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

Overview

This is a single center, open label, phase 1 lead in to determine Recommended Phase 2 Dose (RP2D), followed by a phase 2 trial to evaluate the safety and efficacy of Epo-R-CD19 CAR T with or without CD22 CAR T-cells infused into patients with B cell lymphoma. The study will have the following parts: * Screening * Pre-infusion (cell product preparation and bridging) and infusion (lymphodepletion) * Primary efficacy endpoints * Long term follow up Patients who have high risk B cell lymphoma or relapsed/refractory B cell lymphoma who fufil the trial inclusion and exclusion criteria will undergo leukapheresis following trial enrollment. CAR T-cell products will then be manufactured according to the antigen expression on the patient's biopsied tumor cells. These cells will then undergo stringent testing before the patient undergoes lymphodepletion followed by CART infusion. These patients will be admitted for the infusion and closely monitored for any CRS or ICANS. This study will have a Phase 1 safety run in for the first 3-6 patients who receive the Epo-R-CD19 CAR T (with or without epoetin (erythropoietin)) to determine the tolerability and safety of this product. For the first 3-6 patients, if there are any DLT seen by Day 28, a data safety monitoring committee will be convened to assess the trial. Staggered dosing will be implemented for the first 2 participants in every dose level (DL1, DL2 and DL-1). For Phase 2, the RP2D will depend on DLT. If there is no DLT at DL+1 and DL+2, then the investigators will proceed with DL+2 as the RP2D dose. On the other hand, if there is DLT despite DL-1, then the study will be redesigned. Phase 2 will continue until a total of 20 patients received their CAR T-cell infusions. CAR-T monitoring will be performed at Day 0, 7, 14, 21, 28, month 2, 3, 4, 5, 6, 12 and yearly thereafter. The total duration of the study is 15 years from CAR T infusion.

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.