Phase II Study in Patients With Metastatic Melanoma Using a Non-Myeloablative Lymphocyte Depleting Regimen of Chemotherapy Followed by Infusion of MART-1 Reactive Peripheral Blood Lymphocytes (PBL) With or Without High Dose Aldesleukin
- TIL transfer studies in patients with metastatic melanoma following lymphodepletion
have resulted in 50 percent objective response rates with a 10-15 percent rate of
complete responses. Despite these important clinical findings, adoptive cell transfer
has not become widely available for patient treatment. Significant obstacles to this
therapy are the need for invasive surgery and the inability of some patients to
tolerate high dose aldesleukin. Further, the specific characteristics of the T cells
that are responsible for the therapeutic effect of TIL are unknown, thus, resulting in
significant treatment variability.
- Pre-clinical and correlative clinical studies of adoptive immunotherapy have suggested
putative favorable characteristics for transferred lymphocytes, such as, high avidity
for the target antigen, limited in vitro stimulation, and high expression of CD27+.
However, these characteristics have not been prospectively evaluated in human clinical
- We have developed a novel non invasive T cell isolation strategy using the heteroclitic
MART-1:26-35(27L) peptide for in vitro sensitization of human PBL and high throughput
qPCR screening to rapidly isolate antigen specific CD8+ T cells from the CD4+ T cell
depleted peripheral blood repertoire. These isolated T cells possess the above
mentioned favorable characteristics and recognize the native MART-1:27-35 epitope, an
abundantly expressed melanoma antigen presented by HLA-A2 on the tumor surface.
- The current proposed transfer of these select MART-1:27-35 reactive lymphocytes in
conjunction with a lymphodepleting preparative regimen with or without high dose
aldesleukin would represent a novel therapeutic option for patients with advanced
melanoma and provide a desperately needed option for patients who are not medically
eligible for aldesleukin treatment.
- To determine whether MART-1:27-35 reactive lymphocytes infused with or without the
administration of high-dose aldesleukin may result in clinical tumor regression in
patients with metastatic melanoma receiving a non-myeloablative lymphoid depleting
- To evaluate the safety of the treatment in patients receiving the non-myeloablative
conditioning regimen and cell transfer with or without the administration of high-dose
- To determine the survival in patients, of infused cells following the administration of
the non-myeloablative regimen, using analysis of the sequence of the variable region of
the T cell receptor or flow cytometry (FACS).
-Patients with refractory metastatic melanoma who are greater than or equal to 18 years of
age, are HLA-A2+, who have MART-1:27-35 reactive peripheral blood lymphocytes available and
are physically able to tolerate non-myeloablative chemotherapy. Patients must be refractory
to prior high dose aldesleukin treatment if they are medically eligible to receive it.
Patients who can tolerate high-dose aldesleukin will receive it with cell infusion; those
who cannot tolerate high-dose aldesleukin due to medical comorbidities or refuse high-dose
aldesleukin will receive cell infusion without aldesleukin.
- Patients will receive a non-myeloablative lymphocyte depleting preparative regimen
consisting of cyclophosphamide (60 mg/kg/day X 2 days IV), fludarabine (25 mg/m2/day IV
X 5 days).
- Patients will receive intravenous adoptive transfer of MART-1:27-35 reactive peripheral
blood lymphocytes (minimum 1 X 108 and up to a maximum of 3 X 1011 lymphocytes)
followed by high-dose intravenous (IV) aldesleukin (720,000 IU/kg/dose every 8 hours
for up to 15 doses) or no aldesleukin if they are not medically eligible to receive it.
- A complete evaluation of evaluable lesions will be conducted 4-6 weeks after the last
dose of aldesleukin in the aldesleukin arm and 4-6 weeks after the cell administration
in the no aldesleukin arm. Patients will be enrolled into two cohorts. The cohort
receiving high-dose aldesleukin will be conducted using a small optimal two-stage Phase
II design, initially 19 patients will be enrolled, and if 4 or more of the first 19
patients have a clinical response (PR or CR), accrual will continue to 33 patients,
targeting a 35 percent goal for objective response. For the cohort who will not receive
aldesleukin, the study will be conducted as a Minimax two stage phase II trial.
Initially 12 evaluable patients will be enrolled to this cohort, and if 1 or more the
first 12 have a response, then accrual would continue until a total of 21 patients,
targeting a 20 percent goal for objective response.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Determine whether autologous MART-1:27-35 reactive PBL infused with or without the administration of high-dose aldesleukin may result in clinical tumor regression.
Udai S Kammula, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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