[CANCER RESEARCH 52. 3005-3010, June I. 1992] Polyinosinic-Polycytidylic Acid Complexed with Poly-L-lysine and Carboxymethylcellulose in Combination with Interleukin 2 in Patients with Cancer: Clinical and Immunological Effects' Cynthia H. Ewel, Walter J. Urba,2 William C. Kopp, John W. Smith II, Ronald G. Steis, Jeffrey L. Rossio, Dan L. Longo, Mary Jane Jones, W. Gregory Alvord, Carl M. Pinsky, Joy M. Beveridge, Karen L. McNitt, and Stephen P. Creekmore Clinical Services Program, Program Resources, Inc./DynCorp, National Cancer Institute-Frederick Cancer Research Development Center, Frederick, Maryland 21702 [C. H. E., W. J. I'., W. C. A'., J. L. R., J. M. B.J; Biological Response Modifiers Program, Division of Cancer Treatment, .National Cancer Institute, Frederick, Maryland 21701 ¡R.G. S.. D. L. L., S. P. C.,J. H'. S.J; Frederick Memorial Hospital, Frederick, Maryland 21701 fM. J. J.J; Immunomedics. Inc.. Harren, Ne»'Jersey 07060¡C. M. P./; and Data Management Services, Inc., National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 2/702 ¡K,L. M., H. C. A.I ABSTRACT We have performed a phase IB study of polyinosinic-polycytid) Heacid complexed with poly-i.-lysinc and Carboxymethylcellulose (poly-ICLC) in combination with interleukin 2 (IL-2) in 25 patients with a variety of cancers. Patients received weekly or biweekly poly-ICLC by i.m. injec tion, at doses ranging from 0.01 to 1.0 mg/m2, for 1 month. This was followed by 2 months of outpatient therapy with biweekly i.m. poly-ICLC in combination with IL-2 (3 x III'1units/nr)given i.v. by 24-h continuous infusion twice weekly, using a portable infusion pump. No objective tumor responses were observed. Toxicity was moderate at all poly-ICLC doses tested and increased only slightly following the addition of IL-2. No increases in peripheral blood natural killer (NK) activity were observed after treatment with poly-ICLC alone. However, high dose poly-ICLC (>0.3 mg/m2) in combination with IL-2 resulted in NK activity greater than that seen using the same dose of IL-2 in combination with lower poly-ICLC doses. Increases in the number and percentage of CD56* cells were evident only after initiation of IL-2 therapy and were unaffected by the poly-ICLC dose. In the majority of patients, these increases were preferentially associated with the subset of CD56* cells coexpressing CDS, while the CD56+/CD16+ population was elevated to a lesser extent. Moderate increases in serum neopterin levels and 2',5'-oligoadenylate synthetase activity in peripheral blood mononuclear cells were noted at 72 h following initial treatment with 1.0 mg/m2 poly-ICLC. No induction of a or 7 interferon was detected. This study shows that the addition of poly-ICLC to a well tolerated IL-2 regimen can significantly enhance NK activity. Poly-ICLC can be used to enhance IL-2-induced NK lytic activity without increases in the dose and, therefore, the toxicity of IL-2 treatment. INTRODUCTION Poly-ICLC1 is one of a family of synthetic double-stranded RNA molecules known to be potent interferon inducers. Animal studies have shown that this prototypic biological response modifier has a variety of immunological and antitumor effects (1, 2). Indeed, poly-ICLC is such a potent immune enhancer that it is routinely used as a positive control in preclinical Received 11/26/91 ; accepted 3/19/92. 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. 1This research was sponsored, at least in part, by the National Cancer Institute. DHHS, under Contract N01-CO-74102 with Program Resources. Inc./DynCorp. The contents of this publication do not necessarily reflect the views or policies of the DHHS. nor does mention of trade names, commercial products, or organi zations imply endorsement by the United States Government. J To whom requests for reprints should be addressed, at Clinical Sen ices Program. Program Resources. Inc./DynCorp. NCI-FCRDC. P. O. Box B. Fred erick. MD 21702-1201. 3 The abbreviations used are: poly-ICLC. polyinosinic-polycytidylic acid com plexed with poly-t.-lysine and Carboxymethylcellulose: NK. natural killer: LAK. lymphokine-activated killer: IL-2. interleukin 2: IL-2R, interleukin 2 receptor: PBS. phosphate-buffered saline: PBM. peripheral blood mononuclear cells; MTD. maximal tolerated dose: 2-5A, 2'.5'-oligoadcnylate synthetase. studies testing other biological agents. Despite demonstrable antitumor activity in animal models, poly-ICLC has not pro duced significant antitumor effects in humans. One reason for this lack of efficacy may be that no optimal dose, route, or schedule of poly-ICLC administration for immunomodulatory effects has been established. This may be important, because poly-ICLC is postulated to mediate its antitumor effects via immune rather than direct cytotoxic effects. Previous clinical trials (3) have concentrated on determining a MTD rather than an optimal immunomodulatory dose. Experimental animal data suggest that maximal antitumor effects coincide with optimal NK cell and macrophage activation by poly-ICLC, which are achieved at doses considerably below the MTD (4). The MTD for poly-ICLC in humans is approximately 12 mg/nr, but lower doses of poly-ICLC produce immunomodu latory effects in cancer patients (5). Although no antitumor responses were observed, measurable changes in monocyte func tion and the IFN-inducible enzyme 2-5A, as well as elevation of NK activity, were observed in patients receiving 1 mg/m2 poly-ICLC. In addition, patients treated at 1 mg/m2 were more likely to have increased NK activity than were patients treated at higher doses, where decreased NK activity was frequently observed. Thus, the optimal immunotherapeutic and immuno modulatory dose in humans may be <1 mg/m2. Interleukin 2 can increase the number and activity of NK cells (6), LAK cells (7), cytotoxic T lymphocytes (8), and tumor- infiltrating lymphocytes (9). It has antitumor effects when administered alone (10, 11) or in combination with LAK cells (12) or tumor-infiltrating lymphocytes (13). In a study of Ro senberg et al. (12), six of 46 (13%) cancer patients receiving high dose IL-2 (100,000 units/kg, three times per day) achieved a complete or partial response. Treatment was accompanied by severe toxicities requiring hospitalization, often in an intensive care setting. An outpatient regimen employing daily infusions of low dose IL-2 (3 x IO6units/nr, by 24-h continuous infusion) has been found to increase the number of circulating LAK cells, with tolerable toxicity (14). We wondered if the antitumor activity of IL-2 might be enhanced if it were given in combina tion with a second biological response modifier, such as poly- ICLC, which has the potential to enhance similar immune functions. This study was designed to investigate the toxicity and the immunomodulatory effects of low dose poly-ICLC alone and to explore the possibility of synergistic or additive immunological activity of poly-ICLC combined with IL-2. PATIENTS AND METHODS Patients. Twenty-five patients with a variety of malignancies (Table 1) were entered into the study. All patients were required to meet the 3005 Research. on November 11, 2015. © 1992 American Association for Cancer cancerres.aacrjournals.org Downloaded from