Abstract
Chimeric antigen receptor (CAR) T cell therapy has shown unprecedented success in treating advanced hematological malignancies. Its effectiveness in solid tumors has been limited due to heterogeneous antigen expression, a suppressive tumor microenvironment, suboptimal trafficking to the tumor site and poor CAR T cell persistence. Several approaches have been developed to overcome these obstacles through various strategies including the genetic engineering of CAR T cells to blunt the signaling of immune inhibitory receptors as well as to modulate signaling of cytokine/chemokine molecules and their receptors. In this review we offer our perspective on how genetically modifying cytokine/chemokine molecules and their receptors can improve CAR T cell qualities such as functionality, persistence (e.g. resistance to pro-apoptotic signals) and infiltration into tumor sites. Understanding how such modifications can overcome barriers to CAR T cell effectiveness will undoubtedly enhance the potential of CAR T cells against solid tumors.
Highlights
Surgery, chemotherapy and radiation therapy have been the principal cornerstones of cancer treatment since the middle of the last century
Despite the advancement in the treatment of blood cancers with Chimeric antigen receptor (CAR) T cells, treating solid tumors has been challenging in part due to heterogeneous tumor antigen expression, the presence of immunosuppressive and hostile tumor microenvironment (TME) that exacerbates CAR T cell exhaustion and apoptosis, and insufficient infiltration into the tumor sites [5,6,7]
There are other strategies such as inverted cytokine receptors (ICRs) in which ectodomain of inhibitory cytokine is fused with endodomain of immunostimulatory cytokines [22], and membrane tethered cytokines that can be transferred via viral transduction or sleeping beauty (SB) system (Table 1) [34, 46].In this review we discuss how employing various genetic strategies like incorporating dominant negative receptors, inverted cytokine receptors and immunostimulatory cytokines can diminish and/or reverse negative CAR T cell regulators in the tumor microenvironment and can augment positive regulators of CAR T cells in solid tumors
Summary
Chemotherapy and radiation therapy have been the principal cornerstones of cancer treatment since the middle of the last century. Despite the advancement in the treatment of blood cancers with CAR T cells, treating solid tumors has been challenging in part due to heterogeneous tumor antigen expression, the presence of immunosuppressive and hostile tumor microenvironment (TME) that exacerbates CAR T cell exhaustion and apoptosis, and insufficient infiltration into the tumor sites [5,6,7] It is well-recognized that cytokines, chemokines and their receptors play pivotal roles in regulating the functional and phenotypic features of CAR T cells; influencing parameters such as persistence, trafficking, memory cell formation and proliferation. Binding of sgRNA to targeted gene activates CAS9 endonuclease which leads to cleavage and knocking out of the target gene [13, 14] Another example is incorporation of truncated cytokine receptors into CAR T cells (through viral transduction) which lack a specific intracellular domain. There are other strategies such as inverted cytokine receptors (ICRs) in which ectodomain of inhibitory cytokine is fused with endodomain of immunostimulatory cytokines [22], and membrane tethered cytokines that can be transferred via viral transduction or sleeping beauty (SB) system (excision and insertion of SB transposon into TA dinucleotide repeat of target-cell genome) (Table 1) [34, 46].In this review we discuss how employing various genetic strategies like incorporating dominant negative receptors, inverted cytokine receptors and immunostimulatory cytokines can diminish and/or reverse negative CAR T cell regulators in the tumor microenvironment and can augment positive regulators of CAR T cells (e.g. proliferation and persistence) in solid tumors
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call