A Phase II Study Using Short-Term Cultured, CD8+-Enriched Autologous Tumor-Infiltrating Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Digestive Tract Cancers
- Metastatic digestive tract cancers, in particular esophageal, gastric, pancreatic and
hepatobiliary carcinomas, are associated with poor survival beyond five years and poor
response to existing therapies.
- Data from the Surgery Branch and from the literature support that digestive tract
cancers are potentially immunogenic and that TIL can be grown and expanded from these
- In metastatic melanoma, TIL can mediate the regression of bulky disease at any site
when administered to an autologous patient with high dose aldesleukin (IL-2) following
a non-myeloablative but lymphodepleting chemotherapy preparative regimen.
- The recent young-TIL approach, in which TIL are minimally cultured in vitro, not
selected for tumor recognition, and enriched in CD8+ cells before rapid expansion and
infusion to metastatic melanoma patients, has lead to objective response rates
comparable to previous trials relying on TIL screened for tumor recognition, with no
- We propose to investigate the feasibility, safety, and efficacy of a CD8+young-TIL
adoptive transfer therapy for metastatic digestive tract cancers.
- With approval of amendment D, we propose to investigate the feasibility, safety, and
efficacy of young-TIL adoptive transfer therapy for metastatic digestive tract cancers.
- To determine the ability of autologous CD8+-enriched TIL infused after minimal in vitro
culture in conjunction with high dose aldesleukin following a non-myeloablative
lymphodepleting preparative regimen to mediate tumor regression in patients with
metastatic digestive tract cancers.
- With approval of amendment D, to determine the rate of tumor regression in patients in
cohort 2 with metastatic digestive tract cancers who receive autologous, minimally
cultured tumor infiltrating lymphocytes (TIL) plus aldesleukin following a
lymphodepleting preparative regimen.
- To determine the phenotypic and functional characteristics of TIL derived from
digestive tract cancers.
- To determine the toxicity of this treatment regimen.
Patients who are 18 years of age or older must have:
- Metastatic digestive tract cancers refractory to standard chemotherapy, originating
from a) gastric or gastroesophageal junction, or b) pancreas, liver or biliary tree, or
c) colon or rectum;
- Normal basic laboratory values.
Patients may not have:
- Concurrent major medical illnesses;
- Severe hepatic function impairment due to liver metastatic burden;
- Unpalliated biliary or bowel occlusion, cholangitis, or digestive tract bleeding;
- Any form of immunodeficiency;
- Severe hypersensitivity to any of the agents used in this study;
- Contraindications for high dose aldesleukin administration.
- Patients will undergo resection to obtain tumor for generation of autologous TIL
cultures and autologous cancer cell lines, and for frozen tissue archive. Lymph nodes,
ascites, peritoneal implants, and normal tissue adjacent to metastatic deposit will
also be obtained when possible for assessing phenotypic and functional characteristics
of TIL derived from digestive tract cancers.
- Prior to amendment D, TIL will be expanded according to current TIL-lab standard
operating procedures, minimally cultured and enriched in CD8+ T cells using the
Miltenyi Biotec CliniMACS apparatus prior to rapid expansion for clinical scale
- With approval of amendment D, cohort 1 will be closed and cohort 2 will be opened in
which young TIL will not undergo CD8 enrichment. At this time, unselected young tumor
infiltrating lymphocytes (TIL) cultures will be grown from fragments of patient's
- All 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 CD8+ TIL and then begin
high-dose 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.
- For both cohorts 1 and 2, using a Phase II design for three groups of tumors: a)
gastric and gastroesophageal carcinomas, b) pancreatic and hepatobiliary carcinomas,
and c) colorectal carcinomas, 21 patients will be initially enrolled in each group to
assess toxicity and tumor responses. If two or more of the first 21 patients per groups
shows a clinical response (PR or CR), accrual will continue to 41 patients, targeting a
20% goal for objective response.
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the ability of autologous CD8+-enriched TIL in conjunction with high dose aldesleukin following a non-myeloablative lymphodepleting preparative regimen to meditate tumor regression in patients with metastatic digestive tract cancers...
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|