Elsevier

Immunology Letters

Volume 74, Issue 1, 15 September 2000, Pages 51-58
Immunology Letters

Anti-idiotype vaccine against cancer

https://doi.org/10.1016/S0165-2478(00)00249-2Get rights and content

Abstract

Immunization with anti-idiotype (Id) antibodies represents a novel new approach to active immunotherapy. Extensive studies in animal tumor models have demonstrated the efficacy of anti-Id vaccines in preventing tumor growth and curing mice with established tumor. We have developed and characterized several murine monoclonal anti-Id antibodies (Ab2) which mimic distinct human tumor-associated antigens (TAA) and can be used as surrogate antigens for triggering active anti-tumor immunity in cancer patients. Encouraging results have been obtained in recent clinical trials. In this article, we will review the existing literature and summarize our own findings showing the potential of this approach for various human cancers. We will also discuss where anti-Id vaccines may perform better than traditional antigen vaccines.

Introduction

Active immunotherapy for tumors has been an attractive therapeutic approach because it harnesses the body's immune potential to attack malignant cells in an antigen-specific manner and, compared with passive immunotherapy, does not require the infusion of large doses of anti-tumor antibodies. Active immunotherapy can be further subdivided into those approaches which depend on tumor-derived materials such as TAA or tumor cells, and methods which do not depend on materials derived or extracted from tumors. Id manipulation is the major tumor-specific active approach which does not use tumor-derived material to induce anti-tumor immunity.

Immunotherapy is very effective in certain animal model systems, and it has been used to treat human cancers for several decades [1]. Active immunotherapy of cancer patients with tumor-derived material has been studied by numerous investigators, with positive clinical responses reported. The major problems using tumor material for immunization is that TAAs are typically weakly immunogenic. A common explanation for the absence of anti-tumor immunity is that the immune system has been tolerized by the tumor antigens. If this is true, steps could be taken to break the existing anti-tumor tolerance. An effective method of breaking tolerance is to present the critical epitope in a different molecular environment to the tolerized host [2]. While this can be done with well-defined antigens such as haptens, it is impossible with most tumor antigens because they are chemically ill defined and difficult to purify. Carbohydrate antigens are even more difficult, as they cannot be produced by recombinant techniques.

The immune network hypothesis offers a unique approach to transform epitope structures into Id determinants expressed on the surface of antibodies. Lindemann in 1973 [3] and Jerne in 1974 [4] proposed theories that describe the immune system as a network of interacting antibodies and lymphocytes. According to this original network hypothesis, the Id–anti-Id interactions regulate the immune response of a host to a given antigen. Both Ids and anti-Ids have been used to manipulate cellular and humoral immunity. The network hypothesis predicts that within the immune network the universe of external Ags is mimicked by idiotypes expressed by antibodies and T cell receptors. According to the network concept, immunization with a given Ag will generate the production of antibodies against this Ag termed Ab1. This Ab1 can generate a series of anti-Id antibodies against Ab1 termed Ab2. Some of these Ab2 molecules can effectively mimic the three-dimensional structures of external Ags. These particular anti-Ids called Ab2β, which fit into the paratopes of Ab1, can induce specific immune responses similar to responses induced by nominal Ag. Anti-Id antibodies of the β type express the internal image of the Ag recognized by the Ab1 antibody and can be used as surrogate Ags. Immunization with Ab2β can lead to the generation of anti-anti-Id antibodies (Ab3) that recognize the corresponding original Ag identified by the Ab1. Because of this Ab1-like reactivity, the Ab3 is also called Ab1′ to indicate that it might differ in its other idiotopes from Ab1. Several such Ab2β have been used in animal models to trigger the immune system to induce specific and protective immunity against bacterial, viral (including HIV), and parasitic infections [5]. The administration of Ab2β as surrogate tumor-associated Ags represents another potential application of the Id vaccine concept.

The network hypothesis offers an elegant concept for developing vaccines which is not based on the conventional approach of using nominal antigen. These so-called anti-Id vaccines or internal Ag vaccines take advantage of the fact that the repertoire of external or nominal antigens is mimicked by Id structures on immunoglobulins and possibly on receptors and products of T cells as well. Thus, with this approach, Id-based vaccines do not contain nominal Ag nor its fragments. This excludes the possibility that Id vaccines would have the same undesired side effects which are sometimes associated with conventional antigen vaccines. Also, the predictability of the fine specificities of vaccine-induced immune responses to tumors is higher for anti-Id vaccines than for antigen vaccines. Besides the increased safety of Id vaccines, these new kinds of Ags have other practical, economical and biological advantages over conventional vaccines. Id vaccines do not depend on the availability of large amounts of pure Ag, which often is a limiting economical factor in vaccine production. By virtue of their being proteins, Id vaccines can be easily manipulated; they can be coupled to potent immunogenic carriers to become T-cell-dependent antigens. Eventually, it might be possible to produce fully synthetic Id vaccines using essential sequence information obtained from Id hybridoma Ags.

T-dependent protein vaccines can become a decisive factor in situations where the responding immune system is immature or suppressed. From experimental studies on animals we know that the response to T-cell dependent Ags matures earlier than the T-independent response to carbohydrate Ags, and that often a genetically or acquired abnormal immune system responds better to T-dependent Ags than to T-independent Ags.

Finally, data exists showing that an acquired state of tolerance to one Ag form can be broken by using a different molecular form of the same antigenic moiety. This could become an important consideration in a broader context such as in the immunotherapy of cancer patients, who may be immunodeficient or tolerant against their own tumor. Internal image anti-Ids mimic the three-dimensional shapes of antigens and, thus, are genetically unrestricted and effective across the species barrier. At the same time, antigens can be presented in a different molecular environment.

Active immunization with tumor-specific Id vaccines has been shown to inhibit the growth of tumor in animal models [6]. A series of studies [7] on the effect of anti-Id therapy in a mouse leukemia model L1210 in DBA/2 mice has been described, which has provided us with basic information on B- and T-cell induced responses using the anti-Id approach. These investigators generated a number of anti-Id hybridomas against mAb to the L1210 tumor. These anti-Id mAbs have been shown to induce tumor-specific DTH, inhibition of tumor growth, CTL, antibodies and T helper cells in this system. These findings are very promising since they demonstrate a cross-reaction of nominal Ag and internal image Ag for a tumor-associated Ag system at the T- and B-cell level. In a recent study, 100% cure of established tumors was achieved in DBA/2 mice by combining anti-Id vaccines with cyclophosphamide, whereas 50% cure rate was obtained with anti-Id therapy alone [8]. Similar findings have also been obtained when cyclophosphamide (100 mg/kg), administered in combination with Id vaccines to mice bearing 10-day-old, 1–2 cm diameter subcutaneous B-cell lymphoma (38C13), resulted in a dramatic survival benefit [9]. An anti-Id antibody was used to induce immunity to SV-40 transformed cells [10]. Mice vaccinated with this anti-Id demonstrated prolonged survival after tumor transfer. The role of Id interactions in regulating the immune response of mice to chemically induced, syngeneic sarcomas has been recently studied [11]. Treatment with anti-Id mAb of mice with the established sarcomas (MCA0-490 and MCA-1511) had significant anti-tumor activity. Similarly in another recent study, immunization induced immunity to mutant p53 and tumor rejection in mice [12].

Anti-Id responses have been implicated in the induction of anti-tumor immunity to colorectal cancer [13]. Clinical trials in human colorectal patients [14] with a polyclonal anti-Id raised against the mAb 17-1A that recognizes a colon cancer-associated Ag have shown anti-tumor antibody responses. In another study it was demonstrated that intradermal injection of 2 mg of anti-Id mAb MK2-23, which mimics a high molecular weight human melanoma antigen, elicited anti-tumor antibody responses in melanoma patients [15]. Repeated injections of murine anti-Id mAb were not associated with side effects. Reduction in the size of metastatic lesions were observed in seven of the 37 immunized patients. Another 25 patients with stage IV melanoma were immunized with the mouse anti-Id mAb MK2-23, which bears the internal image of the determinant defined by antihuman high-molecular-weight melanoma antigen (HMW-MAA) mAb 763.74. Fourteen patients developed antibodies that were shown by serologic and immunochemical assays to recognize the same or a spatially close determinant as the anti-HMW-MAA mAb 763.74 and to express the idiotope defined by mAb MK2-23 in their antigen-combining sites. Side effects that were likely to be caused by BCG present in the immunogen consisted of erythema, induration, and ulceration at injection sites. Patients occasionally complained of flu-like symptoms, arthralgias, and myalgias. Three patients who developed anti-HMW-MAA antibodies achieved partial responses, consisting of decreases in the size of metastatic lesions that lasted 52 weeks in one patient and 93 weeks in two others. Survival of the 14 patients who developed anti-HMW-MAA antibodies was significantly longer than that of the nine patients without detectable anti-HMW-MAA immunity development [16].

A human monoclonal Ab2 (105AD7) that interacts with the binding site of 791T/36, a mouse monoclonal antibody against the gp72 antigen, was administered to six patients with advanced colorectal cancer in a phase I clinical study [17]. Cryopreserved peripheral blood mononuclear cells were tested for in vitro proliferative responses by [3H] thymidine incorporation; plasma samples were tested by an enzyme-linked immunosorbent assay for anti-anti-Id and anti-tumor antibodies and for interleukin-2. Proliferative responses to gp72-positive tumor cells were seen in four of five patients tested; parallel in vitro responses to 105AD7 anti-Id antibody were seen in most of these patients. Interleukin-2 was detected in the plasma of the four of six patients after 105AD7 immunization, with peak levels up to 7 units/ml. There was no toxicity related to anti-Id immunization and there were no anti-tumor or anti-anti-Id antibodies reported.

In the following section we will discuss various examples where anti-Id antibodies have been used by us successfully in cancer therapy.

Section snippets

Preclinical and clinical trials with anti-Id vaccines

We have generated monoclonal Id cascades for four different human tumor-associated antigens. The first cascade originated from a T-cell leukemia/lymphoma associated antigen [18], [19], the second one from carcinoembryonic antigen (CEA) [20], the third from human milk fat globule (HMFG) membrane antigen [21] and the fourth one from the disialoganglioside GD2 [22]. In each of these cascades, we have produced TAA-mimicking monoclonal anti-Ids. These monoclonal anti-Ids were characterized

Discussion

There is a renewed interest in the potential of immunologic approaches to cancer therapy. It is, therefore, of considerable interest and importance to discuss the relevance of various vaccine approaches. Anti-Id vaccines represent an elegant approach to generate targeted antigen immunity. The anti-Id approach is less likely to induce autoimmunity if the antigen epitope of interest is not expressed on normal tissues. One of the major problems of human cancer therapy is ‘immune tolerance’, which

Acknowledgements

This work was supported in part by the following grants from the National Institutes of Health (NIH): R01-CA47860; P01-CA57165; R01-CA60000; U01-CA65748; R01-CA72018; RO1-CA 72773 and R01-CA 86025-01. We would like to thank Audrey Morrison for typing the manuscript.

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