Combination of an Anti-PD1 Antibody With Tisagenlecleucel Reinfusion in Children, Adolescents and Young Adults With Acute Lymphoblastic Leukemia After Loss of Persistence

Inclusion Criteria:

* Patients aged from 1 to 25 years (pediatric and young adults) with a history of CD19+ relapsed or refractory B-ALL (any relapse after HSCT, 2nd relapse or later, refractory ALL).
* Patient must have a second tisagenlecleucel (Kymriah ®) product available
* Cohort 1: previously treated by tisagenlecleucel (Kymriah ®), and who present an early loss of B-cell aplasia defined by blood B lymphocytes \< 10 /mm3 and/ or \< 3% of total lymphocytes (\< 6 months after infusion) while still being in CR with undetectable MRD
* Cohort 2: previously treated by tisagenlecleucel (Kymriah ®), who present a loss of B-cell aplasia defined by blood B lymphocytes \< 10 /mm3 and/ or \< 3% of total lymphocytes and a CD19+ ALL detectable disease in the marrow and/or Blood
* Life expectancy \> 12 weeks.
* Karnofsky (age \> 16) Lansky (age \< 16) \> 70 at screening.
* No organ dysfunction
* Who have signed an informed consent
* Affiliation to social security or any health insurance (as a beneficiary or assignee)

Exclusion Criteria:

* Patient has received intervening therapy for leukemia after first tisagenlecleucel infusion (chemotherapy, anti leukemic immunotherapy, ITK, allogeneic HSCT).
* Patient has an active autoimmune disease requiring systemic treatment within the past 2 years.
* Patient has known history of, or any evidence of active, non-infectious pneumonitis.
* Patient has a history of non-infectious pneumonitis that required steroid or has current pneumonitis.
* Had receive prior therapy with an anti-PD1, Anti- PDL1 or anti-PDL2 agent.
* Patient has hypersensivity to pembrolizumab/ nivolumab or one of its excipients
* Patient has received a live vaccine injection within 45 days of planned start of study therapy.
* Patients with concomitant genetic syndromes associated with bone marrow failure states: such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down syndrome will not be excluded.
* Patients with Burkitt's lymphoma/leukemia
* Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
* Prior treatment with any gene therapy product except first tisagenlecleucel (Kymriah ®) injection.
* Prior treatment with any anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy, except for patients pre-treated with blinatumomab and/or tisagenlecleucel (Kymriah®)
* Prior anti-cancer monoclonal antibody within 4 weeks before starting the study.
* Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade1 or at baseline) from adverse events due to a previously administered agent.
* Active or latent hepatitis B or active hepatitis C (test within 8 weeks of Screening), or any uncontrolled infection at Screening.
* Human immunodeficiency virus (HIV) positive test within 8 weeks of Screening.
* Presence of grade 2 to 4 acute or extensive chronic GVHD.
* Active CNS involvement by malignancy, defined as CNS-3 per NCCN guidelines. Note: Patients with history of CNS disease that has been effectively treated will be eligible.
* Uncontrolled acute life threatening bacterial, viral or fungal infection at Screening.
* Previous or concurrent malignancy with the following exceptions:

  * Adequately treated basal cell or squamous cell carcinoma
  * in situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study.
  * A primary malignancy completely resected and in CR for ≥ 5 years
* Pregnant or lactating women (female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion)
* Patient with hypersensivity to Fludarabine and/or cyclophosphamide and/or tisagenlecleucel and/or nivolumab or one of their excipients.