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Next-generation technologies to increase efficacy in solid tumors: CycloCAR® (Cytokine and Chemokine Loaded CAR )

CycloCAR-T cells are CAR-T cells engineered to coexpress cytokine IL-7 and chemokine CCL21 which have the potential to significantly increase the efficacy of CAR-T cells against solid tumors. T-cell recruitment, survival, and proliferation are the important limitations to chimeric antigen receptor (CAR) T cells therapy in the treatment of solid tumors.

 

IL-7 is a cytokine that could enhance the proliferation and survival of CAR-T cells while CCL21 is a chemokine that could drive recruitment of lymphocytes and DCs into tumor sites.

 

In vivo, CycloCAR-T cells revealed superior therapeutic effects to either conventional CAR-T cells or 7x19 CAR-T cells, which coexpress IL7 and CCL19 as previously reported in three different solid tumors without cyclophosphamide precondition.

 

CycloCAR-T cells could also suppress the tumor growth with heterogeneous antigen expression and even induce tumor complete remission. Mechanistically, IL7 and CCL21 significantly improved survival and infiltration of CAR-T cells and dendritic cells in tumor. In addition, CCL21 also inhibited the tumor angiogenesis as proved by IHC. (For more details, please see Luo H, et al. Clin Cancer Res. 2020 Oct 15;26(20):5494-5505.)

Allogeneic CAR T platform: THANK-uCAR®

To reduce the rejection of host T cell against allogeneic CAR-T cells, B2M gene was generally knockout. However, host NK cells shall attack the allogeneic CAR-T cells without B2M, leading to less proliferation and persistence of the allogeneic CAR-T cells.

 

To address this issue, a CAR recognizing NKG2A, a surface protein of NK cells was armored into the allogeneic CAR-T cells to hinder the attack of host NK cells, which is so called THANK(Target to Hinder the Attack of NK cells)-uCAR technology. Our data demonstrated that THANK-uCAR-T cells could survive and proliferate much better than TCR/B2M double knockout allogeneic T cells in the presence of NK cells.

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A powerful platform for precise targeting: LADAR® (Local Action Driven by Artificial Receptor)

Most tumor-associated antigens are also expressed in normal tissues, which poses great challenges for the development of targeting therapies including immune cell therapies. To resolve the challenge with target availability, we continue to explore innovative technologies to enhance drug target availability and therefore make undruggable targets druggable. We developed LADAR® technology, in which the intracellular transcription of the gene of interest is controlled by an artificial receptor which contains a transcript factor (TF) in the intracellular domain. Once the extracellular domain of the LADAR® receptor binds to a sender antigen, the TF was cleaved and translocated to nucleus to trigger the expression of target genes of interest. The gene of interests could be a chimeric antigen receptor (CAR), a cytokine or any therapeutic mediator you need.

 

The LADAR-CAR circuits require a sender antigen for LADAR® and a target antigen for CAR recognition to kill target cells and thus reduce on-target off-tumor toxicities if these two antigens are not simultaneously expressed in the same normal tissues. In our in vitro studies, LADAR® system induced strong gene expression in response to sender antigen engagement and importantly, nearly no leakage expression in the absence of sender antigens.

 

We are also working on other applications of LADAR® system, such as LADAR-cytokine circuits. We believe that LADAR® system is a powerful tool for developing CAR-T cells with reduced on-target off-tumor toxicities and expanding the target availability. Additionally, it could also be applied in precise delivery of cytokines and other therapeutic mediators.

Other Technologies

Except for the technologies mentioned above, CARsgen also have other technologies like fully-human antibody phage display technologies. We have in-house developed fully-human antibody phage display library. Using this technology, we have identified fully-human antibodies against BCMA, mesothelin and other targets.