ECTRIMS 2025 | CAR-T therapy in MS: mechanism of action and potential adverse events

CAR-T therapy stands for chimeric antigen receptor T-cell therapy, and it’s a synthesized engineered hybrid molecule that’s derived from the patient’s own T-cells whether autologously or allogeneically and then often by a viral transducer such as lentivirus. There’s a transduction of the T-cell line to express essentially a B-cell receptor called a single chain variable fragment. What we end up with then is a hybrid molecule that combines the exquisite specificity of recognition of an antibody to the potent cytotoxic cytolytic action of T-cells. So it combines the best of both worlds. As a therapeutic, what this offers is precise target recognition which should minimize off-target effects and yet at the same time potency. With respect to multiple sclerosis, one of the great values of CAR-T therapy is that based on the human’s own T-cells, there is what has been called deep tissue penetration. In neurology, what that means is this molecule, this hybrid molecule that expresses a receptor can get into the central nervous system. So there’s central nervous system penetration with CAR-T molecules and deep tissue penetration otherwise. So we can get you know entrance into lymphatics as well. Given the potential of CAR-T therapy, we designed what to our knowledge is the first prospective Phase I study of using CAR-T therapy, in this case with a CD19 binding site. So that recognizes the glycoprotein that’s expressed over some of the entire spectrum of B-cell development, but spares the marrow, which is important for regeneration and reconstitution of B-cells. And then on the other end the terminal differentiation of mature B-cells which would be plasma cells elaborating antibodies, those are also spared because they don’t typically plasma cells don’t typically express CD19. But the molecule does recognize the series of maturation steps of B-cells essentially in between those two bookends and that includes importantly memory B-cells. So at the same time, while it seems as if there may be great potential for using CAR T-cells for neuroimmune diseases in general and maybe multiple sclerosis in particular, the use of CAR-T therapy in B-cell leukemia, B-cell lymphoma and oncologic purposes has been associated and known to be associated with sometimes very significant side effects which can include cytokine release syndrome and what’s been called immune cell effector associated neurocytotoxicity syndrome or ICANS. So CRS or ICANS. And those are neurologic manifestations that occur by essentially abrupt lysis of large cell masses such as in a CNS B-cell lymphoma. CAR T-cells can recognize the CD19 binding site on these B-cells that collect in large chunks in these cases and there can be a significant release of intracellular contents all at once into the central nervous system. That can result in mental status change, encephalopathy, confusion, tremulousness, dysgraphia, word hesitation and and even seizures. So there can be very significant risks, and there have been significant complications seen with the use of CAR-T in some neurooncologic and neuroimmunologic indications. So we have a balance. On one hand the mechanism of CAR-T suggests potential in multiple sclerosis and great potential perhaps in the treatment of MS given central nervous system penetration. But at the same time, there are risks that remain undefined.

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