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Clinical Cancer Research Vol. 7, 1112-1115, May 2001
© 2001 American Association for Cancer Research

The Biology Behind

Are Solid Tumor Anti-Idiotype Vaccines Ready for Prime Time?

Commentary re: U. Wagner et al., Immunological Consolidation of Ovarian Carcinoma Recurrences with Monoclonal Anti-Idiotype Antibody ACA125: Immune Responses and Survival in Palliative Treatment. Clin. Cancer Res., 7: 1154–1162, 2001.

Kenneth A. Foon1 and Malaya Bhattacharya-Chatterjee

The Barrett Cancer Center, University of Cincinnati, Cincinnati, Ohio 45267-0502 [K. A. F.], and The Vontz Center for Molecular Studies, Cincinnati, Ohio 45267-0509 [M. B-C.]

Immune approaches to the therapy of cancer have evolved substantially over the past years, from treating patients with nonspecific immune stimulants to a focus on the use of tumor-associated antigens (TAAs)2 as specific targets for immunotherapy. Tumor-specific immunological interventions can be categorized into passive immunotherapy with antibodies targeted directly to tumor cells or active immune therapy via vaccination with tumor cells, tumor cell lysates, peptides, carbohydrates, gene constructs encoding proteins, or anti-Id antibodies that mimic TAAs. Immunotherapy is very effective in certain animal model systems, and it has been used to treat human cancers for several decades. Active immunotherapy of cancer patients with tumor-derived material has been studied by numerous investigators, with positive clinical responses reported. The major problem using tumor material for immunization is that TAAs are typically weakly immunogenic. A common explanation for the absence of antitumor immunity is that the immune system has become tolerant to the TAA. The large majority of TAAs in humans are nonmutated self-antigens. They are likely to be expressed at a higher level by malignant cells than by normal cells because of systemic gene deregulation associated with the cell transformation process. Therefore, development of strategies effective in inducing a strong immune response against self-TAA represents one of the major challenges for the active immunotherapy of cancer. Among the many immunization strategies used to break unresponsiveness of self-TAA, one effective method is to present the critical epitope to the now tolerant host in a different molecular environment. Whereas 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 because they cannot be produced by recombinant techniques.

The immune network hypothesis offers a unique approach to transforming epitope structures into idiotypic determinants expressed on the surface of antibodies. Jan Lindemann in 1973 (1) and Niels Jerne in 1974 (2) proposed theories that describe the immune system as a network of interacting antibodies and lymphocytes. According to this original network hypothesis, the idiotypic interactions regulate the immune response of a host to a given antigen. Both idiotypic and anti-idiotypic antibodies have been used to manipulate cellular and humoral immunity.

The network hypothesis predicts that, within the immune network, the universe of external antigen is mimicked by Ids expressed by antibodies and T-cell receptors. According to the network concept, immunization with a given antigen will generate the production of antibodies against this antigen, termed Ab1 (Fig. 1)Citation . This Ab1 can generate a series of anti-idiotypic antibodies against Ab1, termed Ab2. Some of these Ab2 molecules can effectively mimic the three-dimensional structures of external antigens. These particular anti-Ids, called Ab2ß, which fit into the paratopes of Ab1, can induce specific immune responses similar to the responses induced by nominal antigens. Other anti-Ids generated, designated as Ab2{alpha} and Ab2{gamma}, may not mimic the TAAs. Anti-idiotypic antibodies of the ß type express the internal image of the antigen recognized by the Ab1 antibody and can be used as surrogate antigens. Immunization with Ab2ß can lead to the generation of anti-anti-Id antibodies (Ab3) that recognize the corresponding original antigen identified by Ab1. Because of this Ab1-like reactivity, Ab3 is also called Ab1' to indicate that it might differ in its other idiotopes from Ab1. Several such Ab2ßs 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 as well as cancer (reviewed in Ref.3 ).



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  		Fig. 1. The anti-Id cascade.

 
Anti-Id antibodies that mimic distinct TAAs expressed by malignant cells of different histology or distinct determinants of a TAA have been used to implement active specific immunotherapy in patients with malignant diseases. A number of anti-Ids to a variety of solid tumors (predominantly colon cancer and melanoma) have demonstrated active immune responses in patients (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24) . In this issue of Clinical Cancer Research, Wagner et al. (25) present clinical and immune data on a monoclonal anti-Id antibody designated ACA125 that mimics the CA125 TAA. They report specific anti-anti-idiotypic immune response in 28 of 42 (67%) advanced ovarian cancer patients. These patients generated predominantly IgG immune responses, and they confirmed the Ab1' specificity of these responses with specific binding to CA125-positive ovarian cancer cells, without binding to CA125-negative cells. They also demonstrate specific inhibition of binding of the Ab1 murine monoclonal antibody to CA125-positive cells using patients’ Ab3 sera. Perhaps their most interesting finding was the demonstration of lysis of CA125-positive ovarian cancer cells by peripheral blood lymphocytes from patients immunized with ACA125. They demonstrate that 9 of 16 tested patients’ peripheral blood lymphocytes lysed CA125-positive cells with minimal lysis of CA125-negative cells. It would be important to determine the peptides and class I and/or II antigens that mediated these cytolytic responses.

Survival is also addressed by these investigators. They present data demonstrating a mean survival of 5.3 ± 4.3 months for patients who are anti-anti-idiotypic negative and 19.9 ± 3.1 months for patients who generated an anti-anti-idiotypic response. This was highly significant (P < 0.0001). There was no significant difference between the two groups concerning age, performance status, and number of chemotherapy regimens before vaccine therapy. The immune-responding patients had a higher number of immunizations with ACA125 (16.8 ± 10.8; median, 14.5) in contrast to the immunonegative group (4.2 ± 3.0; median, 3.0). They emphasize that patients in the responder group develop measurable Ab3 responses after a median of three immunizations. They therefore felt that the nonresponding patients had received a sufficient number of immunizations with ACA125 to develop an immune response. However, this may be an inaccurate assessment because patients who are unable to generate immune response are typically patients with rapidly progressive disease, who are quickly removed from study and will likely have the poorest survival. Whereas these survival data are interesting, they must be confirmed in Phase III trials.

The putative immune pathways triggered by an anti-Id antibody are presented in Fig. 2Citation . Anti-Id antibodies are exogenous proteins and are endocytosed by antigen-presenting cells and degraded to 14–25-mer peptides that are presented by MHC class II antigens to activate CD4 helper T cells. Activated Th2 CD4 helper T cells secrete cytokines such as IL-4 and IL-10 that stimulate B cells that have been directly activated by the anti-Id (Ab2ß) to produce Ab1'. The Ab1' binds to the original antigen on tumor cells identified by the Ab1 (original immunizing murine antibody). In addition, activated Th1 CD4 helper T cells secrete cytokines that activate T cells, macrophages, and natural killer cells. The latter may lyse target cells directly and/or serve as effector cells for antibody-dependent cell-mediated cytotoxicity. Th1 cytokines such as IL-2 also contribute to the activation of a CD8 cytotoxic T-cell response. A second pathway is represented by the induction by anti-idiotypic antibodies of HLA class I antigen-restricted TAA-specific CTLs because of amino acid sequence homology with TAAs. Furthermore, investigators (26) have shown that a conformational and a linear peptide derived from an antigenic moiety may express the same determinant, despite the lack of amino acid sequence homology. Therefore, peptides derived from the heavy and/or light chain of the anti-Id antibody may mimic the corresponding antigen despite the lack of amino acid sequence homology with the Id mimicking the antigen and with the antigen itself. Peptides that are 9/10-mer and contain HLA class I antigen-binding motifs may be presented in the context of MHC class I antigens to activate CD8 cytotoxic T cells that are also stimulated by IL-2 secreted by Th1 CD4 helper T cells. Activated CD8 cytotoxic T cells secrete perforin, granzymes, IFN-{gamma}, and tumor necrosis factor ß and make direct contact with tumor cells leading to direct cell lysis. This mechanism may account for the generation of TAA-specific cytotoxic T cells after immunizations with anti-Id antibodies that has been described both in an animal model system (27) and in patients with malignant diseases (8 , 20) .



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  		Fig. 2. Putative immune pathways for anti-Id vaccines.

 
These data from different groups, supported by Wagner et al. (25) , clearly indicate that anti-Id antibody vaccines can break immune tolerance to self-TAA and evoke an Ab1-like antibody (Ab1') as well as cellular immune response in cancer patients. The level of immune response may correlate with time to progression and survival. Although complete clinical response was relatively rare, regression of metastatic lesions and survival prolongation have been described in many patients immunized with anti-Id vaccines. Most of these clinical trials accrued patients who failed conventional therapy and had advanced disease for ethical reasons. The encouraging results obtained with the advanced group of patients suggest that anti-Id vaccine therapy might be curative with a smaller tumor burden.

The majority of the anti-Id antibodies used as immunogens, including the vaccine used by Wagner et al. (25) , are murine monoclonal antibodies. One concern was that murine antibodies, by virtue of their xenogeneic origin, will elicit a strong antibody response in humans, which will neutralize the murine antibodies, thus diminishing their half-life through rapid clearance. Although this is true for "passive" i.v. administered murine Ab1 antibodies, it is not the case for "active" immunization with murine anti-Id antibody vaccines. It is most likely that the human antimouse antibodies bind to the anti-Id antibodies, and the entire complex is endocytosed by antigen-presenting cells. Hundreds of patients have been treated with different murine anti-idiotypic antibodies, followed by humoral and cellular responses. High-titer Ab3 (Ab1') responses as well as CD4 T-cell proliferative responses were seen in cancer patients after repeated vaccinations (28) . The human antimouse antibody responses, contrary to expectations, have not been associated with side effects.

Another concern was the duration of the immune response. Although it is true that the immunity from a single vaccination is not necessarily long-lasting, patients have been boosted monthly for more than 5 years. They have continued to generate an immune response. Vaccination is well tolerated, with only swelling and erythema at the site of injection and minimal systemic symptoms. A monthly schedule has been well tolerated.

Another issue is that anti-Id antibodies might primarily generate an IgM immune response because of the conformational mimicry of the three-dimensional shape of TAAs. This is not the case with most anti-Id vaccines. The predominant immunoglobulin response after multiple immunizations is IgG, distributed among most subclasses, including IgG1. In addition, patients’ Ab3 sera routinely mediate antibody-dependent cellular cytotoxicity. Most patients have demonstrated idiotypic-specific and antigen-specific CD4 helper T-cell responses, and in some cases, such as Wagner et al. (25) , CTL activity has been demonstrated (8 , 20) . Like the antibody responses, the T-cell responses are long-lasting and continue to be maintained over the course of vaccine therapy.

The anti-Id antibodies used by different investigators differ markedly in their immunogenicity, as measured by the percentage of immunized patients who raised an immune response and/or by the titer of the TAA-binding Ab3 or TAA-specific T-cell responses. One of the reasons could be the characteristics of the particular anti-Id antibody in terms of the extent to which it structurally and functionally mimics the TAA. The greatest challenge in immunotherapy by means of anti-Id vaccines is to identify the optimal anti-Id antibody (Ab2ß) for a TAA system. In general, the antigen mimicry by anti-Id antibodies reflects structural homology in the majority of the cases, and amino acid sequence homology in a few of them (14 , 29 , 30) .

It is interesting that many anti-Id antibody vaccines are effective in eliciting immune responses despite the absence of a strong adjuvant. Aluminum hydroxide precipitation, although considered weakly immunogenic, appears to be quite adequate in eliciting immune responses with many anti-idiotypic antibodies. Aggregation of soluble idiotypic determinants by aluminum hydroxide precipitation likely helped to increase antigenicity. Also, the antibody is a foreign protein and was injected as an intact immunoglobulin. The Fc portion of the murine immunoglobulin likely served as a "carrier" to help promote the immune responses. In our experience, conjugation of anti-Id to keyhole limpet hemocyanin in combination with a strong adjuvant was necessary to raise optimal immunity in mice. Interestingly, as we moved to higher species, such as rabbits, keyhole limpet hemocyanin coupling was not necessary; only a strong adjuvant was needed, whereas in monkeys and humans, we could use anti-Id vaccines with a weak adjuvant such as aluminum hydroxide precipitation to induce a strong immune response.

As observed with other immunotherapy approaches, heterogeneity of TAA expression may also pose a problem for anti-Id vaccine therapy that may be addressed by using mixtures of anti-Id vaccine preparations directed against multiple-target antigens collectively expressed by the vast majority of tumor cells. For example, both carcinoembryonic antigen and human milk fat globule antigen are expressed by most colon, breast, ovary, and non-small-cell lung carcinomas, and a combination of vaccines could be used to treat these patients. Combining anti-Id vaccines with recombinant vaccines and/or peptides that predominantly target a CD8 cytotoxic T-cell response would also be a logical next approach to anti-Id vaccine therapy.

We believe that the anti-Id vaccine approach may have an important role in the treatment of a variety of human solid tumors, and Phase III trials are currently under way. Active specific immunotherapy with anti-Id antibodies are also being tested in combination with other conventional and experimental therapies to overcome the multiple mechanisms by which tumor cells escape immune recognition and destruction.

FOOTNOTES

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at The Barrett Cancer Center, 234 Goodman Street, Suite 1091, University of Cincinnati, Cincinnati, OH 45267. Phone: (513) 584-7698; Fax: (513) 584-5680; E-mail: kenneth.foon{at}uc.edu Back

2 The abbreviations used are: TAA, tumor-associated antigen; IL, interleukin; Id, idiotype. Back

Received 2/27/01; accepted 3/29/01.

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Key Article

Immunological Consolidation of Ovarian Carcinoma Recurrences with Monoclonal Anti-Idiotype Antibody ACA125: Immune Responses and Survival in Palliative Treatment : See The Biology Behind: K. A. Foon and M. Bhattacharya-Chatterjee, Are Solid Tumor Anti-Idiotype Vaccines Ready for Prime Time? Clin. Cancer Res., 7:1112–1115, 2001.
Uwe Wagner, Siegmund Köhler, Silke Reinartz, Patrick Giffels, Jens Huober, Kirsten Renke, Harald Schlebusch, Hans-Jürgen Biersack, Volker Möbus, Rolf Kreienberg, Thomas Bauknecht, Dieter Krebs, and Diethelm Wallwiener
Clin. Cancer Res. 2001 7: 1154-1162. [Abstract] [Full Text] [PDF]



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