Japanese Journal of Clinical Oncology 30:469-471 (2000)
© 2000 Foundation for Promotion of Cancer Research
Editorial |
On The Immunomodulating Effects of Anti-Cancer Drugs and Their Therapeutic Exploitation
Roswell Park Cancer Institute, Buffalo, NY, USA
INTRODUCTION
Anti-proliferative and cytotoxic agents are widely used alone and in combination among themselves and/or with different modalities of treatment in attempts to design effective anti-cancer therapies. In most cases, drug regimens involve the use of the agents at or near the maximum tolerated dose (MTD) with the aim of eradicating the greatest possible number of neoplastic cells. At present, however, it is becoming increasingly clear that several of these agents, in addition to their antitumor action, also affect host phenomena such as angiogenesis (1) and immune responses (2) and that some of these effects may have therapeutic potential. It should be noted that whereas maximum direct antitumor effects are usually obtained at the MTD, the additional potentially beneficial actions on host biological systems are optimally induced at doses which are lower than the MTD (3,4). For biological agents these doses have been defined as ‘optimal biological response modifier doses’ (OBRMD) (5). In fact, at high doses most anti-proliferative and cytotoxic agents have therapeutically undesirable effects, such as the induction of immunosuppression, temporary as it might be (6).
The anti-angiogenic effects of an anti-cancer drug such as adriamycin (1) or cyclophosphamide (7) are being studied in experimental systems. These drugs are effective at doses and regimens different from those customarily used in cancer chemotherapy, whether given alone or in combination with anti-angiogenic agents (7). The effects of anti-cancer drugs on the immune systems have been studied for the past 40 years but only during the last decade or so have the mechanisms involved in these effects begun to be understood (2,3).
IMMUNOMODULATION BY ANTI-CANCER DRUGS
Initially, anti-cancer drugs were thought to be immunosuppressive based on their anti-proliferative and cytotoxic actions, which also determine their antitumor effects (2). Nevertheless, as early as the 1960s it became apparent that some of these agents can exert curative effects in experimental tumor models owing to the cooperation of host defenses against the tumor (2,6,8,9). It was concluded, therefore, that these agents can be at least permissive in their action such that antitumor host defenses can be activated, not unlike what happens in anti-infection therapies. As more information became available, this early simplistic assumption had to be modified to include the notion that at least some of these agents under certain conditions can directly or indirectly stimulate immune responses (2,3). Thus in a variety of model systems it was found that at low to moderate doses augmentation of the immune response was induced by cyclophosphamide and other alkylating agents, 6-mercaptopurine, methotrexate, 5-fluorouracil, arabinosylcytosine, vinblastine, vincristine, doxorubicin, bleomycin, mitomycin C, cis-platinum and nitrosourea (3). Taxol was more recently found to stimulate macrophage functions in immune systems (2,10). The example of doxorubicin serves to outline the complexities that can characterize the immunomodulation induced by certain anti-cancer agents.
Treatment of mice with doxorubicin at moderate doses, which however have therapeutic antitumor effects in mouse tumor model systems, led to augmentation of cytotoxic T lymphocyte (CTL) responses to syngeneic tumors; the antitumor action of cytotoxic macrophages (MO) was also augmented (2,3). The stimulation of MO activation by the drug also included increased accessory function, production of interleukin 1 (IL-1), prostaglandin E2 and tumor necrosis factor 
(TNF); natural killer (NK) cells were inhibited in the spleen but were stimulated in the peritoneal cavity and the inhibitory effects were reversed by indomethacin (2,3). Also, the activity of lymphokine activated killer (LAK) cells could be augmented or inhibited depending on the conditions (2,3).
Because TNF has autocrine functions in regulating MO activation, it is possible that this action may be in part instrumental in the activation of MO by doxorubicin. The increased production of both IL-1 and TNF following drug treatment is preceded by increases in the corresponding mRNA (11), suggesting that it occurs at the transcriptional level through a basic action on the expression of genes regulating the levels of these cytokines in target cells. Doxorubicin also stimulates the production of interleukin 2 (IL-2) by T helper cells and this effect could also be secondary to MO activation via increased production of IL-1. On the other hand, the drug was found to inhibit T regulatory cells, different from the precursor of T suppressor cells inhibited by cyclophosphamide, and this inhibition may also contribute to the stimulation of CTL development (2,3). It is also possible that the specific apoptosis of CD4+ CD8+ thymocytes induced by the drug is involved in the increased CTL development observed (12). In conclusion, the multiple immunomodulating actions of doxorubicin could be reduced to two basic effects, namely stimulation of MO and augmentation of the development of CTLs. The possible functional relationship between these two effects requires further elucidation.
THERAPEUTIC EXPLOITATION OF THE IMMUNOMODULATING EFFECTS OF DOXORUBICIN
The immunomodulating effects of a drug such as doxorubicin can be instrumental in determining the therapeutic effects of the drug, particularly if the agent is given in combination with certain cytokines or other immunomodifiers. Indeed increased attention is being given also clinically to the therapeutic opportunities offered by the combination of anti-cancer drugs with immunomodifiers. Studies of combinations of doxorubicin with IL-2 in mice bearing a syngeneic tumor have in fact shown that regimens with low non-toxic doses of both combinants induce long-term cures which are dependent on T cell responses (2,3,13,14). It should be noted that in the EL4-C57BL6 mouse model used, 10 lymphoma cells will kill the host. The therapeutic cures were elicited in mice bearing either doxorubicin-sensitive or doxorubicin-resistant tumors, confirming that tumors resistant to a drug are still sensitive to the effects of immune responses (3).
The cured mice had memory T-cell dependent resistance to re-implantation of the same tumors and this resistance lasted more than 2.5 years from the original curative treatment (15). As has now been confirmed in different systems, prolonged treatment with low doses of IL-2 is required to obtain definitive therapeutic effects. It seems promising that the synergistic curative effects of doxorubicin and IL-2 were obtained at doses which are non-toxic and much below those causing the well-known dose-limiting toxicities of the two combinants. In addition, most of the positive immunomodulating effects of doxorubicin were also obtained with 5-iminodaunorubicin, a less cardiotoxic analog, and with doxorubicin encapsulated in liposomes, namely a preparation with greatly reduced cardiotoxicity (3). The overall information available justifies the conclusion that it seems possible to separate the immunomodulation-dependent anti-cancer therapeutic effects of drugs like doxorubicin from its dose-limiting toxic effects (3).
INVESTIGATIONS IN HUMANS
Relatively little work has been done in humans towards verifying the immunomodulating effects of doxorubicin or of other anti-cancer drugs, except for cyclophosphamide (3), and correlations have not been drawn between therapeutic responses to doxorubicin and its effects on the immune system. Regimens with doxorubicin designed to exploit therapeutically the immunomodulating properties of the drug have also not yet been fully tested. In early studies (16,17) of the lymphocyte activation induced by allogeneic cells in a mixed lymphocyte culture, it was found that peripheral blood lymphocytes obtained from cancer patients 7 days after treatment with doxorubicin showed an about twice as high cytotoxicity with respect to the pretreatment control values. Analogous results were obtained with doxorubicin added to the primary stimulation cultures. Increased production of IL-2 was also noted whereas no effects on NK cells seemed to be induced. These results are indeed consistent with the results obtained in mice. Very preliminary results obtained at Roswell Park Cancer Institute in a study aimed at testing in cancer patients the validity of the hypothesis that appropriate combinations of doxorubicin and IL-2 may induce therapeutically profitable immunomodulating effects are also consistent with the overall results obtained in mice (personal communication). Hence it seems reasonable to suggest the realistic possibility that the immunomodulating action of certain anti-cancer drugs may be exploited therapeutically in humans (3).
CONCLUDING REMARKS
Extensive information is being accrued on the molecular and cellular mechanisms of immune responses and on the unique characteristics of tumor immunity and of tumor escape capabilities. The existence of tumor-associated antigens in humans and the demonstrated effects of certain types of immunotherapy also support the expectation that treatments with immunomodulating agents may hold promise in cancer therapeutics. As suggested by the results summarized here, anti-cancer drugs with immunomodulating actions should be included in the group of agents which are to be tested for immunotherapeutic effects; as is the case for other immunotherapy approaches, it may be difficult to optimize such treatments since their efficacy is likely to be dependent on conditions present in individual patients and at certain stages of neoplastic disease progression. The fact that responses may occur according to a bell curve dose relationship and not with dose escalation to MTD adds further to the obstacles to be encountered clinically. Notwithstanding the difficulties alluded to above, based on progress currently achieved with various immunotherapeutic approaches (2), it seems reasonable to reconfirm the expectation formulated some years ago (18) that therapeutic advantages can also be obtained with a judicious exploitation of the immunomodulating effects of certain anti-cancer drugs.
REFERENCES
1 Steiner R. Angiostatic activity of anti-cancer agents in the chick embryo chorioallantoic membrane (CHE-CAM) assay. In: Steiner R, Langer R, editors. Angiogenesis. Key Principles – Science – Technology – Medicine. Basle: Birkhauser Verlag 1992;449–54.
2 Mihich E. Historical overview of biologic response modifiers. Cancer Invest 2000;18:456–66.
3 Mihich E, Ehrke MJ. Immunomodulation by anti-cancer drugs. In: DeVita VT, Hellman S, Rosenburg SA, editors. Biologic Therapy of Cancer. Philadelphia, PA: JB Lippincott 1991;776–86.
4 Ehrke MJ, Mihich E. Immunopharmacology of anti-cancer agents. In: Hadden JW, Szentivanyi V, editors. Immunopharmacology Reviews, Vol. 2. New York: Plenum Press 1996;103–27.
5 Mihich E, Fefer A, editors. Biological Response Modifiers: Subcommittee Report. Monograph No. 63. Washington, DC: National Cancer Institute 1983.
6 Mihich E, editor. Immunity, Cancer and Chemotherapy: Basic Relationships on the Cellular Level. New York: Academic Press 1967.
7 Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O’Reilly MS, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 2000;60:1878–86.
8 Ferrer JF, Mihich E. Prevention of therapeutically-induced regression of sarcoma 180 by immunologic enhancement. Cancer Res 1968;28:245–50.
9 Mihich E. Combined effects of chemotherapy and immunity against leukemia L1210 in DBA/2 mice. Cancer Res 1969;29:848–54.
10 Mullins DW, Alleva DG, Burger CJ, Elgert KD. Taxol, a microtubule-stabilizing antineoplastic agent, differentially regulates normal and tumor-bearing host macrophage nitric oxide production. Immunopharmacology 1997;37:63–73.[Web of Science][Medline]
11 Berleth E, Ujhazy P, Henn A, Meer J, Dolnick B, Ehrke MJ, et al. Doxorubicin (DOX)-induced immunomodulation of murine peritoneal exudate cells (PECs): effect on cytokine mRNA levels and secreted protein. Proc Am Assoc Cancer Res 1997;38:119.
12 Zaleskis G, Berleth E, Ehrke MJ, Mihich E. Doxorubicin induced DNA degradation in murine thymocytes. Mol Pharmacol 1994;46:901–8.[Abstract]
13 Ho RLX, Maccubbin D, Zaleskis G, Krawczyk C, Wing K, Mihich E. Development of a safe and effective adriamycin plus interleukin 2 therapy against both adriamycin sensitive and resistant lymphomas. Oncol Res 1993;5:373–81.[Web of Science][Medline]
14 Ho RLX, Maccubbin D, Ujhazy P, Zaleskis G, Eppolito C, Mihich E. Immunological responses critical to the therapeutic effects of adriamycin plus interleukin 2 in C57B1/6 mice bearing syngeneic EL4 lymphomas. Oncol Res 1993;5:363–72.[Web of Science][Medline]
15 Ehrke MJ, Verstovsek S, Zaleskis G, Ho RLX, Ujhazy P, Maccubbin D, et al. Demonstration of long-term specific anti-primary EL4 lymphoma immunity in 2-year old cured mice. Cancer Immunol Immunother 1996;42:221–30.[Web of Science][Medline]
16 Arinaga S, Akiyoshi T, Tsuji H. Augmentation of the cell-mediated cytotoxic response induced in mixed cell culture by adriamycin. Jpn J Cancer Res 1985;76:414–9.[Web of Science][Medline]
17 Arinaga S, Akiyoshi T, Tsuji H. Augmentation of the generation cell mediated cytotoxicity after a single dose of adriamycin in cancer patients. Cancer Res 1986;46:4213–6.
18 Mihich E. Biological response modifiers in therapeutics: potential and limitations. Cancer Detect Prev 1988;12:531–5.[Web of Science][Medline]
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