Background CAR T cell therapy has had a tremendous impact on the treatment of cancer, specifically hematological cancers. However, it has become clear that many cancers so far remain intractable with this therapeutic modality, for example solid tumors. In addition, many patients exhibit adverse events such as CRS and ICANS which can be severe as well as secondary malignancies. To address these issues Portal is investigating both RNA-based and genomic editing technologies (e.g. CRISPR/Cas9) to design cellular therapies (T and NK cell) with customized functionalities. One of the key advantages of these new technologies is their highly adaptable nature that enables sophisticated cellular engineering, rational design and rapid pursuit of new therapeutic targets.

Methods At Portal, we have developed a gentle silicon membrane-based delivery technology that facilitates mechanoporation of cells and can be easily integrated with existing clinical-scale workflows. Our results in primary immune cells using T and NK cells demonstrate high efficiency and viability of cellular engineering.

Results CRISPR/Cas9 RNPs, mRNAs, circular RNAs, and siRNAs have been successfully delivered as single cargos or in a multiplexed fashion, demonstrating the potential for either single- or multi-step cell engineering workflows which can address several targets. This technology is currently being implemented for research and clinical scale use - including in an integrated Point-of-Care manufacturing system.

Conclusions With continued progress in simplifying cell engineering using both RNA-based and genomic editing technologies, we aim to unlock vast biological potential in the field of cancer immunotherapy while simultaneously reducing or even eliminating safety or manufacturing concerns such as inadvertent genome alteration associated with other delivery modalities such as lentiviral vectors.