Rituximab and Autologous Effector Lymphocytes in Non-Hodgkin Follicular Lymphoma in Response to First Line Chemotherapy

Overview

Nowadays, therapy with monoclonal antibodies is considered to be a standard treatment that increases the rate of remissions and the overall survival in patients with follicular lymphoma. Nevertheless there are an important number of patients who do not benefit from this therapy. A way to improve the efficiency of monoclonal antibodies therapy could be to improve the activity of the effector arm of the immune system. A strategy that has been proposed to obtain this improvement is the utilization of lymphocyte activated killer (LAK) cells. In addition, the combination of LAK cells with monoclonal antibodies might obtain an additive effect across the stimulation of the antibody dependent cellular cytotoxicity (ADCC)activity. The present clinical assay proposes to study the feasibility, safety and effectiveness of treatment with autologous effector cells expanded ex vivo associated with a standard maintenance treatment with rituximab in patients with follicular lymphoma in remission after first-line treatment. In addition, we plan to analyse various biological parameters that can predict the susceptibility of patients to treatment with rituximab. Specifically, we propose to study the polymorphisms of Fc receptor, polymorphisms related to the ability of complement activation, to study both the complement activity and peripheral blood cell subpopulations that can mediate directly or indirectly dependent antibody cytotoxic effect. We will also try to correlate any of these biological parameters with the response to treatment.

There are many mechanisms involved in the antitumor effect of the antibodies including the induction of apoptosis, blocking angiogenesis, blockade of intracellular signaling pathways, and activation of complement leading to lysis of tumor cells. However it appears that the antibody-dependent cellular cytotoxicity (ADCC) is one of the predominant mechanisms of action. It is important to note that in order to obtain a powerful ADCC effect it is necessary the action of the antibody but also the activity of the effector cell, and thus the competence of the immune system of the guest. There are different cellular subpopulations that mediate the ADCC effect. CTL and NK are two of these subpopulations that can be reduced in patients with cancer. A way to improve the efficiency of the monoclonal antibodies would be to improve the activity of the effector arm of the immune system. A strategy that that has been planed is the utilization of LAK cells. The culture of lymphocytes of peripheral blood with IL-2 activates the subpopulations of killer cells. This population of killer cells activated with cytokines (LAK: lymphokine activated killer) has a high number of NK and CTL cells, both with increased cytotoxic capacity. It has been demonstrated that the immunotherapy with LAK cells might be an effective and sure treatment for patients with follicular lymphoma. In a murine model it has been demonstrated that LAK cells associated with monoclonal antibodies increase the antitumoral activity when compared to the administration of antibodies alone. In addition, in this model the combination was also superior to the administration of monoclonal antibodies + IL-2 (Schultz et al., 1990). Other investigators have demonstrated similar results. This information supports the idea of the combined therapy consisting in LAK with anti-CD20 antibodies. This therapy can induce a destruction of CD20 positive cells greater than that with the monoclonal antibodies alone. In addition, it has been reported that the administration of systemic IL-2 and LAK cells improves the ADCC in lymphoma patients treated with rituximab. It is a small pilot study, with 10 patients. Seven of them received LAK cells following a programmed way. The safety of the treatment and the promising results demonstrated in this study encourage to investigate in this line. Since one of the mechanisms of action of the monoclonal antibodies is to promote ADCC , our hypothesis is that the treatment with a suspension of autologous effector lymphocytes expanded ex-vivo with culture should modify the biological effect of the treatment with rituximab in follicular lymphoma patients, with an acceptable safety profile, and probably increasing the efficiency of the monoclonal antibodies. In order to evaluate this hypotesis we propose an open, prospective, historically controlled, phase II clinical study in patients with follicular lymphoma who have achieved a remission after first-line therapy including the anti-CD20 monoclonal antibody rituximab and chemotherapy.