CANCER/TUMOR IMMUNOTHERAPY

Immunotherapy for Cancer

The presence of a cancer elicits both humoral and cell-mediated immune responses. However, neither seem to be effective at preventing the establishment or continued growth of a neoplasm.

Cell-mediated responses, at least in experimental systems, can be quite effective in clearing or preventing a cancer. Thus, an active area of research is directed at finding treatment protocols that might augment the bodies activation of tumor specific CTLs, NK cells, macrophages, and generally, an inflamatory response directed at the tumor.

These include a variety of Gene Therapy approached:

• The use of transfected/irradiated autologous tumor cells that express peptides that are known to produce a tumor specific CTL response,
• Transfected autologous tumor cells with genes that express various cytokines such as Il-2, Il-4, IFN-gamma, and GM-CFS,
• Transfected autologous tumor cells with DNA for co-stimulatory molecules so as to improve tumor antigen presentation to T-helper cells which are necessary for CTL activation,
• the transfer of genes, using viral vectors, into cancer cells that will result in their destruction, and
• DNA vaccines for tumor specific CTL epitopes.

Also under investigation is the use of immunotoxins, i.e., anti-tumor antibodies or anti-idiotypic antibodies linked to cellular toxins that are directed at tumor cells, particularly in B-cell lymphomas in the case of the latter.

The possibility of Gene Therapy in Medicine began with the discovery by Zinder and Lederberg in 1953 that genetic characteristics can be transferred from one bacterial strain to another. In these early experiments, it was found that if a virus (bacteriophage), that had infected one bacterial strain, was used to infect a second bacterial strain, the virus would transfer a genetic characteristic to the second bacterial strain that it had "picked-up" from the first. The virus physically removes a gene (piece of DNA) from the first bacterial strain and inserts this gene into the DNA of the second strain. Thus, the transferred gene is now expressed in the second bacterial strain. This genetic transfer process was subsequently called Transduction, and the virus, generally in this process, a vector.

The question has been: Could this gene transfer take place in humans? The answer, of course, was yes. Thus began Gene Therapy and the possibility of using a viral vector to "correct" a genetic disease, in the treatment of cancer, and, as well, their use in the treatment of an infectious disease such as AIDS. Vectors now are routinely (literally) constructed in the laboratory from various viruses.

But, the Transduction process has always posed serious risks if used to treat human diseases. These risks have as their bases:

1. an immune response to the viral vector that induces a potentially lethal autoimmune reaction,
2. the viral vector, while inactivated, could revert to the disease causing virus from which it was derived, and,
3. the vector inserts itself, and the DNA that it carries, randomly into the DNA of the host. This random insertion can cause mutations in the host DNA seriously disrupting the metabolism of a cell, cause a cancer, or may be lethal.

These problems are not trival biological problems. They need to be looked at with extreme caution in animal models before using this strategy, if at all, to treat human disease.

Image from The New England Journal of Medicine -- November 13, 1997 -- Vol. 337, No. 20. Cutaneous Melanoma Metastases