“THESE CHIMERIC GENES HOLD PROMISE FOR THE
IMMUNOTHERAPY OF CANCER.” – Dr Zelig Eshhar 1989
CAR-T therapy is a revolutionary new cancer treatment option but its development has been decades in the making …
In the 1960s, early attempts to use T cells to treat transplanted mice tumours were unsuccessful due to an inability to multiply and manipulate the T cells in culture.
In 1972 scientists describe the T cell growth factor IL-2 (interleukin-2), paving the way to grow T cells ex vivo. The direct application of high doses of IL-2 inhibited tumour growth in mice.
Studies in the early 1980s demonstrated that intravenous injection of T cells expanded in IL-2 could treat bulky subcutaneous lymphomas, and the administration of IL-2 after cell transfer increased T cell efficacy.
In 1993 Dr Zelig Eshhar and colleagues at the Weizmann Institute in Israel engineer the first-generation CAR molecule. Dr Eshhar had spent time in the United States in 1990 with Dr Steven Rosenberg, surgeon and cancer researcher, where they worked together to design CARs targeted at human melanoma.
In the late 1990s it was found that CARs would be more effective if they were designed with the addition of another molecule – a ‘co-stimulatory’ molecule to work alongside of components of the first-gen CARs that initiate intracellular signaling leading to T cell activation.
In 2010 the first clinical trial of CAR-T therapy was reported, using second-gen CARs and targeted at CD19 in non-Hodkin’s lymphoma, a blood cancer. CD19 is still the predominant CAR-T cell target under investigation.
In 2012 Emily Whitehead became the first paediatric patient to be treated with CAR-T therapy. She is still in remission today.
In 2014 CAR-T therapy received Breakthrough Drug designation from the US Food and Drug Administration for relapsed and/or refractory acute lymphoblastic leukaemia.
Fourth-generation CARs enter the scene. Also known as ‘T cell redirected for universal cytokine-mediated killing’ (TRUCKs), these demonstrated improvements in anti-tumour efficacy.
Third-generation CAR molecules were produced by incorporating two or more co-stimulatory molecules into the CAR construct. These CARs are not necessarily more superior than second-generation (results from comparative studies are inconclusive).