Human cancer detection and immunotherapy with conjugated and non-conjugated monoclonal antibodies

Abstract

Classical therapeutic modalities such as surgery, radiation and chemotherapy not only fail to cure the majority of neoplastic disease, but their employment also leads to severe and debilitating side effects. The severe cancer related morbidity is often associated with the use of radiation and chemotherapy, making them less than ideal forms of therapy. Entirely new approaches to cancer therapy that are tumor cell directed, and specifically lethal to malignant cells and less toxic to normal tissues are being observed and developed, adhering to the old prayer "Destroy the diseased tissues, preserve the normal." Following the initial advances of Ehrlich, immunotherapy as a fourth modality of cancer therapy has already been developed and proven to be quite effective. Unfortunately, the cancer cell population is not a static entity, but rather a continually changing one. Considerable variations have been determined between individual malignant cells. Our strong belief is that it is necessary for present-day clinical oncologists to become aware of the existence of immunotherapy and learn how to employ it in order to improve the efficacy and decrease the side effects of modern cancer therapy. The development of hybridoma technology and the advances in monoclonal antibody (MoAB) production have revitalized the concept concerning the existence of cancer cell-targeted, specific "magic bullets". In addition, a variety of different agents (e.g. toxins, radionuclides, chemotherapeutic drugs) have been conjugated to mouse and human MoABs for selective delivery to cancer cells. Preclinical observations in athymic, nude mice using xenografted human cancers and mouse, anti-human MoABs were more than impressive and have lead to several clinical trials. Strategies for the employment of MoABs for cancer immunotherapy include: a) Immune reaction directed destruction of cancer cells; b) Interference with the growth and differentiation of malignant cells; c) Antigen epitope directed transport of anti-cancer agents to malignant cells; d) Anti-idiotype vaccines. Phase I studies have established the safety of employing immunoconjugates in humans, but the therapeutic results were less impressive. The clinical use of mouse MoABs in humans is limited due to the development of an anti-globulin immune response to the non-human immunoglobulins by the human host. Genetically engineered chimeric human-mouse MoABs have been developed by replacing the mouse Fc region with the human constant region. Moreover, the framework regions of variable domains of rodent immunoglobulins were also experimentally replaced by their human equivalents. These antibodies can also be designed to have specificities and effector functions determined by researchers, which may not appear in nature. The astonishing immunophenotypic (IP) heterogeneity of cancer cells, the different cytotoxic activity associated with the moiety linked to given MoABs, and mostly the impressive genetic modulation capabilities of cancer cells still remain as yet unsolved difficulties in the present immunotherapy of human cancer. Antibodies with two binding ends (bispecific antibodies) provide a great improvement in targeting cancer cells. The existing inadequacies of MoABs in immunotherapy may also be improved by increasing their efficiency with chemical coupling to various agents such as bacterial or plant toxins, radionuclides or cytotoxic drugs. In writing this review article, one of our main goals is to encourage further clinical research with the use of genetically engineered rodent MoABs and various immunoconjugates in the treatment of human cancer, as well as the combination of such immunotherapy with the three conventional modalities of therapy. Finally, we propose that MoAB-based immuno-therapy be accepted as a conventional form of therapy and employed not only in terminal cancer patients, but also, for instance, during and following surgical resection.