The Next Generation in Cancer Immunotherapy

Scientists and clinicians have developed and used immune-based therapies, or more simply immunotherapies, to attack cancer in multiple ways. Immunotherapies encompass a range of treatments from antibodies to vaccines, such as the vaccine against the human papilloma virus that causes cervical cancer.

Recently, researchers have started working on new ways to harness the immune system to directly attack cancer cells, taking advantage of a specialized immune cell type known as T cells.

T cells recognize and attack specific target proteins, known as antigens. In the past five years, scientists have developed systems to create engineered T cells that specifically target cancer cells.

One of these systems is known as chimeric antigen receptor (CAR) T cells. These T cells are engineered to express specific receptors, CARs, which then recognize tumor antigens. While CAR T cells can attack cancer, they also attack bystander cells expressing the same antigens.

To avoid these bystander casualties, the Lim lab at UCSF engineered a clever system where two cancer antigens must be present on a cell in order to activate the T cell.

As written up in a recent issue of Cell, the authors designed a system that uses two dependent receptors. The first receptor is a modified Notch receptor, known as synthetic Notch (synNotch), also developed by the Lim lab. This receptor recognizes an antigen and in response a transcription factor — or a protein that drives expression of other proteins — is released.

The transcription factor then drives expression of the second receptor, a CAR. Once the CAR recognizes the second antigen, the T cell becomes activated. Thus, activation of the T cell is dependent upon recognition of both antigens.

To test whether their system effectively worked, the authors began in Jurkat T cells, a commonly used immortalized T cell line . They expressed synNotch and CAR in their T cells, which were specific for two common tumor antigens (CD19 and mesothelin).

They co-cultured their engineered cells with cancerous cells expressing both antigens, and examined the levels of T cell activation. Only when both antigens were present did the researchers see signs of activation, as measured by changes in protein levels and secreted proteins. When co-cultured with tumor cells that only expressed CD19 or mesothelin, activation did not occur.

The authors tested their system next in primary human T cells and found that these T cells had the same dual antigen control.

Finally, the authors moved into a mouse model, to examine whether the same activation control would occur in vivo. The first question they asked was whether CAR expression would be restricted to the site of the tumor.

To model this, they expressed a fluorescent protein reporter and CAR at the same time under the same synNotch control. When T cells were injected into mice carrying tumors, they could then measure where fluorescence was occurring. The authors found that the fluorescence was restricted to the site of the tumor, indicating that CAR expression only happened where the tumor was present.

Of course, the big clinically relevant question is whether their system could effectively attack and clear dual-antigen tumors in vivo. To test this, the researchers set up a model where one mouse had both single- and double-antigen tumors. They found that the T cells only attacked and cleared the tumors expressing both antigens, leaving the tumors expressing only one antigen rapidly growing.

Their exciting in vivo finding suggests that their dual-antigen T cell could be an effective tool in the clinic.

This new system has two big advantages over previously available immune therapies. First, it improves upon the specificity of immune attacks, making it less likely that bystander cells will be sacrificed in the process.

Secondly, it allows for tumor targeting based on combinations of antigens, rather than a single antigen. This could be used to target two tumor antigens, or alternatively to target immunotherapy activation to a specific tissue (by synNotch) and then to cancer cells in that tissue (by CAR expression). These potential combinations create a wider range of therapeutic possibilities, and hopefully move cancer therapies a step closer to a cure.