directed against CD52 surface antigen of B-lymphocytes)

Mylotarg (Gemtuzumab zogamicin; a humanized antibody-toxic antibiotic conjugate targeted against CD33 antigen found on leukaemic blast cells) Zevalin (Ibritumomab Tiuxetan; murine monoclonal antibody, produced in a CHO cell line, targeted against the CD20 antigen)

Humira (EU & USA; also sold as Trudexa in EU) (adalimumab; r (anti-TNF) human monoclonal antibody created using phage display technology Bexxar (tositumomab; murine monoclonal raised against CD 20 surface antigen, found on the surface of B-lymphocytes) Erbitux (cetuximab; chimaeric antibody raised against human EGF receptor)

Xolair (omalizumab; humanized monoclonal which binds immunoglobulin E at the site of high affinity IgE receptor binding) Raptiva (efalizumab; humanized antibody expressed in CHO cell line. Binds to the LFA-1, which is expressed on all leukocytes) Avastin (humanized monoclonal raised against vascular endothelial growth factor). Tysabri (humanized monoclonal raised against selected leukocyte integrins) NeutroSpec (murine monoclonal antibody raised against CD15 surface antigen of selected leukocytes)

Immunomedics

Organon Teknika

Hoffmann La Roche (see also Rituxan)

Millennium & ILEX (EU); Berlex, ILEX Oncology & Millennium Pharmaceuticals (USA) Wyeth Ayerst

Diagnostic imaging for infection/ inflammation in bone of patients with osteomyelitis

Detection of carcinoma of the colon or rectum

Non-Hodgkin's lymphoma

Chronic lymphocytic leukaemia

Acute myeloid leukaemia

IDEC Pharmaceuticals Non-Hodgkin's lymphoma

Cambridge Antibody Technologies & Abbott (USA) Abbott (EU) Corixa and

GlaxoSmithKline

ImClone Systems and Bristol-Myers-Squibb (USA) Merck (EU) Genentech/Novartis/ Tanox/Sankyo

Genentech (USA) Serono (EU)

Genentech USA) Roche (EU) Biogen Idec/Elan

Palatin Technologies/ Mallinckrodt Inc.

Rheumatoid arthritis

Non-Hodgkin's lymphoma

Treatment of EGF receptor-

expressing metastatic colorectal cancer

Treatment of adults/adolescents with moderate to severe persistent asthma

Treatment of adult patients with chronic moderate to severe plaque psoriasis

Carcinoma of the colon or rectum

Treatment of patients with relapsing forms of MS

Imaging of equivocal appendicitis

• Antibodies that, by binding to the cell surface antigen, mark the tumour cell for destruction. NK cells and macrophages express cell surface receptors that bind to the antibody Fc region (Box 13.2). Thus, antibody bound to tumour antigens directs these immune elements directly to tumour surface. Antibodies also activate complement, which is capable of directly lysing tumour cells.

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