B Cell Lymphoma Clinical Trial
Official title:
Phase I/II Study to Determine the Safety, Tolerability, Biological Activity and Efficacy of Universal CRISPR-Cas9 Gene-Editing CAR-T Cells Targeting CD19(UCART019) in Patients With Relapsed or Refractory CD19+ Leukemia and Lymphoma
Autologous T cells engineered to express chimeric antigen receptors (CARs) against leukemia
antigens such as CD19 on B cells have shown promising results for the treatment of relapsed
or refractory B-cell malignancies. However, a subset of cancer patients especially heavily
pretreated cancer patients could be unable to receive this highly active therapy because of
failed expansion. Moreover, it is still a challenge to manufacture an effective therapeutic
product for infant cancer patients due to their small blood volume. On the other hand, the
inherent characters of autologous CAR-T cell therapy including personalized autologous T
cell manufacturing and widely "distributed" approach result in the difficulty of
industrialization of autologous CAR-T cell therapy. Universal CD19-specific CAR-T
cell(UCART019),derived from one or more healthy unrelated donors but could avoid
graft-versus-host-disease (GVHD) and minimize their immunogenicity, is undoubtedly an
alternative option to address above-mentioned issues. We have generated gene-disrupted
allogeneic CD19-directed BBζ CAR-T cells (termed UCART019) by combining the lentiviral
delivery of CAR and CRISPR RNA electroporation to disrupt endogenous TCR and B2M genes
simultaneously and will test whether it can evade host-mediated immunity and deliver
antileukemic effects without GVHD.
The main goal of the phase 1 portion of this phase 1/2 trial is to evaluate the safety and
tolerability of several doses of UCART019 in patients with relapsed or refractory CD19+
leukemia and lymphoma, so as to establish the recommended dose and/or schedule of UCART019
for phase 2 portion. The recommended Phase 2 dose will be defined as the highest dose level
of UCART019 that induced DLT in fewer than 33% of patients (i.e., one dose level below that
which induced DLT in at least two of six patients). Phase 2 portion of the trial will not be
initiated until the recommended Phase 2 dose is determined. In the phase 2 portion of this
trial, we will mainly determine if UCART019 help the body's immune system eliminate
malignant B-cells. Safety of UCART019 and impact of this treatment on survival will also be
observed.
PRIMARY OBJECTIVES:
1. To evaluate the feasibility and safety of UCART019 in patients with relapsed or
refractory CD19+ leukemia and lymphoma.
2. To evaluate the duration of in vivo persistence of adoptively transferred T cells, and
the phenotype of persisting T cells. Real Time polymerase chain receptor (RT-PCR)
analysis of peripheral blood(PB), bone marrow(BM) and lymph node will be used to detect
and quantify survival of UCART019 over time.
SECONDARY OBJECTIVES:
1. For patients with detectable disease, measure anti-tumor response due to UCART019 cell
infusions.
2. Determine if cellular or humoral host immunity develops against the murine anti-CD19,
and assess correlation with loss of detectable UCART019 (loss of engraftment).
OUTLINE: This is a phase I, dose-escalation study of allogeneic CD19 CAR-T-cells followed by
a phase II study.
The UCART019 will be administered by i.v. injection over 20-30 minutes as a using a "split
dose" approach to dosing: 10% on day 0, 30% on day 1 and 60% on day 2.
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