T cell therapy of cancer is a form of immunotherapy that works by infusing the patient with T cells (either their own or obtained from another person – a donor) which have been manipulated in the laboratory to enhance their cancer-killing properties.
Chimeric antigen receptor (CAR) -based methods work by genetically engineering T cells with a type of T cell receptor that recognises a marker on cancer cells (cancer cell surface antigen) and contains T cell stimulatory components (to maximise T cell activation). Kymriah and Yescarta are two approved CAR-T cell products that target the cell surface antigen CD19 on malignant B cells and have shown unprecedented efficacy in the treatment of certain types of B cell leukemia and lymphoma.
Despite being such an effective form of cancer treatment in these blood cancers, CAR-T cell therapy has so far shown very little efficacy in solid tumors (cancers that come in the form of a lump rather than liquid as is the case for blood cancer), which represent the majority of cancers.
For CAR-T cells to work effectively, they need to be able to reach the tumor site, maintain their activity and expansion capabilities then establish physical contact with the target cancer cells so that they can destroy them. Solid tumors have the following features which interfere with the ability of CAR-T cells to carry out their killing mission:
- Difficult to penetrate tumor structure, with dense stroma and the presence of physical barriers such as collagen, that provide a safe haven for cancer cells protecting them from physical contact with immune cells, which is necessary for cancer-fighting activity.
- Presence of so-called “immune checkpoints”, molecules present on the cell surface of cancer cells that block the activation of incoming anti-tumor immune cells, thus preventing their activation or expansion.
- Altered metabolic activity leading to depletion of key nutrients in the tumor space (also known as the tumor microenvironment); this prevent immune cells from obtaining the necessary metabolic fuels required to sustain full activation.
- The presence of tumor-promoting cell types (e.g. cancer associated fibroblasts, regulatory T cells) that prevent the activation of incoming T cells for example by producing inhibitory soluble factors (so-called cytokines).
- Tumor heterogeneity, that is the presence of many different tumor antigens (targets) on solid tumor cells, is a feature of solid tumors. This makes the destruction of these tumor cells by CAR-T cells (which are programmed to recognize one tumor target) ineffective.
Knowledge and understanding of the challenges that solid tumors present is the first step towards developing treatment strategies that harness the success of CAR T cell as an effective cancer immunotherapy.
A lot of work is ongoing in this area with many laboratory studies and clinical trials beginning to show that improving the efficacy of CAR-T cells in solid tumors may be achievable.
