Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer

Background:

• 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 National Cancer Institute Surgery Branch (NCI-SB) and from the literature support that metastatic cancers are potentially immunogenic and that tumor-infiltrating

lymphocytes (TIL) can be grown and expanded from these tumors.

• 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 nonmyeloablative, lymphodepleting preparative regimen.
• The recent young-TIL approach, in which TIL are minimally cultured in vitro, not selected for tumor recognition, before rapid expansion and infusion to metastatic melanoma patients, has led to objective response rates comparable to previous trials relying on TIL screened for tumor recognition, with no added toxicities.
• In pre-clinical models, the administration of an anti-PD-1 antibody enhances the anti-tumor activity of transferred T-cells.
• We propose to investigate the feasibility, safety, and efficacy of TIL adoptive transfer therapy in combination with pembrolizumab, administered either prior to cell administration or at the time of progressive disease, for metastatic cancers.

Objectives:

-Primary objective:

--With Amendment BB, to determine the rate of tumor regression in patients with metastatic cancer who receive autologous, minimally cultured TIL in conjunction with a non-myeloablative, lymphodepleting preparative regimen, high-dose aldesleukin, and anti-PD-1.

Eligibility:

Patients must be/have:

• Age greater than or equal to 18 years and less than or equal to 72 years
• Metastatic upper or lower gastrointestinal, hepatobiliary, genitourinary, breast, ovarian/endometrial cancer, or endocrine tumors including neuroendocrine tumors refractory to standard chemotherapy

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

Design:

• Patients may undergo resection or biopsy 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 ongoing and future research as described in the NCI-SB cell harvest protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols).
• With the approval of Amendment BB, patients will be enrolled on Arm 3 or Arm 4. All patients will receive a non-myeloablative, lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the infusion of autologous TIL and high-dose aldesleukin. Patients enrolled on Arm 3 will receive pembrolizumab prior to cell administration and three additional doses every three weeks following the cell infusion. Patients enrolled on Arm 4 will receive pembrolizumab within four weeks after meeting progressive disease by RECIST criteria, continuing for up to 8 doses every 3 weeks.
• Clinical and immunologic response will be evaluated about 6 weeks after cell infusion and periodically thereafter.
• Twenty-one patients will initially be 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 (partial response or complete response), accrual will continue to 41 patients, targeting a 20% goal for objective response.
• Up to 332 patients may be enrolled.

• INCLUSION CRITERIA:
• Measurable (per RECIST v1.0 criteria), metastatic cancer of one of the following types: upper or lower gastrointestinal, hepatobiliary, genitourinary, breast, ovarian/endometrial, or endocrine tumors including neuroendocrine tumors. Patients must have at least one lesion that is resectable for TIL generation with minimal morbidity, preferentially using minimal invasive laparoscopic or thoracoscopic surgery for removal of superficial tumor deposit.
• Confirmation of diagnosis of metastatic cancer by the NCI Laboratory of Pathology.
• Refractory to approved standard systemic therapy. Specifically:

• Patients with metastatic colorectal cancer must have received oxaliplatin or irinotecan.
• Patients with hepatocellular carcinoma must have received sorafenib (Nexavar(R)), since level 1 data support a survival benefit with this agent.
• Patients with breast and ovarian cancer must be refractory to both first- and second-line treatments and must have received at least one second-line chemotherapy regimen.
• Patients with 3 or fewer brain metastases that are < 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.
• Age greater than or equal to 18 years and less than or equal to 72 years.
• Clinical performance status of ECOG 0 or 1.
• Patients of both sexes must be willing to practice birth control from the time of enrollment on this study and 12 months after the last dose of combined chemotherapy for individuals of child-bearing potential (IOCBP) and for four months after treatment for individuals that can father children.
• IOCBP must have a negative pregnancy test be a pregnancy test prior to the start of treatment because of the potentially dangerous effects of the treatment on the fetus.

Serology

• Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive may have decreased immune-competence and thus may be less responsive to the experimental treatment and more susceptible to its toxicities.)
• Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then the patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.

Hematology

• ANC > 1000/mm^3 without the support of filgrastim
• WBC greater than or equal to 2500/mm^3
• Platelet count greater than or equal to 80,000/mm^3
• Hemoglobin > 8.0 g/dL. Subjects may be transfused to reach this cut-off.

Chemistry

• Serum ALT/AST less than or equal to 5.0 x ULN
• Serum creatinine less than or equal to 1.5 x ULN
• Total bilirubin less than or equal to 2.0 mg/dL, except in patients with Gilbert s Syndrome, who must have a total bilirubin < 3.0 mg/dL.
• Patients must have completed any prior systemic therapy at the time of enrollment.

Note: Patients may have undergone minor surgical procedures or limited field radiotherapy within the four weeks prior to enrollment, as long as related major organ toxicities have recovered to less than or equal to grade 1.

• Ability of subject to understand and the willingness to sign a written informed consent document.
• Willing to sign a durable power of attorney.
• Subjects must be co-enrolled on protocol 03-C-0277.

Exclusion criteria

• Participants who are pregnant or nursing because of the potentially dangerous effects of the treatment on the fetus or infant.
• Concurrent systemic steroid therapy.
• Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses.
• Advanced primary with impeding occlusion, perforation or bleeding, dependent on transfusion.
• Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS).
• History of major organ autoimmune disease.
• Grade 3 or 4 major organ irAEs clinically attributed to anti-PD-1/PD-L1 therapy.
• Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immunecompetence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
• History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
• History of coronary revascularization or ischemic symptoms.
• For select patients with a clinical history prompting cardiac evaluation: last known LVEF less than or equal to 45%.
• Documented Child-Pugh score of B or C for hepatocellular carcinoma patients with known underlying liver dysfunction.
• For select patients with a clinical history prompting pulmonary evaluation: known FEV1 less than or equal to 50%.
• Patients who are receiving any other investigational agents.