Immune responses to human neoplasms

The first evidence for immune responses to human cancers was published in the late 1960s. However, this area remained controversial until technical advances made it possible to characterize the antigenic targets of the immune responses observed. Antigens recognized by patients' antibodies were identified first. While antibodies have been detected to a few antigens which were individually unique for each patient's tumor, most antibodies have defined antigens that are shared by many tumors, generally irrespective of their histological type.

Cell-mediated immune reactions are demonstrated in assays of either CTL activity or T helper cell responses, with most work nowadays concentrating on antigens recognized by CTLs. Since tumor cell killing by CTL is restricted by the ability of a given patient's MHC class I molecules to present target peptides, an antigen targeted by CTLs will appear as unique to each neoplasm, even if it is shared by many tumors, unless the tumor cells and the CTLs are matched for MHC class I. As a result of recent work taking this into account, as well as earlier studies studying the outcome of T helper cell activity, it has been established that the immune response to human neoplasms is primarily directed towards TADAs that are shared by many tumors. The MAGE group of tumor antigens discovered by Boon's group represents an interesting example. While MAGE antigens were first found in melanoma, they are shared by several other tumors as well. Their degree of tumor selectivity varies between different MAGE antigens but can be very high. Major efforts are presently given to identifying additional families of tumor peptides which can be recognized by human CTLs for use as therapeutic targets.

Much work is presently carried out attempting to devise strategies towards inducing a strong and clinically useful immune response, by developing various therapeutic tumor immunogens ('vaccines'). The logical first step in this direction is to define which tumor antigens are normally recognized by the human immune system or can be made to be so recognized. Progress has been made by working with antibodies in patient sera as well as with mAbs made by humdn hybridomas. For example, several gang-liosides that are expressed on human melanomas are immunogenic in humans, and promising, albeit preliminary, clinical results have been obtained using either mAbs to such antigens or 'vaccines' consisting of antigen plus adjuvant.

Tumor vaccines in the form of recombinant viruses, tumor peptides combined with a suitable adjuvant, and anti-idiotypic antibodies arc all of interest as other potential immunogens, as are tumor cells that have been modified so as to become more immunogenic, e.g. by transfection of genes encoding GM-CSF, B7-1 or some other lymphokine or costimulatory molecule. However, 'vaccines' based on whole cells are less likely to become therapeutic products for various logistical reasons. Targeting of various immunomodulators such as lymphokines and anti-T cell antibodies is also of interest, using bispecific mAbs or tumor-reactive fusion proteins, with the goal to expand an ongoing antitumor immune response. Adoptive transfer of in vitro expanded, specifically immune lymphocytes provides a different approach. It may be applicable even in the face of a relatively large tumor load, while vaccines and targeted agents may be best confined for prolonging survival in patients with micrometastas-es.

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