Biomedicine Xagena
Chimeric antigen receptor ( CAR ) T cell immunotherapy has demonstrated profound results in hematologic malignancies but clinical efficacy in the solid tumor setting has not been observed.
Barriers to T cell entry and function may partially explain this observation.
As solid tumors actively recruit myeloid cells, researchers have hypothesized that macrophages have the potential to be a powerful cellular immunotherapeutic agent in this setting if properly activated and redirected.
It is been described the development of CAR macrophages ( CARMA ), demonstrating the feasibility, mechanism, and efficacy of this platform.
To examine the function of CARs in macrophages, first generation anti-CD19, anti-mesothelin, or anti-HER2 CARs with a CD3ζ intracellular domain were introduced into the THP1 macrophage model.
In vitro function was assessed via quantitative phagocytosis and luciferase-based specific killing assays. CARMA selectively phagocytosed and cleared cognate antigen-bearing tumor cells.
To demonstrate the requirement for CAR-mediated intracellular signaling for activity, a CD3ζ-null CAR construct was tested in vitro.
The deletion of CD3ζ significantly reduced the phagocytic and killing capacity ( p less than 0.01 ) of CARMA.
Researchers have identified Ad5f35, a chimeric adenovirus, as a novel and highly efficient viral vector for the transduction of normal donor and cancer patient macrophages ( more than 70% CAR expression ).
Ad5f35 transduction polarized human macrophages toward a durable immunostimulatory M1 phenotype and rendered CARMA resistant to subversion toward the immunosuppressive M2 phenotype, as defined by surface markers and metabolomics.
CARMA enhanced the proliferative capacity of CD8+ T cells in phytohemagglutinin activation assays and secreted factors that activated by-stander macrophages.
Primary human anti-HER2 CARMA demonstrated targeted phagocytosis and killing of HER2 expressing ovarian and breast cancer cell lines, and exhibited a six-fold higher luciferase-based killing capacity of SKOV3 cells compared to trastuzumab in vitro ( p=0.002 ).
Anti-HER2 CARMA was evaluated in vivo in an intraperitoneal (IP) SKOV3 ovarian cancer xenograft model.
Mice that received IP CARMA had a decrease in tumor burden of approximately two orders of magnitude and had a 30-day survival benefit relative to untreated or control macrophage treated mice ( p=0.018 ).
In a systemically disseminated SKOV3 model, a single dose of IV CARMA led to a durable anti-tumor response ( 38-fold reduction relative to control on day 31 post-treatment; p=0.016 ).
Lastly, researchers have demonstrated that the blockade of the anti-phagocytic CD47/SIRPα axis enhanced the phagocytic capacity of CARMA.
In summary, researchers have demonstrate that human macrophages engineered with a CAR exhibit targeted anti-tumor function in both in vitro and in vivo preclinical models.
This novel cellular immunotherapeutic approach has a clear translational potential for the treatment of solid tumors. ( Xagena )
Source: Cancer Research Annual Meeting, 2017
XagenaMedicine_2017
