This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ettinghausen, S. E. Articles by Rosenberg, S. A. Search for Related Content PubMed PubMed Citation Articles by Ettinghausen, S. E. Articles by Rosenberg, S. A.

Immunotherapy of Murine Sarcomas Using Lymphokine Activated Killer Cells: Optimization of the Schedule and Route of Administration of Recombinant Interleukin-2

Surgery Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20892

Interleukin-2 (IL-2) at high doses or at low doses in concert with lymphokine-activated killer (LAK) cells can produce regression of established pulmonary and hepatic metastases from a variety of tumors in mice. IL-2 appears to mediate its antitumor effect through the generation of LAK cells in vivo from endogenous lymphocytes and by the stimulation of host and transferred LAK cell proliferation in tissues. In this paper we have investigated different strategies for IL-2 administration to determine which regimen produced maximal in vivo proliferation and optimal immunotherapeutic efficacy of LAK cells. Tissue expansion of lymphoid cells was assessed using an assay of in vivo labeling of dividing cells by the thymidine analogue, 5-[¹²⁵I]iododeoxyuridine. The therapeutic effect of the different IL-2 administration protocols was determined by evaluating their efficacy in the treatment of established, 3-day pulmonary metastases from sarcomas in mice. The selection of IL-2 injection regimens for evaluation was based upon pharmacokinetic studies of IL-2 in mice. A single i.v. or i.p. dose yielded high peak IL-2 levels that could be measured for only a few hours after injection, while IL-2 given i.p. thrice daily produced titers that were detectable throughout the study periods (6 units/ml of serum after 100,000 units of IL-2 i.p. thrice daily).

Using the proliferation and therapy models, we tested the same cumulative daily doses of IL-2 administered by i.v. or i.p. once daily, or i.p. thrice daily regimens. The i.p. thrice daily protocol stimulated greater lymphoid cell proliferation in the lungs, for example, than did the other regimens. Similarly, 300,000 units of IL-2 divided i.p. thrice daily were more successful in reducing metastases (n = 16) than was the entire dose given i.v. once daily (n = 190; P < 0.05) or i.p. once daily (n = 71; P < 0.05). When compared to the i.p. or i.v. once daily protocols, the i.p. thrice daily regimen for IL-2 also produced greater proliferation of exogenous LAK cells, as well as a more effective therapeutic outcome when IL-2 was combined with transferred LAK cells. Thus, sustained, lower levels of IL-2 were more effective than brief, high peak titers for stimulation of proliferation and antitumor activity.

We then evaluated the effect of duration of IL-2 treatment as well as the number of LAK cell injections in the two models. When IL-2 was given i.p. thrice daily together with LAK cells, proliferation in the lungs and therapeutic effect were greatest after 6 days of IL-2 as compared with 1 or 3 days. Similarly, two infusions of LAK cells yielded higher levels of 5-[¹²⁵I]iododeoxyuridine uptake in tissues and a greater reduction of lung metastases than did one LAK cell injection.

The establishment of optimal regimens for LAK cell and IL-2 immunotherapy in the murine system has played an important role in the design of similar treatments in ongoing human trials.

¹ To whom requests for reprints should be addressed, at Surgery Branch, National Cancer Institute, Building 10, Room 2B42, Bethesda, MD 20892.

Received 12/ 2/85. Revised 2/24/86. Accepted 2/27/86.

This article has been cited by other articles:

				T. Miyamoto, T. Kaneko, M. Yamashita, Y. Tenda, M. Inami, A. Suzuki, S. Ishii, M. Kimura, K. Hashimoto, H. Shimada, et al. Prolonged skin allograft survival by IL-10 gene-introduced CD4 T cell administration Int. Immunol., June 1, 2005; 17(6): 759 - 768. [Abstract] [Full Text] [PDF]

				T. KOSHIKA, A. ISHIZAKA, I. NAGATOMI, Y. SUDO, N. HASEGAWA, and T. GOTO Pretreatment with FK506 Improves Survival Rate and Gas Exchange in Canine Model of Acute Lung Injury Am. J. Respir. Crit. Care Med., January 1, 2001; 163(1): 79 - 84. [Abstract] [Full Text]

				A. Cabanes, S. Even-Chen, J. Zimberoff, Y. Barenholz, E. Kedar, and A. Gabizon Enhancement of Antitumor Activity of Polyethylene Glycol-coated Liposomal Doxorubicin with Soluble and Liposomal Interleukin 2 Clin. Cancer Res., March 1, 1999; 5(3): 687 - 693. [Abstract] [Full Text] [PDF]

				S.-J. Liu, Y.-P. Sher, C.-C. Ting, K.-W. Liao, C.-P. Yu, and M.-H. Tao Treatment of B-Cell Lymphoma With Chimeric IgG and Single-Chain Fv Antibody-Interleukin-2 Fusion Proteins Blood, September 15, 1998; 92(6): 2103 - 2112. [Abstract] [Full Text] [PDF]

				C. LeBel, L. Langlois, D. Bell, J. Young, W. Kenney, B. Payne, L. Sendelbach, and L. Wong Pharmacokinetic, pharmacodynamic, and pharmacotoxic profiles of recombinant- methionyl human interleukin-2 [alanine- 125] (r-metHuIL-2[ala-125]) following intravenous and subcutaneous administration in rats Human and Experimental Toxicology, November 1, 1995; 14(11): 909 - 915. [Abstract] [PDF]

				S. A. Rosenberg, J. C. Yang, S. L. Topalian, D. J. Schwartzentruber, J. S. Weber, D. R. Parkinson, C. A. Seipp, J. H. Einhorn, and D. E. White Treatment of 283 Consecutive Patients With Metastatic Melanoma or Renal Cell Cancer Using High-Dose Bolus Interleukin 2 JAMA, March 23, 1994; 271(12): 907 - 913. [Abstract] [PDF]