Protecting cell therapies from yourself: hiding transplants from your toxic immune system

TLDR: Making antibodies attach to transplanted cells the wrong way helps hide the cells from the immune system, letting the cells live longer and do their job

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We’re going to stick to last week’s theme and talk about cell therapies again this week. Last week, we took a look at a new form of cell-based cancer treatment called CAR-T cells. This week, we’ll be going through the main points from a just-published paper (January 2023) that deals with how to keep transplanted cells alive for longer so that they can be more effective.

The Study: Protection of cell therapeutics from antibody-mediated killing by CD64 overexpression

Big Takeaways

1. Cell transplants can be rejected like organ transplants

2. Rejection often happens from the patient’s antibodies attaching to the transplanted cells and signaling the immune system to attack

3. Making the antibodies attach the wrong way tricks the immune system into not attacking

4. This lets the transplanted cells last longer and do their jobs

One major problem with cell therapies is that the patient’s native cells kill the transplanted cells. Obviously, the therapy doesn’t work if all the cells are dead.

Organ transplants and cell therapies share some of the same clinical hurdles and chief among them is the outright rejection of the transplant. Rejection is when the patient’s immune system doesn’t accept the transplant and attacks it, leading to all kinds of problems (including the therapy not working).

Rejection occurs for many reasons, but a main one is antibodies telling the immune system to attack the transplant.

Antibodies are a tool your immune system uses to fight foreign invaders. During a transplant rejection, your body views the transplanted cells as foreign objects and decides to get rid of them. This decision is communicated when antibodies attach in a specific way to the transplanted cells, letting the immune cells know they’re a target to eliminate. 

This system relies on antibodies showing the patient's immune cells where to attack. One side of an antibody attaches to a specific target (the Fab domain) and then the other side (the Fc domain) signals the host’s immune system to attack the cell it’s attached to.

Well, the authors realized that they could make antibodies attach to transplanted cells the wrong way. They engineered cell therapies to have a specific protein on their surface that attaches to the Fc domain of antibodies, trapping it in the wrong orientation and preventing it from signaling immune cells (see graphic).  

With the Fc side attached to the transplanted cell instead of the normal Fab side, the antibodies can’t signal the immune system to attack. Without this signal, the immune system never decides that the transplant needs to be destroyed.

And without being attacked and destroyed, the transplant can do its job! The authors show this with cell therapies for cancer (CAR-T again!!), diabetes, and a thyroid condition. In each case, more alive cells = better treatment outcome.

Neil is a Ph.D. Candidate at Stanford University studying Materials Science and Engineering. He works on combining different forms of drug delivery technologies to make more effective treatments.