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CAR-T cell therapy

Immunotherapy is the current “big thing” in cancer biology. The concept of using immune cells to target malignant cells is attractive because, till date, it is an effective treatment over a shorter period of time with tolerable side effects. Immunotherapy, apparently, is a big topic. There are two key technologies in immunotherapy: checkpoint inhibitor and CAR-T cells.

Let’s talk about CAR-T cells but let’s not go deeper.

The idea here is to use T cells to target malignant B cells. This is, in general, for patients with B cells acute lymphoblastic leukemia (B-ALL). In short, we are going to target and kill B cells in patients with B-ALL. Are you following me?

So how do we target malignant B cells here? Fortunately, we have one common target (a.k.a marker) that is present on nearly all B cells, the CD19 glycoprotein. CD19 is expressed on both benign and most malignant B cells, with an extremely limited expression on non-B cells (Fesnak et al., 206). There are alternative markers, CD20 and CD22, that are frequently expressed in non-Hodgkin lymphoma and B-ALL.

When we discuss CAR-T technology, we must realize that we are talking about weaponizing T cells with something it does not naturally express. CAR refers to chimeric antigen receptor, so this antigen must be somehow engineered into our T cells of interest, commonly by ex vivo engineering known as adoptive cell transfer. With ex vivo engineering, researchers extract T cells from patients and then engineer it to produce the chimeric antigen. That is a very generalized version of a really complex procedure.

adoptive cell transfer procedure

There are two important structures for this antigen: the antigen-recognition domain (a.k.a ligand-binding domain) and the signaling domain. The antigen-recognition domain recognizes, in this case, the CD19 glycoprotein on the B cells. Upon recognition with the CD19 glycoprotein the signaling domain fires instruction for the T cell to act, thereby activating the T cell to kill its target.

structure of the chimeric antigen

What’s the next step?

We have scored great successes treating diffuse blood tumor through CAR-T cell therapy but not so much with solid tumors. Nonetheless, researchers are trying. Let’s pray for the best.

Source: Fesnak et al., (2016), Nature Review Cancers 16:566–581 (10.1038/nrc.2016.97)

p.s.: to target CD19, we call the chimeric antigen receptor as anti-CD19.