Next-generation tumour-homing IL-12 expressing CAR-T platform technology to achieve safe and efficacious therapy for solid cancers

Chimeric antigen receptor-(CAR)-expressing (CAR-T) cells are artificially engineered cells that can recognise cancer antigen and kill cancer cells.

CAR-T cells demonstrate remarkable therapeutic efficacy in haematopoietic malignancies in the clinic as an approved therapy.

However, conventional CAR-T cells are inefficacious for solid tumours due to the immune-suppressive tumour microenvironment (TME) and low number of tumour-infiltrating CAR-T cells.

State-of-the-art CAR-T cells that express wild-type (wt) interleukin(IL)-12 are still not satisfactory to overcome this issue, due to limited efficacy and unacceptable side-effects.

Here, the objective is to overcome this critical CAR-T challenge using a tumour-targeting technology that I recently developed.

I aim to develop a new platform technology that CAR-T cells express extracellular matrix (ECM)-binding IL-12 within the TME and test them in cancer-bearing mice.

I previously discovered that the specific collagen-binding domain (CBD) protein accumulates within the tumour following intravenous injection.

Intravenous injection of CBD linked anti-tumour cytokine IL-12 protein displayed superior anti-tumour effects and less side-effects compared to wt IL-12 in multiple tumour models through localisation. CBD-IL-12 recruited anti-tumour immune cells into multiple difficult-to-treat tumours. Therefore, I will make CAR-T cells express CBD-IL-12 upon CAR-T's tumour antigen-recognition locally within the TME.

I hypothesise that CBD-IL-12-expressing CAR-T cells are efficacious for solid cancers with minimal side-effects, solving the marginal response and unacceptable toxicity issues of state-of-the-art CAR-T cells.

My central idea is to reconsider CAR-T cells as next-generation drug delivery platforms through localised protein production.

This timely research has significant clinical translation potential and may transform the landscape of cancer treatment.