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

Zahir Shah; Lei Tian; Zhixin Li; Lewei Jin; Jianying Zhang; Zhenlong Li; Tasha Barr; Hejun Tang; Mingye Feng; Michael A Caligiuri; Jianhua Yu

doi:10.1016/j.stem.2024.03.018

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

Cell Stem Cell. 2024 Apr 17:S1934-5909(24)00124-3. doi: 10.1016/j.stem.2024.03.018. Online ahead of print.

Authors

Zahir Shah¹, Lei Tian¹, Zhixin Li¹, Lewei Jin¹, Jianying Zhang², Zhenlong Li¹, Tasha Barr¹, Hejun Tang¹, Mingye Feng³, Michael A Caligiuri⁴, Jianhua Yu⁵

Affiliations

¹ Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA.
² Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA 91010, USA.
³ Department of Immuno-Oncology, City of Hope, Los Angeles, CA 91010, USA.
⁴ Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA; City of Hope Comprehensive Cancer Center, Los Angeles, CA 91010, USA. Electronic address: mcaligiuri@coh.org.
⁵ Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Department of Immuno-Oncology, City of Hope, Los Angeles, CA 91010, USA; City of Hope Comprehensive Cancer Center, Los Angeles, CA 91010, USA. Electronic address: jiayu@coh.org.

PMID: 38663406
DOI: 10.1016/j.stem.2024.03.018

Abstract

Due to the limitations of autologous chimeric antigen receptor (CAR)-T cells, alternative sources of cellular immunotherapy, including CAR macrophages, are emerging for solid tumors. Human induced pluripotent stem cells (iPSCs) offer an unlimited source for immune cell generation. Here, we develop human iPSC-derived CAR macrophages targeting prostate stem cell antigen (PSCA) (CAR-iMacs), which express membrane-bound interleukin (IL)-15 and truncated epidermal growth factor receptor (EGFR) for immune cell activation and a suicide switch, respectively. These allogeneic CAR-iMacs exhibit strong antitumor activity against human pancreatic solid tumors in vitro and in vivo, leading to reduced tumor burden and improved survival in a pancreatic cancer mouse model. CAR-iMacs appear safe and do not exhibit signs of cytokine release syndrome or other in vivo toxicities. We optimized the cryopreservation of CAR-iMac progenitors that remain functional upon thawing, providing an off-the-shelf, allogeneic cell product that can be developed into CAR-iMacs. Overall, our preclinical data strongly support the potential clinical translation of this human iPSC-derived platform for solid tumors, including pancreatic cancer.

Keywords: cancer immunotherapy; chimeric antigen receptor; cytokine release syndrome; human induced pluripotent stem cells; macrophages; off-the-shelf; pancreatic cancer; prostate stem cell antigen; solid tumor.