Administration of LMP-Specific Cytotoxic T-Lymphocytes to Patients With Relapsed EBV-Positive Lymphoma (ALCI) / Previously Known as: Administration of Neomycin Resistance Gene Marked LMP2A-Specific Cytotoxic T-Lymphocytes to Patents With Relapsed EBV-Positive Lymphoma (ALASCAR)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 74
- 试验地点
- 2
- 主要终点
- Dose Limiting Toxicity (DLT) Rate by the NCI Common Toxicity Criteria (CTCAE) v2.0 and the Method of Przepiorka et al (Protocol Appendix I)
研究概览
简要总结
This protocol is broken up into 2 portions to determine the maximum tolerated dose for treating patients with a type of lymph gland disease.
The 1st portion, called ALASCER are for people with a type of lymph gland cancer called Hodgkin or non-Hodgkin Lymphoma or Lymphoepithelioma which has returned or may return or has not gone away after treatment, including the best treatment we know for Lymphoma. While the 2nd portion (ALCI) also includes Lymphoepithelioma, severe chronic active EBV (SCAEBC), and leiomyosarcoma.
Some patients with Lymphoma 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 up to half the patients with Hodgkin's and non-Hodgkin Lymphoma, suggesting that it may play a role in causing Lymphoma. The cancer cells (in lymphoma) and some B cells (in SCAEBV) infected by EBV are able to hide from the body's immune system and escape destruction. Investigators want to see if special white blood cells, called T cells, that have been trained to kill EBV infected cells can survive in your blood and affect the tumor.
The investigators have used this sort of therapy to treat a different type of cancer that occurs after bone marrow or solid organ transplant called post transplant lymphoma. In this type of cancer the tumor cells have 9 proteins made by EBV on their surface. The investigators grew T cells in the laboratory that recognized all 9 proteins and were able to successfully prevent and treat post transplant lymphoma. However in Hodgkin disease and non-Hodgkin Lymphoma and SCAEBV, the tumor cells and B cells only express 2 EBV proteins. In a previous study we made T cells that recognized all 9 proteins and gave them to patients with Hodgkin disease. Some patients had a partial response to this therapy but no patients had a complete response. Investigators think one reason may be that many of the T cells reacted with proteins that were not on the tumor cells. In this present study we are trying to find out if we can improve this treatment by growing T cells that only recognize one of the proteins expressed on infected EBV Lymphoma cells called LMP-2a, and B cells called LMP1 and LMP2. These special T cells are called LMP specific cytotoxic T-lymphocytes (CTLs).
The purpose of the study is to find the largest safe dose of LMP specific cytotoxic T cells, to learn what the side effects are and to see whether this therapy might help patients with Hodgkin disease, non-Hodgkin Lymphoma, Lymphoepithelioma, SCAEBV or leiomyosarcoma.
详细描述
ALASCER (Part 1 of 2)
We will generate autologous (or syngeneic) or allogeneic LMP2A-specific cytotoxic T-cells and adoptively transfer them to patients with relapsed EBV-positive Hodgkin's or non-Hodgkins Lymphoma or Lymphoepithelioma.
To initiate the LMP-specific CTL line, PBMC will be transduced with an adenovirus vector (Ad5f35-pp65) expressing the LMP2 antigen, at a viral particle (vp) to cell ratio of 30,000:1. For blood samples from normal donors, the monocyte fraction of PBMC may be transduced and will express and present LMP2 peptide epitopes to the LMP2-specific T cell fraction of the PBMC. This step will require 20 to 40 x 106 PBMC from about 40 mL of blood.
When a stronger stimulus is required to reactivate LMP2-specific T cell precursors (i.e. from patients PBMC), then we will make dendritic cell APCs by culture of PBMC-derived monocytes with cytokines (GM-CSF, IL-4) followed by transduction with Ad5f35-LMP2 (vp:cell ratio of 30000:1) and maturation with TNF-a and PGE1. These mature, transduced dendritic cells will be used to stimulate PBMC-derived T cells. In this case, dendritic cells will be prepared from about 40 mL of blood and the T cells will be derived from 20 to 40 mL of blood
To expand the LMP2-specific T cells we will use EBV-transformed B lymphoblastoid cell lines (EBV-LCLs) transduced with Ad5f35-LMP2 (vp:LCL ratio of 100,000:1). This transduction allows the EBV-LCLs to present LMP2 peptides to the T cells. EBV-LCLs are derived from PBMC-B lymphocytes by infection with a clinical grade, laboratory strain of Epstein-Barr virus (EBV). About 5 x 106 PBMC, or 5 to 10 mLs of blood is required to generate the EBV-LCL
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •ALASCER (Part 1 of Study)
- •INCLUSION CRITERIA
- •Any patient, regardless of age or sex, with EBV-positive Lymphoma, or lymphoepithelioma regardless of the histological subtype or EBV (associated)-T/NK-LPD.
- •In second or subsequent relapse (or first relapse or with active disease if immunosuppressive chemotherapy contraindicated or multiply relapsed patients in remission who have a high risk of relapse) OR any patient with primary disease or in first remission if immunosuppressive chemotherapy is contraindicated, e.g. patients who develop Hodgkin disease after solid organ transplantation or if the Lymphoma is a second malignancy e.g. a Richters transformation of CLL. (Group A) OR In remission or with minimal residual disease status after autologous or syngeneic SCT for Hodgkin's or non-Hodgkin's Lymphoma or lymphoepithelioma. (Group B) OR In remission or with detectable disease after allogeneic SCT. (Group C)
- •Patients with life expectancy > 6 weeks.
- •Patients with a Karnofsky/Lansky score of > 50
- •No severe intercurrent infection.
- •Donor HIV negative (if autologous product - patient must be HIV negative)
- •No evidence of GVHD > Grade II at time of enrollment.
- •If post allogeneic SCT must not have less than 50% donor chimerism in either peripheral blood or bone marrow
- •Patient, parent/guardian able to give informed consent.
- •Patients with bilirubin <3x normal, AST <5x normal, and Hgb >8.0 (see Section 7.2).
- •Patients with a creatinine <2x normal for age
- •Patients should have been off other investigational therapy for one month prior to entry in this study.
排除标准
- •Patients with a life expectancy of <6 weeks.
- •Patients with a Karnofsky/Lansky score of <
- •Patients with a severe intercurrent infection.
- •Patients with bilirubin >3x normal. AST >5x normal or abnormal prothrombin time.
- •Patients with a creatinine >2x normal for age
- •Donors who are HIV positive (Patients who are HIV positive - if autologous product)
- •Patients with GVHD Grades III-IV
- •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 investigator's discretion after approval by the CCGT Protocol Review Committee and the FDA reviewer.
- •ALCI and ALCI Expansion (Part 2 of Study)
- •INCLUSION CRITERIA:
- •Any patient, regardless of age or sex, with EBV-positive Hodgkin's or non-Hodgkin's Lymphoma, or lymphoepithelioma or leiomyosarcoma regardless of the histological subtype or EBV (associated)-T/NK-lymphoproliferative disease or Severe Chronic EBV#
- •(#SCAEBV is defined as patients with high EBV viral load in plasma or PBMC (>4000 genomes per ug PBMC DNA) and/or biopsy tissue positive for EBV)
- •a - In second or subsequent relapse (or first relapse or with active disease if immunosuppressive chemotherapy contraindicated or multiply relapsed patients currently in remission who have a high risk of relapse) OR with primary disease or in first or subsequent remission if immunosuppressive chemotherapy is contraindicated, e.g. patients who develop Hodgkin disease after solid organ transplantation or if the Lymphoma is a second malignancy e.g. a Richters transformation of CLL.(Group A)
- •b - In remission or with minimal residual disease status after autologous or syngeneic SCT for Hodgkin's or non-Hodgkin's Lymphoma/Lymphoepithelioma/SCAEBV. (Group B)
- •c - Patients in remission or with detectable disease after allogeneic SCT. (Group C)
- •Patients with life expectancy 6 weeks or greater.
- •Tumor tissue EBV positive
- •Patients with a Karnofsky/Lansky score of 50 or greater
- •Donor HIV negative (if autologous product - patient must be HIV negative)
- •If post allogeneic SCT must not have less than 50% donor chimerism in either peripheral blood or bone marrow
- •Patients with bilirubin 3x normal or less, AST 5x normal or less, 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:
- •Patients with a severe intercurrent infection.
- •Donors who are HIV positive or Patients who are HIV positive if autologous product to be used
- •Patients with greater than Grade II GVHD
- •Due to unknown effects of this therapy on a fetus, pregnant women are excluded from this research. The male partner should use a condom.
研究组 & 干预措施
LMP1/2 CTLs (ALCI - Group A)
Patients receiving CTLs as therapy for relapsed Lymphoma/Lymphoepithelioma/leiomyosarcoma or who are at risk for relapse
干预措施: LMP1/2 CTLs (ALCI - Group A) (Biological)
LMP1/2 CTLs (ALCI - Group B)
Patients receiving CTLs as adjunctive therapy following autologous or syngeneic transplant.
干预措施: LMP1/2 CTLs (ALCI - Group B) (Biological)
LMP1/2 CTLs (ALCI - Group C)
Patients receiving CTLs following allogeneic stem cell transplant.
干预措施: LMP1/2 CTLs (ALCI - Group C) (Biological)
LMP2A CTLs (ALASCER - Group A)
Patients receiving CTLs as therapy for relapsed Lymphoma/Lymphoepithelioma/leiomyosarcoma or who are at risk for relapse
干预措施: LMP2 CTLs (ALSCER - Group A) (Biological)
LMP2A CTLs (ALASCER - Group B)
Patients receiving CTLs as adjunctive therapy following autologous or syngeneic transplant
干预措施: LMP2 CTLs (ALSCER - Group B) (Biological)
LMP2A CTLs (ALASCER - Group C)
Patients receiving CTLs following allogeneic stem cell transplant
干预措施: LMP2 CTLs (ALSCER - Group C) (Biological)
LMP1/2 CTLs (ALCI - Expansion Group A)
Patients receiving CTLs as therapy for relapsed Lymphoma/Lymphoepithelioma/leiomyosarcoma or who are at risk for relapse
干预措施: LMP1/2 CTLs (ALCI - Expansion - Group A) (Biological)
LMP1/2 CTLs (ALCI - Expansion Group B)
Patients receiving CTLs as adjunctive therapy following autologous or syngeneic transplant.
干预措施: LMP1/2 CTLs (ALCI - Expansion Group B) (Biological)
LMP1/2 CTLs (ALCI - Expansion Group C)
Patients receiving CTLs following allogeneic stem cell transplant.
干预措施: LMP1/2 CTLs (ALCI - Expansion Group C) (Biological)
结局指标
主要结局
Dose Limiting Toxicity (DLT) Rate by the NCI Common Toxicity Criteria (CTCAE) v2.0 and the Method of Przepiorka et al (Protocol Appendix I)
时间窗: 6 weeks post second CLT infusion
Dose limiting toxicity (DLT) rate is the proportion of participants with DLT. DLT will be defined as any toxicity that is irreversible, life threatening or Grade 3-4 considered to be primarily related to the LMP-specific cytotoxic T-lymphocytes (CTL) injection or development of Grade III-IV Graft versus host disease (GVHD). Toxicity will be evaluated according to the CTCAE Version 2.0. GVHD will be graded by the method of Przepiorka et al (protocol Appendix I).
次要结局
- Response Rate According to the Harmonization Project (Protocol 8.5.1) or RECIST Criteria.(Up to 4 months after the last infusion)
- Grade III-IV Toxicity Rate in Participants Receiving an Extended Dosage Regimen According to the NCI Common Toxicity Criteria (CTCAE) Version 2.0 and the Method of Przepiorka et. al. (Protocol Appendix I).(6 weeks after the final injection)
研究者
Helen Heslop
Professor
Baylor College of Medicine