Phase II Study of Lymphocytes Generated With Engineered Cells for Costimulation Enhancement in Patients With Metastatic Melanoma Following Lymphodepletion
Background:
- Tumor Infiltrating Lymphocyte (TIL) administration and high dose interleukin (IL)-2
following lymphodepletion can mediate durable complete responses in patients with
refractory melanoma. Obstacles to administration of this therapy include failure to
establish TIL in vitro for about 20% of patients, long delays between tumor resection
and TIL establishment resulting in poor TIL attributes for therapy and patient
ineligibility due to progression, and requirements for large numbers of feeder cells
for TIL expansion to therapeutic numbers.
- The K562 cell line was engineered to express the 4-1BBL costimulatory molecule and CD64
(the high affinity Fc receptor for loading with antibodies such as OKT3). The
K562.CD64.4-1BBL Engineered Cells with Costimulation Enhancement (ECCE) replaced up to
75% of feeder cells in large scale TIL expansions. ECCE added to tumor cell suspensions
provided costimulation in trans resulting in rapid and reliable lymphocyte growth
even from tumors with no TIL growth under standard conditions.
- A cloned K562.CD64.4-1BBL-7F11 ECCE line was produced under Good Manufacturing Practice
(GMP) conditions and a master cell bank has been generated. An optimized protocol was
established to rapidly expand (REP) young TIL using minimum feeders and 7F11. These
ECCE REPed TIL retained tumor recognition and some other attributes of standard TIL,
but differed from standard TIL by containing fewer CD4+ cells and more natural killer
cells.
When 7F11ECCE were added directly to single cell tumor suspensions, young TIL cultures were
reliably generated even from patients who otherwise would not have a standard young TIL
culture for treatment.
Objectives:
Primary objectives:
- In cohort 1, to evaluate whether young TIL that are rapidly expanded using 7F11 ECCE to
replace some feeder cells and administered with IL-2 in patients following a non
-myeloablative conditioning regimen will result in clinical tumor regression in
patients with refractory metastatic melanoma.
- In Cohort 2, to evaluate whether young TIL generated using in trans costimulation
with 7F11 ECCE in patients for whom standard young TIL did not grow can mediate tumor
regression after a nonmyeloablative conditioning with high dose IL-2 in patients with
refractory metastatic melanoma.
- Determine the toxicity of ECCE young TIL in these treatment regimens
Eligibility:
Patients who are 18 years of age or older must have:
- metastatic melanoma;
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- One or more lesions 2 cm or greater suitable for resection for TIL culture
Patients may not have:
- Concurrent major medical illnesses;
- Any form of immunodeficiency;
- Severe hypersensitivity to any of the agents used in this study;
- Contraindications for high dose IL-2 administration.
Design:
- Patients will undergo resection to obtain tumor for generation of autologous young TIL
cultures.
- Parallel TIL cultures will be established using a) the standard technique with IL-2
only and b) the Engineered Cells with Costimulation Enhancement (ECCE) protocol using
irradiated K562.CD64.4-1BBL-7F11 (7F11) cells.
- After 10 to 20 days cultures will undergo evaluation for TIL establishment. Standard
TIL will be used preferentially and patients who have TIL established by standard
methods will be assigned to Cohort 1
- Cohort 1:
- TIL will undergo ECCE REP by exposure to OKT-3, IL-2, feeder cells and irradiated
7F11.
- Patients will receive a non-myeloablative lymphocyte depleting preparative regimen
of cyclophosphamide (60 mg/kg/day intravenous (IV)) on days -7 and -6 and
fludarabine (25 mg/m^2/day IV) on days -5 through -1.
- On day 0 patients will receive the infusion of autologous young TIL and then begin
highdose aldesleukin (720,000 IU/kg IV every 8 hours for up to 15 doses).
- Clinical and immunologic response will be evaluated about 4-6 weeks after
treatment.
- Using an optimal two-stage Phase II design, initially 18 patients will be
enrolled, and if three or more of the first 18 patients have a clinical response
(partial response (PR) or complete response (CR)), accrual will continue to 35
patients, targeting a 30% goal for objective response.
- If standard young TIL fail to grow then ECCE young TIL will be evaluated and patients
who have ECCE TIL available will be assigned to Cohort 2 .
- Cohort 2:
- Cultures from patients in Cohort 2 will be evaluated for ECCE TIL establishment.
If adequate ECCE TIL are available, TIL will undergo ECCE REP by exposure to
OKT-3, IL-2, feeder cells and irradiated 7F11.
- Patients will receive a non-myeloablative lymphocyte depleting preparative regimen
of cyclophosphamide (60 mg/kg/day IV) on days -7 and -6 and fludarabine (25
mg/m^2/day IV) on days -5 through -1.
- On day 0 patients will receive the infusion of autologous young TIL and then begin
highdose aldesleukin (720,000 IU/kg IV every 8 hours for up to 15 doses).
- Clinical and immunologic response will be evaluated about 4-6 weeks after TIL
infusion.
- Using a small optimal two-stage Phase II design, initially 9 patients will be
enrolled, and if one or more of the first 9 patients has a clinical response (PR
or CR), accrual will continue to 24 patients, targeting a 25% goal for objective
response.
- If TIL cultures were not established by either standard methods or ECCE young TIL
protocols, patients will be eligible for re-resection and evaluation of TIL from a
different site.
Interventional
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Clinical Tumor Regression.
Clinical tumor regression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is a 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. Progression (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 (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum LD.
3 years
No
Steven A Rosenberg, M.D.
Principal Investigator
National Cancer Institute (NCI)
United States: Federal Government
110163
NCT01369875
May 2011
November 2012
Name | Location |
---|---|
National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda, Maryland 20892 |