- Email: [email protected]
Present status of biological response modifiers in cancer
BIOLOGICAL II. Cancer
RESPONSE MODIFIERS:
Present Status of Biological Response Modifiers DAVID
R. PARKINSON, M.D.,
Bethesda,
Maryland
iological response modification therapies in cancer may be defined as new therapies based on the developing knowledge of the biology of the interaction between tumor and host. This article will discuss single-agent cytokine therapy, leaving the integration of cytokines with other therapies to be addressed in other articles in this symposium. Since genetic engineering has made recombinant cytokines available in pharmaceutical quantities, interleukin 2 (IL-2) has been the most frequently employed of these agents. IL-2 activity is extraordinarily dose- and schedule-dependent. Studies by Rosenberg and his colleagues’ in the 1980s showed that after administering a single intravenous bolus of IL-2, rebound lymphocytosis occurred, associated with activated natural killer cells or so-called lymphokine-activated killer (LAK) cells. One could harvest extraordinary quantities of these activated and often cytotoxic lymphocytes, incubate them, and give them back to the patient. Such high-dose IL-2 treatment was the first form of biologic therapy that gave reproducible antitumor activity with an agent that does not directly affect tumor cells but alters host immune reactions. Randomized clinical trials of IL-2 therapy have been carried out in patients with renal cell cancer and with melanoma. Approximately 5% of renal cell cancer patients go into complete remission with a high-dose IL-2 regimen. Approximately 15%’ of such patients go into partial remission, and in about 33% of these? the partial remission is sustained. How do patients who respond to this treatment diff’er from those who do not? From the beginning of such trials it was clear that toxicity varies from patient to patient.. Some tolerate the cytokine whereas others experience hypotension and other dose-limiting problems related to increased vascular permeability after one or two doses of high-dose B-2. Thanks to studies in the late 1980s such as Mier et al.’ we now know that much of the cardiovascular toxicity of 1L-2 is mediated by the IL-2 induction of
B
6A-54s
December
29, 1995
in Cancer
The Amencan
Journal of Medune
tumor necrosis factor-a (TNF-LU). The TNF-(w genes are located on the short arm of chromosome 6, in the middle of the major histocompatability complex. We can show a definite linkage between a subclass of the human leukocyte antigens governed by genes of this complex and the ability to tolerate IL-2.” Thus, genetic differences between individuals translate into quantitative differences in their production of TNF-LU in response to the same stimulus. Many issues related to the therapeutic use of IL-2 remain unresolved. The approved regimen in the United States is a high-dose bolus three times a day, whereas in Europe it tends to be a continuous infusion However in both Europe and North America 95% of IL-2 used is administered chronically, subcutaneously, and in low doses, despite little published evidence that these regimens lead to durable, complete remission. Important randomized trials examining different doses and schedules of IL-2 as a single agent in renal-cell cancer and of IL-2 therapy after bone marrow transplantation in non-Hodgkin’s lymphoma are now underway. The National Institutes of Health is also sponsoring randomized trials to evaluate the usefulness of IL-2 to maintain remission in patients with acute myeloblastic leukemia, based on the observation that low-dose IL-2 regimens in some animal models have remarkable adjuvant effect. The biology of the dose-limiting toxicity of IL-2 is largely understood; studies are trying to obviate such toxicity without effecting its antitumor activity.’ Trials of other single-agent cytokines have been going on for several years. IL-4 has some activity, largely in B-cell lymphomas and in myeloma. IL-6 has antitumor activity in some animal models, but interest is now focused more on its use as a thrombopoietin than as an antitumor agent. The National Cancer Institute is now planning Phase I and Phase II trials of IL-12, probably the most interesting cytokine currently entering investigation. This cytokine is composed of two relatively large, cova-
Volume 99 (suppl 6A)
SYMPOSIUM ON CHEMOTHERAPY/ PARKINSON
cannot only be prevented but also t.reated by such a lently linked peptitles. Its half-life is thus measured vaccine approach. in hours, as compared to that of other cytokines, It is probable that many currently outstanding whose half-lives are measured in minutes. It is of issues in the cancer vaccine field, such RSwhich promore interest now in t,reating infectious disease and teins to use and whether to use epitopes or whole as an adjuvant to cancer vaccine development than proteins, will be resolved in the nest 2 years. as a single agent against tumors.” The filet that a gene can be put into a somatic cell Studies of therapies using IL-2 and LAK cells in and made to express a functioning protein is being combination do not clearly show that LAK cells applied in a number of other therapy strategies; adds to the anti-tumor activity of IL-2. As a result, >lOO gene therapy cancer protocols are currently there is a move to study lymphocytes actually haractive in the I!nited States. IZetroviruses have been vested from within the tumor itself, the so-called tumor-infiltrating lymphocytes (TIL). Good re- the most widely used vehicle for delivering genes. sponse rates have been observed in patients who In both animal models anti humans, gene therapy received very-high-dose IL-2 plus TII, cells; some has been able to induce the generation, even from previously nonimmunogenic tumors, of antigenpatients respond to TIL therapy after failing IL-2 specific antitumor T cells. Making TII, cells more alone.” An important contribution of such studies has adive by transfecting them with the gene for TNF, however, has proven difficult. in clinical practice. been the chwtcterization of the antigens that. TIL A different approach is to use tumor blood vessel cells recognize. Initially, lymphocytes harvested from a melanoma are not, activated; they cannot be biology as a basis for biological therapeutic strdegies. There is a remarkable interaction between shown to be cytotoxic or releasing cytokines. They tumor cells, the host. and T-cell-intluced blood vesbecome activated when cultured in high-(lose IL-2 sel formation. Many tumors encourage the growth and eliminate any melanoma cells from the culture. of their own blood supply by manifesting a series uf These cytotoxic T cells recognize :mtigens thitt oligopeptitles or polypeptides. (+rowth factors that are present, as small oligopeptides, usually breakdown pro~lucts of cellular prwteins. Perhaps the stimulate endothelial cell growth and blood vessel most remarkxble paradigm change over the last formation are also proclucetl in the interact,ions bedecade has been the realization that essentially an) twen tumor cells and inflamm~~tory ~11s. A Roston protein within the cell (aan serv(’ as an antigen. study found high levels of fihroblast growth factors Small oligopeptides are transported to the cell sur- c~scretetl in thd urine of pa&n t s with blatltler ( wftf’ace by ~vell-nl?der.stoud mechanisms and sit in thP tissue sawomt~s, and other t.unlors. Numerous H,utlgroove of the clnss I major llistocomp~~tability anti- ies have now clocumented that t,he more hloocl vesgen. A T cell, on recognizing these peptides, can be sels there are per unit, of space in a primary tumor. activated to become cytot.oxic 0~ wtual1.v ln~~tluce the> mow aggwssive it is. Thus, thwe is abundant cytokines. evi(lencc that tumors cannot ~t*ow without forming These findings have led to the tlevrlol~mrnt of t,loocI vessels. UXI that blocking thew angiogenic new recombinant cancer vaccines. The idea of can- pt~ptitles may halt tumor gr~owt.h.7 Many agents that have anti-all~iogc~nic activity in cer vaccines is its old as I,ouis Pasteur, but until recently the literature on the subject was unconvitro or in animal models, such as interferon-a, and vincing. Most vaccine mixtures were crude. Antithalidomide-of low toxicity except in the first trigens were undefined. It was difficult to determine mester of pregnancy---are nwv entering clinic:*1 whether a vaccination was even inducing an antitutrials. mor response, let alone what the nature of that reAnother therapeutic strategy relates to antitusponse was. The National Cancer Institute is now mw neovasculature. Such agents as TNF-tu ant1 carrying out or sponsoring >50 cancer vaccine tr*i- CM-101 appear to act directly on the tumor entloAS, each of which is looking at a defined potential thelium. atdigen, including MART-I, gp100, ant1 tyrosinase TNF-cu has proven to be very active when used in for treatment of melanom:~s; carcinoembryonic an- combination with melphalan in isol;ltetl limb perfutigen (CEA) for adenocarcinomas; some of the pap- sion of recurrent melanoma ant1 soft-tissue sarilloma viruses for cervical cancer: ant1 mutatetl on- COWld cogenes such as ras and P-53. UwlOl, a complex polysacchtwitle producetl by One interesting approach uses ;1 virus jnto \vhi& /3-hemolytic streptococcus, can kill newborn infants a gene for a tumor vaccine has been integratetl. A by binding to the pulmonary entlothelium and inPhase I trial at the National Cancer Institute has ducing inflammation. Tumors also express t,he reshown in murine models that CEA-positive tumors ceptor to which this polysacch;u*ide binds. Experi-
Derember
29, 1995
The American
Journal of Medicine
Volume 99 (suppl 6A)
6A-55s
SYMPOSIUM ON CHEMOTHERAPY/ TURSZ
mentally, therapy with CM-101 can result in tumor necrosis secondary to obliteration of tumor vasculature.” The therapeutic window this opens has been explored in a Phase 1 trial of CM-101. Unlike the agents discussed above, which work through the immune system or through blood vessel disruption, differentiation agents work directly on tumor cells. A host of them are in, or going into, clinical trials. Differentiation therapy either up- or down-regulates the expression of genes that control proteins involved in signal transduction or in cellcycle regulation. The most commonly used agents, the retinoids, some of which are approved for clinical use in the United States. Such compounds, derived from vitamin A, are taken up within a cell and bind to nuclear receptors where they act as transcriptional regulators. TJsing this mechanism therapeutically has led to comp1et.e responses in molecularly defined cases of acute promyelocytic leukemia. In combination with interferon, 134s retinoic acid has been used in squamous-cell tumors.!’ In summary, the emerging understanding of the biology of the relationship of tumors with the host has made it possible to manipulate subtle differences between host and tumor POas to treat c’dncer. Modern medicine is beginning to understand the antigens and the antitumor mechanisms, and it
Combination THOMAS
TURSZ,M.D.,
Ph.D.,
19%
REFERENCES 1. Rosenberg SA, Lotze MT, Muul LM, et al. Observatrons on the systemic admInIstration of autdogous iymphokme-activated kllier cells and recombinant rnterleukm-2 to patients wrth metastatic cancer. N Engl J Med 1985; 313: 14851492. 2. Mier JW, Vachino G, Van Der Meer JWM, et al. Induction of circulatrng tumor necrosis factor (TNF alpha) as the mechanism for the febrile response to Interleukln-2 (IL-21 rn cancer patients. J Clan lmmunol 1988; 8: 426-436. 3. Marincola FM, Venron D, White D. et al. HLA association with response and toxtcIty In melanoma pabents treated with tnterleuktn 2-based Immunotherapy. Cancer Res 1992; 52: 6561-6566. 4. Sznol M, Parkinson DR. Cllnrcal applrcatrons of IL-2. Oncology 1994; 8 61-67. 5. Brunda MJ, Luistro L, Warner RR, et al. Antrtumor and antimetastatic activrty of Interleukrn-12 agatnst munne tumors. J Exp Med 1993; 178: 1223-1230. 6. Rosenberg SA, Yannelil JR, Yang JC, et al. Treatment of patients with metastatlc melanoma using autologous lnftltrattng lymphocytes and Interleukrn-2. J Nat1 Cancer inst 1994; 86: 1159-l 166. 7. Folkman J. Anglogenesis and breast cancer. J Clan Oncol. 1994; 12: 441-443. 8. Hellerqvlst CG, Thurman GB, Page DL, et al. Antitumor effects of GBS toxrn: a polysaccharrde exotoxin from group B beta-hemolytlc streptococcus. J Cancer Res Clan Oncol 1993; 120: 63-70. 9. Degos L, Parkinson DR leds) Retlnolds In Oncology, Berlin: Springer, 1995.
Wlejuif,France
minority of the marriages between biologic response modifiers (BRMs) and conventional chemotherapy are synergistic. The vast majority are merely additive or neutral, and some are antagonistic, with high-grade toxicity. Despite much experimental work, current medical knowledge is still unable to predict whether any such marriage of oncologic treatments will succeed. Most animal and experimental models for stutlying the association between BRIMS and chemolherapeutic agents have immunologically intact hosts, tumors sensitive to cytokine treatment, or other features that, because they are isolated from the complexity of interactions within the human body, have iittle relevance to real human cancers. Some chemotherapy agents may have minor immunomodulatory properties that synergize with some immunotherapeutic agents. For example, to December 29,
tional Cancer Institute. NatIonal Institutes of Health, 6130 Executive Boulevard,
of BRMs with Chemotherapy
A
6A-566
should be possible to use these mechanisms much more intelligently, and hopefully with more success and less toxicity, in the future.
The American
Journal
of Medicine
consider agents such as interferon and interleukin-2 (IL-Z) solely as pure immunomodulatory drugs would be a mistake. Such agents have a broad spectrum of action including nonimmunologic uses. IL-Z, for instance, is responsible for the capillary leakage syndrome, which affects the pharmacokinetics and thus the distribution of some drugs in the body. Studies have shown that IL-2 (foes not affect the pharmacokinetics of cisplatinum. There are indications that IL-2 can modify the pharmacokinetics of dacarbazine (DTIC), but this has not yet led to clinical application. There are indications of connections between drug resistance and immunosensitivity. For example, there are data showing that those non-smallcell lung carcinoma cells that are resistant to cisplatinum are also more sensitive to natural killer toxicity.
Volume 99 (suppl 6A)
RESPONSE MODIFIERS:
Present Status of Biological Response Modifiers DAVID
R. PARKINSON, M.D.,
Bethesda,
Maryland
iological response modification therapies in cancer may be defined as new therapies based on the developing knowledge of the biology of the interaction between tumor and host. This article will discuss single-agent cytokine therapy, leaving the integration of cytokines with other therapies to be addressed in other articles in this symposium. Since genetic engineering has made recombinant cytokines available in pharmaceutical quantities, interleukin 2 (IL-2) has been the most frequently employed of these agents. IL-2 activity is extraordinarily dose- and schedule-dependent. Studies by Rosenberg and his colleagues’ in the 1980s showed that after administering a single intravenous bolus of IL-2, rebound lymphocytosis occurred, associated with activated natural killer cells or so-called lymphokine-activated killer (LAK) cells. One could harvest extraordinary quantities of these activated and often cytotoxic lymphocytes, incubate them, and give them back to the patient. Such high-dose IL-2 treatment was the first form of biologic therapy that gave reproducible antitumor activity with an agent that does not directly affect tumor cells but alters host immune reactions. Randomized clinical trials of IL-2 therapy have been carried out in patients with renal cell cancer and with melanoma. Approximately 5% of renal cell cancer patients go into complete remission with a high-dose IL-2 regimen. Approximately 15%’ of such patients go into partial remission, and in about 33% of these? the partial remission is sustained. How do patients who respond to this treatment diff’er from those who do not? From the beginning of such trials it was clear that toxicity varies from patient to patient.. Some tolerate the cytokine whereas others experience hypotension and other dose-limiting problems related to increased vascular permeability after one or two doses of high-dose B-2. Thanks to studies in the late 1980s such as Mier et al.’ we now know that much of the cardiovascular toxicity of 1L-2 is mediated by the IL-2 induction of
B
6A-54s
December
29, 1995
in Cancer
The Amencan
Journal of Medune
tumor necrosis factor-a (TNF-LU). The TNF-(w genes are located on the short arm of chromosome 6, in the middle of the major histocompatability complex. We can show a definite linkage between a subclass of the human leukocyte antigens governed by genes of this complex and the ability to tolerate IL-2.” Thus, genetic differences between individuals translate into quantitative differences in their production of TNF-LU in response to the same stimulus. Many issues related to the therapeutic use of IL-2 remain unresolved. The approved regimen in the United States is a high-dose bolus three times a day, whereas in Europe it tends to be a continuous infusion However in both Europe and North America 95% of IL-2 used is administered chronically, subcutaneously, and in low doses, despite little published evidence that these regimens lead to durable, complete remission. Important randomized trials examining different doses and schedules of IL-2 as a single agent in renal-cell cancer and of IL-2 therapy after bone marrow transplantation in non-Hodgkin’s lymphoma are now underway. The National Institutes of Health is also sponsoring randomized trials to evaluate the usefulness of IL-2 to maintain remission in patients with acute myeloblastic leukemia, based on the observation that low-dose IL-2 regimens in some animal models have remarkable adjuvant effect. The biology of the dose-limiting toxicity of IL-2 is largely understood; studies are trying to obviate such toxicity without effecting its antitumor activity.’ Trials of other single-agent cytokines have been going on for several years. IL-4 has some activity, largely in B-cell lymphomas and in myeloma. IL-6 has antitumor activity in some animal models, but interest is now focused more on its use as a thrombopoietin than as an antitumor agent. The National Cancer Institute is now planning Phase I and Phase II trials of IL-12, probably the most interesting cytokine currently entering investigation. This cytokine is composed of two relatively large, cova-
Volume 99 (suppl 6A)
SYMPOSIUM ON CHEMOTHERAPY/ PARKINSON
cannot only be prevented but also t.reated by such a lently linked peptitles. Its half-life is thus measured vaccine approach. in hours, as compared to that of other cytokines, It is probable that many currently outstanding whose half-lives are measured in minutes. It is of issues in the cancer vaccine field, such RSwhich promore interest now in t,reating infectious disease and teins to use and whether to use epitopes or whole as an adjuvant to cancer vaccine development than proteins, will be resolved in the nest 2 years. as a single agent against tumors.” The filet that a gene can be put into a somatic cell Studies of therapies using IL-2 and LAK cells in and made to express a functioning protein is being combination do not clearly show that LAK cells applied in a number of other therapy strategies; adds to the anti-tumor activity of IL-2. As a result, >lOO gene therapy cancer protocols are currently there is a move to study lymphocytes actually haractive in the I!nited States. IZetroviruses have been vested from within the tumor itself, the so-called tumor-infiltrating lymphocytes (TIL). Good re- the most widely used vehicle for delivering genes. sponse rates have been observed in patients who In both animal models anti humans, gene therapy received very-high-dose IL-2 plus TII, cells; some has been able to induce the generation, even from previously nonimmunogenic tumors, of antigenpatients respond to TIL therapy after failing IL-2 specific antitumor T cells. Making TII, cells more alone.” An important contribution of such studies has adive by transfecting them with the gene for TNF, however, has proven difficult. in clinical practice. been the chwtcterization of the antigens that. TIL A different approach is to use tumor blood vessel cells recognize. Initially, lymphocytes harvested from a melanoma are not, activated; they cannot be biology as a basis for biological therapeutic strdegies. There is a remarkable interaction between shown to be cytotoxic or releasing cytokines. They tumor cells, the host. and T-cell-intluced blood vesbecome activated when cultured in high-(lose IL-2 sel formation. Many tumors encourage the growth and eliminate any melanoma cells from the culture. of their own blood supply by manifesting a series uf These cytotoxic T cells recognize :mtigens thitt oligopeptitles or polypeptides. (+rowth factors that are present, as small oligopeptides, usually breakdown pro~lucts of cellular prwteins. Perhaps the stimulate endothelial cell growth and blood vessel most remarkxble paradigm change over the last formation are also proclucetl in the interact,ions bedecade has been the realization that essentially an) twen tumor cells and inflamm~~tory ~11s. A Roston protein within the cell (aan serv(’ as an antigen. study found high levels of fihroblast growth factors Small oligopeptides are transported to the cell sur- c~scretetl in thd urine of pa&n t s with blatltler ( wftf’ace by ~vell-nl?der.stoud mechanisms and sit in thP tissue sawomt~s, and other t.unlors. Numerous H,utlgroove of the clnss I major llistocomp~~tability anti- ies have now clocumented that t,he more hloocl vesgen. A T cell, on recognizing these peptides, can be sels there are per unit, of space in a primary tumor. activated to become cytot.oxic 0~ wtual1.v ln~~tluce the> mow aggwssive it is. Thus, thwe is abundant cytokines. evi(lencc that tumors cannot ~t*ow without forming These findings have led to the tlevrlol~mrnt of t,loocI vessels. UXI that blocking thew angiogenic new recombinant cancer vaccines. The idea of can- pt~ptitles may halt tumor gr~owt.h.7 Many agents that have anti-all~iogc~nic activity in cer vaccines is its old as I,ouis Pasteur, but until recently the literature on the subject was unconvitro or in animal models, such as interferon-a, and vincing. Most vaccine mixtures were crude. Antithalidomide-of low toxicity except in the first trigens were undefined. It was difficult to determine mester of pregnancy---are nwv entering clinic:*1 whether a vaccination was even inducing an antitutrials. mor response, let alone what the nature of that reAnother therapeutic strategy relates to antitusponse was. The National Cancer Institute is now mw neovasculature. Such agents as TNF-tu ant1 carrying out or sponsoring >50 cancer vaccine tr*i- CM-101 appear to act directly on the tumor entloAS, each of which is looking at a defined potential thelium. atdigen, including MART-I, gp100, ant1 tyrosinase TNF-cu has proven to be very active when used in for treatment of melanom:~s; carcinoembryonic an- combination with melphalan in isol;ltetl limb perfutigen (CEA) for adenocarcinomas; some of the pap- sion of recurrent melanoma ant1 soft-tissue sarilloma viruses for cervical cancer: ant1 mutatetl on- COWld cogenes such as ras and P-53. UwlOl, a complex polysacchtwitle producetl by One interesting approach uses ;1 virus jnto \vhi& /3-hemolytic streptococcus, can kill newborn infants a gene for a tumor vaccine has been integratetl. A by binding to the pulmonary entlothelium and inPhase I trial at the National Cancer Institute has ducing inflammation. Tumors also express t,he reshown in murine models that CEA-positive tumors ceptor to which this polysacch;u*ide binds. Experi-
Derember
29, 1995
The American
Journal of Medicine
Volume 99 (suppl 6A)
6A-55s
SYMPOSIUM ON CHEMOTHERAPY/ TURSZ
mentally, therapy with CM-101 can result in tumor necrosis secondary to obliteration of tumor vasculature.” The therapeutic window this opens has been explored in a Phase 1 trial of CM-101. Unlike the agents discussed above, which work through the immune system or through blood vessel disruption, differentiation agents work directly on tumor cells. A host of them are in, or going into, clinical trials. Differentiation therapy either up- or down-regulates the expression of genes that control proteins involved in signal transduction or in cellcycle regulation. The most commonly used agents, the retinoids, some of which are approved for clinical use in the United States. Such compounds, derived from vitamin A, are taken up within a cell and bind to nuclear receptors where they act as transcriptional regulators. TJsing this mechanism therapeutically has led to comp1et.e responses in molecularly defined cases of acute promyelocytic leukemia. In combination with interferon, 134s retinoic acid has been used in squamous-cell tumors.!’ In summary, the emerging understanding of the biology of the relationship of tumors with the host has made it possible to manipulate subtle differences between host and tumor POas to treat c’dncer. Modern medicine is beginning to understand the antigens and the antitumor mechanisms, and it
Combination THOMAS
TURSZ,M.D.,
Ph.D.,
19%
REFERENCES 1. Rosenberg SA, Lotze MT, Muul LM, et al. Observatrons on the systemic admInIstration of autdogous iymphokme-activated kllier cells and recombinant rnterleukm-2 to patients wrth metastatic cancer. N Engl J Med 1985; 313: 14851492. 2. Mier JW, Vachino G, Van Der Meer JWM, et al. Induction of circulatrng tumor necrosis factor (TNF alpha) as the mechanism for the febrile response to Interleukln-2 (IL-21 rn cancer patients. J Clan lmmunol 1988; 8: 426-436. 3. Marincola FM, Venron D, White D. et al. HLA association with response and toxtcIty In melanoma pabents treated with tnterleuktn 2-based Immunotherapy. Cancer Res 1992; 52: 6561-6566. 4. Sznol M, Parkinson DR. Cllnrcal applrcatrons of IL-2. Oncology 1994; 8 61-67. 5. Brunda MJ, Luistro L, Warner RR, et al. Antrtumor and antimetastatic activrty of Interleukrn-12 agatnst munne tumors. J Exp Med 1993; 178: 1223-1230. 6. Rosenberg SA, Yannelil JR, Yang JC, et al. Treatment of patients with metastatlc melanoma using autologous lnftltrattng lymphocytes and Interleukrn-2. J Nat1 Cancer inst 1994; 86: 1159-l 166. 7. Folkman J. Anglogenesis and breast cancer. J Clan Oncol. 1994; 12: 441-443. 8. Hellerqvlst CG, Thurman GB, Page DL, et al. Antitumor effects of GBS toxrn: a polysaccharrde exotoxin from group B beta-hemolytlc streptococcus. J Cancer Res Clan Oncol 1993; 120: 63-70. 9. Degos L, Parkinson DR leds) Retlnolds In Oncology, Berlin: Springer, 1995.
Wlejuif,France
minority of the marriages between biologic response modifiers (BRMs) and conventional chemotherapy are synergistic. The vast majority are merely additive or neutral, and some are antagonistic, with high-grade toxicity. Despite much experimental work, current medical knowledge is still unable to predict whether any such marriage of oncologic treatments will succeed. Most animal and experimental models for stutlying the association between BRIMS and chemolherapeutic agents have immunologically intact hosts, tumors sensitive to cytokine treatment, or other features that, because they are isolated from the complexity of interactions within the human body, have iittle relevance to real human cancers. Some chemotherapy agents may have minor immunomodulatory properties that synergize with some immunotherapeutic agents. For example, to December 29,
tional Cancer Institute. NatIonal Institutes of Health, 6130 Executive Boulevard,
of BRMs with Chemotherapy
A
6A-566
should be possible to use these mechanisms much more intelligently, and hopefully with more success and less toxicity, in the future.
The American
Journal
of Medicine
consider agents such as interferon and interleukin-2 (IL-Z) solely as pure immunomodulatory drugs would be a mistake. Such agents have a broad spectrum of action including nonimmunologic uses. IL-Z, for instance, is responsible for the capillary leakage syndrome, which affects the pharmacokinetics and thus the distribution of some drugs in the body. Studies have shown that IL-2 (foes not affect the pharmacokinetics of cisplatinum. There are indications that IL-2 can modify the pharmacokinetics of dacarbazine (DTIC), but this has not yet led to clinical application. There are indications of connections between drug resistance and immunosensitivity. For example, there are data showing that those non-smallcell lung carcinoma cells that are resistant to cisplatinum are also more sensitive to natural killer toxicity.
Volume 99 (suppl 6A)