CAR T Cell Receptor Immunotherapy for Patients With B-cell Lymphoma

Phase 1

Completed

Conditions: Diffuse, Large B-cell Lymphoma
Mantle Cell
Primary Mediastinal B-cell Lymphoma
Diffuse Large B-Cell Lymphoma Transformed From Follicular Lymphoma

Interventions: Biological: Anti-cluster of differentiation 19 (CD19)-CAR PBL
Drug: Fludarabine
Drug: Cyclophosphamide
Drug: Aldesleukin

Registration Number: NCT00924326

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with B cell lymphomas or leukemias that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. In this protocol, we are modifying the patient s white blood cells with a retrovirus that has the gene for anti-cluster of differentiation 19 (CD19) incorporated in the retrovirus.

Objective:

The purpose of this study is to determine a safe number of these cells to infuse and to see if these particular tumor-fighting cells (anti-CD19 cells) cause tumors to shrink.

Eligibility:

- Adults age 18-70 with B cell lymphomas or leukemias expressing the CD19 molecule.

Design:

Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed

Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti-CD19 cells. Leukapheresis is a common procedure, which removes only the white blood cells from the patient.

Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy and the anti-CD19 cells. They will stay in the hospital for about 4 weeks for the treatment.

Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits will take up to 2 days.

Detailed Description: BACKGROUND:

* We have constructed a retroviral vector that encodes an anti-cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR) that recognizes the CD19 antigen. This chimeric receptor also contains the signaling domains of cluster of differentiation 28 (CD28) and cluster of differentiation 3 (CD3)-zeta. The retroviral vector can be used to mediate genetic transfer of this CAR to T cells with high efficiency (\> 50%) without the need to perform any selection.

* In co-cultures with CD19-expressing target cells, anti-CD19-CAR-transduced T-cells secreted significant amounts of interferon gamma (IFN-y) and interleukin 2 (IL-2).

* We have developed a process for cryopreserving the cell product which may lead to the ability for this product to be manufactured at a central location and shipped to other institutions for treatment of a broader patient population

OBJECTIVE:

- Primary objective:

--With the approval of amendment S, to determine the safety and feasibility of the administration of cryopreserved anti-CD19-CAR engineered peripheral blood lymphocytes with a non-myeloablative conditioning regimen in patients with Bcell lymphomas.

ELIGIBILITY:

Patients of 18 years of age or older must:

* Have a CD19-expressing B-cell lymphoma

* Be a non-responder to, or recurred after one or more standard chemotherapy-containing regimens for their malignancy

* Currently require treatment due to progressive malignancy

* Be deemed to be incurable by standard therapy

Patients may not have:

* A history of allogeneic stem cell transplantation

* Central nervous system (CNS) disease

DESIGN:

* Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis (approximately 5.0x 10\^9 cells) will be cultured in the presence of anti-CD3 (muromonab-CD3 (OKT3)) and aldesleukin in order to stimulate T-cell proliferation.

* Transduction is initiated by exposure of approximately 1.0x 10\^8 to 5.0x 10\^8 cells to retroviral vector supernatant containing the anti-CD19 CAR.

* With the approval of Amendment S, patients will receive fludarabine and cyclophosphamide chemotherapy (NMA) for lymphodepletion, followed by cryopreserved anti-CD19-CAR-transduced T-cells.

* Patients will be followed until disease progression.

* Patients who have responded to treatment and then progress may receive one retreatment.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 43

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
1.0x10^6 cells/kg (Reduced chemo)	Anti-cluster of differentiation 19 (CD19)-CAR PBL	-
1x10^9-1x10^10 + high dose Retreat	Anti-cluster of differentiation 19 (CD19)-CAR PBL	-
0.5x10^7 cells/kg	Cyclophosphamide	-
1.0x10^6 cells/kg	Anti-cluster of differentiation 19 (CD19)-CAR PBL	-
1x10^9-1x10^10+ high dose Interleukin-2	Fludarabine	Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + cryopreserved anti-CD19-CAR PBL
1x10^9-1x10^10+ high dose Interleukin-2	Anti-cluster of differentiation 19 (CD19)-CAR PBL	Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + cryopreserved anti-CD19-CAR PBL
0.5x10^7 cells/kg	Anti-cluster of differentiation 19 (CD19)-CAR PBL	-
2.5x10^6 cells/kg	Anti-cluster of differentiation 19 (CD19)-CAR PBL	-
6.0x10^6 cells/kg (Reduced chemo)	Anti-cluster of differentiation 19 (CD19)-CAR PBL	-
2.0x10^6 cells/kg (Moderate chemo)	Anti-cluster of differentiation 19 (CD19)-CAR PBL	-
2.0x10^6 cells/kg (Reduced chemo)	Anti-cluster of differentiation 19 (CD19)-CAR PBL	-
2.0x10^6 cells/kg (9-12 days culture)	Anti-cluster of differentiation 19 (CD19)-CAR PBL	-
2.5x10^6 cells/kg	Fludarabine	-
2.0x10^6 cells/kg (Moderate chemo)	Fludarabine	-
1.0x10^6 cells/kg	Cyclophosphamide	-
1.0x10^6 cells/kg (Reduced chemo)	Fludarabine	-
1x10^9-1x10^10+ high dose Interleukin-2	Cyclophosphamide	Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + cryopreserved anti-CD19-CAR PBL
1x10^9-1x10^10 + high dose Retreat	Cyclophosphamide	-
1x10^9-1x10^10 + high dose Retreat	Fludarabine	-
1x10^9-1x10^10+ high dose Interleukin-2	Aldesleukin	Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + cryopreserved anti-CD19-CAR PBL
0.5x10^7 cells/kg	Fludarabine	-
2.5x10^6 cells/kg	Cyclophosphamide	-
1.0x10^6 cells/kg	Fludarabine	-
1.0x10^6 cells/kg (Reduced chemo)	Cyclophosphamide	-
2.0x10^6 cells/kg (Reduced chemo)	Fludarabine	-
2.0x10^6 cells/kg (Reduced chemo)	Cyclophosphamide	-
6.0x10^6 cells/kg (Reduced chemo)	Fludarabine	-
6.0x10^6 cells/kg (Reduced chemo)	Cyclophosphamide	-
2.0x10^6 cells/kg (Moderate chemo)	Cyclophosphamide	-
2.0x10^6 cells/kg (9-12 days culture)	Fludarabine	-
2.0x10^6 cells/kg (9-12 days culture)	Cyclophosphamide	-
1x10^9-1x10^10 + high dose Retreat	Aldesleukin	-

Primary Outcome Measures

Name	Time	Method
Number of Participants With a Response Assessed by the Response Criteria for Malignant Lymphoma	Scans performed at 6 weeks, 12 weeks and every 3-6 months for approximately 2 years	Participants were assessed by the Response Criteria for Malignant Lymphoma. Complete Remission (CR) is complete disappearance of all detectable evidence of disease and disease-related symptoms if present before therapy. Partial Remission (PR) requires ≥50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease. Progressive disease (PD) is defined by ≥50% increase from nadir in the sum of the products of at least two lymph nodes, or if a single node is involved at least a 50% increase in the product of the diameters of this one node; and appearance of a new lesion greater than 1.5 cm in any axis even if other lesions are decreasing in size. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0).	Date treatment consent signed to date off study, approximately 101 months and 17 days.	Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.