Over the last six years, immunotherapy has changed the treatment paradigm in a wide range of cancers. This clinical efficacy followed key findings in basic immunology that were translated to the clinic. To date, two main forms of immunotherapy have been effective, checkpoint blockade inhibitors (CBI) and chimeric antigen receptor T cells (CAR-T). Checkpoint blockade inhibitors target negative regulators of the immune response, enabling either priming of a new response and expansion of TCR repertoire (anti-CTLA4), or release of a pre-existing anti-tumour T cell response (anti-PD-1) from suppression leading to T cell activation, proliferation and effective tumour regression. A wide range of additional immunotherapy agents (eg. new CBI, agonistic antibodies, and adenosine inhibitors) are currently in clinical trial as mono- or combination therapy, indicating the initial clinical success of this form of immunotherapy may well be even more effective in the future.
CAR-T cells are T cells that have been genetically modified to express a chimeric protein encoding an antibody fragment (scFv or single chain variable fragment), transmembrane and cytoplasmic signalling domains, commonly CD28 or 41BB and CD3ζ signalling domains. Binding of the scFV to cognate antigen induces CAR-T activation, cytokine secretion, and release of effector molecules leading to tumour cell apoptosis. CAR-T cells directed to CD19 have been very successful in refractory pediatric and adult ALL, as well as refractory B cell lymphoma and CLL. In some patients refractory to CART19 therapy, subsequent CBI therapy targeting PD-1 has reinvigorated their anti-tumour response leading to systemic tumour regression. Unfortunately, this CART19 success in refractory ALL/NHL has not occurred in solid cancers. Reasons for this include issues with trafficking and persistence at the tumour site, and the immune-suppressive nature of solid tumours.
Resistance to both major forms of immunotherapy is an active area of investigation. To explore immunotherapy resistance, new technologies have been rapidly developed to enable an accurate assessment of the immune context of human tumours. This data has revealed tumour vs immune intrinsic defects contributing to resistance, as well as classifying human cancer immune context into categories. Ultimately, this information will be critical in developing algorithms to help guide patient treatment.
In conclusion, immunotherapy has now changed the treatment paradigm for many patients with cancer. The challenge for the immediate future includes increasing response rates and durability. To address this issue, clinical trials are underway exploring combination immunotherapy with therapy which targets the tumour microenvironment (eg radiotherapy, small molecule inhibitors or epigenetic modifiers) to enable penetration of the tumour by antigen-specific T cells.