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Clinical and Immunological Effects of Granulocyte-Macrophage Colony-Stimulating Factor Coadministered with Interleukin 2: a Phase IB Study 1

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Clinical and Immunological Effects of Granulocyte-Macrophage Colony-Stimulating Factor Coadministered with Interleukin 2: a Phase IB Study 1 Vol. 2, 319-330, February 1996 Clinical Cancer Research 319 Clinical and Immunological Effects of Granulocyte-Macrophage Colony-stimulating Factor Coadministered with Interleukin 2: A Phase IB Study 1 Joan H. Schiller, 2 Jacquelyn A. Hank, tivity and CD16 expression on monocytes and lymphocytes Masoud Khorsand, Barry Storer, and CD56 expression on lymphocytes were significantly lower in patients receiving GM-CSF simultaneously with Agnes Borchert, Karen Huseby-Moore, IL-2 than in patients receiving the sequential treatment. Dan Burns, Osvaldo Wesly, Antitumor activity was observed in the lungs of four of Mark R. Albertini, George Wilding, eight renal cell carcinoma patients with pulmonary metas- and Paul M. Sondel tases treated with concurrent GM-CSF and IL-2. Although University of Wisconsin Comprehensive Cancer Center, Departments no or minimal shrinkage was observed in the patients' large of Human Oncology and Medicine, Madison, Wisconsin 53792 primary tumors, these results warrant further study. The recommended initial Phase II dose and schedule is 1.25 p~g/kg/day GM-CSF, given concurrently with 1.5 million ABSTRACT Roche units/m2/day (4.5 x 106 international units/m2/day) Interleukin 2 (IL-2) and granulocytes-macrophage col- IL-2, with subsequent escalation of GM-CSF to 2.5 Ixg/kg/ ony-stimulating factor (GM-CSF) are activators of the lym- day after careful observation for toxicities. phocyte and granulocyte/macrophage series, respectively. We conducted a phase IB trial to identify the maximally INTRODUCTION tolerated dose and to assess immunological effects of the The failure of cytotoxic chemotherapy to induce long- combination. Thirty-four patients with incurable cancers lasting remissions in the majority of solid tumors has prompted received 2.5, 5, or 10 Ixg/kg GM-CSF s.c. either before or investigation of new treatment modalities, including antitumor concurrently with 1.5 or 3.0 million units/m2/day IL-2. immunotherapies. The ability of various biological response The most common laboratory and clinical side effects modifiers, such as IL-23 and IFNs, to enhance cellular immunity included an elevation of the total WBC or eosinophil count suggests a potential therapeutic role for these agents in certain due to GM-CSF, and constitutional symptoms due to IL-2. neoplastic diseases, such as melanoma and renal cell carcinoma Grade 3 or 4 toxicities included hypotension, thrombocyto- (1-5). IL-2, a M r 15,000 protein produced by helper T cells penia, elevations in aspartate aminotransferase or bilirubin, following activation by antigens or mitogens, can activate ef- renal toxicity, gastrointestinal hemorrhage, arrhythmia, and fector T-cell populations and NK cells to lyse tumor cells in constitutional symptoms. Two patients receiving 5.0 Ixg/kg vitro and in vivo and can augment ADCC in vitro when used in GM-CSF plus concurrent 3.0 million units IL-2 experienced combination with MoAbs (6-10). As a single agent, it can dose-limiting grade 3 or 4 neurological toxicity, which re- induce antitumor responses in 10-15% of patients with renal versed almost completely. cell carcinoma or metastatic melanoma (1-5, 11). Toxicities, An increase in the serum-soluble IL-2 c~ chain receptor however, are significant, thus promoting continued efforts at was observed with administration of GM-CSF, IL-2, or the identifying methods to enhance antitumor effects by increasing combination. IL-2 therapy enhanced lymphokine-activated the specificity of the immune-mediated tumor destruction while killer activity, antibody-dependent cellular cytotoxicity, and modifying treatment programs to reduce toxicity (2, 11). lymphocyte activation, with increased CD16 and CD56 ex- One possible method for enhancing antitumor effects in- pression. GM-CSF increased expression of human leukocyte cludes combining IL-2 with other immunotherapies. Although antigen DR on peripheral blood monocytes and decreased IL-2 has been combined with IFNs and certain MoAbs, such as surface expression of CD16 on circulating monocytes and the anti-CD3 MoAb, with limited success (12-16), IL-2 has not polymorphonuclear cells. Lymphokine-activated killer ac- been studied extensively in combination with CSFs. CSFs are a family of regulatory glycoproteins that were first identified because of their ability to stimulate precursor hematopoietic Received 7/26/95; revised 10/6/95; accepted 10/18/95. 1 This research was supported by NIH Grants and Contracts CA53441, CA05436, CA32685, CM87290, CA14520, CA13539, CM47669, 3 The abbreviations used are: IL, interleukin; NK, natural killer; ADCC, HL02143, and RR03186, and American Cancer Society Grant CH-237. antibody-dependentcellular cytotoxicity; MoAb, monoclonal antibody; J. H. S. and G. W. are also supported in part by the Veterans Admin- GM-CSF, granulocyte-macrophage colony-stimulating factor; M-CSF, istration. monocyte CSF; BRMP, Biological Response Modifiers Program; PBM, 2 To whom requests for reprints should be addressed, at Department of peripheral blood mononuclear; PMN, polymorphonuclear;E:T, effector: Medicine, University of Wisconsin Comprehensive Cancer Center, K4/ target; LAK, lymphokine-activatedkiller; HLA, human leukocyte anti- 666 Clinical Science Center, 600 Highland Avenue, Madison, WI gen; IL-2R, IL-2 receptor; MRI, magnetic resonance imaging; TNF, 53792. Phone: (608) 263-8600; Fax: (608) 263-8613. tumor necrosis factor. Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 1996 American Association for Cancer Research. 320 Phase IB Study of GM-CSF and IL-2 cells to form colonies of progenitor cells. However, it is now Table 1 Schema of treatment clear that they are not simply proliferative stimuli but can Dose of regulate the functional activity of mature hematopoietic cells No. of GM-CSF Dose of IL-2 (17). GM-CSF, for example, is necessary for cell survival in Sequence patients (lxg/kg/day) (million units/mZ/day) vitro of both progenitor and mature granulocytes and macro- Sequential, 6 5.0 3.0 phages and also can affect the activation, cell mobility, phago- GM-CSF ~ IL-2 6 10.0 3.0 cytic activity, and ADCC of these cells (17). The effects of Concurrent, 6 2.5 1.5 GM-CSF + IL-2 4 2.5 3.0 GM-CSF and M-CSF on neutrophils and monocytes may trans- 12 5.0 1.5 late into antitumor effects in vitro or in preclinical models (18-25). Clinically, treatment with GM-CSF or M-CSF can enhance monocyte activation and induce monocytosis (26-28). Patients with significant central nervous system disease, central Combining IL-2, a lymphocyte activator, with GM-CSF, nervous system metastases, or serious recent infections, or those an activator of the monocyte/macrophage and granulocyte lin- who required continued therapy with corticosteroids, aspirin, or eage, may be a reasonable approach to the treatment strategy of nonsteroidal antiinflammatory agents were ineligible. Patients activation of multiple effector cell populations. Therefore, we with histories of chronic obstructive pulmonary disease were conducted a Phase IB trial of GM-CSF and IL-2 to determine required to have adequate ventilatory function (forced expira- the maximally tolerated dose, to identify toxicities, and to assess tory volume, ->60% of predicted). All patients underwent place- the immunological effects of the combination. ment of in-dwelling venous catheters. MATERIALS AND METHODS Treatment Program Reagents Patients were scheduled to receive 2.5, 5, or 10 ~g/kg GM-CSF and either 1.5 or 3.0 × 10 6 units/m2/day IL-2 on a IL-2 and GM-CSF sequential or concurrent schedule (Table 1). Patients were en- Human recombinant IL-2 and GM-CSF for clinical treat- tered in groups of six to ensure adequate numbers for statistical ment and in vitro studies were provided by Hoffmann-LaRoche evaluation of the immunological studies. Patients without dose- Inc. (Nutley, NJ) and Immunex Corp. (Seattle, WA), respec- limiting toxicity or progressive disease in the first course were tively, through the Cancer Therapy Evaluation Program of the eligible to receive a second course of treatment following a National Cancer Institute. IL-2 and GM-CSF are highly purified 2-week rest period. products produced in Escherichia coli and yeast expression Patients were registered sequentially to receive one of two vectors, respectively, using recombinant DNA techniques. IL-2 different treatment schedules (Table 1 and Fig. 1): GM-CSF for units are expressed in BRMP or Hoffmann-LaRoche units, and this 12 days followed by IL-2 (sequential treatment) or concurrently compares to the international standard (in which 1 BRMP unit = with IL-2 starting on day 8. -3 international units; Ref. 29). Thus, the 1.5 × 106-unit/m2/day Sequential GM-CSF Followed by IL-2. To assess the regimen used here with Hoffman-LaRoche IL-2 would correspond effects of GM-CSF and IL-2 individually, the first 12 patients to 4.5 × 106 international units/m2/day commercially available received GM-CSF followed by IL-2 (Fig. 1). GM-CSF was Aldesleukin (IL-2; Chiron, Inc., Emeryville, CA). given s.c. on days 1-12 or until hematological toxicity occurred, as defined below. Following a 3-day rest period, three consec- Clinical Protocol utive weekly 4-day continuous infusions of IL-2 commenced (days 15-18, 22-25, and 29-32). Patients GM-CSF Administered Concurrently with IL-2. To Thirty-four patients were enrolled in this Phase I trial determine the clinical and biological effects of a combination of (National Cancer Institute BRMP protocol B92-0001). All pa- IL-2 and GM-CSF, patients 13-34 received IL-2 as a 4-day tients had refractory cancers, for which other proven effective continuous infusion for 3 weeks (days 1-4, 8-11, and 15-18) treatments were not available, and all signed approved informed with GM-CSF starting the second week of IL-2 (day 8). Again, consent forms. Patients had an Eastern Cooperative Oncology GM-CSF was administered for 12 days (days 8-19) or until Group performance status of 0-1 (Karnofsky, 80-100) and a treatment-limiting toxicity occurred (Fig.
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