Reduction of therapeutic efficacy by a second cycle of PEG-IL-2
| Autor: | Lianne T. M. Balemans, Kremer Bh, Den Otter W, P. A. Steerenberg, Koppenhagen Fj, De Mulder Ph |
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| Rok vydání: | 1995 |
| Předmět: |
Cancer Research
Carcinoma Hepatocellular medicine.drug_class medicine.medical_treatment Intratumoral Therapy Immunology Guinea Pigs Pharmacology Immunostimulant Metastasis Polyethylene Glycols Guinea pig Liver Neoplasms Experimental medicine Immunology and Allergy Animals Immunization Schedule biology business.industry Immunotherapy medicine.disease Primary tumor Immunization Antibody Formation biology.protein Interleukin-2 Female Antibody business Immunosuppressive Agents |
| Zdroj: | Journal of immunotherapy with emphasis on tumor immunology : official journal of the Society for Biological Therapy. 18(1) |
| ISSN: | 1067-5582 |
| Popis: | The formation of antibodies with interleukin-2 (IL-2)-neutralizing capacity and their possible impact on successful locoregional PEG-IL-2 therapy was studied in the guinea pig Line 10 (L10) tumor model. Previously it was shown in this animal model that intratumoral therapy with polyethylene glycol-modified human recombinant IL-2 (PEG-IL-2) induced tumor regression and eradication of lymph node metastases. Therefore, the putative negative effects of IL-2-neutralizing antibodies can be studied in this model. In two similar experiments, animals were immunized by subcutaneous injections (3x/week for 5 weeks) with PBS/BSA, rIL-2, or PEG-IL-2. One week after the last injection, L10 tumor cells were inoculated contralaterally on the flank. Seven days after tumor transplantation, intratumoral treatment with PBS/BSA or PEG-IL-2 was started. During immunization and subsequent intratumoral therapy, sera were collected from the guinea pigs and tested in the CTLL-16 bioassay for IL-2-inhibitory activity. Intratumoral injections with PBS/BSA after immunization only incidently resulted in cure of tumor and metastases, suggesting that by sensitization treatment alone, the immune system was not sufficiently activated to eradicate a tumor inoculum. PBS/BSA immunization followed by intratumoral PEG-IL-2 therapy resulted in complete cure of primary tumor and lymph node metastases in all treated animals. Immunization with rIL-2 evoked IL-2-inhibitory activity in the serum of all guinea pigs. Nonetheless, six of these 11 rIL-2-immunized animals were completely cured by intratumoral PEG-IL-2 therapy. PEG-IL-2 immunization resulted in IL-2-inhibitory serum activity in three of 12 guinea pigs. The guinea pigs with high IL-2-neutralizing activity in their serum showed progressive growth of tumor and metastases, whereas the other animals were completely cured. The level of IL-2-neutralizing capacity in the sera from rIL-2-pretreated animals was higher than that from PEG-IL-2-pretreated guinea pigs, confirming a reduced immunogenicity of PEG-IL-2 as reported after intravenous administration. Passage of the sera from the immunized guinea pigs over a protein G column drastically reduced IL-2-inhibitory activity, implying IgG-related IL-2 inactivation. In conclusion, IL-2-neutralizing activity, possibly mediated by IgG antibodies, is more readily induced by intradermal rIL-2 administration than by PEG-IL-2 injections. Our data suggest that local treatment of cancer patients with a second cycle of PEG-IL-2 after previous therapy with rIL-2 or PEG-IL-2 may reduce the therapeutic efficacy of PEG-IL-2. |
| Databáze: | OpenAIRE |
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