Clinical Trial Update: Gene-edited CAR T Therapies
This week’s clinical update looks at 3 clinical trials for CRISPR-edited CAR T therapies for the treatment of B-cell cancers or multiple myeloma (MM).
The 3 new therapies are developed by Bioray Laboratories, a Shanghai-based company focused on gene and cell-based therapies, and all 3 trials are seeking to evaluate the safety and efficacy of novel therapies that are either engineered to target the cell surface antigen CD19 or the B cell maturation antigen (BCMA).
CD19 is expressed on the surfaces of all B-cell cancers, a feature that has made it a highly attractive target for cancer immunotherapy. The first two CAR-T therapies to be approved in 2017 target CD19 and many more are in development for relapsed or refractory B-cell cancers such as leukaemia and lymphoma. BCMA is a cell surface protein universally expressed on malignant plasma cells and it has become a major target for MM.
Quikin: a CD19-CAR T Therapy for Relapsed or Refractory B-Cell Lymphoma
The first trial is for Quikin, a CD19-targeting and PD1 knockout autologous CAR T-cell therapy, where CRISPR-Cas9 gene-editing technology is used to knock out the PD-1 gene and engineer the anti-CD19 chimeric antigen receptor (CAR). PD-1 encodes the PD-1 protein which functions as a safety switch on T cells that cancer cells turn on to protect themselves from T cell-mediated immune responses. PD-1 disruption is sometimes included in CAR T-cell development to enhance anti-tumour activity.
The trial, which is still recruiting, is a non-randomised, open label, single-site study that aims to enroll 20 adult participants with relapsed or refractory B-cell lymphoma.
During the trial, participants will undergo leukapheresis (white blood cell isolation), the cells will be CRISPR-engineered and then transfused intravenously back into patients in 1 of 3 acscending doses. Four to six days before dosing, participants will undergo lymphodepletion with cyclophosphamide and fludarabine to deplete endogenous T cells. This step is widely included in CAR T treatment regimens as an attempt to prolong the persistence of infused cells and thereby increase the effectiveness of the treatment.
The primary outcome measure is an assessment of dose-limiting toxicity, i.e. identifying potential side effects of the therapy that are serious enough to prevent additional or increased dosing. Secondary outcome measures include evaluating the anti-tumour response and progress free survival at 3 months post-treatment using disease-specific parameters.
The estimated study completion date is April 2022. After completion of study treatment, subject participation for this study will be followed up to 15 years.
CD19-UCART for the Treatment of Relapsed or Refractory B Cell Cancer
The next trial is for CD19-UCART, an "off-the-shelf" CAR T therapy that is developed from donor-derived peripheral blood mononuclear cells (PBMCs).
The trial is an open-label, dose escalation study to evaluate the safety and anti-tumor efficacy of CD19-UCART in the treatment of relapsed or refractory acute lymphoblastic leukaemia (ALL) and non hodgkin lymphoma (NHL).
The study will enroll twenty participants from 6 to 65 years of age, split into participants aged 6 to 30 years with ALL and participants aged 16 to 65 years with NHL. Each participant will receive a single intravenous injection of CD19-UCART cells at 1 of 3 ascending doses. Prior to dosing, partipicants will undergo lymphodepletion therapy.
The primary study outcome is to assess dose-limiting toxicities i.e. adverse events related to the administered doses. Secondary outcomes include evaluation of partial or complete anti-cancer response according to disease-specific parameters and the duration of persistence of the CD19-UCART cells after infusion via flow cytometry or quantitative PCR methods. The expected study completion date is December 2022.
BCMA-UCART for the Treatment of Relapsed or Refractory Multiple Myeloma
The last trial in this week’s update concerns a BCMA-targeting CAR T-cell therapy that is developed to treat relapsed or refractory multiple myeloma. This therapy, called BCMA-UCART, is generated from healthy donor-derived T cells.
This open-label, dose-escalation study aims to evaluate the safety and anti-tumor efficacy of BCMA-UCART in 20 adult participants, each of whom will receive a single intravenous injection of BCMA-UCART cells at 1 of 3 acsending doses, following a preconditioning lymphodepletion treatment.
The primary study measure will examine the objective response rate up to 90 days post-treatment. Patients will be assessed for either partial or complete response in accordance with standard disease-specific criteria for MM. Secondary outcome measures encompass 1) an assessment of adverse events as a measure of safety and tolerability of the new therapy, in the period up to 35 days post-treatment, and 2) assessment of the persistence of BCMA-UCART cells at up to 1 year post-treatment; this will be evaluated via flow cytometry or quantitative PCR methods.
The expected study completion date is November 2023.
For a complete overview of current gene editing clinical trials, check out CRISPR Medicine News' Clinical Trials Database.
First Affiliated Hospital of Guangdong Pharmaceutical University
The First Affiliated Hospital of Guangdong Pharmaceutical University