TY - JOUR
T1 - Perspectives on chimeric antigen receptor T-cell immunotherapy for solid tumors
AU - Kosti, Paris
AU - Maher, John
AU - Arnold, James N.
PY - 2018/5/22
Y1 - 2018/5/22
N2 - Chimeric antigen receptor (CAR) T-cell therapy entails the genetic engineering of a patient's T-cells to express membrane spanning fusion receptors with defined specificities for tumor-associated antigens. These CARs are capable of eliciting robust T-cell activation to initiate killing of the target tumor cells. This therapeutic approach has produced unprecedented clinical outcomes in the treatment of "liquid" hematologic cancers, but to date has not produced comparable responses in targeting solid malignancies. Advances in our understanding of the immunobiology of solid tumors have highlighted several hurdles which currently hinder the efficacy of this therapy. These barriers include the insufficient accumulation of CAR T-cells in the tumor due to poor trafficking or physical exclusion and the exposure of infiltrating CAR T-cells to a panoply of immune suppressive checkpoint molecules, cytokines, and metabolic stresses that are not conducive to efficient immune reactions and can thereby render these cells anergic, exhausted, or apoptotic. This mini-review summarizes these hurdles and describes some recent approaches and innovations to genetically re-engineer CAR T-cells to counter inhibitory influences found in the tumor microenvironment. Novel immunotherapy drug combinations to potentiate the activity of CAR T-cells are also discussed. As our understanding of the immune landscape of tumors improves and our repertoire of immunotherapeutic drugs expands, it is envisaged that the efficacy of CAR T-cells against solid tumors might be potentiated using combination therapies, which it is hoped may lead to meaningful improvements in clinical outcome for patients with refractory solid malignancies.
AB - Chimeric antigen receptor (CAR) T-cell therapy entails the genetic engineering of a patient's T-cells to express membrane spanning fusion receptors with defined specificities for tumor-associated antigens. These CARs are capable of eliciting robust T-cell activation to initiate killing of the target tumor cells. This therapeutic approach has produced unprecedented clinical outcomes in the treatment of "liquid" hematologic cancers, but to date has not produced comparable responses in targeting solid malignancies. Advances in our understanding of the immunobiology of solid tumors have highlighted several hurdles which currently hinder the efficacy of this therapy. These barriers include the insufficient accumulation of CAR T-cells in the tumor due to poor trafficking or physical exclusion and the exposure of infiltrating CAR T-cells to a panoply of immune suppressive checkpoint molecules, cytokines, and metabolic stresses that are not conducive to efficient immune reactions and can thereby render these cells anergic, exhausted, or apoptotic. This mini-review summarizes these hurdles and describes some recent approaches and innovations to genetically re-engineer CAR T-cells to counter inhibitory influences found in the tumor microenvironment. Novel immunotherapy drug combinations to potentiate the activity of CAR T-cells are also discussed. As our understanding of the immune landscape of tumors improves and our repertoire of immunotherapeutic drugs expands, it is envisaged that the efficacy of CAR T-cells against solid tumors might be potentiated using combination therapies, which it is hoped may lead to meaningful improvements in clinical outcome for patients with refractory solid malignancies.
KW - Chimeric antigen receptor
KW - Immunotherapy
KW - Solid tumor
KW - T-cells
KW - Tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85047325359&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2018.01104
DO - 10.3389/fimmu.2018.01104
M3 - Short survey
AN - SCOPUS:85047325359
SN - 1664-3224
VL - 9
JO - Frontiers in Immunology
JF - Frontiers in Immunology
IS - MAY
M1 - 1104
ER -