To improve the efficacy of immunotherapy for cancer, recent studies focused on specific targets to redirect the immune network toward eradicating a variety of tumors and ameliorating the self-destructive process. A clinically relevant immune escape mechanism in melanoma is the activation of the Programmed cell Death-1 (PD-1) receptor on infiltrating T cells. By blocking PD-1 receptors with anti-PD-1 monoclonal antibodies (mAbs), T-cells are unaffected by the PD-L1 expressed on tumor cells and the patients T cells are free to respond to melanoma antigens and attack tumor cells. So the objective of this trial is to evaluate the safety and the efficacy of a combined therapy Nivolumab and adoptive T cell therapy in metastatic melanoma patients.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
11
The patients will receive Nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks from day0 until week52. Two TIL (Tumor Infiltrating Lymphocytes) injections will be performed: at week 14 and at week 18. The TIL injections are systematically followed by subcutaneous injections of Proleukin® (IL-2) at a concentration of 6 million international unit (IU) per day for 5 days.
Nantes University Hospital
Nantes, France
RECRUITINGIncidence of Treatment (adoptive T cell therapy associated to intravenous injections of Nivolumab) - Emergent Adverse Events
Clinical and biological criteria defined by the NCI (Common Terminology Criteria for Adverse Events - version 4.0, may 2009, http://ctep.cancer.gov)
Time frame: Within 12 months
Efficacy of adoptive T cell therapy associated to intravenous injections of Nivolumab
The overall tumor response will be evaluated according to the guidelines for Response Evaluation Criteria in Solid Tumors (RECIST1.1) and immune-related Response Criteria (irRC)
Time frame: At 12 months
Duration of the clinical response
Time interval between the evaluation of the first objective response and the first evaluation of disease progression or death, whichever occurs first
Time frame: Within 12 months of follow-up
Progression-free survival
Evaluation of the progression-free survival of patients treated with adoptive T cell therapy in combination with intravenous injections of Nivolumab
Time frame: From the date of the first infusion of Nivolumab until the date of the first documented progression or the date of death from any cause, whichever came first, assessed up to 12 months
Overall survival
Evaluation of the overall survival of patients treated with adoptive T cell therapy in combination with intravenous injections of Nivolumab
Time frame: From the date of the first infusion of Nivolumab until the date of death, assessed up to 12 months
Specific immune monitoring n°1: Evaluate the fraction of TIL specific to Melan-A and MELOE-1
Evaluation of the fraction of TIL specific to two Human Leukocyte Antigen (HLA)-peptide complexes (Melan-A and MELOE-1)
Time frame: Week 14 + week 18
Specific immune monitoring n°2: Evaluate the proportion of regulatory T cells
Evaluation of the proportion of regulatory T cells
Time frame: Day 0 (1st Nivolumab injection) + week 14 + week 18 + week 26 + week 38 + at the date of disease progression assessed up to 12 months
Specific immune monitoring n°3: Analyse the expression of tumor antigens
Analysis of the expression of tumor antigens
Time frame: Week 10 + week 38
Specific immune monitoring n°4: Analyse the expression of immunosuppressive cytokines
Analysis of the expression of immunosuppressive cytokines
Time frame: Week 10 + week 38
Specific immune monitoring n°5: Analyse the expression of indoleamine 2,3-dioxygenase (IDO)
Analysis of the expression of IDO
Time frame: Week 10 + week 38
Specific immune monitoring n°6: Analyse the expression of FoxP3
Analysis of the expression of FoxP3
Time frame: Week 10 + week 38
Specific immune monitoring n°7: Analyse the expression of regulatory molecules
Analysis of the expression of regulatory molecules
Time frame: Week 10 + week 38
Specific immune monitoring n°8: Analyse the mutations of BRAF
Analysis of BRAF mutations
Time frame: Week 10 + week 38
Specific immune monitoring n°9: Analyse the mutations of Neuroblastoma Ras viral oncogene homolog (NRAS)
Analysis of NRAS mutations
Time frame: Week 10 + week 38
Specific immune monitoring n°10: Analyse the mutations of proto-oncogene ckit (cKit)
Analysis of cKit mutations
Time frame: Week 10 + week 38
Specific immune monitoring n°11: Determine the percentage of reactive T cells in the expanded cells
Produce tumor cell line and determine the percentage of reactive T cells in the expanded cells
Time frame: Week 10
Specific immune monitoring n°12: Determine the phenotype of the expanded T cells
Produce tumor cell line and determine the phenotype of the expanded T cells
Time frame: Week 10
Specific immune monitoring n°13: Test TIL reactivity
Produce tumor cell line and test TIL reactivity
Time frame: Week 10
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