Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity

Mol Ther. 2021 Jul 7;29(7):2335-2349. doi: 10.1016/j.ymthe.2021.02.024. Epub 2021 Feb 27.


Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its effectiveness in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate and pancreas cancer, including those targeting prostate stem cell antigen (PSCA), are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human PSCA knockin (hPSCA-KI) immunocompetent mouse model, we evaluated the safety and therapeutic efficacy of PSCA-CAR T cells. We demonstrated that cyclophosphamide (Cy) pre-conditioning significantly modified the immunosuppressive TME and was required to uncover the efficacy of PSCA-CAR T cells in metastatic prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous expression of PSCA. This combination dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, as well as endogenous and adoptively transferred T cells, resulting in long-term anti-tumor immunity.

Keywords: adoptive cellular immunotherapy; chimeric antigen receptor; cyclophosphamide; immunosuppression; pancreatic cancer; pre-conditioning; prostate cancer; prostate stem cell antigen; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, Neoplasm / genetics
  • Apoptosis
  • Cell Proliferation
  • Cyclophosphamide / pharmacology*
  • GPI-Linked Proteins / antagonists & inhibitors
  • GPI-Linked Proteins / genetics
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myeloablative Agonists / pharmacology
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / genetics
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / therapy*
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / therapy*
  • Tumor Cells, Cultured
  • Tumor Microenvironment*
  • Xenograft Model Antitumor Assays


  • Antigens, Neoplasm
  • GPI-Linked Proteins
  • Myeloablative Agonists
  • Neoplasm Proteins
  • PSCA protein, human
  • Cyclophosphamide