Three major challenges in making effective
CAR-T cell therapies for solid tumours

1. A lack of ideal solid cancer target antigens

2. CAR-T cells’ limited access to solid tumours

3. The immunosuppressive nature of the tumour microenvironment

The challenges…

1. A lack of ideal solid cancer target antigens

The current CAR-T market is driven largely by CAR-T cells targeted at blood cancers and at very few antigens (the main one being CD19). CD19 is the target antigen for the only two FDA-approved CAR-T therapies (Kymriah and Yescarta, both approved for use in in the US 2017 and Kymriah approved for use in Australia in December 2018). However, CD19 is only present on B cells and no other cells, so a CAR-T expressing a CD19 CAR is only useful against malignancies of B cells.

In solid cancer clinical trials, there has been little positive data for most of the antigens studied. Further, the vast majority of antigens targeted in clinical trials so far have not been specific for solid cancer cells, but are over-expressed on tumour cells but also still present on healthy cells. Significant on-target off-tumour effects have been recorded where the CAR-Ts have attacked both diseased and healthy cells.

2. CAR-T cells’ limited access to solid tumours

So far it has proven a challenge to deliver clinically effective doses of CAR-T cells to solid tumours or resection (after surgery) sites. One of the issues to overcome is that it is difficult for CAR-T cells to get “up close and personal” with tumour cells, and they often move away from the tumour/resection site before they have had a chance to get to work and kill tumour cells.

3. The immunosuppressive nature of the tumour microenvironment

A tumour consists of a mass of cancer cells as well as a variety of other cells (including immune cells) and non-cellular components such as cytokines, chemokines, growth factors, inflammatory mediators and aberrant tumour vasculature networks. This highly heterogenous and complex milieu is collectively known as the tumour microenvironment (TME), and the progression of a tumour is strongly influenced by the interactions within it. The success of cancer immunotherapy relies on detailed knowledge of the TME and its role in tumour differentiation, epigenetics, dissemination and immune evasion.

Carina’s solutions…

1. Developing new CAR-T cells that attack atypical solid cancer antigens

Carina Biotech is developing CAR-T cells targeted at molecular markers found on a broad range of cancer types. Our lead candidate LGR5-targeted CAR-T cells have demonstrated the ability to kill a wide range of cancer cells in vitro and in animal models.

We are developing CAR-T therapies that have potent cancer-killing power yet result in few off-cancer side effects. Our researchers are currently progressing a number of antigen-directed CAR-T cells through pre-clinical testing. Click here to see our pipeline.

2. Chemokine receptor-mediated CAR-T active migration to tumours with our proprietary Multifunctional Chemokine Receptor Platform

Tumour cells and cells in the tumour microenvironment produce small molecules called chemokines. Each cancer has a specific chemokine profile and their production by the cancer results in a ‘chemokine concentration gradient’ forming around the cancer.

Our proprietary Multifunctional Chemokine Receptor Platform is producing dual-transduced “supercharged” CAR-T cells expressing chemokine receptors that ‘home in’ to the chemokine gradient and more effectively direct the CAR-T cells to kill tumour cells.

3. CAR-T construct armoury with functional advantages

Carina Biotech’s proprietary manufacturing process leads to greater efficiency in CAR-T manufacturing, resulting in high-potency cells with lower proportions of exhausted phenotypes.