A Phase 1/2 interventional study of Autologous tumor-infiltrating lymphocytes and Ipilimumab in Cancer, sponsored by Inge Marie Svane. Completed at 1 site in Denmark. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2024-10-26.
Sponsored by Inge Marie Svane · Phase 1/2, Interventional, and Treatment
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.
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.
Only patients within the Danish Healthcare system are eligible for enrollment.
Inclusion Criteria:
Exclusion Criteria:
Biological: Autologous tumor-infiltrating lymphocytes · Drug: Ipilimumab · Drug: Nivolumab · Drug: proleukin · Drug: Cyclophosphamide · Drug: Fludara
Tumor-infiltrating lymphocytes grown ex-vivo from resected from cancer tissue and reapplied to the patient via an intravenous infusion.
One treatment with ipilimumab (3 mg/kg) prior to tumor resection.
4 doses of nivolumab. Starting 2 days prior to TIL infusion and every 2 weeks hereafter.
2 MIE s.c. injection, after TIL infusion and continuing for 2 weeks
2 doses (60 mg/kg) prior to TIL infusion
5 doses (25 mg/m2) prior to TIL infusion
Number of Participants and Type of Reported Adverse Events
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
Time frame: Up to 2,5 years from begin of study
Time to Disease Progression
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
Time frame: Until study completion
Overall Survival
Duration of survival measured in days after adoptive cell therapy until death or end of follow-up/censoring.
Time frame: Until study completion
Overall Response Rate
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.
Time frame: The patients were evaluated every 6-12 weeks (median 90 days) and after therapy and until study completion (max 220 days).
| Milestone | All Participants |
|---|---|
| Started | 25 |
| Completed | 25 |
| Not completed | 0 |
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
| Participants | All Participants |
|---|---|
| Neutropenia | 25 |
| Trombocytopenia | 22 |
| Anemia | 22 |
| Infection | 6 |
| Hyponatremia | 2 |
| Hemorrhagic cystitis | 1 |
| Fatique | 6 |
| Vertigo | 1 |
| Performance status drop | 4 |
| Thrombosis | 1 |
| Fever | 16 |
| Dyspnea | 6 |
| Hepatitis | 2 |
| Colitis | 2 |
| Transaminase elevation | 2 |
| Vomiting | 2 |
| Hallucination | 1 |
| Elevated creatinine | 1 |
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
| Days | Treated Participants |
|---|---|
| Time to Disease Progression | 89 (12 to 211) |
Duration of survival measured in days after adoptive cell therapy until death or end of follow-up/censoring.
| Days | Treated Participants |
|---|---|
| Overall Survival | 227 (50 to 870) |
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.
| Participants | Treated Participants |
|---|---|
| Overall Response Rate | 2 |
Collected over The data was collected throughout the duration of the clinical trial. From October 2017 and until study Completion in july, 2020. For the individual patient, the reporting started at the study enrolment and ended with study exclusion but with a minimum of 6 months follow-up after the adoptive cell therapy or until study completion. Information on adverse events were collected every 6 weeks for the first 3 months and every 3 months hereafter.. Non-serious events are listed at a 4% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Treated Participants | 23/25 (92%) | 9/25 (36%) | 25/25 (100%) |
| Event | Treated Participants |
|---|---|
| ColitisGastrointestinal disorders | 2/25 |
| Elevated bilirubinHepatobiliary disorders | 1/25 |
| Urinary tract infectionInfections and infestations | 1/25 |
| Refractory trombocytopeniaBlood and lymphatic system disorders | 1/25 |
| ChylosSkin and subcutaneous tissue disorders | 1/25 |
| Neutropenic feverInfections and infestations | 1/25 |
| Thrombosis in central katheterBlood and lymphatic system disorders | 1/25 |
| Upper respiratory tract infectionInfections and infestations | 1/25 |
| Addisions crisisGeneral disorders | 1/25 |
| DyspneaRespiratory, thoracic and mediastinal disorders | 1/25 |
| Event | Treated Participants |
|---|---|
| NeutropeniaBlood and lymphatic system disorders | 25/25 |
| NauseaGeneral disorders | 24/25 |
| TrombocytopeniaBlood and lymphatic system disorders | 23/25 |
| Febrile neutropeniaGeneral disorders | 23/25 |
| AnemiaBlood and lymphatic system disorders | 22/25 |
| FatigueGeneral disorders | 20/25 |
| FeverGeneral disorders | 18/25 |
| DyspneaRespiratory, thoracic and mediastinal disorders | 15/25 |
| Oral mucositisInfections and infestations | 14/25 |
| VomitingGastrointestinal disorders | 12/25 |
Patients who received TIL therapy
| Age, Categorical(Participants) | All Participants |
|---|---|
| <=18 years | 0 |
| Between 18 and 65 years | 22 |
| >=65 years | 3 |
| Sex: Female, Male(Participants) | All Participants |
|---|---|
| Female | 14 |
| Male | 11 |
| Race and Ethnicity Not Collected(Participants) | All Participants |
|---|
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Inge Marie Svane