Improved Chimeric Antigen Receptor Therapies B-cell Malignancies

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In the past year, we have designed and selected an optimal bicistronic CAR construct that targets both CD19 and CD20. The bicistronic construct encodes 2 CARs, one of the CARs is the previously -described Hu19-CD828Z CAR. The second CAR is an anti-CD20 CAR designated Hu20-CD8BBZ. The entire bicistronic construct is designated Hu19-CD828-Hu20BB, and the construct is encoded by a gammaretroviral vector. We plan to start a clinical trial with bicistronic CAR designs targeting CD19 and CD20 in late 2022. We have spent extensive time optimizing the DNA sequence of the bicistronic vector to eliminate deletion events driven by homologous DNA sequences. We have an optimized gene therapy vector that has been produced under GMP conditions. An IND will be submitted to the FDA very soon. We have also prepared a producer cell clone that generates a gamma-retrovirus encoding the Hu19-CD828Z anti-CD19 CAR. GMP-grade vector has been produced from this master cell bank. We plan to use this vector in a clinical trial that will enroll CLL patients. Substantial time and effort has been expended in the past year to prepare required regulatory documents for the two upcoming clinical trials. We have also carried out experiments to examine the impact of cytokines on CAR toxicity including the role of corticosteroids, which are used to treat CAR T-cell toxicity on CAR T cells.