CAR: Anatomy and Generations
The immune system is an expert at defending us from dangers, but when faced with cancer cells, the immune system often fails. Cancer cells are normal human cells that have been transformed into rogues. They usually have many genetic changes that allow them to grow without normal limitations. Unfortunately, most of these genetic changes mutate proteins that are inside the cancer cell, so the immune system may not detect them. Today, researchers are developing ways to retool the immune system to fight specific forms of cancer.
Chimeric antigen receptors are built by connecting several functional parts from different proteins, each with a specific job. A single-chain antibody variable fragment (Fv) recognizes a known cancer cell protein, targeting the tumour. These are generally engineered from monoclonal antibodies by using only the domains at the tip of the antibody and connecting the two chains with a flexible linker. The antibody portion is connected to a transmembrane segment with another flexible linker. Inside the cell, one or more domains are taken from signalling proteins, which will activate the immune cell once it finds a tumour cell.
Many immune cells have posed targets for docking CARs:
CAR-T: Elicitation of immune response via T cells has been enhanced by docking CARs onto T cells. Subsets of T cells are one of the immune cells that play a central role in eliminating cancer. Many CAR T candidates are currently undergoing clinical trials and few of them are approved for therapeutic use.
CAR-M: Researchers are trying to use macrophages modified with CAR (CAR-M) against solid tumours in order to equip them with the ability to bind to the tumour cell surface via specific antigen identification and subsequently activate macrophage activity against tumour cells.
CAR-NK: CAR-NK cells eliminate tumours not only through the ability of CAR to specifically recognize antigen-expressing tumours but also through NK cell receptors themselves. It is the balance of stimulatory and inhibitory signals, not antigen specificity, that determines NK cell activity. Thus, targeted lysis by CAR-NK cells is based on both CAR-dependent and NK receptor-dependent mechanisms, and lysis is also applicable to tumours with antigen-negative membranes.
Over the years, different types of CARs have been designed to react more efficiently with cancer cells.
First-generation CARs possess only the CD3 zeta domain. These CARs were unable to prime resting T cells or direct lasting T cell responses or exhibited cytokine release syndrome in patients due in large part to their limiting signalling capacity.
Circumvention of the drawbacks led to the formulation of second-generation CARs, which had an additional co-stimulatory domain. These are the basis of currently-approved CAR T cell therapy. The currently marketed CAR T cells are infamously known as 'living drugs'
Third-generation CARs incorporated 2 co-stimulatory domains.
Fourth and the last generation of CARs, also known as armoured CARs have the ability to release cytokines, which are chemical messengers to interconnect the branches of the immune system.
CAR T-cell therapy has the potential to cause a host of side effects, which highly trained medical care team can help manage.
CAR T-cell therapy can cause cytokine release syndrome (CRS), which can cause high fevers, fatigue, difficulty breathing, neurotoxicity and a sharp drop in blood pressure.
Other general side effects can include:
Loss of balance
Highly trained medical teams in side effect management can help deal with any issues that arise.
In 1987, an Israeli immunologist, Dr. Zelig Eshhar from The Weizmann Institute of Science, created the world’s first “chimeric antigen receptor” (CAR). First FDA approvals of CAR T cells was done in 2017. Since then, as of today, over one hundred companies are developing CAR-T technologies from across the globe.
Supported by a growing investment flowing into CAR-T research and landmark approvals of the CAR-T cell therapies, various companies from small start-ups to billion dollar organizations, CAR-T companies have proliferated in all healthcare markets worldwide. Kymriah, Yescarta, Tecartus, and Breyanzi and various CAR-T companies are established therapies around the world in US, Europe and China. Research on new applications on different types of Cancer and “Off the Shelf” product categories are being done at rapid pace in leading research centers.