Intratumoral therapy with IL13-PE38 results in effective CTL-mediated suppression of IL-13Ralpha2-expressing contralateral tumors.
OBJECTIVE
IL13-PE38, a targeted cytotoxin comprised of interleukin 13 (IL-13) and a mutated form of Pseudomonas exotoxin, induces specific killing of tumor cells expressing abundant levels of the IL-13Ralpha2 chain. We hypothesized that tumor cells killed by the cytotoxin may release antigens and/or apoptotic bodies when cells are dying, which then induce adoptive immunity, and that the PE38 portion of IL13-PE38 may act as a stimulant for the induction of a CTL response.


METHODS
To test this hypothesis, we established D5 melanoma tumors with or without expression of the IL-13Ralpha2 chain in both flanks of C57BL/6 mice, and then IL13-PE38 was injected in the right flank tumors only.


CONCLUSIONS
When animals with IL-13Ralpha2-expressing D5 tumor (right) were injected with IL13-PE38, right flank tumors expressing the IL-13Ralpha2 chain not only showed dramatic regression but contralateral tumors (left flank) also showed tumor regression. Cell depletion experiments in tumor-bearing animals indicated that both CD8(+) and CD4(+) T cells contribute to the regression of contralateral tumors through CTL activation in the periphery and cellular infiltration into tumors. In addition, intratumoral treatment into s.c. tumors of mice bearing metastatic lung tumors with IL13-PE38 showed not only the reduction of treated s.c. tumor but also the reduction of lung metastasis. Thus, IL13-PE38 mediates an antitumor effect not only directly but also indirectly by inducing a host CD8(+) T cell immune response. Accordingly, targeted cytotoxins may be used to treat local disease even if they cannot be administered systemically, and yet may still induce a reasonable systemic antitumor response.
Kawakami
Koji
K
Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville Pike, Rockville, Maryland, USA. kawakami-k@umin.ac.jp
Terabe
Masaki
M
Kioi
Mitomu
M
Berzofsky
Jay A
JA
Puri
Raj K
RK
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005098:Exotoxins / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D015552:Injections, Intralesional; D007279:Injections, Subcutaneous; D018793:Interleukin-13 / Q000008:administration & dosage / Q000627:therapeutic use*; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011550:Pseudomonas aeruginosa / Q000737:chemistry; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
D005098:Exotoxins; D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit