The long-term objectives of this study are to implement experimental animal-tumor models which are responsive to the cytoreductive effects of cyclophosphamide and therapeutically enhanced, in terms of tumor regression, by the in vivo administration of purified Interleukin 2. It is hoped that these tumor-animal systems, which are responsive to cyclophosphamide and Interleukin 2, may provide the necessary background and methodology for similar trials in the clinic. The rationale for this approach derives from the fact that cyclophosophamide, a potent anti-neoplastic agent, leaves intact a significant number of host cytotoxic precursor cells. The precursors can be expanded in vitro and in vivo with purified Interleukin 2 or recombinant DNA derived Interleukin 2. If Interleukin 2 is present in sufficient concentrations, these cytotoxic precursors (which are characterized as thymus-derived T-cells) can be expanded in the presence or absence of antigen and differentiate into cytotoxic effectors capable of lysing a wide variety of neoplastic cells. These neoplastic targets include allogeneic and syngeneic primary tumor explants and most importantly Natural Killer cell insensitive targets.
The specific aims of this proposal are to determine the optimal in vivo regimens for demonstrating the inhibitory effects of Interleukin 2 on primary tumor growth (spontaneous mammary adenocarcinoma). Interleukin 2 will be administered in escalated doses in conjunction with cytoreductive doses of cyclophosphamide. In addition to primary tumor growth, attempts will be made to inhibit or eradicate lung metastases by the same procedures. Routes and methodologies of Interleukin 2 delivery will vary depending upon the target organ and systemic versus local delivery. Separate studies of the same nature will be undertaken but using transplantable and spontaneous leukemia as the target of therapy. In this system both T and B cell leukemias will be utilized. In addition, transplantable AKR derived T cell leukemias, responsive and non-responsive to the direct effects of Interleukin 2 will be used. It is possible that Interleukin 2 as an adjunct to chemotherapy for leukemia will be beneficial but only in circumstances where the leukemia cells do not respond directly to Interleukin 2. Mechanistic studies will be performed as a separate aim but concurrently with the therapy protocols. These studies include the isolation and characterization of Interleukin 2 induced-effector cells at the site of the tumor and draining lymph nodes. Selection for tumor cells resistant to Interleukin 2-induced cytotoxic cells will also be performed.
