Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Symptoms and General Pathology

Rare Diseases

Lymphoma

Leukemia

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Lymphoma, Follicular

Lymphoma, Large B-Cell, Diffuse

Lymphoma, B-Cell

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, Non-Hodgkin

Lymphosarcoma

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

Follicular Lymphoma

B-cell Lymphoma

Diffuse Large B-Cell Lymphoma

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Infective Agents

Analgesics

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Aldesleukin

Immunomodulating Agents

Interleukin-2

Vidarabine

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antimetabolites

Antiviral Agents

Analgesics, Non-Narcotic

Anti-HIV Agents

Anti-Retroviral Agents

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + cryopreserved anti-CD19-CAR PBL

Days -5 to -1 (after administration of cyclophosphamide): 25 mg/m\^2 intravenous (IV) over 30 minutes

Days -5 to -4: 60mg/kg intravenous (IV) over 60 minutes

Anti-cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR) peripheral blood lymphocytes ( PBL).

Day 0 (two to four days after the last dose of fludarabine); Cells will be infused via intravenous (IV) on the Patient Care Unit over 20-30 minutes.

Anti-cluster of differentiation 19 (CD19)-CAR PBL

Day 0: 720,000 IU/kg intravenously (IV) every 8 hours for a maximum of 15 doses.

Days -5 to -3 (after administration of cyclophosphamide): 30 mg/m\^2 intravenous (IV) over 30 minutes

Days -5 to -3: 300mg/m\^2 intravenous (IV) over 60 minutes

Steven A Rosenberg, M.D., Ph.D.

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.

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.

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

An Assessment of the Safety and Feasibility of Administering T-Cells Expressing an Anti-CD19 Chimeric Antigen Receptor to Patients With B-Cell Lymphoma

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.

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.

National Cancer Institute (NCI)

Principal Investigator

Cyclophosphamide (Days -5 to -4): 60mg/kg intravenous (IV) over 60 minutes

Fludarabine (Days -5 to -1 after administration of cyclophosphamide): 25 mg/m\^2 intravenous (IV) over 30 minutes

Anti-CD19 CAR PBL (Day 0 two to four days after the last dose of fludarabine); Cells will be infused via intravenous (IV) on the Patient Care Unit over 20-30 minutes.

Aldesleukin (Day 0): 720,000 IU/kg intravenously (IV) every 8 hours for a maximum of 15 doses.

1x10^9-1x10^10 Cells/kg + High-dose Interleukin-2

1x10^9-1x10^10 Cells/kg + High-dose Interleukin-2 Retreat

Cyclophosphamide (Days -5 to -4): 60mg/kg intravenous (IV) over 60 minutes

Fludarabine (Days -5 to -1 after administration of cyclophosphamide): 25 mg/m\^2 intravenous (IV) over 30 minutes

Anti-CD19 CAR PBL (Day 0 two to four days after the last dose of fludarabine); Cells will be infused via intravenous (IV) on the Patient Care Unit over 20-30 minutes.

0.5x10^7 Cells/kg

2.5x10^6 Cells/kg

1.0x10^6 Cells/kg

Cyclophosphamide (Days -5 to -3): 300mg/m\^2 intravenous (IV) over 60 minutes

Fludarabine (Days -5 to -3: after administration of cyclophosphamide): 30 mg/m\^2 intravenous (IV) over 30 minutes

Anti-CD19 CAR PBL (Day 0, two to four days after the last dose of fludarabine): Cells will be infused via intravenous (IV) on the Patient Care Unit over 20-30 minutes.

1.0x10^6 Cells/kg (Reduced Chemo)

2.0x10^6 Cells/kg (Reduced Chemo)

6.0x10^6 Cells/kg (Reduced Chemo)

2.0x10^6 Cells/kg (Moderate Chemo)

2.0x10^6 Cells/kg (9-12 Days Culture)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Steven Rosenberg, M.D., Ph.D.

Complete Remission

Partial Remission

Stable Disease

Progressive Disease

Not Evaluable

1x10\^9-1x10\^10 Cells/kg + High-dose Interleukin-2 Retreat Arm/Group: "3 participants in group 1 (1x10e9-1x10e10 cells/kg + high-dose IL2)) initially responded but were then retreated in group 2 after progression."

Number of Participants With a Response Assessed by the Response Criteria for Malignant Lymphoma

Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0).

Dose Administration

1x10^9-1x10^10 + High Dose Retreat

Skin and Connective Tissue Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Vaccines

Monatide (IMS 3015)

Freund's Adjuvant

Adjuvants, Immunologic

Patients receive anti-MART-1 F5 TCR-transduced peripheral blood lymphocytes (PBLs) intravenously (IV) over 20-30 minutes on day 0. 1 x 10e9 to 5 x 10e10 IV.

Patients receive anti-MART-1 F5 TCR-transduced PBLs as in arm I and MART-1:26-35(27L) peptide vaccine emulsified in Montanide ISA-51 subcutaneously (SC) on days 0 and 30. 1 x 10e9 to 5 x 10e10 IV + 1.0 mg peptide subcutaneously.

Patients receive anti-MART-1 F5 TCR-transduced PBLs as in arm I and aldesleukin SC on days 0-4. 1 x 10e9 to 5 x 10e10 IV + IL-2 (based on body weight) 125,000 IU/kg/day subcutaneously.

Patients receive anti-MART-1 F5 TCR-transduced PBLs as in arm I, MART-1:26-35(27L) peptide vaccine emulsified in Montanide ISA-51 as in arm II, and aldesleukin as in arm III. 1 x 10e9 to 5 x 10e10 IV + 1.0 mg peptide subcutaneously + IL-2 (based on body weight) 125,000 IU/kg/day subcutaneously.

Patients receive anti-MART-1 F5 TCR-transduced PBLs IV over 20-30 minutes on day 0, and ALVAC-MART-1 vaccine SC on days 0 and 14. 1 x 10e9 to 5 x 10e10 IV + ALVAC vaccine 0.5 ml containing target dose of 10e7 CCID50 (with a range of approximately 10\^6.4 to 10\^7.9/mL subcutaneously (total of 4 x 10e7 CCID50/2 mL).

Patients receive anti-MART-1 F5 TCR-transduced PBLs and ALVAC-MART-1 vaccine as in arm V, and low-dose aldesleukin SC on days 0-4. 1 x 10e9 to 5 x 10e10 IV + ALVAC vaccine 0.5 ml containing target dose of 10e7 CCID50 (with a range of approximately 10\^6.4 to 10\^7.9/mL subcutaneously (total of 4 x 10e7 CCID50/2 mL)+ 125,000 IU/kg/day subcutaneously.

Patients receive ALVAC-MART-1 vaccine SC on days 0 and 14. ALVAC vaccine 0.5 ml containing target dose of 10e7 CCID50 (with a range of approximately 10\^6.4 to 10\^7.9/mL subcutaneously (total of 4 x 10e7 CCID50/2 mL).

ALVAC-MART-1 vaccine

MART-1:26-35(27L) peptide vaccine

autologous anti-MART-1 F5 T-cell receptor gene-engineered peripheral blood lymphocytes

incomplete Freund's adjuvant

Steven Rosenberg, M.D.

Background:

* Melanoma antigen recognized by T cells (MART-1) is a gene that is present in melanoma cells.
* This study tests an experimental treatment that uses the patient's own lymphocytes (type of white blood cell), which are specially selected and genetically modified with a gene called anti-MART-1 transduced cells (F5) to target and destroy their tumor. Some of the cells are given as an infusion and others are given as a vaccine.
* The anti-MART-1 F5 cells are currently being studied in other patients in combination with chemotherapy and IL-2 (aldesleukin) therapy.

Objectives:

-To determine if the anti-MART-1 F5 treatment can improve the immune system's ability to shrink tumors and to prevent melanoma from recurring.

Eligibility:

* Patients 18 years of age and older whose melanoma has been removed and are currently disease-free, but who are at risk for recurrence.
* Patients who do not have ocular or mucosal melanoma.
* Patients with tissue type human leukocyte antigens (HLA-A)\*0201).

Design:

* Workup: Patients have scans, x-rays, laboratory tests, other tests as needed and leukapheresis, a procedure for collecting white cells to modify in the laboratory and later reinfuse into the patient.
* Patients are assigned to one of four study groups:

  * Group 1 receives anti-MART-1 F5 cells by 30-minute infusion through a vein on day 0.
  * Group 2 receives anti-MART-1 F5 cells on day 0 followed by injections of MART-1 vaccine, which contains MART-1 and an oil-based liquid called Montanide ISA-51 VG. The vaccine is repeated on day 30.
  * Group 3 receives anti-MART-1 F5 cells on day 0 followed by injections of low-dose IL-2 for 5 days (days 0-4).
  * Group 4 receives anti-MART-1 F5 cells on day 0 followed by MART-1 vaccine and low-dose IL-2 for 5 days. The vaccine is repeated on day 30.
* Recovery: Patients are monitored closely and given medicines to prevent or treat any side effects of therapy.
* Leukapheresis: Patients undergo leukapheresis at 1 and 3 months after therapy to collect cells to examine the effects of the treatment on the immune system.
* Follow-up: Patients return to National Institutes of Health (NIH) 35 days after completing treatment and then at 3 months and every 6 months thereafter for evaluation with a physical examination, review of side effects, laboratory tests and scans. They have blood tests at 3, 6 and 12 months after treatment and then once a year after that. A biopsy may be requested after treatment ends to examine the effects of treatment on the immune system. All patients return to NIH for a physical examination once a year for 5 years and then complete a follow-up questionnaire for another 10 years.

Background:

We have engineered human peripheral blood lymphocytes (PBLs) to express an anti-MART-1 T-cell receptor (TCR) that recognizes an HLA-A\*0201 restricted epitope derived from the tumor infiltrating lymphocytes (TIL) clone DMF5.

We constructed a single retroviral vector that encodes both alpha and beta chains and can mediate genetic transfer of this T cell receptor (TCR) with high efficiency without the need to perform any selection.

In co-cultures with HLA-A\*0201 positive melanoma, anti-MART-1 F5 TCR transduced T cells secreted significant amount of IFN- but no significant secretion was observed in control co-cultures with cell lines.

The anti-MART-1 F5 TCR transduced PBL could efficiently kill HLA-A\*0201 positive tumors. There was little or no recognition of normal fibroblasts cells.

This TCR is over 10 times more reactive with melanoma cells than the MART-1 F4 TCR that mediated tumor regression in two patients with metastatic melanoma.

Poxviruses encoding melanoma antigens, similar to the ALVAC MART-1 vaccine have been shown to successfully immunize patients against these antigens.

Objectives:

Primary objectives:

To evaluate the ability of four different strategies to enhance the persistence of anti-tumor T cells in the circulation at 5-10 days, and at 31-35 days after treatment (defined as F5 cells in cohorts 1 and 2, and aldesleukin in cohorts 3 and 4) and potentially select one strategy for further study.

With Amendment E, the primary objective is to evaluate the ability of three different strategies to enhance the persistence of anti-tumor T cells in the circulation at 5-10 days and at 31-35 days after treatment (defined as F5 cells in cohort 5, aldesleukin in cohort 6, and ALVAC MART-1 vaccine in cohort 7) and potentially select one strategy for further study.

Eligibility:

Patients who are HLA-A\*0201 positive and 18 years of age or older must have:

* primary melanomas with lesions that are ulcerated and greater than or equal to 2.0 mm, or any lesions that are greater than or equal to 4.0 mm in thickness, or greater than or equal to 1 positive lymph node, or local recurrence, or resected metastatic disease, within 6 months of surgical resection.
* must be clinically disease free at the time of protocol entry as documented by radiologic studies within 4 weeks of patient entry.
* may have had prior adjuvant treatment with immunotherapy, including interferon, as long as 3 weeks have elapsed since prior systemic therapy.
* normal values for basic laboratory values.

Patients may not have:

* ocular or mucosal melanoma;
* been previously immunized with MART-1;
* concurrent major medical illnesses;
* any form of primary or secondary immunodeficiency;
* severe hypersensitivity to any of the agents used in this study;

Design:

Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis (approximately 1 times 10\^10 cells) will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth.

Transduction is initiated by exposure of approximately 10\^8 to 5 times 10\^9 cells to retroviral vector supernatant containing the anti-MART-1 F5 TCR genes. These transduced cells (called F5 cells) will be expanded and tested for their anti-tumor activity.

F5 cells will be administered intravenously at a dose of 1 times 10\^9 to 7 times 10\^10 cells.

Patients will be randomized into one of the following four cohorts:

1. F5 cells on day 0 alone
2. F5 cells on day 0 followed by the subcutaneous injection of 1.0 mg MART-1:26-35(27L) peptide in Montanide ISA-51 VG on day 0 and day 30.
3. F5 cells on day 0 followed by the subcutaneous injection of 125,000 IU/kg/day aldesleukin on days 0-4.
4. F5 cells on day 0 plus MART-1:26-35(27L) peptide in Montanide ISA-51 VG on day 0 and day 30, and 125,000 IU/kg aldesleukin on days 0-4.

   Starting with amendment E, the four cohorts above will be closed to accrual and patients will be randomized to the following cohorts:
5. F5 cells on day 0 following subcutaneous injection of ALVAC MART-1 vaccine. Second dose of ALVAC MART-1 vaccine is given on day 14.
6. F5 cells on day 0 following subcutaneous injection of ALVAC MART-1 vaccine and then subcutaneous injection of 125,000 IU/kg/day aldesleukin on days 0-4. Second dose of ALVAC MART-1 vaccine is given on day 14.
7. ALVAC MART-1 vaccine on days 0 and 14.

Patients will undergo complete evaluation with physical examination, computed tomography (CT) of the chest, abdomen and pelvis (3 months and thereafter only) and clinical laboratory evaluation at day 35, and 3 months after treatment and then every six months or until off study criteria are met.

Each of the cohorts will be conducted using a two-stage MiniMax design. This design will try to determine whether each of the modalities of administration can produce persistence of the transferred cells at a frequency of greater than or equal to 5 percent of circulating cluster of differentiation 8 (CD8) plus cells in 35 percent of patients as opposed to undesirably low (15 percent), with a 3 percent probability of accepting a poor schedule and 15 percent probability of rejecting a good schedule.

Initially 22 patients will be enrolled in each cohort. If four immunologic responses (persistence) are noted in a given cohort, then accrual to 39 patients would take place. The cohort with the highest number of patients exhibiting persistence will be considered immunologically active and will be considered worthy of further development. If this arm has fewer than 11 of 39 patients with persistence, it will not be considered worthy of further consideration.

Starting with amendment E, 10 patients will be enrolled in each new cohort (cohorts 5-7). If on any of the three arms, there are 2 or more of 10 patients with 5% CD8+ circulating cells, then this cohort will be considered worthy of further consideration.

Anti-MART-1 F5 Lymphocytes to Treat High-Risk Melanoma Patients

Transfer of Autologous T Cells Transduced With the Anti-MART-1 F5 T Cell Receptor in High Risk Melanoma

Percentage of participants with an immunologic response of \>20 spots/100,000 cells measured by IFN gamma secretion using enzyme linked immunosorbent spot (ELISPOT) assay. This was done using ELISPOT assay which measures immune response at the single cell level.

Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.

Arm I

Arm II

Arm III

Arm IV

Arm V

Arm VI

Arm VII

Dr. Steven Rosenberg

Arm I - Adj-4 A2 F5 cells Arm II-Adj-4 A2 F5 cells + MART-1:26-35(27L) Peptide Arm III-Adj-4 A2 F5 cells + SQ IL-2 Arm IV-Adj-4 A2 F5 cells + MART-1:26-35(27L) Peptide+SQ IL-2 Arm V-Adj-4 A2 F5 cells + ALVAC MART-1:26-35(27L) Vaccine Arm VI-Adj-4 A2 F5 cells + ALVAC MART-1 Vaccine + SQ IL-2

Arm I - 6

Arms 1-6 were evaluated in patients who received F5 cells. Arm 7 was not included in the evaluation because the participants did not receive F5 cells.The immunological response was measured for the total percentage of pts whom specimen was available for analysis. This was not captured per Arm. No statistically significant responses were observed.

Percentage of Participants With Immunologic Response

Arm I - Adj-4 A2 F5 Cells

Arm II-Adj-4 A2 F5 Cells + MART-1:26-35(27L) Peptide

Arm III - Adj-4 A2 F5 Cells + SQ IL-2

Arm IV-Adj-4 A2 F5 Cells + MART-1:26-35(27L) Peptide + SQ IL-2

Arm V-Adj-4 A2 F5 Cells + ALVAC MART-1:26-35(27L) Vaccine

Arm VI-Adj-4 A2 F5 Cells + ALVAC MART-1 Vaccine + SQ IL-2

Arm VII - Adj-4 A2 ALVAC MART-1 Vaccine

Number of Participants With Adverse Events

Overall Study

Hematologic Neoplasms

Hematologic Diseases

Patients screening for, participating in, or have participated in a POB gene therapy clinical trial and have received/or be scheduled to receive a genetically engineered cellular therapy.

anti-CD19 CAR

Nirali N Shah, M.D.

Background:

- Gene therapy involves changing the genes inside the body s cells to stop disease. It is very closely regulated. People who have had this therapy may have problems months or even years later. Researchers do not know the long-term side effects, so they want to study people who have had the therapy. They want the study to continue over the next 15 years.

Objective:

- To study over time the negative side effects from genetically engineered cellular therapy. This will be studied in people who have been in Pediatric Oncology Branch (POB) gene therapy trials.

Eligibility:

- People who are currently or were previously in a research study with gene therapy in the National Cancer Institute POB.

Design:

* Participants blood will be tested right before they get the genetically changed cells. They will get the cells as part of another study.
* For the next year, they will come back to the clinic or see their doctor at home at least every 3 months. They will answer questions about their health and blood will be drawn.
* For the next 5 years, they will go to the clinic or see their own doctor once a year. They will have physical exam and blood will be drawn.
* For 10 years after that, they will be asked every year for health information.
* Participants will keep their contact information up to date with researchers. They may be phoned for more health information.
* If the participant was under 18 years old when given the gene therapy and turns 18 during this follow-up, they will be asked to sign a new consent form when they turn 18.

Background:

* Study subjects exposed to gene therapy interventions may be at risk for delayed or longterm adverse consequences. The U.S. Food and Drug Administration (FDA) has issued Long Term Follow-up After Administration of Human Gene Therapy Products: Guidance for Industry and Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up: Guidance for Industry, which outlines a framework to assess the risk of gene therapy-related delayed adverse events and the essential elements appropriate for the conduct of long-term follow up observations.
* Accordingly, some vector designs (i.e. use of an adenovirus), based on duration of persistence accompanied by cumulative preclinical and clinical evidence, may require shorter periods of observation than other vector designs (i.e. use of a lentivirus).

Objective:

-To conduct long term safety evaluations for adverse events associated with genetically engineered cellular therapy in subjects who have participated in Pediatric Oncology Branch (POB) clinical trials.

Eligibility:

-Subjects who are planned to receive or have received at least one dose of a genetically engineered cellular therapy on a POB gene therapy clinical trial are eligible to participate.

Design:

* Subjects will be evaluated for long term safety and occurrence of adverse events according to the requirements established by the FDA guidance and the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines), to include:
* Long term follow-up after genetically engineered cellular therapy may include:

  * Post-cell infusion evaluations for T-Cell persistence (if applicable)
  * Monitoring for replication-competent retrovirus (RCR) or replication-competent lentivirus (RCL)
  * Physical examination
  * Questionnaire to detect delayed adverse events
  * Medical record review related to long term adverse events
* To ensure adequate follow up for participants in POB receiving genetically engineered cellular therapy, a maximum accrual of 500 participants will be allowed on this study. To accommodate 15-year follow-up of all participants, this study will remain open until

Follow-Up Evaluation for Gene-Therapy-Related Delayed Adverse Events After Participation in Pediatric Oncology Branch Clinical Trials

Follow-Up Evaluation for Gene-Therapy Related Delayed Adverse Events After Participation in Pediatric Oncology Branch Clinical Trials

.All IPD recorded in the medical record will be shared with intramural investigators upon request.

PCR results (for RCR/RCL, gene transduced cells)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
CAR T Cell Receptor Immunotherapy for Patients With B-cell Lymphoma	NCT00924326	Primary Mediast... Diffuse, Large ... Diffuse Large B... Mantle Cell	Fludarabine Cyclophosphamid... Anti-cluster of... Aldesleukin Fludarabine Cyclophosphamid...	18 Years - 70 Years	National Institutes of Health Clinical Center (CC)
Anti-MART-1 F5 Lymphocytes to Treat High-Risk Melanoma Patients	NCT00706992	Melanoma	ALVAC-MART-1 va... MART-1:26-35(27... Aldesleukin autologous anti... incomplete Freu...	18 Years -	National Institutes of Health Clinical Center (CC)
Anti-MART-1 F5 Lymphocytes to Treat High-Risk Melanoma Patients	NCT00706992	Melanoma	ALVAC-MART-1 va... MART-1:26-35(27... Aldesleukin autologous anti... incomplete Freu...	18 Years -	National Institutes of Health Clinical Center (CC)
Follow-Up Evaluation for Gene-Therapy-Related Delayed Adverse Events After Participation in Pediatric Oncology Branch Clinical Trials	NCT02315599	Pediatric Cance... Hematologic Mal... Solid Tumors	anti-CD19 CAR	1 Year - 99 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for t cell persistence