Phase I/II Study of Metastatic Cancer Using Lymphodepleting Conditioning Followed by Infusion of Anti-mesothelin Gene Engineered Lymphocytes
- We have constructed a single retroviral vector that contains a chimeric T cell receptor
(CAR) that recognizes mesothelin, which can be used to mediate genetic transfer of this
CAR with high efficiency (> 50%) without the need to perform any selection.
- In co-cultures with mesothelin expressing cells, anti-mesothelin transduced T cells
secreted significant amounts of IFN-gamma with high specificity.
- To evaluate the safety of the administration of anti-mesothelin CAR engineered
peripheral blood lymphocytes in patients receiving a non- myeloablative conditioning
regimen, and aldesleukin.
- Determine if the administration anti-mesothelin CAR 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
-Determine the in vivo survival of CAR gene-engineered cells.
Patients who are 18 years of age or older must have
- Metastatic or unresectable cancer that expresses mesothelin;
- Previously received and have been a non-responder to or recurred after standard care;
Patients may not have:
-Contraindications for low dose aldesleukin administration.
- PBMC obtained by leukapheresis will be cultured in order to stimulate T-cell growth.
- Transduction is initiated by exposure of approximately 108 to 5 X 108 cells to
retroviral vector supernatant containing the anti-mesothelin CAR.
- 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 PBMC plus low dose IV aldesleukin
- 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. 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 mesothelioma, and
cohort 2 will include patients with other types of cancer that express mesothelin.
- 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.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Evaluate safety of anti-mesothelin CAR engineered PBL in patients receiving the protocol regimen.
Steven A Rosenberg, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|