Is CAR-T dangerous?

When the body encounters a foreign material, it releases inflammatory molecules called cytokines that signal to other cells to fight against the invader. These cytokines are what CAR-T cells are engineered to release when they find cancer cells. The most recent version of CAR-T has allowed an increase of cytokines to be released, which have been found to be more efficacious in eliminating tumors compared to previous generations.

However, everything comes at a cost. High cytokine concentrations produced by working CAR-T therapy can lead to Cytokine Release Syndrome. The cytokines released by our overworking immune system can damage our bodies and lead to associated toxicity such as fever and blockage of arteries. The more cancer cells we have, the more aggressive CAR-T responds and so the greater the release of cytokines.

Additionally, neurological toxicity was detected in patients receiving CAR-T transfer, contributed by the cytokine release resulting in symptoms of confusion, seizures and delirium. Moreover, studies have found CAR-T therapy could contribute to cerebral oedema , which is fluid buildup in the brain. However, these are just some observational data, and the field must be further investigated to instigate whether the issue corerlates directly with therapy or adoptive cell transfer. More info.

Another problem with CAR-T therapy is known as “on target, off tumor” effects, which occurs when CAR-T kills non-cancer cells that happen to have the same molecular signature being targeted from the tumour. As current CAR-T cell therapies are used to treat acute myeloid leukemia, off tumor effects result in a problem known as B cell aplasia (killing of our own white blood cells). Worse, this could result in attack on different organs around our body such as the gut or the lungs.

Other potential problems with CAR-T includes graft versus host disease (GVHD) , which is when our bodies reject CAR-T cells as they are seen as foreign material, dosage problems and the inability for CAR-T to keep up with growing cancer cells. Current CAR-T receptors are engineered with mice proteins which have been observed to cause anaphylaxis stemming from GVHD. Furthermore, studies of CAR-T cells against breast cancer cells have reported to develop respiratory failure, potentially because we still do not know what the best dose is for this therapy.

However, the amount of dose required for CAR-T cells also depends on what type of cancer you have, which adds more layers of difficulty. As cancers have a property of changing their surface proteins to trick our immune system, another problem scientists must face is targeting the most dominant protein for each cancer. As an example, in testicular cancer, targeting a protein called MAGE showed to be toxic to the heart, but targeting another protein called NY found to be less toxic.

Many of the complications associated with CAR-T toxicity stems from lack of understanding provided CAR-T is at the frontier of immunotherapy, the good news is, we have potential solutions.

To overcome Cytokine Release Syndrome, it has been found that CAR-T therapy followed by the usage of steroids to inflammation can reverse Cytokine Release Syndrome symptoms. However, the disadvantage is albating CAR-T cell function, because steroids have a global effect on our bodies halting all immune inflammatory processes.

Alternatively, use of biologics targeting specific inflammatory receptors (ie. IL-6R) provides promising results to counteract Cytokine Release Syndrome and is less limiting of CAR-T function compared to using steroids. Currently, grading Cytokine Release Syndrome risk has been used to evaluate probability of developing adverse responses to CAR-T therapy , which could aid monitoring the suitability of certain candidates to undergo treatment.

In overcoming on target off tumor effects, CAR-T therapy research aims to discover localization methods of the cell towards the tumor, preventing non-specific inflammation on our normal organs and cells.

Associated toxicities relevant to dosage require further examination of patients receiving therapy, inclusive of analysis on both the highly expressed cancer protein followed by examination of CAR-T toxicity associated with targeting the molecule (weighing costs and benefits), given that many cancers actually disguise themselves with our own proteins!

Fortunately, GVHD can be mitigated by humanizing CAR-T cells, or using stem cell transplantation from the donor (repopulating recipient cell lines) prior to CAR-T in order for our immune system to not see the T cells are foreign.

Further suggestions as an alternative to CAR-T, also at the frontier of immunotherapy, is using checkpoint inhibitor blockade to restore functionality in exhausted T cells. Although CAR-T therapy is considered an efficacious, target specific cellular therapy treatment, more investigations on associated toxicities, tumor antigen targeting as well as the necessity of taking patient history and current condition analysis must be taken into account.