Human anti-PSCA CAR macrophages possess potent antitumor activity against pancreatic cancer.

Human-induced pluripotent stem cells (iPSCs) are a promising resource for creating immune cells to treat diseases. However, they haven’t been widely used to make chimeric antigen receptor (CAR) immune cells. CAR-T cells, a type of engineered immune cell, have been groundbreaking in treating blood cancers but haven’t worked as well for solid tumors. This is partly because they struggle to reach and penetrate solid tumors. CAR-T cells also have serious risks, like life-threatening side effects, and are very expensive, limiting their use for solid tumors. To address these challenges, researchers have started exploring CAR macrophages, another type of immune cell as a potential alternative. However, since this field is still in its early stages, progress has been slower compared to CAR-T cells. To help fill this gap, we developed a new type of CAR macrophages derived from iPSCs that target prostate stem cell antigen (PSCA), a protein often found on pancreatic cancer cells. These cells, called CAR-iMacs, were created using a feeder-free method, making the process more efficient. Our CAR-iMacs retained high levels of CAR molecules, which are key for recognizing and attacking cancer cells. The CAR design also included protein called membrane-bound IL-15, that could activate other immune cells, like T cells and natural killer (NK) cells, to boost the immune response. Additionally, we added a safety mechanism to remove the CAR-iMacs if needed. When tested in laboratory experiments and animal models, our CAR-iMacs showed strong, targeted antitumor activity against pancreatic cancer cells. In mice with metastatic pancreatic cancer, these cells significantly reduced tumor size and improved survival without causing noticeable side effects, a major improvement compared to CAR-T cells. In summary, our study introduces a groundbreaking iPSC-based approach to create CAR-iMacs, offering a potentially safer, more effective, and scalable therapy for solid tumors like pancreatic cancer. This platform could eventually be used in clinical treatments to help patients with these hard-to-treat cancers.