Phase II Study Using a Myeloablative Lymphocyte Depleting Regimen of Chemotherapy and Intensive Total Body Irradiation Followed by Infusion of Tumor Reactive Lymphocytes and Reconstitution With CD34+ Stem Cells in Metastatic Melanoma
The use of immunosuppression prior to adoptive transfer of lymphocytes from tumor bearing
mice was based on a variety of murine models demonstrating improved therapeutic
effectiveness of the adoptive transfer of lymphocytes following immunosuppression of the
Because the degree of immunosuppression has been highly correlated with the ability to
eliminate large tumors in murine models, we have been conducting a clinical trial,
04-C-0288, in which 200cGy of total body irradiation is used in conjunction with the same
cyclophosphamide and fludarabine regimen used in our prior adoptive cell therapy trials
which have demonstrated significant clinical responses.
We have measured T-regulatory cells in patients participating in 04-C-0288 and have
demonstrated that despite the addition of 200cGy total body irradiation (TBI), T-regulatory
cells promptly reconstituted in the host. Complete clinical responses have not been
significantly improved over other adoptive cell therapy regimens.
Thus, in this trial we would like to more adequately test our hypothesis that more intensive
lymphodepletion will increase complete responses and persistence of the transferred cells.
To determine whether tumor reactive lymphocytes infused in conjunction with the
administration of high-dose IL-2 in patients who have received prior therapy with IL-2 and
those who have not may result in complete clinical tumor regression in patients with
metastatic melanoma receiving a myeloablative lymphoid depleting preparative regimen.
To evaluate the safety of the treatment in patients receiving the myeloablative conditioning
regimen, cell transfer and IL-2.
To determine the survival in patients, of infused cells following the administration of the
myeloablative regimen, using analysis of the sequence of the variable region of the T cell
receptor or flow cytometry (FACS).
Patients who are greater than or equal to 18 years of age who have tumor reactive cells
available, with metastatic melanoma, and are physically able to tolerate high-dose IL-2.
Patients will be assigned to one of two cohorts, those having received prior therapy with
IL-2 and those who have not.
Patients will receive a myeloablative lymphocyte depleting preparative regimen consisting of
cyclophosphamide (60 mg/kg/day x 2 days IV), fludarabine (25mg/m^2/day IV X 5 days) and 1200
cGy total body irradiation (TBI).
Patients will receive intravenous adoptive transfer of tumor reactive lymphocytes (minimum
3 X 10 (9) and up to a maximum of 3 X 10(11) lymphocytes) followed by high-dose intravenous
(IV) IL-2 (720,000 IU/kg/dose every 8 hours for up to 15 doses).
On day 1 of patients will receive intravenous administration of cryopreserved autologous
A complete evaluation of evaluable lesions will be conducted 4-6 weeks after cell infusion.
Patients will be enrolled into two strata, using a phase II optimal design to rule out a
modest CR rate of 24%, with 33-54 patients enrolled in each strata.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Determine if the combination of high dose aldesleukin, reinfused cells after lymphocyte depleting chemotherapy and 1200 cGy total body irradiation (TBI) is able to be associated with a modest fraction of patients with metastatic melanoma who can experience a complete response to therapy. Complete response (CR) is a disappearance of all target lesions.
Steven A Rosenberg, M.D.
National Cancer Institute, National Institutes of Health
United States: Federal Government
|National Cancer Institute (NCI)||Bethesda, Maryland 20892|