Paula Livernois- reporter, assistant to recorder
Jennifer McLaughlin-focus, recorder
Erin Murphy-time manager, editor
Scott Wolfrom-skeptic, reporter
17 November 1997
Cytokine therapy has proven to be a novel therapeutic approach in treating patients with advanced malignancies (a). The purpose of this type of therapy is to manipulate the immune response in such a way as to generate the appropriate immune effector cells to eradicate solid tumors. This form of therapy is administrated only after the conventional form of therapies have been performed such as chemotherapy, radiotherapy, and surgery. Various regimens of cytokine administration have been implemented in eradicating solid tumors in patients with melanoma and renal cell cancer. There have been clinical trials executed involving the administration of interferon-gamma, interferon-alpha, Interleukin-2, tumor necrosis factor-alpha, and Interleukin-12. Advances in cytokine therapy have been thwarted by the relatively high level of toxicity associated with the administration of cytokines. Common toxicities include nausea, vomiting, fever/chills, fatigue, and headache. Dose escalation of a particular cytokine halts once three patients at a particular dose level experience grade three toxicity. The maximum tolerated dose of the cytokine is designated as the preceding dose. In turn, determining the schedule of treatment is another challenge at hand for clinicians. Partial or complete tumor regression has been noted in some clinical trials which offers hope in finding the appropriate cytokine or combination of cytokines and dose level to effectively treat advanced malignancies without being too toxic to the patient (above information from source 1).
APPLICATIONS OF INTERLEUKIN-2 THERAPY
One of the first clinical trials performed was the administration of recombinant Interleukin-2 (IL-2) intravenously. IL-2 plays a central role in the immune response by promoting the proliferation and differentiation of helper T cells, cytotoxic T cells, and B cells. Moreover, it augments innate immunity by stimulating the expansion of natural killer cells (NK cells). Based on this information, IL-2 was delivered to patients with advanced cancer with the intention of eradicating the tumor by selectively expanding natural killer cells for an extended period of time with only minimal toxicity to the patient. From a clinical standpoint, the treatment of solid tumors with IL-2 has been disappointing, with low response rates of 10-20% demonstrable for melanoma and renal cell cancer. High doses of IL-2 used in the clinical trials were accompanied by significant toxicity, while lower doses exhibited less toxicity while preserving the modest response rate (6). Currently, IL-2 is no longer being administered to patients with solid tumors, only to recipients of allogeneic, T cell-depleted bone marrow transplants. The aim of this approach is to augment any NK cell-mediated anti-tumor effect following transplant in order to eliminate any residual leukemia and thereby prevent disease relapse. Nonetheless, IL-2, in the treatment of solid tumors, has been proven to be a failure and so has forced clinicians to turn to another comparable cytokine, IL-12, in the treatment of advanced malignancies (2).
APPLICATIONS OF INTERLEUKIN-12 THERAPY...A MORE PROMISING APPROACH
Interleukin-12 is a potent immunomodulatory cytokine with a
demonstrated ability to stimulate various subsets of lymphocytes,
including T, NK, and B cells. Activation of T lymphocytes and NK cells by
IL-12 results in cellular proliferation, interferon-gamma production, and
the induction of cytolytic activity (5). Animal models have suggested
that the observed effects of IL-12 in vitro can be translated into a
clinically effective treatment modality for human malignancies. For
instance, murine models have shown that the anti-tumor activity of IL-12
can eradicate solid tumors such as melanoma and renal cell carcinoma.
>From this research, the administration of IL-12 was approved by the Human
Investigation Review Board and is currently being delivered to patients in
various cancer centers in the United States (1).
Thus far, the phase I Interleukin-12 studies have delivered IL-12 in cycles consisting of either i.v. boluses for five consecutive days or subcutaneous injections for two consecutive weeks. A test dose is administered two weeks before the regular administration of IL-12. This test dose has shown to be important because it exerts a protective effect against subsequent toxicity. For intravenously administered IL-12, the maximum tolerated dose was determined to be 500ng/kg, at which dose level the primary toxicities were constitutional symptoms, reversible anemia, thrombocytopenia, and mild stomatitis. Interferon-gamma production was strongly induced with the first cycle of IL-12, but the magnitude of this induction was attenuated with subsequent cycles. Many of the side effects associated with IL-12 administration is attributed to interferon-gamma production. These side effects include liver test abnormalities , hyperglycemia, fever, and flu-like symptoms. For subcutaneously administered IL-12, similar toxicities have been observed thus far at the 300 and 500 ng/kg dose levels, with the maximum tolerated dose being 500ng/kg. Of the forty patients enrolled in the intravenously administered IL-12 study, two patients had objective tumor responses (1,5). Therefore, additional Phase I trials need to be conducted to examine alternative schedules of treatments.
In Phase II of the intravenous IL-12 trials, the initial predose was not administered, and the 500ng/kg daily dose schedule was carried out as in Phase I. This proved to be severely toxic to the patients, requiring the cessation of the Phase II trials. According to Atkins et al., "although the reason for the severe toxicity in this Phase II trial is still being explored, initial results indicate that the omission of the test dose was a major contributing factor" (1). Studies by Coughlin et al. with murine tumors showed that a predose of recombinant IL-12 improved the tolerance of rIL-12, reducing its toxicity and allowing higher doses to be administered safely (3). Coughlin et al. caution that although predosing reduces the toxicity of rmIL-12 and allows higher doses to be given safely, these results should not be extrapolated to humans due to differences in human and mice IL-12s (3). They caution the use of predosing as a way to enhance the effectiveness of rIL-12 in cancer clinical trials due to the fact that predosing with rmIL-12 does not improve rIL-12's therapeutic outcome and appears to attenuate the therapeutic outcome (3).
WHAT ARE THE FUTURE POSSIBILITIES OF CYTOKINE THERAPY?
Future applications of cytokine therapy may involve a combination of cytokines in the treatment of advanced malignancies. In particular, the combination of IL-2 and IL-12 may prove to be the most effective regimen. A rational strategy might include low-dose continuous infusions of IL-2 to expand NK cells in vivo, followed by administration of IL-12 to augment NK cell cytolytic activity. IL-12 administered in low doses would be less toxic than high doses of IL-2, while producing similar activation of NK cytotoxicity. However, further studies need to be conducted to confirm whether the administration of these cytokines may be too toxic to patients. In one report, researchers have determined that combination cytokine therapy may prove to be too toxic by inducing extremely high levels of tumor necroses factor-alpha and interferon-gamma while simultaneously inducing apoptosis in NK cells. The mechanism of cytokine-induced apoptosis of human NK cells appears to involve NK cell production of tumor necrosis factor-alpha. In turn, blocking tumor necrosis factor-alpha decreases the cytokine-induced apoptosis. Thus, the investigators recommend extreme caution in delivering combinations of IL-12 and IL-2 and suggest careful consideration would have to be given to the dose and schedule of combination cytokine therapy (7).
In summary, the clinical trials that have been conducted thus far have made a major impact in the treatment of cancer by providing more information about the cytokine network and how we can manipulate it in such a way as to combat malignancies such as melanoma and renal cell cancer. New and innovative cytokine regimes need to be designed and implemented to successfully eradicate tumors with only minimal toxicity. Combination cytokine therapy offers promise in the treatment of advanced malignancies. Additional studies need to be performed to determine whether the delivery of two cytokines simultaneously would prove to be too toxic to cancer patients. A better understanding of the mechanisms of tumor destruction by cytokines is needed before their use in cancer treatments will markedly improve in their effectiveness and safety. One limitation of this research is that it is used on end-stage patients who have less than a year to live. If this therapy was less toxic and used on patients in the early stages of cancer, it might prove to be a more useful treatment in tumor eradication.
(a) Cytokines are "low molecular weight proteins that are secreted by cells to regulate the intensity and duration of which an immune response occurs by inducing a variety of effects on lymphocytes and other immune cells" (4).