How Does CAR T-cell Therapy Stop Working?

A tumor cell's ability to become invisible to treatment is the primary reason why powerful CAR T-cell therapies can stop working. Understanding the mechanism for how myeloma cells evade CAR-T therapy is an important step in preventing this from happening.

At the 2025 International Myeloma Society conference, Dr. Samir Parekh shared recent research showing the different ways myeloma cells are able to change to avoid being targeted. Advanced immunotherapies, like CAR T-cell therapy, rely on a “lock and key” system. The therapy is the key. The lock is the specific protein or antigen on the cancer cell’s surface. When the cancer cell changes or removes that lock, the therapy fails, leading to relapse.

How myeloma develops resistance to BCMA therapies

Much of the research has focused on therapies targeting an antigen called BCMA. Dr. Parekh outlined several ways myeloma cells learn to evade these treatments.

Deleting the antigen. The simplest method is for the cell to completely delete both copies of the BCMA gene, removing the target entirely.

Survival of the fittest. Sometimes, a small number of myeloma cells that naturally lack BCMA are present from the start. The therapy kills all the BCMA-positive cells, leaving these resistant ones to grow and take over.

Changing the lock. A growing concern is the emergence of tiny changes, or point mutations, in the BCMA protein. These mutations alter the shape of the "lock," preventing the therapeutic "key" from fitting. Critically, a mutation might break one key but not another. A specific mutation could make a cell resistant to one drug, but still vulnerable to another therapy. 

This finding suggests that by sequencing a patient's tumor DNA before treatment, doctors could select the anti-BCMA therapy most likely to work, personalizing the approach.

Research also shows that these resistance-causing mutations are not created by the therapy itself. Instead, they exist in tiny amounts before treatment begins and are "selected" to grow when the other cancer cells are killed. This opens the door to monitoring patients' blood for these rare mutations during treatment, potentially allowing doctors to switch therapies before a full relapse occurs.

How myeloma develops resistance to GPRC5D therapies

This same pattern of resistance is now being seen in therapies targeting another antigen, GPRC5D. Patients are relapsing because their myeloma cells either delete the GPRC5D gene or acquire mutations in it.

Dr. Parekh shared a fascinating case where a patient's relapsed tumor had two different GPRC5D mutations. When scientists studied these mutations in the lab, they made a key discovery. The mutated GPRC5D protein was being made by the cell, but it was getting trapped inside and never made it to the cell surface. The cancer cell became invisible to the therapy not because it stopped making the antigen, but because it couldn't display it properly.

The path forward: Staying one step ahead of cancer

Understanding how resistance develops allows scientists to design strategies to overcome it. Dr. Parekh outlined a multi-pronged approach for the future:

Proactive monitoring. Doctors need to screen for mutations in target antigens like BCMA and GPRC5D both before and during therapy to catch resistance early.

Smarter dosing. The constant pressure of a continuous therapy might encourage resistance. Exploring therapies with a fixed, limited duration could be a way to reduce this risk.

Combination and sequential therapy. Using treatments that target multiple antigens at once (or one after another) could be a powerful strategy. If a cancer cell hides one antigen, it can still be attacked through another.

Building better therapies. The ultimate goal is to design new drugs and CAR T-cells that are resilient to these mutations, for instance, by binding to multiple parts of the same antigen. Research is ongoing to find new ways to prevent myeloma cells from evading CAR T-cell therapy.

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