Switchable CAR T Cells May Be Safer in Pancreatic Cancer

Switchable chimeric antigen receptor (CAR) T cells with a switch directed towards human epidermal growth factor receptor 2 (HER2) in pancreatic ductal adenocarcinoma (PDAC) has similar efficacy as conventional HER2 CAR T cells while also having a greater control over treatment toxicities.

PDAC is the fourth leading cause of cancer-related deaths, with less than 20% of patients having resectable tumors. While CAR T-cell treatments have shown substantial efficacy in hematological malignancies, outcomes in solid tumors such as pancreatic cancer have been limited. Further, since the antigen is expressed on tumors as well as normal tissue, CAR T-cell toxicities can affect healthy organs as well. Attempts are currently being made to create “switchable” CAR T cells whose activity can be titrated in vivo so that they are more specific toward tumors. Allowing CAR T cells to bind a peptide specifically onto a tumor-binding Fab molecule creates a bridge that can connect the target tumor and effector T-cells, thereby regulating treatment and enhancing safety.

In their study published in Gut, Raj et al used CAR T cells drawn from patients with stage IV PDAC to determine if switchable CAR T cells have comparable efficacy as conventional CAR-T cells while targeting HER2, a viable target in PDAC. When comparing conventional CAR-T cells with switchable CAR-T cells, both were able to induce cytotoxicity in HER2-expressing PDAC cells. In addition, when an inactive switch of a wild-type HER2 Fab was placed, there was no cytotoxic effect on PDAC cells, identifying the importance of the switch.

To further examine the effectiveness of CAR T cells in PDAC, investigators created a microenvironment of cancer stem cells—a physical barrier for T cell connection with tumor cells in vitro. Following a few days of culture, CAR T-cell activity was observed in both treatment groups, marked by increased T cell proliferation and enhanced production of the cytotoxic molecule granzyme B.

Subsequent studies evaluated the efficacy of HER2 CAR T and switchable CAR T cells in vivo. Immunocompromised mice were implanted with patient PDAC cells and treated with both types of CAR T-cell therapy. Non-invasive bioluminescence imaging of the mice showed reduced tumor growth by day 3 and tumors disappeared by day 10 as. However, mice that had received no treatment or CAR T-cell treatment with an inactive switch continued to progress.

The efficacy of switchable CAR T and conventional CAR T therapy were also compared through dose titrations. Similar tumor regression was observed in both treatment groups, with similar interferon and tumor necrosis factor cytokine release at each T cell dose, with the exception that IL-2 was higher in the conventional CAR-T cell group.

Finally, when comparing conventional CAR T with switchable CAR T-cell therapy in disseminated metastasis, rapid tumor clearance was observed in both treatment groups. The mice treated with either therapies remained tumor free for the remainder of the study, which was 5 months following T cell administration. From these mouse models, it seems that switchable CAR T therapy can be effectively used to treat PDAC even in the more advanced cases, while also having a better safety profile than conventional CAR-T therapy.

Reference

Raj D, Yang M, Rodgers D, et al. Switchable CAR-T cells mediate remission in metastatic pancreatic ductal adenocarcinoma [published online August 18, 2018]. Gut.doi: 10.1136/gutjnl-2018-316595.