Ignite Creation Date:
2024-05-05 @ 11:31 AM
Last Modification Date:
2024-10-26 @ 9:08 AM
Study NCT ID:
NCT00062868
Status:
COMPLETED
Last Update Posted:
2020-06-09
First Post:
2003-06-17
Brief Title:
LMP-specific T-cells for Patients With Relapsed EBV-positive Lymphoma
Sponsor:
Baylor College of Medicine
Organization:
Baylor College of Medicine
Study Overview
Official Title:
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
Status:
COMPLETED
Status Verified Date:
2020-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ALCI
Brief Summary:
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 Hodgkins 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 bodys 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
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 Hodgkins 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 bodys 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
Detailed Description:
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 Hodgkins 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 300001 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 ie 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 vpcell ratio of 300001 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 vpLCL ratio of 1000001 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
At the end of the CTL culture period the frequency of LMP2 specific CTL will be determined using tetramer reagents if available
Transduction with the Neomycin Resistance Gene optional - based on patient preference and availability of the vector Established CTLs will be transduced with the retroviral vectors of the LN series
Patients will be evaluated in the clinic and 2-4 doses of CTL will be administered each two weeks apart Patients will be monitored for clinical toxicity by the NCI Common Toxicity Criteria Scale Version 20 located at httpctepcancergov In addition we will determine the kinetics of CTL survival by monitoring the presence of the marker gene in peripheral blood in patients who receive marked cells We will also analyze immunological parameters including phenotype and CTL frequencies by tetramer studies in patients who have HLA types where such reagents are available Functional analyses will be done by cytotoxicity or ELISPOTELISA assays The levels of EBV DNA in peripheral blood before and following infusion will be compared A time period of 8 weeks will constitute the time for clinical safety monitoring If patients have had a partial response or have stable disease they will be eligible to receive up to 6 further doses of CTLs each of which will consist of the same number as their second injection
ALCI Part 2 of 2
This is the 2nd part of the ALASCER study ALCI reflected modification in the manufacturing process to enrich the CTL product for cells recognizing the LMP1 as well as the LMP2 antigen The change in manufacturing required to enrich for both LMP2a and LMP1 is solely to substitute ALCIs Ad5f35LMP12 vector for the previously used Ad5f35LMP2 vector used to transduce the antigen presenting cells used ex vivo to stimulate the T cells during the manufacturing process in our GMP laboratories
We initially used the AD5f35LMP2 vector and now use the Ad5f35LMP12 vector to generate LMP-specific CTL Our preliminary data indicates that these two vectors are identical and produce similar enrichment of LMP2 specific CTL By using the Ad5f35LMP12 vector instead of the Ad5f35 vector encoding LMP2 alone we should better enrich T cell clones recognizing both of the LMP antigens expressed by the malignant cells in Hodgkins disease and non-Hodgkins Lymphoma Our analysis strategies include plans to perform comparisons between these vector types
Like the ALASCER product the ALCI product continued to be a CTL line specific for EBV antigens but enriched for T cells recognizing LMP1 as well as LMP2 The ALASCER product already contains some LMP1 specific T cells along with T cell specific for other EBV antigens and the only change was enrich for these cells Therefore the ALCI Ad5f35 LMP12 adenoviral vector is an ancillary reagent in the manufacturing process used only to transduce antigen presenting cells used as stimulator cells and is not infused in the final product This vector completed testing and was approved for use under ALASCER IND 6387
Additionally the ALASCER protocol design was amended to allow for the addition of a separate arm to the study depending on the vector used for the manufacturing process and the data is analyzed separately
In both ALASCER ALCI the cells will then be thawed and injected into the patient over 10 minutes Initially two doses of T cells will be given two weeks apart If after the second infusion there is a reduction in the size of the lymphoma on CT or MRI scan as assessed by a radiologist the patient can receive up to six additional doses of the T cells if the patient wishes This is a dose escalation study which means that for some patients the second dose may be larger than the first All of the treatments will be given by the Center for Cell and Gene Therapy at Texas Childrens Hospital or the Methodist Hospital
The patient will be followed after the injections They will either be seen in the clinic or will be contacted by a research nurse yearly for 5 years To learn more about the way the T cells are working in the patients body an extra 20-40 mL 4-8 teaspoons of blood will be taken before each infusion and then 4 hours after each infusion optional and 3-4 days after each infusion optional and then weekly for 2 weeks after each infusion total of 9 times Two weeks after the last infusion blood will then be taken again and then every 3 months for 1 year then once a year for 5 years Investigators will use this blood to see how long the T cells last and to look at the immune response to the patients cancer
ALCI Expansion cohort
Once the dose escalation safety phase of the study is completed ie once at least 3 patients have been treated at dose level 3 and no treatment-related DLT has occurred we plan to treat additional patients at dose level 1 to evaluate the immunological response in patients who receive CTL that have been generated using DC matured with the additional maturation cytokines IL-1b and IL-6 in the presence of IL-15 We will treat an additional 30 16 and 16 patients on Groups A B and C respectively
We will generate autologous or syngeneic or allogeneic LMP2A-specific cytotoxic T-cells and adoptively transfer them to patients with relapsed EBV-positive Hodgkins 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 300001 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 ie 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 vpcell ratio of 300001 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 vpLCL ratio of 1000001 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
At the end of the CTL culture period the frequency of LMP2 specific CTL will be determined using tetramer reagents if available
Transduction with the Neomycin Resistance Gene optional - based on patient preference and availability of the vector Established CTLs will be transduced with the retroviral vectors of the LN series
Patients will be evaluated in the clinic and 2-4 doses of CTL will be administered each two weeks apart Patients will be monitored for clinical toxicity by the NCI Common Toxicity Criteria Scale Version 20 located at httpctepcancergov In addition we will determine the kinetics of CTL survival by monitoring the presence of the marker gene in peripheral blood in patients who receive marked cells We will also analyze immunological parameters including phenotype and CTL frequencies by tetramer studies in patients who have HLA types where such reagents are available Functional analyses will be done by cytotoxicity or ELISPOTELISA assays The levels of EBV DNA in peripheral blood before and following infusion will be compared A time period of 8 weeks will constitute the time for clinical safety monitoring If patients have had a partial response or have stable disease they will be eligible to receive up to 6 further doses of CTLs each of which will consist of the same number as their second injection
ALCI Part 2 of 2
This is the 2nd part of the ALASCER study ALCI reflected modification in the manufacturing process to enrich the CTL product for cells recognizing the LMP1 as well as the LMP2 antigen The change in manufacturing required to enrich for both LMP2a and LMP1 is solely to substitute ALCIs Ad5f35LMP12 vector for the previously used Ad5f35LMP2 vector used to transduce the antigen presenting cells used ex vivo to stimulate the T cells during the manufacturing process in our GMP laboratories
We initially used the AD5f35LMP2 vector and now use the Ad5f35LMP12 vector to generate LMP-specific CTL Our preliminary data indicates that these two vectors are identical and produce similar enrichment of LMP2 specific CTL By using the Ad5f35LMP12 vector instead of the Ad5f35 vector encoding LMP2 alone we should better enrich T cell clones recognizing both of the LMP antigens expressed by the malignant cells in Hodgkins disease and non-Hodgkins Lymphoma Our analysis strategies include plans to perform comparisons between these vector types
Like the ALASCER product the ALCI product continued to be a CTL line specific for EBV antigens but enriched for T cells recognizing LMP1 as well as LMP2 The ALASCER product already contains some LMP1 specific T cells along with T cell specific for other EBV antigens and the only change was enrich for these cells Therefore the ALCI Ad5f35 LMP12 adenoviral vector is an ancillary reagent in the manufacturing process used only to transduce antigen presenting cells used as stimulator cells and is not infused in the final product This vector completed testing and was approved for use under ALASCER IND 6387
Additionally the ALASCER protocol design was amended to allow for the addition of a separate arm to the study depending on the vector used for the manufacturing process and the data is analyzed separately
In both ALASCER ALCI the cells will then be thawed and injected into the patient over 10 minutes Initially two doses of T cells will be given two weeks apart If after the second infusion there is a reduction in the size of the lymphoma on CT or MRI scan as assessed by a radiologist the patient can receive up to six additional doses of the T cells if the patient wishes This is a dose escalation study which means that for some patients the second dose may be larger than the first All of the treatments will be given by the Center for Cell and Gene Therapy at Texas Childrens Hospital or the Methodist Hospital
The patient will be followed after the injections They will either be seen in the clinic or will be contacted by a research nurse yearly for 5 years To learn more about the way the T cells are working in the patients body an extra 20-40 mL 4-8 teaspoons of blood will be taken before each infusion and then 4 hours after each infusion optional and 3-4 days after each infusion optional and then weekly for 2 weeks after each infusion total of 9 times Two weeks after the last infusion blood will then be taken again and then every 3 months for 1 year then once a year for 5 years Investigators will use this blood to see how long the T cells last and to look at the immune response to the patients cancer
ALCI Expansion cohort
Once the dose escalation safety phase of the study is completed ie once at least 3 patients have been treated at dose level 3 and no treatment-related DLT has occurred we plan to treat additional patients at dose level 1 to evaluate the immunological response in patients who receive CTL that have been generated using DC matured with the additional maturation cytokines IL-1b and IL-6 in the presence of IL-15 We will treat an additional 30 16 and 16 patients on Groups A B and C respectively
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| ALCI | OTHER | None | None |
| ALASCAR | OTHER | Baylor College of Medicine | None |