Adoptive Cell Therapy Across Cancer Diagnoses

Phase 1

Completed

Conditions: Cancer

Interventions: Biological: Autologous tumor-infiltrating lymphocytes
Drug: Ipilimumab
Drug: Nivolumab
Drug: proleukin
Drug: Cyclophosphamide
Drug: Fludara

Registration Number: NCT03296137

Lead Sponsor: Inge Marie Svane

Brief Summary: This study will perform tumor-infiltrating lymphocyte (TIL)-based adoptive T-cell therapy in combination with checkpoint inhibition on cancer patients across all cancer diagnoses.

Detailed Description: Adoptive cell therapy (ACT) is a personalized form of immunotherapy, where lymphocytes isolated from the patient's own tumor tissue are expanded 1000-fold ex-vivo and then infused back into the patient. The lymphocytes are then able to recognize and attack remaining cancer cells. This approach has shown remarkable clinical results in several trials conducted worldwide for patients with advanced melanoma - some with durable remissions. Promising clinical results were obtained in smaller trials where patients with disparate solid tumors were treated with tumor-infiltrating lymphocytes (TILs). At Center for Cancer Immune Therapy (CCIT) at Herlev Hospital, there are currently clinical trials undergoing in ovarian and renal cancer, and internationally ACT is being tested in an increasing number of cancer diagnoses, some trials are even recruiting patients across cancer types. Studies have shown that a high intratumoral infiltration with TILs in is correlated to the general clinical outcome of the disease in virtually all solid tumors, and thus clinical trials with TIL-based ACT to different cancer diagnoses have been undertaken.

To support the TIL-mediated tumor elimination, in classical ACT protocols patients go through a highly specialized treatment regime before and after TIL infusion. This regime includes lymphodepletion with 7 days non-myeloablative chemotherapy, to provide an immunological window of opportunity for the infused TILs, and concomitant immune stimulation with interleukin-2 (IL-2). Checkpoint inhibition to support the anti-tumor activity of TILs is currently under extensive investigation in several other trials worldwide. Thus, lymphodepletion and IL-2 stimulation are well-established as supportive therapy and already an integrated part of current ACT protocols and while checkpoint inhibition is a new addition at CCIT; internationally other centers have ongoing comparable trials.

Drug-based immunotherapy in the form of checkpoint inhibitors (anti-PD-1 and anti-CTLA-4) has yielded impressive clinical results across tumor histologies. Recent results indicate that the effect of immunotherapy relies not so much on the cancer diagnoses but rather on the genomic and immunologic features of the individual patient's cancer disease. Both ACT and checkpoint inhibition work by tipping the immunological balance in favor of activation and away from suppression or avoidance by the cancer cells. Scientific evidence now show that administering anti-CTLA-4 and PD-1 could provide a benefit in the ACT setting, and several ongoing clinical trials are testing combinations of ACT and checkpoint inhibition. To synergistically maximize the immunological potential, we wish to combine ACT with an anti-CTLA-4 antibody (Ipilimumab) prior to tumor resection and an anti-PD-1 antibody (Nivolumab) in combination with TIL infusion.

Patients will be treated with one dose of Ipilimumab 14 days before undergoing surgery to harvest tumor material for TIL production. Patients is admitted on day -8 in order to undergo lymphodepleting chemotherapy with cyclophosphamide and fludara starting day -7. On day -2 patients will start treatment with Nivolumab every 2 weeks for a total of 4 doses to increase the activity of the infused TIL product.

Available evidence indicates that ACT is a safe and feasible treatment option in an increasing number of solid tumors, and that it should be tested in all cancer patients regardless of their cancer diagnosis.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 25

Inclusion Criteria

Histologically verified metastatic or locally advanced cancer diagnosis
At least one lesion (>1 cm3) available for surgical resection
Not candidate for standard treatment options
Age of 18-70 years
Performance status of 1 or 0.
Life expectancy > 6 months
One or more measurable parameter according to RECIST 1.1.
No significant toxicity from previous cancer treatments (CTC≤1). Except alopecia (CTC≤2) or neuropathy (CTC≤2)
Sufficient organ function, including:
Absolute neutrophil count (ANC) ≥ 1.500 /µl
Leucocyte count ≥ normal limit
Platelets ≥ 100.000 /µl and <700.000 /µl
Hemoglobin ≥ 6,0 mmol/l (regardless of prior transfusion)
S-creatinine < 140
S-bilirubin ≤ 1,5 times upper normal limit
ASAT/ALAT ≤ 2,5 times upper normal limit
Alkaline phosphatase ≤ 5 times upper normal limit
Lactate dehydrogenase (LDH) ≤ 5 times upper normal limit
Sufficient coagulation: PP-time>40 and INR<1,5
Women in the fertile age must use effective contraception. This applies from inclusion and until 6 months after treatment. Birth control pills, spiral, depot injection with gestagen, subdermal implantation, hormonal vaginal ring and transdermal depot patch are all considered safe contraceptives.
Signed statement of consent after receiving oral and written study information
Willingness to participate in the planned treatment and follow-up and capable of handling toxicities.

Exclusion Criteria

A history of prior malignancies. Patients treated for another malignancy can only participate if they are without signs of disease for a minimum of 3 years after last treatment.
Primary brain tumor or verified brain metastases
Known hypersensitivity to one of the active drugs or excipients.
Significant medical conditions, including but not limited to severe asthma/COLD, significant cardiac disease, poorly regulated insulin dependent diabetes mellitus.
Creatinine clearance below 70 ml/min .
Acute or chronic infections with HIV, hepatitis, syphilis etc.
Severe allergies or previous anaphylactic reactions.
Active autoimmune disease, such as autoimmune neutropenia/thrombocytopenia or hemolytic anemia, systemic lupus erythematosus, Sjögren's syndrome, sclerodermia, myasthenia gravis, goodpastures disease, addison's disease, hashimoto's thyroiditis, graves' disease etc.
Pregnant women and women who are breastfeeding.
Simultaneous treatment with systemic immunosuppressive drugs (including prednisolone methotrexate etc.)
Simultaneous treatment with other experimental drugs.
Simultaneous treatment with other systemic anti-cancer treatments.
Patients with active or uncontrollable hypercalcemia.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Tumor-infiltrating Lymphocyte (TIL) Therapy with checkpoint inhibitors	Autologous tumor-infiltrating lymphocytes	-
Tumor-infiltrating Lymphocyte (TIL) Therapy with checkpoint inhibitors	Ipilimumab	-
Tumor-infiltrating Lymphocyte (TIL) Therapy with checkpoint inhibitors	Nivolumab	-
Tumor-infiltrating Lymphocyte (TIL) Therapy with checkpoint inhibitors	proleukin	-
Tumor-infiltrating Lymphocyte (TIL) Therapy with checkpoint inhibitors	Cyclophosphamide	-
Tumor-infiltrating Lymphocyte (TIL) Therapy with checkpoint inhibitors	Fludara	-

Primary Outcome Measures

Name	Time	Method
Number of Participants and Type of Reported Adverse Events	Up to 2,5 years from begin of study	Determine the safety of the administration of TIL therapy including checkpoint inhibitors, lymphodepleting chemotherapy and Interleukin-2 for patients with cancer by reporting grade \>2 adverse events according to CTCAE v. 4.0

Secondary Outcome Measures

Name	Time	Method
Time to Disease Progression	Until study completion	Days of follow-up from TIL infusion until progressive cancer disease, end of follow-up or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Overall Survival	Until study completion	Duration of survival measured in days after adoptive cell therapy until death or end of follow-up/censoring.
Overall Response Rate	The patients were evaluated every 6-12 weeks (median 90 days) and after therapy and until study completion (max 220 days).	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CAT scan: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.