CTLs Expressing CD19 Chimeric Receptors, CD19 Positive Malignancies Post SCT, MULTIPRAT
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Purpose
Subjects are having a bone marrow or stem cell transplant for either a type of cancer of the blood called Leukemia or a cancer of the lymph nodes called non- Hodgkin's Lymphoma. Although a transplant can cure leukemia or lymphoma, some people will relapse (return of the disease). In those who relapse, current treatment cures only a very small percentage. Although giving patients a dose of donor immune cells (donor lymphocyte infusion or DLI) before relapse can prevent relapse of the leukemia or lymphoma, DLI can also cause a serious complication called graft versus host disease (GVHD). For these reasons, subjects are being asked to volunteer to take part in a gene transfer research study using special immune cells which are specific for these cancer cells.
The body has different ways of fighting infection and disease. This study combines two of those ways, antibodies and T cells. Antibodies are proteins that protect the body from bacterial and other diseases. T cells (CTLs or cytotoxic T cells) are infection-fighting blood cells that can kill cells, including tumor cells. 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.
The antibody used in this study is called anti-CD19. This antibody sticks to leukemia cells because of a substance on the outside of these cells called CD19. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood it is now joined to T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor.
In the laboratory, we have found that T cells that are trained to recognize common viruses can stay in the blood stream for many years. By joining the anti-CD19 antibody to CTLs that recognize viruses, we believe that we will also be able to make a cell that can last a long time in the body, provide protection from viruses and recognize and kill leukemia. The CTLs which we will join the anti-CD19 antibody to attack three viruses (trivirus-specific CTLs), cytomegalovirus (CMV), Epstein-Barr virus (EBV) and adenovirus.
CMV is a virus that rarely causes problems in healthy people but can cause serious infections in patients with suppressed immune systems. It can cause a very serious pneumonia, and can also affect the intestinal tract, liver and eyes. 2/3 of normal people harbor this virus in their body. If the subject or donor are positive for CMV, the subject is at risk of developing CMV disease after transplant.
EBV causes mononucleosis or "mono" (infection with fatigue, high fever, and swollen lymph nodes). It is normally controlled by a healthy immune system but when the immune system is weak after bone marrow transplant it can cause fevers, enlarged lymph nodes and a type of cancer called lymphoma.
Adenovirus is a virus that causes symptoms of a common cold but can cause life-threatening infections in patients with weak immune systems. It usually affects the lungs, but it can also affect the gut, liver, pancreas and eyes.
Studies have shown that trivirus-specific CTLs grown from the stem cell donor can be given safely to transplant recipients and can stop these viruses from causing severe infections. In this study we are going to see if adding the CD19 chimeric receptor to these cells will provide additional benefit for the prevention or treatment of leukemia or lymphoma relapse and if they persist in the body in the long term. These CD19 chimeric receptor trivirus specific T cells are an investigational product not approved by the Food and Drug Administration.
These CTLs will be reinfused in the body either early after the transplant or when tests indicate relapse of the leukemia or lymphoma. By analyzing the blood periodically, we will see if they remain in the body and effectively combat viruses and leukemia.
The purpose of this study is to find the biggest dose of chimeric T cells that is safe to administer, to assess what the side effects are, to see how long the T cells last and to evaluate whether this therapy might help prevent infections and relapse in people with CD19+ leukemia or lymphoma having a stem cell transplant.
| Condition | Intervention | Phase |
|---|---|---|
|
Stem Cell Transplant Acute Lymphoblastic Leukemia (ALL) Chronic Lymphocytic Leukemia (CLL) Non Hodgkin's Lymphoma |
Genetic: CD19CAR/virus specific T cells |
Phase 1 Phase 2 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Phase I/II Study of the Administration of Multi-Virus-Specific Cytotoxic T Lymphocytes Expressing CD19 Chimeric Receptors for Prophylaxis or Therapy of Relapse of CD19 Positive Malignancies Post Hematopoietic Stem Cell Transplantation |
- Evaluate safety/persistence of escalating doses of allogeneic CMV, EBV and Adenovirus specific CTLs modified to express artificial T-cell receptors targeting CD19 molecule given for prophylaxis, persistence or relapse of high risk B-cell ALL post HSCT [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
- To evaluate the effects of gene modified CTL on measurable disease. [ Time Frame: 15 years ] [ Designated as safety issue: Yes ]
- To evaluate the impact of the gene modified CTL on virus-specific T-lymphocyte immune reconstitution. [ Time Frame: 15 years ] [ Designated as safety issue: Yes ]
- To evaluate the impact of the gene modified CTL on normal CD19+ B-cell immune reconstitution post-HSCT. [ Time Frame: 15 years ] [ Designated as safety issue: Yes ]
| Estimated Enrollment: | 36 |
| Study Start Date: | April 2009 |
| Estimated Study Completion Date: | April 2029 |
| Estimated Primary Completion Date: | April 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
| Experimental: CD19CAR/virus specific T cells |
Genetic: CD19CAR/virus specific T cells
CD19CAR/virus specific T cells will be thawed and given by intravenous injection from day +30 post transplant. Subjects will receive one of the following dose levels: Dose Level 1: 1.5 x 10^7/m2 Dose Level 2: 4.5 x 10^7/m2 Dose Level 3: 1.2 x 10^8/m2 If patients with relapse have 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 first injection. |
Show Detailed Description Eligibility| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
INCLUSION CRITERIA:
Any patient regardless of sex or age with CD19+ B-ALL undergoing allogeneic HSCT (Group A). OR Any patient regardless of sex or age with CD19+ B-CLL or NHL undergoing allogeneic HSCT (Group B). With minimal residual disease (MRD) or relapse post-HSCT (for the phase I dose escalation) Any patient regardless of sex or age with CD19+ B-ALL undergoing allogeneic HSCT (Group A). OR Any patient regardless of sex or age with CD19+ B-CLL or NHL undergoing allogeneic HSCT (Group B). With minimal residual disease (MRD) or relapse post-HSCT (for the phase I dose escalation) as evidenced by PCR positivity, specific cytogenetic abnormalities, an abnormal population on flow cytometry or increased blasts on bone marrow biopsy or in the peripheral blood.
MRD will be defined as detection in blood or marrow of: 1) Any leukemia specific marker (such as t(9:22) or t(4:11)) documented in the patient's leukemia cells pre transplant on a post transplant evaluation 2) A TCR or immune globulin rearrangement known to be a disease marker for this patient post transplant 3) A leukemia specific phenotype post transplant at a level of > 0.01% 4) Mixed donor chimerism
OR
With no evidence of ALL or CLL/NHL post-HSCT (to be included in the phase II extension). Please note that this population will not be enrolled without FDA review and approval of safety data from Phase I of this protocol.
2) Patients with life expectancy greater than or equal to 6 weeks
3) Patients with a Karnofsky/Lansky score greater than or equal to 50
4) Donor HIV negative
5) Patient or parent/guardian capable of providing informed consent
6) Patients with bilirubin 2x normal or less, AST 3x normal or less, creatinine less than or equal to 2x normal for age and Hgb greater than 8.0
7) Pulse oximetry of greater than 90% on room air
8) Sexually active patients must be willing to utilize one of the more effective birth control methods for 6 months after the CTL infusion. The male partner should use a condom.
9) Available allogeneic CD19CAR transduced tri-virus-specific cytotoxic T lymphocytes with greater than or equal to15% expression of CD19CAR determined by flow-cytometry and greater than 10% killing of one or more viral antigen pulsed targets in a cytotoxicity assay at an effector:target ratio of 20:1.*
10) Patients should have been off other investigational antiviral or antitumor therapy for one month prior to entry in this study.
*Note: Cell dose is based on total cell numbers and not individual antivirus or antileukemic cell numbers.
EXCLUSION CRITERIA:
- Severe intercurrent infection
- Evidence of graft versus host disease >grade II
- Pregnant or lactating
- History of hypersensitivity reactions to murine protein-containing products.
- Currently taking corticosteroids for therapy of GVHD.
Contacts and Locations| Contact: Catherine M Bollard, MD | 832-824-4781 | cmbollar@txch.org |
| Contact: Elizabeth Pacheco | 713-441-3942 | epacheco@tmhs.org |
| United States, Texas | |
| Texas Children's Hospital | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: Catherine M Bollard, MD 832-824-4781 cmbollar@txch.org | |
| Contact: Elizabeth Pacheco 713-441-3942 epacheco@tmhs.org | |
| The Methodist Hospital | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: George Carrum, MD 713-441-1450 gcarrum@bcm.edu | |
| Contact: Elizabeth Pacheco 713-441-3942 epacheco@tmhs.org | |
| Principal Investigator: | Catherine M Bollard, MD | Baylor College of Medicine |
More Information
No publications provided
| Responsible Party: | catherine bollard, Associate Professor, Baylor College of Medicine |
| ClinicalTrials.gov Identifier: | NCT00840853 History of Changes |
| Other Study ID Numbers: | 23637-MULTIPRAT, MultiPRAT |
| Study First Received: | February 9, 2009 |
| Last Updated: | August 8, 2012 |
| Health Authority: | United States: Food and Drug Administration United States: Institutional Review Board |
Keywords provided by Baylor College of Medicine:
|
Stem cell transplant Acute Lymphoblastic Leukemia (ALL) Chronic Lymphocytic Leukemia (CLL) Non Hodgkin's Lymphoma |
Cytotoxic T lymphocytes CTL CD-19 chimeric receptor |
Additional relevant MeSH terms:
|
Leukemia Leukemia, Lymphocytic, Chronic, B-Cell Leukemia, Lymphoid Precursor Cell Lymphoblastic Leukemia-Lymphoma Lymphoma Lymphoma, Non-Hodgkin Neoplasms by Histologic Type |
Neoplasms Leukemia, B-Cell Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases |
ClinicalTrials.gov processed this record on May 22, 2013