Abstract
MASTER-produced CAR T cells are functional with improved expansion and persistence compared to conventional CARs.
Major Finding: MASTER-produced CAR T cells are functional with improved expansion and persistence compared to conventional CARs.
Concept: This method allows for in vivo CAR manufacturing through subcutaneous implantation and viral gene transfer.
Impact: Use of this described scaffold can ultimately reduce the time and cost needed for CAR T-cell production.
One of the major barriers to clinical use of chimeric antigen receptor (CAR) T cells is the complexities involved in their manufacturing, including the time and expense involved. To minimize these issues, Agarwalla and colleagues developed Multifunctional Alginate Scaffold for T Cell Engineering and Release (MASTER), which allows for CAR T-cell generation in vivo over only 1 day. Alginate was used as the scaffold due to its biocompatibility and biodegradability with anti-CD3 and anti-CD28 antibodies immobilized within to promote T-cell activation as well as encapsulation of IL2 to promote T-cell proliferation. As retroviral transduction was shown to be possible within the scaffold, a CD19-specific CAR was introduced, and when compared to conventionally created CAR T cells, MASTER-generated CARs had similar proliferative capacity, exhaustion markers, and cytotoxic effects; however, they were significantly less differentiated. Implantation of MASTER into immunocompetent mice demonstrated no deleterious effects or toxicities, while testing of transduction into surrounding host cells revealed that, when coseeded with peripheral blood mononuclear cells, transduction of virus into fibroblasts did not occur nor did this occur in the blood or skin surrounding the scaffold. To test antitumor efficacy of MASTER-produced CAR T cells, a murine xenograft model was used and showed control of tumor growth for up to 100 days after infusion. Moreover, examination into persistence of MASTER-produced CAR T cells revealed a 30-fold improvement to absolute counts in the blood, bone marrow, and spleen as compared to conventional CAR T cells, with these MASTER-produced CAR T cells also performing better in terms of controlling tumor growth under stressed dose conditions. The improvement to persistence was further observed in rechallenge experiments where 100% of mice treated with MASTER-generated CARs were tumor-free 30 days after rechallenge as compared to the 17% of mice treated with conventional CARs. Overall, this study defines the use of MASTER for in vivo production of CAR T cells, providing a quicker and cheaper method for their manufacturing.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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