Phase I/II Study of Metastatic Cancer Using Lymphodepleting Conditioning Followed by Infusion of Anti-VEGFR2 Gene Engineered CD8+ Lymphocytes
- We have constructed a single retroviral vector that contains a chimeric T cell receptor
(CAR) that recognizes the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), which
can be used to mediate genetic transfer of this CAR with high efficiency (> 50%)
without the need to perform any selection. Administration of VEGFR2 CAR transduced
cells inhibited tumor growth in several different models in different mouse strains.
- In co-cultures with VEGFR2 expressing cells, anti-VEGFR2 transduced T cells secreted
significant amounts of IFN gamma with high specificity.
- To evaluate the safety of the administration of anti-VEGFR2 -CAR engineered CD8+
peripheral blood lymphocytes in patients receiving a non- myeloablative conditioning
regimen, and aldesleukin.
- Determine if the administration of anti-VEGFR2 -CAR engineered CD8+ peripheral blood
lymphocytes and aldesleukin to patients following a nonmyeloablative but lymphoid
depleting preparative regimen will result in clinical tumor regression in patients with
-Determine the in vivo survival of CAR gene-engineered cells.
Patients who are 18 years of age or older must have:
- metastatic cancer;
- previously received and have been a non-responder to or recurred after standard care
for metastatic disease;
Patients may not have:
-contraindications for high dose aldesleukin administration.
- PBMC obtained by leukapheresis (approximately 5 times 10(9) 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(8) cells to
retroviral vector supernatant containing the VEGFR2 genes.
- Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen
consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex
vivo CAR gene-transduced CD8+ PBMC plus IV aldesleukin. With approval of amendment C,
aldesleukin (based on total body weight) will be administered at a dose of 72,000 IU/kg
as an intravenous bolus over a 15 minute period every eight hours (+/- 1 hour)
beginning within 24 hours of the cell infusion and continuing for up to 5 days (maximum
- 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. If the patient has SD or tumor shrinkage, repeat complete evaluations will
be performed every 1-3 months. After the first year, patients continuing to respond
will continue to be followed with this evaluation every 3-4 months until off study
criteria are met.
- The study will be conducted using a Phase I/II optimal design. The protocol will
proceed in a phase 1 dose escalation design. Initially, the protocol will enroll 1
patient in each dose cohort unless that patient experiences a dose limiting toxicity
(DLT). Should a single patient experience a dose limiting toxicity due to the cell
transfer at a particular dose level, additional patients would be treated at that dose
to confirm that no greater than 1/6 patients have a DLT prior to proceeding to the
next higher level. If a level with 2 or more DLTs in 3-6 patients has been identified,
three additional patients will be accrued at the next-lowest dose, for a total of 6,
in order to further characterize the safety of the maximum tolerated dose prior to
starting the phase II portion. If a dose limiting toxicity occurs in the first cohort,
that cohort will be expanded to 6 patients. If 2 DLTs are encountered in this cohort,
the study will be terminated. If IFN-gamma levels increase substantially (as defined
in the protocol) in the patient in a cohort compared to the prior patient, the cohort
would be expanded to an n=3 to obtain more data on this phenomenon. If one of these 3
patients experience a DLT, the cohort will be expanded to six patients. Following
amendment C, patients will be enrolled in cohorts 8-11, with the non-myeloablative
chemotherapy regimen, cells and low dose aldesleukin following a conventional 3+3
design. Once the MTD has been determined, the study then would proceed to the phase II
portion. Patients will be entered into two cohorts based on histology: cohort 1 will
include patients with metastatic melanoma and renal cancer, and 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.
- The objective will be to determine if the combination of aldesleukin, lymphocyte
depleting chemotherapy, and anti-VEGFR2 CAR-gene engineered CD8+ 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 Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To evaluate the safety of the administration of anti-VegFR2-CAR engineered peripheral blood lymphocytes in patients receiving a non-myeloablative conditioning regimen, and aldesleukin.
Steven A Rosenberg, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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