Multilineage hematopoietic recovery with concomitant antitumor effects using low dose Interleukin-12 in myelosuppressed tumor-bearing mice.
BACKGROUND
Interleukin-12 (IL-12) is a cytokine well known for its role in immunity. A lesser known function of IL-12 is its role in hematopoiesis. The promising data obtained in the preclinical models of antitumor immunotherapy raised hope that IL-12 could be a powerful therapeutic agent against cancer. However, excessive clinical toxicity, largely due to repeat dose regimens, and modest clinical response observed in the clinical trials have pointed to the necessity to design protocols that minimize toxicity without affecting the anti-tumor effect of IL-12. We have focused on the lesser known role of IL-12 in hematopoiesis and hypothesized that an important clinical role for IL-12 in cancer may be as an adjuvant hematological cancer therapy. In this putative clinical function, IL-12 is utilized for the prevention of cancer therapy-related cytopenias, while providing concomitant anti-tumor responses over and above responses observed with the primary therapy alone. This putative clinical function of IL-12 focuses on the dual role of IL-12 in hematopoiesis and immunity.


METHODS
We assessed the ability of IL-12 to facilitate hematopoietic recovery from radiation (625 rad) and chemotherapy (cyclophosphamide) in two tumor-bearing murine models, namely the EL4 lymphoma and the Lewis lung cancer models. Antitumor effects and changes in bone marrow cellularity were also assessed.


RESULTS
We show herein that carefully designed protocols, in mice, utilizing IL-12 as an adjuvant to radiation or chemotherapy yield facile and consistent, multilineage hematopoietic recovery from cancer therapy-induced cytopenias, as compared to vehicle and the clinically-utilized cytokine granulocyte colony-stimulating factor (G-CSF) (positive control), while still providing concomitant antitumor responses over and above the effects of the primary therapy alone. Moreover, our protocol design utilizes single, low doses of IL-12 that did not yield any apparent toxicity.


CONCLUSIONS
Our results portend that despite its past failure, IL-12 appears to have significant clinical potential as a hematological adjuvant cancer therapy.
Basile
Lena A
LA
Neumedicines Inc., 2275 East Foothill Blvd., Pasadena, California, USA. basile@neumedicines.com
Gallaher
Timothy K
TK
Shibata
Darryl
D
Miller
Joseph D
JD
Douer
Dan
D
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D003131:Combined Modality Therapy / Q000379:methods; D003520:Cyclophosphamide / Q000627:therapeutic use; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D007167:Immunotherapy / Q000379:methods; D018664:Interleukin-12 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation
D000970:Antineoplastic Agents; D016179:Granulocyte Colony-Stimulating Factor; D018664:Interleukin-12; D003520:Cyclophosphamide