Phase II Study of Metastatic Melanoma Using Lymphodepleting Conditioning Followed by Infusion of Anti-MART-1 F5 TCR-Gene Engineered Lymphocytes
- We have engineered human TIL (tumor infiltrating lymphocytes) and peripheral blood
lymphocytes (PBLs) to express an anti-MART-1 T-cell receptor that recognizes an
HLA-A*0201 restricted epitope derived from the TIL clone DMF5.
- We constructed a single retroviral vector that contains both alpha and beta chains and
can mediate genetic transfer of this TCR with high efficiency without the need to
perform any selection.
- In co-cultures with HLA-A*0201 positive melanoma, anti-MART-1 F5 TCR transduced T cells
secreted significant amount of interferon (IFN)-gamma (but no significant secretion was
observed in control co-cultures with cell lines.
- The anti-MART-1 F5 TCR transduced T-cells could efficiently kill HLA-A*0201 positive
tumors. There was little or no recognition of normal fibroblasts cells.
- This TCR is over 10 times more reactive with melanoma cells than the MART-1 TCR that
mediated tumor regression in two patients with metastatic melanoma.
-Determine if the administration of anti-MART-1 F5 TCR -engineered peripheral blood
lymphocytes (PBL) or tumor infiltrating lymphocytes (TIL) and aldesleukin to patients
following a nonmyeloablative but lymphoid depleting preparative regimen will result in
clinical tumor regression in patients with metastatic melanoma.
- Determine the in vivo survival of TCR gene-engineered cells.
- Determine the toxicity profile of this treatment regimen.
Patients who are HLA-A 0201 positive and 18 years of age or older must have:
- metastatic melanoma;
- previously received and have been a non-responder to or recurred after aldesleukin;
- 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.
- If TIL can be obtained and grown, but are non-reactive, patients will be assigned to
receive TIL transduced with the anti-MART-1 F5 TCR retroviral vector. If TIL cannot be
obtained, PBMC will be obtained by leukapheresis (approximately 5 X 10(9) cells) and
cultured in the presence of anti-CD3 (OKT3) and aldesleukin and transduced with the
anti-MART-1 F5 TCR retroviral vector. If TIL cells are reactive to autologous tumor or
major histocompatibility complex (MHC)-matched tumor cells or PBL cannot be grown,
patients will not be treated on this protocol.
- Transduction is initiated by exposure of approximately 10(8) to 5 times 10(8) cells to
retroviral vector supernatant containing the anti-MART-1 F5 TCR genes. These
transduced cells will be expanded and tested for their anti-tumor activity.
- Once engineered lymphocytes are demonstrated to be biologically active according to the
strict criteria outlined in the Certificate of Analysis, patients will receive a
nonmyeloablative but lymphocyte depleting preparative regimen consisting of
cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo tumor
reactive, TCR gene transduced cells plus IV aldesleukin (720,000 IU/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
- The study will be conducted using a phase II optimal design where initially 21
evaluable patients will be enrolled into each of two cohorts. If 0 or 1 of the 21
patients per cohort experiences a clinical response, then no further patients will be
enrolled but if 2 or more of the first 21 evaluable patients enrolled in that cohort
have a clinical response, then accrual to that cohort will continue until a total of 41
evaluable patients have been enrolled in that cohort.
- The objective will be to determine in two cohorts if the combination of high dose
aldesleukin, lymphocyte depleting chemotherapy, and anti-MART-1 F5 TCR-gene engineered
lymphocytes (TIL and PBL) 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 (partial response) + CR (complete
response) rate (p1=0.20).
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Clinical Tumor Regression.
Tumor regression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progressive disease (PD) is at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD.
Steven Rosenberg, M.D.
National Cancer Institute, National Institutes of Health
United States: Federal Government
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