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 ofCD19+ 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 anearly 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 withundetectable MRD

• Cohort 2: previously treated by tisagenlecleucel (Kymriah ®), who present a loss ofB-cell aplasia defined by blood B lymphocytes < 10 /mm3 and/ or < 3% of totallymphocytes 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 orassignee)

Exclusion Criteria:

• Patient has received intervening therapy for leukemia after first tisagenlecleucelinfusion (chemotherapy, anti leukemic immunotherapy, ITK, allogeneic HSCT).

• Patient has an active autoimmune disease requiring systemic treatment within thepast 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 hascurrent 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 ofstudy therapy.

• Patients with concomitant genetic syndromes associated with bone marrow failurestates: such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndromeor any other known bone marrow failure syndrome. Patients with Down syndrome willnot be excluded.

• Patients with Burkitt's lymphoma/leukemia

• Prior malignancy, except carcinoma in situ of the skin or cervix treated withcurative 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 2weeks 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 ofScreening), 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 beeligible.

• Uncontrolled acute life threatening bacterial, viral or fungal infection atScreening.

• 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 withoutevidence 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 potentialmust have a negative serum or urine pregnancy test performed within 48 hours beforeinfusion)

• Patient with hypersensivity to Fludarabine and/or cyclophosphamide and/ortisagenlecleucel and/or nivolumab or one of their excipients.