Chimeric antigen receptor
(CAR) T cells have shown remarkable effectiveness in treating patients with
multiple myeloma who have received extensive prior therapy. However, to maximize their efficacy, further modifications are necessary. Preclinical studies have indicated that the provision of cytokine support can enhance the expansion and longevity of CAR T cells, thereby improving their long-term antitumor capabilities. Although combining CAR T cells with systemic cytokines or cytokine analogs can lead to toxicity and adverse reactions, an alternative approach involves the intrinsic expression of a Constitutively Active Chimeric Cytokine Receptor (CACCR) within CAR T cells. This can be achieved by fusing a
thrombopoietin receptor (TpoR) derived domain with a signaling domain from a cytokine receptor to create a CACCR.
Our research has focused on the effects of CACCR expression on the characteristics, efficacy, longevity, and safety of allogeneic CAR T cells designed to target
BCMA, with the goal of developing a second-generation allogeneic BCMA CAR T cell product. These cells were derived from healthy donors and modified using a CAR construct and gene editing techniques to inactivate specific loci. The resulting allogeneic BCMA TurboCAR T cells, which express both the CAR and a CACCR, were found to have a high proportion of stem cell memory/central memory T cells. In vitro tests showed that these cells exhibited increased cytokine production, polyfunctionality, and superior serial killing capabilities.
In a mouse model with disseminated multiple myeloma, the TurboCAR T cells demonstrated a significant increase in peak expansion and improved survival and persistence, leading to extended antitumor effects and delayed relapses. It was also observed that the expansion and long-term activity of these cells were dependent on exposure to target cells, with no evidence of uncontrolled proliferation.
Considering the potential for toxicities in adoptive cell therapies, we explored methods to regulate the activity of the BCMA TurboCAR T cells. One approach involved incorporating a
CD20-based off-switch within the CAR to make the cells sensitive to
rituximab, which effectively depleted the TurboCAR T cells in vitro and in vivo. Another approach was the use of
dasatinib, a
protein tyrosine kinase inhibitor, which rapidly inhibited the cells by interfering with
LCK activity.
The sustained antitumor effects and favorable safety profile observed in preclinical models suggest that the second-generation allogeneic BCMA TurboCAR T cells warrant further clinical investigation for the treatment of
relapsed or refractory multiple myeloma. The disclosures section indicates that several authors are currently employed by and hold equity in
Allogene Therapeutics, Inc.How to Use Synapse Database to Search and Analyze Translational Medicine Data?
The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

Click on the image below to go directly to the Translational Medicine search interface.
