Immunotherapeutic strategies (2)
Tumor immunity
A. Production of Engineered Tumor-specific TCRs
Many tumors are extensively infiltrated by lymphocytes. Tumor infiltrating lymphocytes (TIL) used to be removed from surgical specimens, especially from melanomas and renal cell carcinomas, then isolated and retransfused after proliferation.
However, the results were rather disappointing. It is now possible to identify the DNA sequences on the variable domains of the o: and B chains of the T cell receptors of TIL Using viral vectors, genetically engineered T lymphocytes that specifically react with the tumor can be produced.
Adoptive therapy could then be performed by administering such exvivo expanded T cells. Currently. one of the major limitations is the difficulty of gene transfer in normal T cells, but improved methods are being generated. Also, endogenous TCR must be downregulated.
B. Antibody Therapies
Monoclonal antibodies (MAb) have been used in cancer treatment for about 20 years now. Most antibodies have been generated in mice. Treatment with murine MAb leads to the formation of human anti murine antibodies (HAMA), which reduce the efficacy of murine MAb. therefore humanized" monoclonal antibodies were developed (1).
In humanized monoclonal antibodies, the greater portion of the molecule is of human origin. and only the F(ab) fragment or the variable region of F(ab) is of murine origin. Humanized mono clonal antibodies have a significantly longer half life in the patient's blood and they activate the immune effector cells more efficiently than murine monoclonal antibodies.
Two humanized monoclonal antibodies have achieved remarkable results in the past three years: the CD20 antibody Rituximab (Rituxanm) has activity against B cell lymphomas. and the antibody trastuzumab (Herceptinu) directed against human epidermal growth factor receptor 2 (HERZ) is active in breast cancer.
A number of other antibodies appear promising. Bispeci fie" antibodies are another new development (2). They are produced by fusion of two hy bridomas, each of which secretes a specific monoclonal antibody. The hybridomas bind si rnultaneously to the epitope of the tumor cell and to T cells (CD3). The T cells are therefore brought in contact with the tumor cells and are activated by CD3.
Synthetic single chain
antibodies are an improvement of this strategy (3). These are genetically engineered antibody derivatives that consist only of the light and heavy chain of the variable region [Fv) of the monoclonal Ab. Single chains from two differ ent antibodies can be connected by a binding fragment (spacer). Alternatively. single chain antibodies that recognize a tumor epitope can be linked to the - chain. which plays an im portant role in the transduction of TCR signals.
T cells can be transfected with such constructs. so that they can recognize a tumor antigen in the same way as antibodies do. and the signal will be transmitted to the inside of the cell by the connected TCR - chain. Antibodies directed against tumor associated antigens can also be linked to immunotoxins or radioisotopes [8.4). In immunotoxins,
the toxic components that block the synthesis of RNA are released after internalization of the antibody. in radio labeled immunoconjugates, a radioactive sub stance (usually radioactive yttrium or iodine) induces the lysis of target cells but also of adjacent cells (so called bystander effect").
C. Mechanisms of Monoclonal Antibody Therapy
A monoclonal antibody can imitate or block the natural ligands of a receptor. An anti CD95 anti body can. for example. activate the Fas/APO 1 receptor (C095). thereby triggering apoptosis (1). On the other hand, antibodies can activate complement and thus induce pore formation in the cell membrane (2).
ln antibody dependent cell mediated cytotoxicity, Fc receptor bearing natural killer cells recognize the Fc fragment of a cell bound antibody and thus release cyto plasmic granules containing cytotoxic perforins and granzymes (3. see also p. 39). As mentioned, murine Ab can induce HAMA. Some of these anti murine antibodies may be directed against the specific idiotypic binding region of murine Ab (4). In this case. the anti idiotypic antibodies imitate tumor anti gens and can serve as a tumor surrogate in vaccines. On the other hand. they can also lead to the formation of anti anti idiotypic monoclonal antibodies. which like murine MAbs recognize the tumor antigen. The effect of the murine monoclonal antibodies is en hanced by this cascade
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