Breaking Down T-Cell Therapies: TCR and CAR T Mechanisms

Paulina Velasquez, MD, assistant faculty member, St. Jude Children’s Research Hospital, discusses the differences between T-cell receptor (TCR)-based and chimeric antigen receptor (CAR) T-cell therapies.

These 2 approaches share similarities but differ significantly in their mechanisms and antigen recognition capabilities. TCR-based T cells are MHC-dependent, meaning they are limited to treating patients with specific MHC types. They can recognize both intracellular and cell surface antigens by associating with MHC, providing a broad range of targets. Their exclusive specificity minimizes off-target effects. However, TCR T cells lack additional co-stimulatory signals, which can limit their expansion but reduce the likelihood of exhaustion, making them potentially longer-lasting.

In contrast, CAR T cells are MHC-independent, enabling them to treat a broader patient population regardless of MHC type. They primarily target cell surface antigens and incorporate co-stimulatory domains, which promote greater expansion and persistence of T cells. However, the increased activation and persistence can also lead to higher rates of T cell exhaustion, potentially reducing their long-term effectiveness.

Each approach offers unique advantages and limitations. TCR-based therapies are versatile in antigen recognition but restricted to certain populations and may not expand as effectively. CAR T cells offer broader accessibility and better initial expansion but face challenges with exhaustion and antigen specificity. The balance between these factors guides the choice of therapy based on the clinical scenario.

Transcription:

0:10 | Talking about T-cell–based cell therapies, there are 2 different strategies that are the mainstay at the moment, one being TCR–based T-cell therapies and the other ones being chimeric antigen receptor–based T-cell therapies.

0:26 | Those 2 strategies use T cells, and although they have similarities, when you think about the way they work, they differ in what antigen is being recognized. For example, one strategy, the TCR-based strategy, is MHC-dependent. So it is going to work for just a certain group of people.

0:55 | CAR T cells, on the other hand, operate through an MHC-independent mechanism. This is advantageous because it removes the limitation to a certain population. However, they are mostly limited to targeting cell surface antigens. CAR T cells do have additional co-stimulation, which allows them to persist longer and expand better. But at the same time, as mentioned, the flip side is that they can become more exhausted, which can impact their effectiveness.

This transcription has been edited for clarity with AI.