Targeting Acute Myeloid Leukemia Using the RevCAR Platform: A Programmable, Switchable and Combinatorial Strategy.

Area of Science:

• Immunotherapy
• Oncology
• Cellular Engineering

Background:

• Clinical application of chimeric antigen receptor (CAR) T-cells for acute myeloid leukemia (AML) faces challenges including immune escape and disease relapse.
• Improvements in CAR design are crucial for effective AML immunotherapy.

Purpose of the Study:

• To introduce and evaluate the novel switchable, flexible, and programmable adaptor Reverse (Rev) CAR platform for targeting myeloid malignancies like AML.
• To demonstrate the efficacy of the RevCAR platform in overcoming limitations of current CAR T-cell therapies.

Main Methods:

• Engineered T-cells with RevCARs, which are initially inactive and require bispecific antibodies for activation and tumor targeting.
• Utilized in vitro and in vivo models to assess RevCAR T-cell activity against AML cell lines and patient-derived AML blasts.
• Investigated combinatorial targeting using Boolean logic gates, specifically a Boolean AND gate targeting strategy.

Main Results:

• The RevCAR platform demonstrated efficient killing of AML cell lines and patient-derived AML blasts by redirected RevCAR T-cells targeting CD33 and CD123.
• The platform enabled flexible targeting of myeloid leukemia cells.
• Achieved Boolean AND gate logic targeting by simultaneously targeting CD33 and CD123 antigens.

Conclusions:

• The RevCAR platform is applicable for targeting myeloid malignancies, including AML.
• This adaptable immunotherapy approach offers a potential solution to immune escape and relapse in AML treatment.
• The RevCAR platform paves the way for improved and personalized immunotherapies for AML patients.