T cell engagers - dark horses of immunotherapy

Chimeric antigen receptor (CAR) technology has attracted a lot of attention and investment in recent years, but the potential of T cell Engager technology should not be underestimated.

CARs are engineered proteins having a target protein-binding region, linked to a region which provides for cell activation following binding of the CAR to its target protein.  A patient’s T cells can be modified to kill cells expressing a given target protein by engineering them to express a CAR specific for the target protein.

Another strategy for re-directing T cells against a given target is to use a T cell engager.  These agents have a target protein-binding region joined by a linker to a region capable of binding to a component of the T cell receptor.  The classical example of a T cell engager is a bispecific T cell engager, or ‘BiTE’.  The basic principle is the same as for a CAR – the T cell engager causes activation of the T cell and killing of cells expressing the target protein, except in this instance through binding simultaneously to the target protein and the T cell receptor.

Both classes of technology have been shown to be effective, as reflected by the FDA’s approval of the BiTE Blincyto back in 2014, and CAR-T therapies Yescarta and Kymriah in 2017.

Notwithstanding exciting activity in the CAR-T field, certain technical differences between CARs and T cell engagers identify the latter as an attractive class of agent that should not be overlooked in the ongoing development of immunotherapies.

A key issue for widespread adoption of autologous CAR-T therapy is the per patient cost.  Individual patients’ T cells need to be modified to express the relevant CAR, such that each patient is essentially treated with a personalised drug.  This is expensive, requiring considerable expertise and specialist facilities to produce the CAR-T cells and expand them to a therapeutic quantity.  Storage and handling of the so-called ‘living drug’ also presents a technical challenge.

By contrast, T cell engagers are ‘off-the-shelf’ agents, and are suitable for use in substantially any patient that would benefit from killing cells expressing the relevant target protein.  Such molecules can be produced in large quantities and stored in accordance with well-established practices for polypeptide therapeutics, to be administered to patients as and when it is desired to direct a T cell response against cells expressing the target protein.  This is a very important advantageous feature of T cell engager technology.

The patient experience may also be quite different.  Multiple rounds of administration of CAR-T therapy require several blood draws in order to obtain T cells to be engineered to express the CAR, as well as multiple infusions of the CAR-T cells into the patient.  On the other hand, T cell engagers can simply be administered to the patient to be treated.

That’s not to say that T cell engagers are more attractive than CAR-T cells in every aspect.  CARs provide the opportunity for greater control over the signal delivered to the T cell, and consequently the nature of the T cell response, following target cell recognition in the patient.  CAR-T cells also actively traffick to their target cells, and may proliferate and persist for longer in the patient than T cell engagers, which rely on chance encounters with cells expressing the target protein, and may be rapidly eliminated from the patient.

Nevertheless, T cell engagers could be particularly useful for the treatment hematological malignancies such as lymphomas and myelomas, where the target cells are circulating in the patient’s blood.

Future development of T cell engagers will likely focus on producing novel formats and tweaked affinities, aimed at reducing toxicity and increasing on-target potency.  It may be possible to achieve such improvements by adapting approaches developed for CAR-T therapies.

Keep an eye out for the (re)emergence of T cell engager technology on the immunotherapy landscape.