How T cells interpret signaling delivered through chimeric antigen receptor (CAR)

Recently chimeric antigen receptor (CAR)-transduced T cell-based immunotherapy made headlines around the globe. Human trials conducted mostly against B cell-derived malignancies showed extraordinary medical benefits in large percentage of treated patients by extending their disease-free episodes for several years.

Below is a diagram of CAR molecule borrowed from Juno Therapeutics’ home page. Juno is one out of several biotech/pharma companies leading this field. As shown here, it is clear that current CAR construct contains several sub-signaling pathways (CD3zeta, CD28, etc).

 

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Now, people who are familiar with basic immunology would notice that CAR construct artificially combines two principally distinct signaling pathways commonly known as signal 1 (CD3zeta) and signal 2 (CD28, etc). It is believed that such combination of two signaling pathways increases CAR T cells vitality and effector differentiation.

I would like to remind the readers that two-signaling model of T cell activation was introduced to account for tolerance towards self-antigens. It is thought to operate a kind of fail-safe mechanism to discriminate between self and nonself antigens. Since vast majority of nonself antigens would carry other attributes of “foreignness”, 2nd signal would be selectively available to nonself-specific T cells, but rarely to self-specific T cells.

Separation of signal 1 and signal 2 in T cells had to have some biological significance on how T cells interpret incoming signaling. This is especially critical for generation of long-term memory since unlike short-term immune response, memory cells with self-renewal potential could clearly cause long-term damage to the host’s tissue when inappropriately activated.

In my opinion, this is why innate cells, including NK cells, in most part, lack truly long-term memory potential. Innate cells are typically signal 1-only cells, meaning they could get fully activated after receiving specific signal 1. However, absence of memory formation among innate cells ensures that they would not go on and continue to damage host’s tissue once they are activated.

So, I can visualize similarities between how innate cells interpret activation signaling and CAR signaling in T cells. Absence of spatio-temporal separation of two signaling pathways in CAR-T cells may affect their memory differentiation potential, essentially transforming CAR-T cells into signal-1-only cells. If this model is correct, persistence and self-renewal potential of CAR-T cells in the hosts will be drastically reduced compared to normal memory T cells. Practically this could translate into diminished long-term medical benefits.

posted by David Usharauli

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