Intratumoral interleukin-2 immunotherapy: activation of tumor-infiltrating and splenic lymphocytes in vivo.
Direct intratumoral injection of interleukin-2 (IL-2) was evaluated in a murine model. Balb/c mice received 5 x 10(4) Line 1 alveolar carcinoma cells (L1C2) by subcutaneous injection. On the third day following tumor implantation, mice received injections of IL-2 (5 x 10(3)-5 x 10(4) units) or diluent twice daily, either by i.p. or intratumoral injection, 5 days/week for 3 weeks. Intratumoral injection of 5 x 10(4) units IL-2 significantly reduced tumor volume (P < 0.05 versus control), increased median survival time (P = 0.0001), and resulted in a 23.5% cure rate (P = 0.008). There were no long-term survivors in the other treatment groups. Both tumor-infiltrating lymphocytes (TIL) and splenic lymphocytes isolated directly from IL-2-treated mice demonstrated enhanced cytolytic activity compared to diluent-treated controls. To determine whether non-T-cell-mediated antitumor responses were active in our model, intratumoral immunotherapy was evaluated in athymic Balb/c nu/nu mice. In order to decrease the recruitment of lymphocyte precursors, nude mice were splenectomized and received cyclophosphamide prior to tumor injection and IL-2 therapy. Intratumoral IL-2 immunotherapy also significantly decreased tumor volume in these immunodeficient mice (P < 0.02), but did not lead to long-term survival. We conclude that both TIL and splenic lymphocytes are activated in vivo in response to intratumoral IL-2 immunotherapy, suggesting that intratumoral therapy with IL-2 activates both local and systemic antitumor responses.
Dubinett
S M
SM
Pulmonary Immunology Laboratory, UCLA School of Medicine 90073.
Patrone
L
L
Tobias
J
J
Cochran
A J
AJ
Wen
D R
DR
McBride
W H
WH
D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000276:immunology / Q000473:pathology / Q000628:therapy; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive; D015552:Injections, Intralesional; D007376:Interleukin-2 / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013154:Spleen / Q000166:cytology / Q000276:immunology
D007376:Interleukin-2