Our goal is to combine activation of innate and adaptive immunity. We are investigating the relevant immune activation mechanisms, e.g. IL-12 alone (Manuel et al., PNAS 1996, Khiem et al., Int. J. Cancer 1999), or in combination with agonism of co-stimulatory molecules 4-1BB (Martinet et al., J. of National Cancer Ins. 2000, Chen et al., Mol. Therapy 2000, Xu et al., 2003 Int. J. of Cancer), OX40 (Pan et al., Mol. Therapy 2002), and/or CD40 (manuscript in preparation). We have observed a dramatic synergistic therapeutic effect with the combination of IL-12 + 4-1BB activation, which translated to greater therapeutic efficacy than with either reagent alone. This allowed a greater than 18-fold reduction of the IL-12 viral dose while still achieving treatment goals.
These immune enhancing strategies have been actively studied in metastatic models of colorectal carcinoma, breast cancer, and melanoma with similar results. We hypothesize that IL-12 activated NK cells initiate the innate immune response by regulating the activation of and proliferation of DCs. More importantly, these activated DCs can be further activated and maturation induced by ligation of the co-stimulatory molecules with agonistic 4-1BB or CD40 antibodies or the corresponding natural ligands. Subsequently, these activated DCs can migrate into lymphoid organs where they activate nave T cells. These primed CD8+ and CD4+ T cell can be further activated and induced to undergo clonal expansion by 4-1BB and OX40 co-stimulation.
Results from studies detailing the in vivo immune mechanisms underlying these treatment modalities have been accepted or are under the revision for publication (Li et al., 2003, Pan et al., 2003, Xu et al., 2003). Currently, Phase I clinical trials are investigating adenoviral human IL-12 gene delivery for breast and colon cancer metastases to the liver. Also, a combination therapy trial for breast cancer is waiting final development of GMP-grade reagents. Clinical response and relevant information from treated patients will help improve our treatment paradigms and thinking.
Future directions in my laboratory include continued focus upon the interaction between NK and DCs; the effect of 4-1BB, OX40, and CD40 ligation on DC activation; and identification of receptors involved in NK/DC activation and linkage of innate and adaptive immune responses.
