Bispecific CD19/CD22 CAR-T for Treatment of Children and Young Adults With r/r B-ALL

The main objectives of the study are:

• To investigate the incidence of adverse events of grade 3-5 within after CD19/CD22 CAR lymphocyte infusion by day 28,
• To evaluate the incidence of complete remission and MRD-negative CR by day 28
• To evaluate the long-term effectiveness of CD19/CD22 CAR-T therapy (cumulative incidence of relapse, event-free survival, overall survival) at 1, 2, and 5 years after infusion.
• To evaluate the persistence of CD19/CD22 CAR-T cells and duration of B-cell aplasia (<1% B-cells in the blood) and hypogammaglobulinemia In order to prevent the development of CRS, all patients will receive an infusion of tocilizumab at 8 mg/kg body weight on day 0 before CAR-T cells infusion.

Step-down and step-up dosing will be used to adapt the trial to the scenario of excess toxicity and/or suboptimal effect. Reevaluation of dosing will be done for each cohort separately after the enrollment 5th study subject reaches day 28 or earlier if the threshold for excess toxicity or suboptimal effect is achieved.

Based on interim analysis in March 2021 after the enrollment 5th study subject reaches day 28 study population will be divided into three cohorts:

• CD19-positive (both CD19 and CD22 expressed on over 50% of leukemia cells), low and high disease burden.
• CD19-negative (CD22 expressed on over 50% of leukemia cells) low and high disease burden;
• Allogeneic HSCT+ allogeneic CAR-T cohort

Inclusion criteria

• Ability to give informed consent (for patients > 14 years old). For subjects < 18 years old their legal guardian must give informed consent
• CD19 or CD22 expression must be detected on greater than 50% of leukemic cells by flow cytometry
• Presence of a measurable mass of tumor cells in the bone marrow or extramedullary sites at the time of patient's inclusion in the study
• Patients with relapsed or refractory CD19 and CD22-expressing B-cell ALL:

• Induction failure
• MRD ≥ 0,1% after 2nd chemotherapy course for high-risk group patients.
• First bone marrow or combined relapse of acute lymphoblastic leukemia, no CR or MRD ≥ 0,1% after 1-course 2nd line therapy
• Second and further relapse of ALL
• Relapse or MRD ≥ 0,1% of ALL after hematopoietic stem cell transplant (> 60 days post alloHSCT)o There must be no available alternative approved curative therapies
• Patient Clinical Performance Status: Karnofsky >50% or Lansky >50%
• Patient Life Expectancy > 4 weeks
• Patients recovered from acute toxic effects of prior chemotherapy, immune- or radiotherapy
• Patient absolute blood naïve (CD45RA+) T-lymphocyte count ≥ 50/mm3
• Patient cardiac function left ventricular ejection fraction greater than or equal to 40% by MUGA or cardiac MRI, or fractional shortening greater than or equal to 28% by ECHO or left ventricular ejection fraction greater than or equal to 50% by ECHO.
• Patients who agree to long-term follow up for up to 5 years (if received CD19/CD22 CAR-T cell infusion)
• March 2021 amendment: Healthy HLA-matched related or haploidentical donor (only for HSCT cohort)

Exclusion criteria

• <50% expression of both CD19 and CD22 on the leukemic population
• Active (detectable viremia) hepatitis B, C or HIV infection
• Oxygen saturation ≤ 90%
• Bilirubin >3x upper norma limit
• Creatinine >3x upper norma limit
• Active acute GVHD overall grade ≥2 (Seattle criteria)
• Moderate/severe chronic GVHD (NIH consensus) requiring systemic steroids
• Clinical signs of grade > 3 CNS disorders (seizure disorder, paresis, aphasia, cerebrovascular, ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder)
• Pregnant or lactating women.
• Active (unresolved) severe infection