The Cancer Journal - Volume 8, Number 6 (November-December 1995)
Cancer vaccines - myth or reality ?
In the present issue of the Cancer Journal, Subiza et al. review the present status of human tumour antigens and the various approaches leading to therapeutically active cancer vaccines. Their conclusion states that "although there is still a long way to go before cancer vaccines become a reality in practical medicine, the concepts and the tools are nowadays much clearer than ever before" (1). No-one could agree with this statement more than I. However, the difficulties met on the long road from the experimental approaches in the laboratory to the clinical reality in the hospital may come from sources other than those expected from studies restricted to anti-tumour immune responses.
From the clinic to the laboratory : in-vivo situation of the immune system of tumour-bearing patients - Based upon the exceptional spontaneous regressions of established human tumours that were interpreted by many as "natural" validations of the immune surveillance theory (2), numerous attempts have been made to stimulate the immune system of tumour-bearing patients. It is obviously out of the scope of this editorial to review all of them, from the use of tumour cell-derived preparations to that of non-antigen-specific stimulants of the immune system. It is striking that the limited, but undoubtedly beneficial therapeutic, results were generally reported using non specific approaches. One explanation is certainly that it is unlikely that a strong specific immune response was obtained using the tumour cell-derived preparations, which limits the interpretation of most of the published data. It certainly remains a major problem in present-day cancer vaccines, as analyzed by Subiza et al. (1). Meanwhile, let us look at the positive results. The use of non-antigen-specific adjuvants, such as BCG has led to significant, although not always reproducible, therapeutic responses in different tumours, such as breast cancer (3). BCG is still used as a therapeutic agent in superficial bladder cancer in man (4). Extensive studies have been conducted on human cells from patients treated with BCG, as well as in experimental in-vivo tumour models to try to understand how it could influence disease outcome. The major cellular target of BCG being the macrophage, much attention was focused on the antitumour activity of this cell type. Indeed, activated macrophages may limit tumour progression by inhibiting the proliferation of, or killing, tumour cells (5). Clinical trials using cytokine-activated macrophages, called Macrophage Activated killers (MAK), are in progress (6). However, whatever the result, we will still be far from understanding the macrophage-mediated clinical effect of BCG, since, beside their anti-tumour activities, activated macrophages also influence the host immune responses, in a complex manner, being antigen-presenting cells as well as producers of suppressive cytokines, such as Transforming Growth Factor bbb (TGFbbb). Everybody accepts that BCG is a complex, almost prehistoric, model for analyzing the mechanisms by which a drug modifies the evolution of a disease. It is composed of living microorganisms, has multiple targets in the body andhas complicated pharmacology. It is therefore inappropriate to use it as a reference.
The 1970s and the early 1980s saw a tremendous breakthrough in our understanding of the immune system. The structures and functions of the molecules of the Major Histocompatibility Complex (MHC) have been characterized, and the way in which immune response genes function has been clarified. The understanding of how T and B lymphocytes "see" antigen has followed the identification of the T cell receptor (TCR). The schemes of cooperation between immunocompetent cells leading to immune response or tolerance are emerging. Finally, relevant to all these phenomenon, and especially to tumour immunology, cytokines were discovered, their genes were cloned, and recombinant, biologically active, proteins were produced industrially. A new era of immunotherapy could then start (7).
Among the cytokines potentially active in cancer, Interleukin-2 (IL-2) occupies a pivotal place. IL-2 is the major growth and differentiation factor of immunocompetent killer cells, including the cytotoxic T lymphocytes (CTL), Natural Killer (NK) cells and monocytes. Indeed, as pioneered by S.A. Rosenberg and his colleagues, (8), many clinical trials were conducted throughout the world, and, after initial enthusiasm (7), led to mixed feelings. In metastatic renal cell cancer and melanoma IL-2-based treatments have induced therapeutic responses. Efficacy of IL-2 as a single agent has been reported in 15-25% of cases in these diseases and could possibly be increased by the addition of other agents such as interferon or chemotherapy (8-10). There is no striking therapeutic effect of IL-2-based therapies in other malignant diseases.
The analysis of a decade of IL-2 therapeutic trials leads to modesty in discussing the impact of immunologically targeted therapeutic approaches. However, these trials demonstrated that the manipulation of the immune system, in the absence of any other known target for IL-2, was sufficient to induce, in some cases, a complete regression of metastatic tumours, leading, in rare but documented patients, to complete cure. In my view, this has been the major knowledge that we have obtained from IL-2-based trials and allows us to try going further with more specific, more active and less toxic approaches.
What have learned about the mechanisms by which IL-2 exerts its beneficial, or detrimental effects? It should have been easier than with BCG since IL-2 is a simple, structurally charactarized, agent, with a limited number of targets in the body and a well defined pharmacology. However, despite rare, and sometimes contradictory reports, suggesting the activation of NK cells (11), the increase of serum soluble IL-2 receptors (12) or that of TNFaaa (13) as surrogates of IL-2-induced clinical responses, the major paramater appears still to be the clinical status of the patients (14). However, in the course of these studies, an interesting observation was made. Both in renal cell carcinoma (15) and in melanoma (16), the serum concentration of another cytokine, IL-6, was predictive of the response to subsequent IL-2 treatment. No patient with an elevated level of plasmatic IL-6 responded to IL-2. In addition, both IL-6 and the CRP induced by IL-6 serum levels were significantly associated with patient survival: an elevated level - before any treatment - being a marker of poor prognosis (16). In fact, IL-6 is thought to be a growth factor for a series of tumours, in their disseminated phase, including multiple myeloma, ovarian cancer lymphoma as well as renal cell cancer and melanoma (reviewed in 11). In contrast, IL-6 has been reported to inhibit the proliferation of primary melanoma cells lines (18). Since the administration of IL-2 induces the production of other cytokines, including IL-6, one sees how complex the understanding of the clinical effects of IL-2 and other cytokines remains.
From the laboratory to the clinic : driving simple concepts to complex physiological situations - In the 1990s, a series of discoveries, underlined by Subiza et al. (1) that may change the overall approach of immunotherapy, from non specific stimulation to specific cancer vaccines, were made.
First of all, the existence of the always postulated, sometimes vaguely described, human tumour-specific antigens was demonstrated, first in melanoma, then in other tumours (19). This finding obviously changes the target of immune intervention from cells to molecules. Secondly, vectors, mostly viral, able to recombine "therapeutic" genes and to introduce them into relevant cells in humans are being constructed, and the first therapeutic trials, using such vectors, are in progress. Thirdly, human monoclonal antibodies are being produced and should provide highly specific, as well as poorly immunogenic, tools for treatment of humans (20).
Therefore, the time has come, finally, when the way leads from science to therapy, rather than trying to understand incomprehensible clinical results. The way may be long but it is charted; there certainly is hope. However, besides the technical points to be resolved, such as the choice of efficient biological or chemical adjuvants usable in humans or learning how to induce a strong cytotoxic T cell response to externally introduced peptides, major issues need to be resolved before the next stretch of the way is clear. Without discussing all of them, I would like to stress the point that the positive effects of the non-specific immunotherapeutic agents, such as BCG or IL-2, may be due to general effects as well as to antigen-specific responses. It is striking, for instance, that the infusion of tumour-derived specific cytotoxic T cells did not always induce better responses than IL-2 alone (21, 22) and that no proof of their advantage has been really provided, although, if a specific immune reaction were responsible for the beneficial effect of IL-2, they should have repeatedly shown an advantage. We have recently observed that tumour-derived T lymphocytes, devoid of cytotoxic activity against the host tumour, were able to complete IL-2-induced therapeutic responses in renal cancer (23), probably through the production of other cytokines exerting an endocrine-like regulatory activity. Also, it should be remembered that a correlation between the therapeutic effects of IL-2 and its endocrine modifying effect, especially on thyro‹d function, has been reported (24).
Conclusion - To conclude, I therefore would stress that, although reductionist approaches designed to analyze specific responses to cancer vaccines are needed to dissect anti-tumour immune responses, as well as to understand immunoselection and tumour escape, they may not be the major step in "scientific" cancer treatment. Rather, the design of scientifically based comprehensive immunotherapeutic approaches will need more basic knowledge on the interaction of the immune systeme with the other systems involved in homeostatis, such as the central nervous system and the endocrine network. Cancer being seen as a systemic disease, even if apparentely localized at certain stages, the manipulation of the immune system to influence the general homeostasis of the body may be a very powerful therapeutic approach. In such a view, antigen-specific tumour vaccines may help in targeting the immune reaction to the tumour sites and, in association with other immuno- or endocrine-modulating agents, provoke a local modification of the tumour environment. If accompanied by a systemic effect, this may result in tumour cell death, or differentiation, or dormancy... The way leading to the use of tumour antigens as vaccines is now open. The way leading to a comprehensive biological treatment of cancers is obviously still not clear and major scientific discoveries are still needed.
Wolf H. Fridman
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