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normal division, differentiation and cell death (apoptosis) it becomes cancerous. So, cancer is the result of an abnormal proliferation of
cells without differentiation and apoptosis. Cancer harms the body when cells divide uncontrollably to form lumps or masses of tissue
called tumors. Tumors can be of two types benign and malignant. In benign tumor, cells remain clustered together in a single mass and
do not spread to other sites [20]. More dangerous form of cancer is malignant tumor. In this form of tumour, cells don’t remain localized
at one site and becomes progressively invasive and spread to other tissues i.e become malignant. When a tumor successfully spreads to
other parts of the body and grows, invading and destroying other healthy tissues, it is said to have metastasized. This process itself is called
metastasis, and the result is a serious condition that is very difficult to treat. The term cancer refers specifically to malignant tumour.
Both benign and malignant tumors are classified according to the type of cell from which they arise. Most cancer fall into three major
groups- carcinomas (tumors that arise from ectodermal or endodermal tissues), sarcomas (malignancies of mesodermal connective
tissues) and leukemia or lymphomas (from blood forming tissues and cells of immune system).
Therapeutic approaches
Variety of therapeutic approaches are followed in the treatment of cancer including surgery, radiotherapy, chemotherapy, hormone
therapy, anti angiogenesis therapy, and most common which is in scope of this chapter immune therapy ( discussed below).Use of
monoclonal antibodies, immune adjuvants, and vaccines against different form of cancers is referred to as immune therapy. Established
therapies employ a variety of manipulations to either to kill tumour cells or to activate antitumor immunity. Collectively, these strategies
attempt to augment protective antitumor immunity and to disrupt or kill the tumour cells or the immune-regulatory circuits that are
critical for maintaining tumor. Since treatment of cancer by monoclonals is one of the most common and effective way of combating
cancer, it is highlighted here.
Monoclonal antibodies: Antibodies are known to play an essential role in providing protective immunity to microorganisms, and
the administration of tumor-targeting monoclonal antibodies has proven to be one of the most successful forms of immune therapy for
cancer. The proper use of monoclonal antibodies is based on the fact that the tumour cell expresses antigen/antigenic determinants that
are unique to that particular cell and not found on neighbouring healthy cells. This is due to the fact that transformation of normal cell to
tumour cells is normally associated with expression of unique surface antigens on tumor cells that appear foreign to host immune system.
Such antigens (called tumor antigens) are usually not expressed at all on normal cells, or expressed at very low concentration. Targeting
of such antigens by monoclonal antibodies can have desired effect [20].
The infusion of preformed monoclonal antibodies can generate an immediate immune response while bypassing many of the
limitations that impede endogenous immunity. The target specificity and optimal affinity of manufactured monoclonal antibodies can
be carefully selected, and the quantity of antibody infused can be set to achieve biologically active antibody titers. Moreover monoclonal
antibody therapies are typically not as toxic as conventional cytotoxic cancer chemotherapy. Many of the obstacles in initial use of murine
monoclonal antibodies have been overcome by the generation of chimeric and humanised antibodies that contain less content of murine
protein [21,22]. Murine proteins are generally considered foreign when administered to humans and hence immune response occurs that
clears such proteins( including murine monoclonals) from the human system. Monoclonal antibodies consisting of mouse variable (Fab)
regions and human constant (Fc) region are referred to as chimeric antibodies and hybrid antibodies that carry only murine CDRs in an
otherwise human antibodies are referred to as humanized antibodies.
Several monoclonal antibodies, targeting tumor-associated proteins, are clinically approved for the treatment of cancer [23]. Five
of these antibodies bind surface proteins that are highly expressed on tumors (Figure 5) namely CD52 in chronic lymphocytic leukemia
(CLL) (alemtuzumab), CD33 in acute myelogenous leukemia (AML) (gentuzumab), and CD20 in non-Hodgkin’s lymphoma (NHL)
and CLL (rituximab, ibritumomab tiuxetan and tositumomab). Alemtuzumab (Campath) which is used to treat patients with CLL,
cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma. Alemtuzumab binds to CD52 antigen ( present on the surface of mature B
and T cells) and targets these cells for destruction. Bevacizumab is a recombinant humanized monoclonal antibody that binds to vascular
endothelial growth factor (VEGF) and cetuximab, a chimeric antibody, targets epidermal growth factor receptor (EGFR). Intracellular
signaling pathways related to VEGF and EGFR- both play a central role in tumorigenesis as well as tumor growth, and are therefore
rational targets for anti-cancer drug development (Table 1). Targeting of such antigens by monoclonal antibodies can have desired
effect i.e. they can be used to kill the target cell by antibody dependent cell mediated cytotoxicity (ADCC) (e.g in monoclonal antibodies
targeted towards CD20 in follicular lymphoma in humans, induced ADCC) or complement mediated cell lysis (some antitumor effects of
rituximab – a monoclonal antibody used in treatment of non-Hodgkin lymphoma are because of complement mediated cell lysis) (Figure
6). Complement dependent cytotoxicity constitutes a good tumor cell killing mechanism except solid tumor cells which have proved to
be complement resistant.
Figure 5: Some important cancer antigens that are targeted in therapy.
Monoclonal antibodies can also be used to deliver cytotoxic agents directly to tumors by conjugating them with radioactive isotopes
or toxic chemicals, drugs or prodrugs [20,21,24]. Monoclonal antibodies attached to a radioactive substance, drug, or toxin, are referred
to as conjugated monoclonal antibodies. The monoclonals are used as a targeting device to deliver these payloads directly to the cancer
cells. Conjugated monoclonal antibodies circulate in the body until they can find and bind onto the target antigen on the tumour cell. It
then delivers the toxic payload where it is needed most. This lessens the damage to normal bystander cells in other or neighbouring part
of the body.
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