TGF-beta Resistant Cytotoxic T-lymphocytes in Treatment of EBV-positive Nasopharyngeal Carcinoma / RESIST-NPC
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|ClinicalTrials.gov Identifier: NCT02065362|
Recruitment Status : Active, not recruiting
First Posted : February 19, 2014
Last Update Posted : February 2, 2021
Patients have nasopharyngeal carcinoma (NPC). This study is a gene transfer research study using special immune cells.
Most patients with NPC show evidence of infection with the virus that causes infectious mononucleosis Epstein Barr virus (EBV) before or at the time of their diagnosis. EBV is found in the cancer cells of almost all patients with advanced stage NPC, suggesting that it may play a role in causing the disease. The cancer cells infected by EBV are able to hide from the body's immune system and escape destruction. We want to see if special white blood cells, called T cells, that have been trained to recognize and kill special parts of EBV infected cells can survive in patient's blood and affect the tumor.
We already have given EBV-specific cytotoxic T cells to 30 patients with active NPC and have seen anti-tumor activity in 14 of 30 patients. We are now trying to find out if we can improve this treatment.
First, we want to give T cells where more of the cells recognize at least two of the four EBV proteins expressed on NPC cells. We call these cells NPC-specific cytotoxic T cells.
Second, we found that T cells work better if we add a receptor to the T cells called DNR (Dominant Negative Receptor). DNR makes T cells resistant to TGFbeta, a factor secreted by cancer cells that helps them escape being killed by the immune system. In this study we will therefore place the DNR gene into NPC-specific T cells (DNR.NPC-specific T cells).
In other clinical studies using T cells, some investigators found that giving chemotherapy before the T cell infusion can improve the amount of time the T cells stay in the body and therefore the effect the T cells can have. Giving chemotherapy before a T cell infusion is called lymphodepletion since the chemotherapy is specifically chosen to decrease the number of lymphocytes in the body. Decreasing the number of patient's lymphocytes first should allow the T cells we infuse to expand and stay longer in their body, and potentially kill cancer cells more effectively.
The chemotherapy we will use for lymphodepletion is a combination of cyclophosphamide and fludarabine. Cyclophosphamide and fludarabine are the chemotherapy agents most commonly used for lymphodepletion in immunotherapy clinical trials.
|Condition or disease||Intervention/treatment||Phase|
|EBV-positive Nasopharyngeal Carcinoma||Biological: DNR.NPC-specific T cells Biological: DNR.NPC-specific T cells + cyclophosphamide + fludarabine||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||14 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Administration Of TGF-beta Resistant Cytotoxic T-Lymphocytes to Patients With EBV-positive Nasopharyngeal Carcinoma (RESIST-NPC)|
|Study Start Date :||February 2015|
|Actual Primary Completion Date :||March 2017|
|Estimated Study Completion Date :||February 2033|
Experimental: DNR.NPC-specific T cells or DNR.NPC-specific T cells + c/f
DNR.NPC-specific T cells or DNR.NPC-specific T cells + c/f
Biological: DNR.NPC-specific T cells
Each patient will receive 2 infusions, 14 days apart, according to the following dosing schedule:
Dose Level 1:
Day 0: 2 x 10^7 cells/m^2
Day 14: 2 x 10^7 cells/m^2
The doses are calculated according to the total T cell number.
Biological: DNR.NPC-specific T cells + cyclophosphamide + fludarabine
Patients will receive cyclophosphamide and fludarabine for 3 days before receiving the DNR.NPC-specific T cells.
Each patient will receive infusions according to the following dosing schedule:
Dose Level 2:
Cy/Flu on Days -4 to -2 and then 4 x 10^7 cells/m^2 on Day 0, Day 1 or Day 2
Dose Level 3:
Cy/Flu on Days -4 to -2 and then 1 x 10^8 cells/m^2 on Day 0, Day 1, or Day 2
- Number of subjects with a dose limiting toxicity [ Time Frame: 8 weeks ]Determine the safety of escalating doses of intravenous infusions of autologous TGFbeta-resistant NPC-specific cytotoxic T-lymphocytes with lymphodepleting chemotherapy for dose levels 2 and 3 in patients with EBV-positive nasopharyngeal carcinoma (NPC).
- Amount of T cells in the blood after the infusions [ Time Frame: 15 years ]Determine the survival and the immune function of TGFbeta-resistant NPC specific T cells.
- Number of patients with a response to the T cells [ Time Frame: 8 weeks ]Assess the anti-viral and anti-tumor effects of TGFbeta-resistant NPC specific T cells.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02065362
|United States, Texas|
|Texas Children's Hospital|
|Houston, Texas, United States, 77030|
|Principal Investigator:||Helen Heslop, MD||Baylor College of Medicine/Texas Children's Hospital /Houston Methodist Hospital|