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Melanoma is a serious form of skin cancer that develops in the skin cells that make our skin color (melanocytes).

Peripheral blood lymphocytes are harvested by lymphapheresis and engineered to express a T cell receptor that binds to P53.

anti-protein 53 or tumor protein 53 (p53) T-cell receptor transduced peripheral blood lymphocytes

720,000 IU/kg intravenously over 15 minutes every 8 hours for up to 5 days

aldesleukin

Beginning on day 1 or 2, administered subcutaneously at a dose of 5 mcg/kg/day (not to exceed 300 mcg/day); continue daily until neutrophil count \> 1.0 x 10\^9/L x 3 days or \> 5.0 x 10\^9/L.

filgrastim

60 mg/kg/day x 2 days intravenously in 250ml dextrose 5% in water (D5W) with mesna 15 mg/kg/day x 2 days over 1 hour.

cyclophosphamide

25 mg/m2/day intravenously piggyback (IVPB) daily over 30 minutes for 5 days.

fludarabine phosphate

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

Background:

The p53 gene normally suppresses tumor growth, but when it is mutated, or damaged, tumors can grow unchecked.

In cancers where the p53 gene has mutated, an increased level of p53(overexpression of p53) can be measured in the tumor.

Objectives To determine whether advanced cancers that overexpress p53 can be treated effectively with lymphocytes (white blood cells) that have been genetically engineered to contain an anti-p53 protein.

Eligibility Patients 18 years of age and older with metastatic cancer (cancer that has spread beyond the original site) Patient's tumor overexpresses p53 Patient's leukocyte antigen type is HLA-A 0201 Design

Patients undergo the following procedures:

Leukapheresis (on two occasions). This is a method of collecting large numbers of white blood cells. The cells obtained in the first leukapheresis procedure are grown in the laboratory, and the anti-p53 protein is inserted into the cells using an inactivated (harmless)virus in a process called transduction. Cells collected in the second leukapheresis procedure are used to evaluate the effectiveness of the study treatment.

Chemotherapy. Patients are given chemotherapy through a vein (intravenously, IV) for 1 week to suppress the immune system so that the patients immune cells do not interfere with the treatment.

Treatment with anti-p53 cells. Patients receive an IV infusion of the transduced cells containing anti-p53 protein, followed by infusions of a drug called IL-2, which helps boost the effectiveness of the transduced white cells.

Patients may undergo a tumor biopsy (removal of a small piece of tumor tissue). Patients are evaluated with laboratory tests and imaging tests, such as computed tomography (CT) scans 4 to 6 weeks after treatment and then once a month 3 to 4 months to determine the response to treatment.

Patients have blood tests at 1, 3, 6 and 12 months and then annually for the next 10 years.

Background:

Human peripheral blood lymphocytes (PBL's) can be engineered to express alpha T-cell receptor that recognizes an human leukocyte antigen serotype witin HLA-A A serotype group) HLA-A2. 1 restricted epitope derived from the p53 protein.

We constructed a single retroviral vector that contains both alpha and existent chains and can mediate genetic transfer of this TCR with high efficacy (less than 30%) without the need to perform any selection.

In co-cultures with HLA-A2 and p53 double positive tumors including melanoma, hepatoma, sarcoma, small-cell lung cancer, esophageal and breast tumors, p53-TCR transduced T cells secreted significant amount of IFN-(but no significant secretion was observed in control co-cultures with either HLA-A2+/p53- or HLA-A2-p53+cell lines.

Additional secretion of cytokines (IL-2, IL-4, IL-10,granulocyte macrophage stimulating factor (GM-CSF),tumor necrosis factor alpha (TNFalpha)) and chemokines (regulated upon activation, normal T cell expressed and secreted (RANTES), macrophage inflammatory protein 1 alpha (MIP-1 alpha)) was also observed in co-cultures with HLA-A2+/p53+tumor lines.

p53-TCR transduced PBL could efficiently kill HLA-A2, 1/p53 expressing tumors (H2087, MDA-MB 231, Saos2/143, BE-3).

In addition, we also tested for specific lysis of normal tissues by p53-TCR transduced cells and there was little or no lysis of the normal fibroblasts, renal epithelia cells, resting or activated normal PBLs compared to control HLA_A2+/p53+H2087 tumor.

Objectives:

Primary objective:

Determine of the administration of anti-p53 TCR-engineered peripheral blood lymphocytes and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic cancer overexpressing p53.

Secondary objectives:

Determine the in vivo survival of TCR gene-engineered cells. Determine the toxicity profile of this treatment regimen.

Eligibility:

Patients who are HLA A0201 and 18 years of age or older must have metastatic cancer whose tumors overexpress p53; previously received and have been a non-responder or recurred to standard care for metastatic disease; biopsy available to evaluate p53 expression; normal values for basic laboratory values; Patients may not have: concurrent major medical illnesses; any form of primary or secondary immunodeficiency; severe hypersensitivity to any of the agents used in this study; contraindications for high dose aldesleukin administration.

Design:

PBMC, obtained by leukapheresis (approximately 5 x 10\^9 cells) will be cultured in the presence of anti-CD3 Muromonab-CD3( OKT3) and IL-2 in order to stimulate T-cell growth.

Transduction is initiated by exposure of approximately 10\^8 to 5 x 10\^8 cells to supernatant containing the anti-p53 TCR retroviral vector. These transduced cells will be expanded and tested for their anti-tumor activity.

Patients will receive a nonmyeloablative but lymphocyte depleting preparative regiment consisting of cyclophosphamide and fludarabine followed by intravenous infusion of in vitro tumor reactive, TCR gene-transduced PBL plus IV aldesleukin (720,000IU/kg q8h for a maximum of 15 doses).

Patients will undergo complete evaluation of tumor with physical examination, CT of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment and then monthly for approximately 3 to 4 months or until off study criteria are met.

Patients will be entered into two cohorts based on histology: cohort 1 will include patients with metastatic melanoma or renal cell cancer, cohort 2 will include patients with other types of metastatic cancer.

For each of the 2 strata evaluated, the study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled. For each of these two arms of the trial, if 0 or 1 of the 21 patients experiences a clinical response, then no further patients will be enrolled but if 2 or more of the first 21 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled in that stratum.

For both strata, the objective will be to determine if the combination of high dose aldesleukin, lymphocyte depleting chemotherapy, and anti-p53 TCR-gene engineered lymphocytes is able to be associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of a modest 20% PR + CR rate (p1=0.20).

Phase II Study of Metastatic Cancer That Overexpresses P53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-P53 TCR-Gene Engineered Lymphocytes

Phase II Study of Metastatic Cancer That Overexpresses p53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-p53 T Cell Receptor (TCR)-Gene Engineered Lymphocytes

Response Evaluation Criteria In Solid Tumors (RECIST).

See the protocol Link module for full criteria if desired.

Here are the total number of participants with adverse events. Adverse events were described using the Common Terminology Criteria for Adverse Events (CTCAE) version 3. For the detailed list of adverse events see the adverse event module.

Survival of TCR gene-engineered cells is defined as \>10% murine TCR positive cells.

National Cancer Institute (NCI)

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

Metastatic Melanoma

Other Metastatic Cancers

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.

Melanoma is a serious form of skin cancer that develops in the skin cells that make our skin color (melanocytes).

There are no statistical differences between the arms, therefore, they can be combined for this outcome measure.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase II Study of Metastatic Cancer That Overexpresses P53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-P53 TCR-Gene Engineered Lymphocytes	NCT00393029	Anti-p53 TCR-Ge...	anti-protein 53... aldesleukin filgrastim cyclophosphamid... fludarabine pho...	18 Years -	National Institutes of Health Clinical Center (CC)
Phase II Study of Metastatic Cancer That Overexpresses P53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-P53 TCR-Gene Engineered Lymphocytes	NCT00393029	Anti-p53 TCR-Ge...	anti-protein 53... aldesleukin filgrastim cyclophosphamid... fludarabine pho...	18 Years -	National Institutes of Health Clinical Center (CC)
Phase II Study of Metastatic Cancer That Overexpresses P53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-P53 TCR-Gene Engineered Lymphocytes	NCT00393029	Anti-p53 TCR-Ge...	anti-protein 53... aldesleukin filgrastim cyclophosphamid... fludarabine pho...	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for in vivo cell survival