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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

Phase 2
18 Years
Not Enrolling
Anti-p53 TCR-Gene

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Trial Information

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


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.


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.


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


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

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).

Inclusion Criteria:

- Patients must have metastatic cancer that overexpresses p53 as assessed by
immunohistochemistry, as determined by positive staining of tumor sample. when
compared to negative controls per procedure in Appendix 1. The immunohistochemical
staining will be performed in the Pathology Laboratory Center for Cancer Research
(CCR), National Cancer Institute (NCI) on fresh or archival tissue and will be
supervised by Dr. Maria Merino. The criteria used to determine overexpression will be
that used in the Laboratory of Dr. Curt Harris. Ten fields will be evaluated at 40 X
magnification and if greater than 5% of cells stain positive, the tumor will be
categorized as an overexpressor.

- Patients with melanoma or renal cell cancer must have previously received
interleukin-2 (IL-2) and have been either non-responders (progressive disease) or
have recurred. Patients with other histologies,not including hematologic
malignancies, must have previously received first line and second line or higher
systemic standard care(or effective salvage chemotherapy regimens) for metastatic
disease,if known to be effective for that disease and have been either non-responders
(progressive disease) or have recurred.

- Age greater than or equal to 18 years.

- Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 to 1.

- Life expectancy of greater than three months.

- Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental
treatment being evaluated in this protocol depends on an intact immune system.
Patients who are HIV seropositive can have decreased immune competence and thus be
less responsive to the experimental and more susceptible to its toxicities).

- Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen

- Patients must be human leukocyte antigen A(HLA-A) 0201 positive.

- Patients of both genders must be willing to practice birth control for four months
after receiving the preparative regimen.

- Absolute neutrophil count greater than 1000/mm^3, and normal white blood cells (WBC)
(greater than 3000/mm^3).

- Platelet count greater than 100,000/mm^3.

- Hemoglobin greater than 8.0 g/dl.

- Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than the
upper limit of normal.

- Serum creatinine less than or equal to 1.6 mg/dl.

- Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's
Syndrome who must have a total bilirubin less than 3.0 mg/dl.

- More than four weeks must have elapsed since any prior systemic therapy at the time
the patient receives the preparative regimen, and patients toxicities must have
recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).
Six weeks must have elapsed since prior Ipilimumab (MDX-010) therapy to allow
antibody levels to decline, and patients who have previously received MDX-010 must
have a normal colonoscopy with normal colonic biopsies.

- Women of child-bearing potential must have a negative pregnancy test because of the
potentially dangerous effects of the preparative chemotherapy on the fetus.

- A biopsy must be evaluable to evaluate p53 expression and to confirm the diagnosis by
the Laboratory of Pathology, CCR, NCI.

Exclusion Criteria:

- Patients requiring systemic steroid therapy

- Patients with active systemic infections, coagulation disorders or other major
medical illnesses of the cardiovascular, respiratory or immune system, myocardial
infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.

- Patients with any form of primary immunodeficiency (such as Severe Combined
Immunodeficiency Disease and acquired immune deficiency syndrome (AIDS)). Patients
with opportunistic infections will be excluded. (The experimental treatment being
evaluated in this protocol depends on an intact immune system. Patients who have
decreased immune competence may be less responsive to the experimental treatment and
more susceptible to its toxicities).

- Patients with history of severe immediate hypersensitivity reaction to any of the
agents used in this study.

- Patient is not willing to sign a durable power of attorney.

- Patient is not able to understand and sign the Informed Consent Document.

- Since aldesleukin will be excluded if they have a history of electrocardio- gram
(EKG) abnormalities, symptoms of cardiac ischemia or arrhythmias and have a left
ventricular ejection fraction (LVEF) less than 45% on a cardiac stress test (stress
thallium, stress multi-gated acquisition scan (MUGA), dobutamine echocardiogram, or
other stress test).

- Similarly, patients who are greater than or equal to 50 years old with a LVEF less
than 45% will be excluded.

- Patients with a prolonged history of cigarette smoking (greater than 20 pack/year
within the past 2 years) or symptoms of respiratory dysfunction (e.g. grade 2 dyspnea
or hypoxia) who do not have a normal pulmonary function test as evidenced by a FEV(1)
less than 60% predicted will be excluded.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Clinical Tumor Regression

Outcome Description:

Response Evaluation Criteria In Solid Tumors (RECIST). See the protocol Link module for full criteria if desired.

Outcome Time Frame:

1-11 months

Safety Issue:


Principal Investigator

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

Investigator Role:

Principal Investigator

Investigator Affiliation:



United States: Food and Drug Administration

Study ID:




Start Date:

October 2006

Completion Date:

November 2008

Related Keywords:

  • Anti-p53 TCR-Gene
  • Tumor Regression
  • In Vivo Cell Survival
  • Toxicity Profile
  • Metastatic Renal Cell Cancer
  • Cancer
  • Metastatic Cancer
  • Neoplasm Metastasis
  • Neoplasms
  • Neoplasms, Second Primary



National Institutes of Health Bethesda, Maryland  20892