Phase II Clinical Trial of Immunotherapy With Rituximab and Autologous Effector Lymphocytes in Patients With Non-Hodgkin Follicular Lymphoma in Response to First Line Chemotherapy
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
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Progression free survival (PFS) from the entry in the study.
The PFS is defined as the time from the entry in the study up to the progression of the disease.
Spain: Agencia Española de Medicamentos y Productos Sanitarios