Therapeutics
personalised oncology therapies through the Orphan Drug Act, which provides incentives to develop treatments for rare diseases, including rare cancers, for example. One of the most powerful examples of preci-
sion medicine is immuno-oncology (IO) therapy, which is transforming how cancer is treated. Where traditional cancer treatments worked by directly attacking rapidly-proliferating cancer cells, IO therapy leverages the patient’s own immune response to fight against cancer. Checkpoint inhibitors, such as anti-PD-1, PD-L1 and CTLA-4, are among the most well-known IO drugs and a real breakthrough in IO therapy. Checkpoints are a family of proteins that cancer cells may use to protect themselves from being attacked by immune cells like T-cells. Checkpoint inhibitor therapy is an antibody-based therapy that binds to immune-checkpoint proteins expressed either on a tumour or on T-cells and unlock the cytotoxic T-cells’ ability to kill tumours. By blocking or inhibiting a checkpoint’s ‘protective’ signals, T-cells are less inhibited to kill cells, including cancer. While checkpoint inhibitors have been highly
successful in some cancer patients, they have proven ineffective in a subset of the patient popu- lation, spurring investigators to continue their quest for improved immunotherapies with reduced risks. As T-cell-based therapy continued its evolu- tion, the next wave was development of bi-specif- ic-antibody-engagers such as BLINCYTO® (Blinatumomab) a BiTE® (bi-specific T-cell engager) therapy from Amgen. One side of this
Drug Discovery World Spring 2018
antibody-derived medication binds to T-cells and the other side binds to the protein expressed on a type of cancer derived from B cells. BLINCYTO assists the T cells’ killing capability and brings them closer to the cancer target. Both checkpoint inhibitors and BiTE therapy
such as BLINCYTO are antibody-based therapies that leverage and recruit T-cells. In 2017, the US FDA approved an entirely new T-cell therapy approach which instead makes the T-cell itself the drug. Chimeric antigen receptor (CAR)-T-cell ther- apy, often called ‘cell and gene therapy’ or a ‘living drug’, uses T-cells that are genetically modified to express a section of antibody on their surface. Instead of providing T-cells with additional help through an antibody therapy such as a checkpoint inhibitor, the patient’s own T-cells are expanded and genetically modified, making them capable of targeting proteins expressed on the tumour and killing the cancer cells. All three types of IO medication utilise one type
of immune cell, the T-cell. However, a human immune system consists of a wide range of cells beyond T-cells. While T-cell-mediated IO drugs showcased how powerful T-cells can be in the fight against cancer, they also demonstrated the T- cell-based medication’s dependent side-effects, such as cytokine storm and neurotoxicity. In addi- tion, potential limitations with T-cell-based thera- pies have raised concerns. For instance, a patient who is already immuno-depressed from a first-line treatment may not have sufficient T-cells to modi- fy or stimulate. For these reasons, investigators are now looking
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