Antigen Targeted T Cell Therapy for Relapsed/Refractory B Cell Lymphomas

2.1 Hypothesis 1. The infusion of CD19 with or without CD 22 targeted CAR T-cells in patients with high risk or R/R BCL will improve the overall response rates and survival outcomes. The choice of antigen target is determined by detailed flow cytometric profiling of biopsied lymphoma cells if possible. 2. The co-expression of Epo-R in our CD19 CAR T-cells will allow endogenous or exogenous Epo levels to support survival and expansion of infused T cells, thus overcoming the issue of suboptimal T-cell expansion and persistence due to prior chemotherapies in patients with high risk or R/R DLBCL. 2.2 Objectives for Phase 1: Primary objective of Phase 1 lead in is to determine safety, as defined by incidence of dose limiting toxicities (DLT) associated to the Epo-R-CD19 CAR and CD22 pooled products, as well as determination of the RP2D of the Epo-R-CD19 The secondary objective is to assess efficacy of the Epo-R-CD19 CAR as defined by: i) Percentage of patients who achieve peak CAR T level within Month 1 \> 30 CD 19 CAR-T cells/uL ii) Proportion of patients who achieved no evidence of disease as determined PET-CT using the Lugano criteria at 1 month and the best overall response by 6 months as assessed by PET-CT (Lugano criteria). 2.3 Objectives For Phase 2: The primary objective of Phase 2 is efficacy. The primary endpoints are: a. To determine the efficacy of a single Epo-R-CD19 CAR T-cell or a pool of CAR T-cells targeting CD19 and CD22 antigens based on detailed flow cytometric profiling of high risk or R/R BCL patients. The efficacy is determined by the proportion of patients who achieved no evidence of disease as determined PET-CT using the Lugano criteria at 1 month and the best overall response by 6 months as assessed by PET-CT (Lugano criteria). Our secondary endpoints are: 1. To determine the safety of the Epo-R-CD19 and CD22. The investigators will collect data on CAR T related toxicities: This includes incidence of dose limiting toxicities (Section 5), treatment related adverse events (Section Table 4.9) and adverse events of special interest (Section 2.5). 2. To determine the peripheral blood levels of CAR CD19 and CD22 at D0, D5, D7, D14, D21 and 1 month, 3 months, 6 months, 1 year and 2 years. The investigators will compare our Epo-R-CD19 CAR T-cell levels against CD22 and published commercial CAR T expansion. 3. To study the 1-year Event free survival defined by any event involving disease recurrence or persistence disease at 6 months, death from any cause. Planned HSCT, after CAR T infusion, is not an event 4. To study the 1-year Overall Survival 5. Cumulative risk of relapse (CIR), defined as proportion of patients surviving 1-year after CAR T-cell infusion.