Kappa-CD28 T Lymphocytes, Chronic Lymphocytic Leukemia, B-cell Lymphoma or Multiple Myeloma, CHARKALL (CHARKALL)
Patients have a type of cancer called NHL, Multiple Myeloma (MM) or CLL. The lymphoma, MM or CLL has come back or has not gone away after treatment. There is no standard treatment for the cancer at this time or the currently used treatments do not work completely in all cases like these. This is a gene transfer research study using special immune cells.
The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting disease, antibodies and T cells, that investigators hope will work together. Antibodies are types of proteins that protect the body from bacterial and other diseases. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells. Both antibodies and T cells have been used to treat patients with cancers; they have shown promise, but have not been strong enough to cure most patients.
T lymphocytes can kill tumor cells but there normally are not enough of them or they are not able to kill all the tumor cells. Some researchers have taken T cells from a person's blood, grown more of them in the laboratory and then given them back to the person.
The antibody used in this study recognizes a protein on the lymphoma, MM or CLL cells called kappa immunoglobulin. Antibodies can stick to lymphoma, MM or CLL cells when it recognizes the kappa molecules present on the tumor cells. For this study, the kappa antibody has been changed so that instead of floating free in the blood it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These chimeric receptor-T cells seem to kill some of the tumor, but they don't last very long and so their chances of fighting the cancer are limited.
In the laboratory, investigators found that T cells work better if they also add a protein that stimulates T cells to grow called CD28. By joining the anti-kappa antibody to the T cells and adding the CD28, the investigators expect to be able to make cells that will last for a longer time in the body (because of the presence of the CD28). They are hoping this will make the cells work better. This research is taking place to assess the safety of different doses of these cells. These chimeric T cells (kappa-CD28) are an investigational product not approved by the FDA.
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Study of Adoptive Transfer of Autologous T Lymphocytes Engrafted With a Chimeric Antigen Receptor Targeting the Kappa Light Chain of Immunoglobulin Expressed in Patients With CLL, B-Cell Lymphoma or Multiple Myeloma|
- Number of Patients with Dose-Limiting Toxicities (DLT) [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]DLT will be defined as any grade 3-5 toxicity that is NOT (1) pre-existing, or (2) due to infection (to which patients with CLL and NHL are so predisposed), or (3) due to underlying malignancy, and that is considered to be possibly, probably, or definitely related to the study drug. Toxicity will be evaluated using NCI criteria version 4.X.
- Survival and Function of CAR-K+ T cells [ Time Frame: 15 years ] [ Designated as safety issue: No ]The frequency of T cells expressing CAR-Kappa will be summarized at pre and post-infusion time points using mean ± SD, medians and ranges to evaluate their expansion and persistence. Plots of growth curves will be generated to graphically illustrate patterns of T-cell expansion. Plots will be generated to depict patterns of survival and expansion of T cells for each of the two vectors. Longitudinal modeling techniques will also be used.
- To measure the anti-tumor effects of CAR-K+ T lymphocytes. [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]We will summarize tumor response by calculating overall response rates. Tumor sites will be measured before and after T cell therapy using RECIST.
|Study Start Date:||July 2009|
|Estimated Study Completion Date:||July 2034|
|Estimated Primary Completion Date:||July 2019 (Final data collection date for primary outcome measure)|
Experimental: Kappa CD28 T cells
T cells will be infused 4 days after cyclophosphamide. Three dose levels will be evaluated. Cohorts of size 2 will be enrolled at each dose level. Each patient will receive one injection 2-30 mL of each dose over 1 to 10 minutes.
Biological: Kappa CD28 T cells
Patients with B-CLL will receive 12.5 mg/kg of Cyclophosphamide as a single i.v. infusion. In contrast patients with lymphoma will receive cyclophosphamide only if the count of CD3+ lymphocytes in the peripheral blood is >500 ul.
Group 1: Day 0 2x10^7 cells/m^2 CAR-Kappa
Group 2: Day 0 1x10^8 cells/m^2 CAR-Kappa
Group 3: Day 0 2x10^8 cells/m^2 CAR-Kappa
To prepare the lymphoma, MM or CLL specific T cells investigators will take 240 ml (up to 16 tablespoonfuls)of blood from the patient. This would be drawn as 2 (two) separate blood collections of 120 ml (up to 8 tablespoonfuls) of blood.
To get the kappa antibody (with CD28) to attach to the surface of the T cell, investigators inserted the antibody gene into the T cell. This is done with a virus called a retrovirus that has been made for this study and will carry the antibody gene into the T cell. This virus also helps investigators find the T cells in the patient's blood after they're injected. Because the patient has received cells with a new gene in them patients will be followed for a total of 15 years to see if there are any long term side effects of gene transfer.
When a subject enrolls on this study, patients will be assigned to one of three groups of different doses receiving kappa-CD28 T cells.
Several studies suggest that the infused T cells need room to be able to grow and accomplish their functions and that this may not happen if there are too many other T cells in circulation. Because of that, if the level of circulating T cells is relatively high or the patient has B-CLL, the patient may receive one treatment of cyclophosphamide four to seven days prior to the infusion of the T cells. This drug will decrease the numbers of the patients own T cells before infusion of the kappa-CD28 T cells. Although investigators don't expect any effect on the tumor with the dose that the patient will receive, this drug is part of many regimens that are used to treat lymphoma, MM or CLL.
Patients will be given an injection of cells into the vein through an IV line at the assigned dose. The injection will take about 20 minutes. Investigators will follow the patient in the clinic after the injection for up to 3 hours. The treatment will be given by the Center for Cell and Gene Therapy at Texas Childrens Hospital or The Methodist Hospital.
If after a 4-6 week evaluation period after the infusion, the patient seems to be experiencing a benefit (confirmed by radiological studies, physical exam and/or symptoms), the patient may be able to receive additional doses of the T cells if they wish. These additional infusions would be at least 4-6 weeks apart and at the same dose level they received the first time or a lower dose.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00881920
|United States, Texas|
|Houston Methodist Hospital|
|Houston, Texas, United States, 77030|
|Texas Children's Hospital|
|Houston, Texas, United States, 77030|
|Principal Investigator:||Carlos Ramos, MD||Baylor College of Medicine/Texas Children's Hospital|