Effect of interleukin-1 alpha on the in vitro activation of tumor-draining lymph node cells for adoptive immunotherapy.
Adoptive immunotherapy using in vitro activated T-cells can mediate the destruction of metastatic tumor deposits in animal models. These antitumor effector cells can be generated from mice with subcutaneous tumor by the sequential in vitro activation of tumor-draining lymph node (TDLN) cells with monoclonal antibody to the T-cell receptor complex (anti-CD3) and expansion in low concentrations of interleukin-2 (IL-2). In this animal model, the concomitant presence of visceral tumor can suppress the sensitization of tumor-reactive TDLN cells. We investigated whether IL-1 alpha added during in vitro activation and/or expansion of TDLNs could augment their antitumor activity in adoptive therapy. Mice were inoculated subcutaneously with MCA 205 tumor. TDLN cells were harvested and activated in vitro with 1 microgram/ml anti-CD3 for 2 days (anti-CD3 phase), followed by expansion in 10 U/ml IL-2 for 3 days (IL-2 phase). Experimental cultures had IL-1 (10-10,000 U/ml) added in either or both phases. After the 5-day culture period, cells were counted to determine in vitro cellular proliferation and then adoptively transferred to mice bearing 3-day established lung metastases to assess in vivo antitumor efficacy. IL-1 added during the anti-CD3 or IL-2 phase did not alter in vitro cellular proliferation. The presence of IL-1 during the anti-CD3 phase led to the generation of cells that were significantly more therapeutically efficacious than cells generated in the absence of IL-1. The effect of IL-1 during anti-CD3 activation appeared to be dose dependent in the concentration range 10-1,000 U/ml. The addition of IL-1 during the IL-2 phase only did not enhance the antitumor reactivity of the activated cells. The beneficial effect of IL-1 during the anti-CD3 activation phase was specific for the tumor against which the TDLN had been initially sensitized; also, there was no evidence that non-tumor bearer lymphocytes developed significant antitumor reactivity when "activated" with IL-1 and anti-CD3. Furthermore, addition of IL-1 during the anti-CD3 activation phase abrogated suppression induced by the concomitant presence of lung metastases during subcutaneous tumor growth. IL-1 appears to up-regulate the in vitro activation of tumor-reactive lymphocytes derived from TDLN, in both the presence and the absence of visceral metastases.
Hammel
J M
JM
Department of Surgery, University of Michigan Medical Center, Ann Arbor.
Tuck
M K
MK
Hain
J M
JM
Chang
A E
AE
Sondak
V K
VK
D000818:Animals; D017252:CD3 Complex / Q000187:drug effects / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004305:Dose-Response Relationship, Drug; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D016219:Immunotherapy, Adoptive; D007375:Interleukin-1 / Q000494:pharmacology* / Q000627:therapeutic use; D007376:Interleukin-2 / Q000494:pharmacology* / Q000627:therapeutic use; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008198:Lymph Nodes / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation
D017252:CD3 Complex; D007375:Interleukin-1; D007376:Interleukin-2