Monoclonal antibodies and cytokines for therapy of patients with advanced colorectal carcinoma : a clinical and immunological study

Sammanfattning: There is a great need for developing and improving treatment alternatives in colorectal carcinoma (CRC). The tumour associated antigen (TAA) GA733/CO17-1A is expressed by more than 90% of all CRCs, on the majority of both primary and metastatic CRC cells. This antigen can be utilised as a target structure for passive as well as active immunotherapy. Mouse MAb17-1A has been produced against this antigen and shown to induce clinical responses in patients. The clinical effect might be improved by adding cytokines, which might augment immune effector functions utilised by MAb. In this study we have analysed clinical and immunological in vivo functions of patients with advanced CRC treated with a combination of the MAb 17-1A, GM-CSF and IL-2. The first analysis concerned the clinical effect of IL-2 alone, without MAb. Low doses of IL-2 were given in combination with IFN-[alpha] to 15 patients with metastatic CRC. No patient showed a major response. Six patients had a stable disease. In the subsequent study the clinical response and immune effector functions were analysed when IL-2 was added to a combination of MAb/GM-CSF, the so far best treatment regimen. 20 patients with metastatic CRC were included in this study. One patient obtained a partial remission and 2 patients stable disease. The therapeutic effect did not seem to be improved when IL-2 was added to MAb/GM-CSF therapy, which was in contrast to expectations from preclinical data. There might be a tendency to a lower response rate and impaired survival for MAb/GM-CSF/IL-2 treated patients as compared to patients treated with MAb/GM-CSF. When analysing different in vivo effects a suppressed human anti-mouse (HAMA) and antiidiotypic antibody (Ab2) response as well as an impaired antibody dependent cellular cytotoxicity (ADCC) was observed. There was also a tendency to reduction of the frequency and severity of allergic reactions in MAb/GM-CSF/IL-2 treated patients as compared to MAb/GM-CSF treated patients. A highly significant increase in neopterin and sIL-2R serum concentration was noted in the MAb/GM-CSF/IL-2 treatment group as compared to the MAb/GM-CSF group. These data may indicate induction of immune suppression when IL-2 was added to MAb/GM-CSF. Increases in neopterin and sIL-2R concentrations may reflect activation of cellular immune responses mainly involving macrophages and lymphocytes. High concentrations of these serum markers might indicate generation of oxidative stress. Induction of cytokine antibodies has earlier been shown to hamper the clinical responses of biotherapeutic agents. This study revealed differences in immunogenicity between different preparations of GM-CSF and that neutralising anti-GM-CSF antibodies had biological implications. Furthermore, it was obvious that non-neutralising IL-2 antibodies had a profound impact on IL-2 pharmacokinetics. In IL-2 antibody positive patients a decreased cytokine induced increment of leukocytes was observed. As the use of therapeutic cytokines is increasing it seems to be of particular importance to establish the optimal biological doses of different cytokines as well as to carefully evaluate the induction of cytokine antibodies to be able to use cytokines rationally in the clinic.