Extracellular matrix (ECM) degradation helps CAR-T cells to control solid tumors

Chimeric antigen receptor-transduced T cells (CAR-T) represent a new and powerful mode of cancer immunotherapy. Results generated so far clearly indicate that CAR-T cells are very good against fluid tumors such as B cell-derived lymphomas. It is not surprising. Anyone working in immunology knows that B cells are one of the best targets for cytotoxic assays. But what about solid tumors? Not so. Why?

New study in Nature Medicine may shed light on this issue. The authors reported that conventional CAR-T cells lack enzyme, heparanase, necessary to degrade ECM that coats solid tumors.

This is a short study, just 4 figures, but the results are very impressive. Initially, the authors showed that long-term culture of ex vivo-expanded (LTE) CAR-T cells down-regulates heparanase activity. Heparanase cleaves heparan sulfate proteoglycans, a part of ECM.

Next, the authors showed that heparanase-transduced CAR-T cells maintain enzyme activity long-term and show improved invasion activity in Matrigel assay. [Of note, the authors results indicate that baseline Matrigel-invasion activity of long-term cultured CAR-T cells is too variable (compare Fig. 1a vs. Fig. 2d; 8% ± 6% vs. 29% ± 18% for the same long-term cultured CAR-T cells)].

Still, in an in vivo assays, heparanse-transduced CAR-T cells showed far superior anti-tumor activity against solid tumors (against neuroblastoma and melanoma) compared to control CAR-T cells. As expected, CAR-T activity against B cell malignancy was not improved by heparanase activity.

In summary, these results suggest that optimization of CAR-T cell therapy against solid tumors would require improving ECM-degradation capacity of CAR-T cells.

David Usharauli