Award Title: Next-generation tumour-homing IL-12 expressing CAR-T platform technology to achieve safe and efficacious therapy for solid cancers
Funder: The Academy of Medical Sciences

Abstract: 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.

Lay Abstract: According to the World Health Organization, cancer is responsible for an estimated 9.6 million deaths accounting for 1 in 6 deaths. Recently, immunotherapy has presented revolutionary solutions for the treatment of cancer by engineering immune cells to attack cancer. There is a new approach to cancer immunotherapy, called CAR-T cells. CAR-T cells are designed to find and kill cancer cells. CAR-T cells are extremely effective for blood cancer patients. For example, 70-95% of patients showed cure in certain types of blood cancer. However, CAR-T cells are not very effective for other types of cancers so far, which means >90% of cancer patients have not benefited from CAR-T therapy. This is because of the hostile solid cancer character, where CAR-T cells are inactivated and/or excluded. I previously developed a new technology that can make protein drugs stay in the tumour by collagen binding, which makes cancer therapy more effective and safe. Combining this technology, here, I will develop and test new CAR-T cells that are effective for solid cancer with minimal side-effects. In the new design, CAR-T cells produce tumour-homing collagen-binding protein drugs. The CAR-T-derived drug stays in the tumour, and then CAR-T cells will be activated more to attack solid cancer cells. I will analyse the anti-tumour efficacy, side-effects, and immunological mechanism of action to evaluate this new generation CAR-T cells. The new CAR-T technology holds high translational potential. I propose an idea of localised CAR-T therapy to directly address the issues of CAR-T cells in the clinic.

Research Activity Codes: 5.2 CELLULAR AND GENE THERAPIES
Health Categories: CANCER AND NEOPLASMS