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Administration of LMP1- and LMP2-Specific Cytotoxic T-Lymphocytes Following CD45 Antibody Administration to Patients With EBV-Positive Nasopharyngeal Carcinoma

Phase 1
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Trial Information

Administration of LMP1- and LMP2-Specific Cytotoxic T-Lymphocytes Following CD45 Antibody Administration to Patients With EBV-Positive Nasopharyngeal Carcinoma

While patients with nasopharyngeal carcinoma (NPC) may be cured by chemotherapy and
radiotherapy, the outlook for patients who are resistant to this treatment or who relapse is
poor. Almost all patients with undifferentiated nasopharyngeal carcinoma have the EBV virus
in their tumors which may be a target for immunotherapy approaches. We have successfully
used specialized immune system cells grown in the laboratory and trained to recognize and
kill EBV infected cells (EBV-specific cytotoxic T-lymphocytes [EBV-CTL]) to prevent and
treat another type of cancer called post transplant lymphoma that occurs after bone marrow
transplant. In post transplant lymphoma, the tumor cells have 9 proteins made by EBV on
their surface. However in nasopharyngeal carcinoma that develops in patients with a normal
immune system, the tumor cells only express 2 EBV proteins that are much harder for the
immune system to recognize. In a previous study we made EBV-CTL that recognized all 9
proteins and gave them to patients with NPC. For patients without evidence of active disease
at the time of therapy, there disease remains in remission. For those patients with active
disease at the time they received CTL, some patients had a partial response to this therapy,
and only three patients had a complete response. We think the main reason for this is that
many of the T cells reacted with EBV proteins that were not on the tumor cells, and the
other is that the infused T cells have not enough space to grow.

The two EBV proteins present on NPC tumor cells that are good targets for T-cell therapies
are called LMP1 and LMP2. We are therefore planing to generate T cells specific for LMP1 and
LMP2 and infuse these cells into NPC patients. To make LMP1- and LMP2-CTL, we have obtained
blood from the patients and grown special type of cell called a dendritic cell (DC) and EBV
infected lymphoblastoid cells (LCL). We have then transferred an adenovirus vector that
carries the LMP1 and LMP2 gene into the DC and the LCL. These DC and LCL are then treated
with radiation so they cannot grow and are used to stimulate and expand LMP1- and LMP2-CTL.
This stimulation trains the T cells to kill cancer cells with LMP1 and LMP2 on their

To 'create space' for EBV-CTL growth after infusion in NPC patients we have already used a
special protein called a CD45 antibody, which removes for a short period of time most of the
patient's T cells. The preliminary results of this study is encouraging: the use of the CD45
antibody is safe and we observed enhanced EBV-CTL growth after infusion. In addition, all
patients who has EBV-CTL growth had clinical responses.

We and others have demonstrated the feasibility of CTL therapy for EBV-positive NPC in
immunocompetent patients, providing preliminary evidence of anti-tumor activity of EBV-CTL
in this patient population. Not all patients responded, however, suggesting the need for
further improvement. We propose that CTL failure can be overcome by increasing the
specificity of the infused CTL product. That is, infusion of CTL specific for LMP1 and LMP2
will produce greater clinical benefit than EBV-specific CTL. The rationale for this approach
is straight forward: EBV-specific CTL lines generated by standard methods are dominated by
T-cell clones not reactive to the subdominant EBV proteins LMP1 and LMP2 expressed in NPC.
We also propose that the failure of adoptively transferred CTL to measurably expand in the
peripheral blood of NPC patients is a consequence both of lymphoid homeostasis in these
lympho-replete patients and of the inhibitory T-cell infiltrate at the sites of disease. We
will therefore use monoclonal antibodies targeting the CD45 antigen (CD45 MAbs), to
lymphodeplete NPC patients prior to the infusion of EBV-specific CTL. Preliminary results
indicate that CD45 MAb depletion can augment CTL expansion, and that such expansion is
associated with a higher disease response rate. We will confirm and extend these promising
new data in this Phase I clinical trial.

Inclusion Criteria:

All patients with NPC in first or subsequent relapse or with primary refractory disease or
high risk (T3 or T4, or node positive) in whom the EBV genome or antigens have been
demonstrated in tissue biopsies will be eligible for this trial.

Any patient with EBV positive NPC, in relapse or with primary resistant disease

Patients with a life expectancy 6 weeks or greater.

Patients with a Karnofsky score (age at least 16; for Karnofsky scale see full protocol)
or Lansky score (less than 16; for Lansky scale see full protocol) of 50 or greater as
described below:

Patients with bilirubin <2x normal, SGOT <3x normal, and Hgb greater than 8.0.

Patients with a creatinine 2x normal or less for age.

Patients should have been off other investigational therapy for one month prior to entry
in this study.

Patient, parent/guardian able to give informed consent.

Exclusion Criteria:

Severe intercurrent infection.

Due to unknown effects of this therapy on a fetus, pregnant women are excluded from this
research. The male partner should use a condom.

Note: Patients who would be excluded from the protocol strictly for laboratory
abnormalities can be included at the investigatorĀ”-s discretion after approval by the CCGT
Protocol Review Committee and the FDA reviewer.

Type of Study:


Study Design:

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

Outcome Measure:

To determine the safety of autologous LMP1- and LMP2- specific cytotoxic T-lymphocytes (CTL) in combination with CD45 monoclonal antibody (MAb) in patients with EBV-positive nasopharyngeal carcinoma (NPC).

Outcome Time Frame:

12 months

Safety Issue:


Principal Investigator

Stephen Gottschalk, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Baylor College of Medicine


United States: Food and Drug Administration

Study ID:




Start Date:

August 2007

Completion Date:

August 2010

Related Keywords:

  • Nasopharyngeal Carcinoma
  • Carcinoma
  • Nasopharyngeal Neoplasms