The antitumor activity of Interleukin-2 (IL-2) has been more limited than initially anticipated. Nevertheless, the durable complete response observed in a subset of patients with extensive metastatic disease warrants further investigation of IL-2. One of the major obstacles with IL-2-based therapy has been the substantial acute toxicity observed in patients receiving high dose IL-2. One of our approaches to decrease IL-2-induced toxicity and simultaneously increase its antitumor activity is to combine low dose (LDIL-2) with bryostatin-l. Bryostatin-l has direct antitumor and immunomodulatory effects. Furthermore, it synergizes with IL-2 in activating the immune system and this is important because patients with cancer have an impaired immune response. The biological basis of this observation is poorly understood. However, several authors have reported that antigen presenting cells (APCs) are dysfunctional in tumor-bearing hosts suggesting that defective antigen presentation in cancer patients may account for, at lease in part to the lack of an efficient antitumor response. Preliminary data suggest the following: 1)the combination of bryostatin-1 and LDIL-2 inhibits tumor growth in vivo without the acute toxicity associated with high-dose IL-2; and 2) IL-2 and bryostatin-1 may enhance the ability of monocytes to act as efficient APCs. We hypothesize that the low antigen presentation capability of human monocytes in cancer patients can be increased by bryostatin-1 and LDIL-2. If so, the enhanced function may result in an improved antitumor response. Therefore, as a necessary step toward the development of novel immune strategies and to test our hypothesis we plan to conduct a phase Ib clinical trial in patients with cancer that will address the following three key issues: 1) the toxicity associated with this regimen; 2) the effects of this regimen in APCs; and 3) the antitumor response that may occur in response to this regimen.
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