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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

Phase 2
18 Years
75 Years
Open (Enrolling)
Follicular Lymphoma, Follicular Non-Hodgkin´s Lymphoma, Autologous Effector Lymphocytes

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Trial Information

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
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.

Inclusion Criteria:

- Patients with histologically-confirmed follicular lymphoma CD20-positive grade 1, 2 ó

- Patients with aptitude to sign the written informed consent and to express his desire
to fulfill all the requirements of the protocol during the period of study.

- Patients not treated before. The induction treatment with rituximab and chemotherapy
must be the first line for the patients who are included in the study.

- Patients undergoing maintenance therapy with rituximab every two/three months.

- Ann Arbor stage II, III o IV before receiving the induction treatment with rituximab
and chemotherapy.

- The patient must have achieved a partial or complete response based on the revised
International Workshop Response Criteria (IWRC) (Cheson, et al 2007) following the
induction treatment.

- Age >18 years and <75 years.

- Performance status <2 following the Eastern Cooperative Oncology Group (ECOG).

- Screening laboratory values obtained 28 days before registry (unless due to lymphoma
involvement of the bone marrow): Hemoglobin > 8,0 g/dL (5,0 mmol/L), Neutrophil
absolute count > 1,5 x 109/L,Platelets > 100 x 109/L

Exclusion Criteria:

- Patients with transformed follicular lymphoma into diffuse large B-cell lymphoma.

- Patients with evidence of follicular lymphoma grade 3b.

- Patients with evidence of primary cutaneous or gastrointestinal follicular lymphoma.

- Patients with evidence of current central nervous system involvement.

- Patients who received previous induction treatment other than rituximab and

- Patients receiving chronic immunosuppressive agents in the last 4 weeks. Patients may
be receiving stable chronic doses of corticosteroids with a maximum dose of 20
mg/day of prednisone or equivalent.

- Patients who have a history of another primary malignancy < 3 years, with the
exception of non-melanoma skin cancer and carcinoma in situ of the uterine cervix.

- Decompensated renal function: serum creatininea > 2,0 mg/dL (197 u.mol/L.

- Decompensated hepatic function: total bilirrubine > 2,0 mg/dL (34 umol/L), AST (SGOT)
> 3 x ULN, unless due to lymphoma involvement

- Patients with a known history of human immunodeficiency virus (HIV) seropositivity,
chronic hepatitis or other active viral infections due to hepatitis B virus (HBV) or
hepatitis C virus (HVC).

- Patients with underlying serious diseases that in the criteria of the investigator
could concern the capacity of the patient to take part in the test (for example,
infection in process, not controlled diabetes mellitus, gastric ulcers, autoimmune
active disease).

- Life expectancy <6 months.

- Female patients who are pregnant or breast feeding.

- Patients with known hypersensitivity to rituximab or other murine proteins or to any
of the excipients.

- Patients who are using other investigational agents or who have received
investigational drus 30 days prior to study drug start.

- Any other medical or psychological coexistent condition that rejects the
participation in the study or compromises the aptitude to give the informed consent.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression free survival (PFS) from the entry in the study.

Outcome Description:

The PFS is defined as the time from the entry in the study up to the progression of the disease.

Outcome Time Frame:


Safety Issue:



Spain: Agencia Española de Medicamentos y Productos Sanitarios

Study ID:




Start Date:

March 2011

Completion Date:

March 2015

Related Keywords:

  • Follicular Lymphoma
  • Follicular Non-Hodgkin´s Lymphoma
  • Autologous Effector Lymphocytes
  • Follicular lymphoma
  • Follicular non-Hodgkin´s lymphoma
  • Autologous effector lymphocytes
  • Cell Therapy
  • Maintenance therapy
  • Rituximab
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Non-Hodgkin