TUMOUR IMMUNOLOGY

Presented By: Payal Goyal M.Sc. Biotechnology (Sem-2) ICG, Jaipur

Cancer immunology
Cancer immunology is the study of interactions between the immune system and cancer cells (also called tumors or malignancies). It is also a growing field of research that aims to discover innovative cancer immunotherapy's to treat and retard progression of this disease. The immune response, including the recognition of cancer-specific antigens is of particular interest in this field as knowledge gained drives the development of new vaccines and antibody therapies.

Immunosurveillance and immunoediting

the concept of cancer Immunosurveillance and immunoediting based on (i) protection against development of spontaneous and chemically-induced tumors in animal systems. (ii) identification of targets for immune recognition of human cancer.

Immunosurveillance
Cancer Immunosurveillance appears to be an important host protection process that inhibits carcinogenesis and maintains regular cellular homeostasis . Testing of immune status in the diagnosis and therapy of cancer, immunoproliferative and immunodeficiency disorders, and autoimmune abnormalities. Changes in immune parameters are of special significance before, during and following organ transplantation. Strategies include measurement of tumor antigen and other markers (often by RADIOIMMUNOASSAY), studies of cellular or humoral immunity in cancer etiology, IMMUNOTHERAPY trials, etc.

Immunoediting
Immunoediting is a process by which a person is protected from cancer growth and the development of tumour immunogenicity by their immune system. It has three main phases: elimination, equilibrium and escape. The elimination phase consists of the following four phases: Elimination: Phase 1 The first phase of elimination involves the initiation of antitumor immune response. During this phase, the infiltrating lymphocytes such as the natural killer cells and T cells are stimulated to produce IFN-gamma. Elimination: Phase 2 In the second phase of elimination, newly synthesized IFN-gamma induces tumour death (to a limited amount) as well as promoting the production of chemokines CXCL10, CXCL9 and CXCL11. These chemokines play an important role in promoting tumor death by blocking the formation of new blood vessels.

Elimination: Phase 3
In the third phase, natural killer cells and macrophages transactivate one another via the reciprocal production of IFN-gamma and IL-12. This again promotes more tumor killing by these cells via apoptosis and the production of reactive oxygen and nitrogen intermediates.

Elimination: Phase 4
In the final phase of elimination, tumor-specific CD4+ and CD8+ T cells home to the tumor site and the cytolytic T lymphocytes then destroy the antigen-bearing tumor cells which remain at the site.

Equilibrium and Escape

Tumor cell variants which have survived the elimination phase enter the equilibrium phase. In this phase, lymphocytes and IFN-gamma exert a selection pressure on tumor cells which are genetically unstable and rapidly mutating. Tumor cell variants which have acquired resistance to elimination then enter the escape phase. In this phase, tumor cells continue to grow and expand in an uncontrolled manner and may eventually lead to malignancies.

Tumor-associated antigens (TAA)

TAA are found on tumor cells and on normal cells during fetal life (onco-fetal antigens), after birth in selected organs, or in many cells but at much lower concentration than on tumor cells. There are 2 main types of tumor antigens:

Tumor-specific transplantation antigens (TSTA) which are unique to tumor cells and not expressed on normal cells. They are responsible for rejection of the tumor. Tumor associated transplantation antigens (TATA) that are expressed by tumor cells and normal cells.

Tumor Antigens
Antigen Cyclin-dependent kinase 4 -catenin Caspase-8 MAGE-1 MAGE-3 Tyrosinase Surface Ig idiotype Her-2/neu MUC-1 HPV E6 and E7 Antigen Function Cell cycle regulator Signal transduction Apoptosis regulator Normal testicular proteins Melanin synthesis BCR Receptor tyrosine kinase Underglycosylated mucin Viral gene products Expressed On Melanoma Melanoma Squamous cell carcinoma Melanoma, breast, glioma tumors; Melanoma Lymphoma Breast and ovarian cancer Breast and pancreatic tumors Cervical carcinoma

IMMUNITY AGAINST TUMORS

There is many evidence for anti-tumor immune reactivity in humans, evidence for immunity against malignancy comes mostly from experimental studies with animals.

Immunotherapy
Immunotherapy has been used as a novel means of treating cancer. Both active and passive means of stimulating the non-specific and specific immune systems have been employed, in some cases with significant success.

Active Immunotherapy
In this, the host actively participates in mounting an immune response. Specific activation is achieved by using vaccine.

Passive Immunotherapy
This involves transfer of preformed antibodies, immune cells and other factors into the hosts.

Immunotherapy of tumors
nonspecific BCG, Propionibacterium acnes, levamisole, cytokine genes, etc. killed tumor cells or their extract, recombinant antigens, idiotype, costimulatory molecule genes, etc.

active
specific

nonspecific LAK cells, cytokines antibodies alone or coupled to drugs, pro-drug toxins or radioisotope; bispecific antibodies; T-cells

passive specific

combined

LAK cells and bispecific antibody

Chemotherapy
Targeted carrier systems for drug delivery
Many chemotherapeutics are characterized by a limited therapeutic efficacy, often due to severe side effects at higher doses and rapid elimination from the body due to

their small size. Encapsulation of small therapeutic molecules into Nano particular
carrier systems, such as liposome or polymers, can improve the pharmacokinetic and pharmacodynamics properties and protects the active compound from degradation. Furthermore, equipping these carrier systems with target cell specific ligands increases selectivity and efficacy.

Biotherapy
Cytotoxic fusion proteins

The direct fusion of effecter molecules to ligands. allows for the generation of targeted cytotoxic molecules. Using different ligands against vascular structures fused to effecter molecules such as toxins or cytokines we plan to develop novel vascular targeting agents.

This process allow for analyze their efficacy, selectivity and safety in animal
models.