Two Cancer Therapies - Using Immunologic Distinctions to Combat Neoplasia - Essay Example

Essay Two:

Two Cancer Therapies: Using Immunologic Distinctions to Combat Neoplasia

Introduction

A better understanding of the gene regulation mechanisms that govern the workings of the immune system and the unravelling of the genetic differences between mutant cancer cells and their normal counterparts has advanced medical techniques. Now specific strategies can be devised to treat and prevent specific types of cancer by using therapies based on immunologic distinctions between the specific mutant cells and their healthy counterparts (Laheru et al, 2005). This immunotherapy for cancer is at a crucial juncture at the present moment and certain clinical trials are already being undertaken with specific mutant cell associated antigens and associated signalling molecules being targeted by therapeutic molecules and bodies (Laheru et al, 2005). There are two broad strategies involved in designing therapies for specific types of cancer. The first of these makes use of the immunosurveillance theory. It is well established presently that certain T-cells can actively recognise and mobilise against specific tumour cell antigens. So the first therapeutic strategy involves recruitment and activation of such tumour antigen specific T-cells (Laheru et al, 2005). The second strategy involves designing recombinant monoclonal antibodies that can target specific tumour antigens. It is noted that already a number of such monoclonal antibodies have been approved by the FDA (USA) for treatment of certain types of lymphomas and breast cancer (Laheru et al, 2005).

This paper shall now review two cancer therapies strategies that utilise either of the aforementioned strategies.

The HER2/neu Peptides: It has already been observed in this paper that certain antigens have been associated wit particular types of cancerous cells. This particular strategy under study here envisions one such set of TAAs (tumour associated antigens) – the HER2/neu peptides – that are found to be expressed or over-expressed by cancerous types (Correa and Plunkett, 2001). The HER2/neu antigen is over-expressed in 10-40% of breast cancers and other carcinomas (Correa and Plunkett, 2001). The antigen is a 185 kDa transmembranic glycoprotein found amplified or over-expressed not only in 10-40% breast cancers but also in other carcinomas like ovarian, rectal, gastric and colorectal ones (Correa and Plunkett, 2001).

It is noted that cytotoxic T lymphocytes have been described for HER2/neu peptides that they have not always endogenously recognised the antigen on tumour cells. Where such recognition has been possible the concentration of the antigen required for cell surface presentation has been high in comparison to that required for viral proteins (Correa and Plunkett, 2001). In the case of helper T cells, only low affinity cells have been found for the antigen. The generation of high affinity T cells require conditions that are very high compared to those required for viral proteins (Correa and Plunkett, 2001). This has prompted that conclusion that there is immunologic tolerance for the HER2/neu antigen in the body. This is of great concern to research wanting to develop a cancer vaccine based on the antigen. It has been found that, where there is natural tolerance, high avidity T cells are eliminated naturally and only low affinity ones remains expressed (Correa and Plunkett, 2001). Other studies have shown that only high affinity T cells are required for tumour cell elimination in vivo but it has to be studied whether there is any significance for the low affinity ones in this role as cancer cell eliminators (Correa and Plunkett, 2001).

It is noted that while the Correa and Plunkett, 2001, is slightly dated a later one by Woll et al, 2004, suggests that clinical trials are still under way with the antigen-based vaccines. The Woll et al, 2004, study is concerned with the role of HER2/neu peptides in recurrent prostrate cancer and envisions developing an anti-HER2/neu vaccine that immunises patients against the relevant cancers, including prostrate cancer.

The paper this particular antigen-specific vaccine still under trial as an example of how immunologic properties of tumour cells relatively distinct from normal cells can be used against them. Here the HER2/neu is found often exclusively over-expressed in certain cancers like breast cancers and this element of the mutant cells can be targeted by a vaccine to generate a steady immune response against the mutants.

The Cationic Liposomes: This is more a strategy that is based on a carrier vesicle – the cationic liposome – that is known to selectively target tumour vascular endothelial cells (VEC) (Dass and Choong, 2006). It is still hypothetical how these easily-engineered vesicles target tumour endothelium and the hypotheses range from receptor-mediated endocytosis, charge-dependent binding (these vesicles are positively charged) and special attractive properties for the possibly altered glycocalyx of the tumoural microvessels (Schmitt-Sody et al, 2003). What is certain is that these are ideal vectors as they are noninfective, low in immunogenecity, low in toxicity, high in stability and cheaply manufactured (Nakanishi et al, 2003). At present, a great deal of research has gone into studying the prospects of a delivered drug travelling from its point of administration to target sites in sufficient numbers to be of pathologic use (Dass and Choong, 2006). Mutant cancer cells are notoriously resistant to drugs. They grow at enormous rates, actively reject drugs targeted at them and travel to secondary spots through the bloodstream (Dass and Choong, 2006). Thus, it is the challenge of any drug delivery system to deliver the drug at the target site in sufficient concentrations and in such a manner that the target cells cannot easily reject the drug. It has been shown recently that cationic liposomes (CLs) are capable of targeting certain tumour cells (LS174T and MCAIV at two locations – cranial window and dorsal skin fold center) and delivering drugs (in this case relevant antibodies targeted against specific and exclusive tumour antigens) to the mutant vascular endothelial cell system (Dass and Choong, 2006). Since the endothelium system, though it is the least accessible in mutant cells, is a suppliant one that offers little resistance this is especially useful and researchers are hopeful of developing cancer therapies based on this fact. Specific angiogenic and anti-vascular activities arranged for the drug can do irreparable damage to the mutant cells (Dass and Choong, 2006). Studies show that since the tumour vasculature is much smaller than the entire tumour interstitium relatively large doses of antiangiogenic substances can be delivered to it in vivo for maximum effect (Dass and Choong, 2006). When PEGylated (polyethylene glycol – PEG) lipids were added to the liposome surface the circulation half-life increased without significant change to vesicle distribution within the tumour. This selective targeting by liposomes is better known as lipofection (transfection by lipids) (Dass and Choong, 2006). There is no dearth of research studies involving these vesicles. One such study, Nakanishi et al, 2003, has noted that concentrations of the human IFN- protein (coded by the gene IAB-1) loaded onto cationic multilamellar (two types of the vesicles are available – unilamellar (small) and multilamellar (large)) liposomes have been deployed on metastatic renal carcinoma cells with clear evidence of induced apoptosis in the mutant cells (Nakanishi et al, 2003). Though the killing the tumour cells was done by the protein the targeting was done by the cationic liposomes. Otherwise the protein would not have effectively accessed the mutant cells. These vesicles have been in use for a long time in biological experiments. The evidence of this can be gathered from another study, Meyer et al, 1998, where antisense oligodeoxyribonucleotides (ODNs) specifically structured against HER2 peptides overexpressed on certain cancer cells were conveyed to the mutant cells by cationic liposomes. Some success was evident (Meyer et al, 1998). The ODNs can inhibit gene expression by blocking translation, transcription and splicing processes. There are other numerous studies at present involving these vesicles are proposed carriers of specific bodies that are targeted against specific cancers. It is hoped that they will one day prove an efficient and viable drug delivery system against cancers.

Conclusion

While very little clinical progress can be considered at present for these aforementioned therapies the trials continue and the ensuing results are encouraging enough to allow the present generation of humankind to expect more efficiency later on from such therapies.