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.
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
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).
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Clinical Tumor Regression
Response Evaluation Criteria In Solid Tumors (RECIST). See the protocol Link module for full criteria if desired.
Steven A Rosenberg, M.D., Ph.D
United States: Food and Drug Administration
|National Institutes of Health||Bethesda, Maryland 20892|