A UC Irvine Team Names Five Mitochondrial Drug Classes for CAR-T Neurotoxicity, and Says Nobody Is Testing Any of Them
The candidate list is specific enough to act on, and every compound on it is generic, preclinical or owned by somebody else. A perspective in Frontiers in Pharmacology argues that mitochondrial dysfunction sustains ICANS after peripheral cytokines are controlled, sets out four criteria for selecting repurposing candidates, and states that none of the resulting classes is under formal investigation for ICANS.
A perspective article, not original experimental work. The authors synthesise published mechanism data on mitochondrial contributions to neuroinflammation, then apply a four-domain selection filter, mechanistic relevance, CNS bioavailability, oncologic safety and translational precedent, to generate a candidate set. Leflunomide is worked through as a prototype, with a proposed four-stage evaluation pathway from preclinical validation to a randomised trial against standard prophylaxis.
Findings
- Five candidate classes are named: DHODH inhibitors (leflunomide, teriflunomide), mitochondrial-targeted antioxidants (elamipretide, SS-31), NLRP3 inhibitors with mitochondrial activity (MCC950, OLT1177), AMPK activators (metformin), and cGAS-STING inhibitors. The authors state that none is currently under formal investigation for ICANS prophylaxis or treatment.
- The mechanistic claim is that mitochondrial damage-associated patterns sustain CNS inflammation autonomously through microglia and astrocytes, which the authors offer as an explanation for why ICANS can persist or worsen after peripheral cytokine control is achieved.
- Leflunomide satisfies all four criteria on paper: DHODH sits on the inner mitochondrial membrane, its metabolite teriflunomide is approved for relapsing multiple sclerosis with cerebrospinal fluid levels measured in trial populations, and it carries a long rheumatoid arthritis safety record plus activity against cytomegalovirus.
- The obvious objection is addressed directly. DHODH inhibition could suppress CAR T-cell expansion, and the authors propose three mitigations: the inhibition is reversible, it preferentially hits rapidly proliferating cells, and it can be rescued with uridine supplementation, alongside dosing holidays across the expansion window.
- The comparison set is steroids. Grade 1 to 2 ICANS is treated with 10 mg dexamethasone doses and grade 3 to 4 escalates to 1000 mg methylprednisolone, with high-grade ICANS reported in up to 10% of cases in pooled analyses.
The commercial reading sits in the sentence the authors intend as an opportunity. A therapeutic space is open because leflunomide is a generic isoxazole approved in 1998, metformin costs pennies, and MCC950 and OLT1177 are tool compounds without a late-stage sponsor. Elamipretide is the only candidate with an obvious commercial owner. The named steroid-sparing agents already in trials, tocilizumab, anakinra, dasatinib, ruxolitinib, lenzilumab, all have sponsors with a reason to fund the study. A randomised ICANS prophylaxis trial of a generic has no such party, which is the standard failure mode of repurposing rather than a gap in the science.
No new experimental data, no ICANS-specific preclinical validation of any named candidate, and no clinical evidence in this indication. The mitochondrial mechanism is inferred from adjacent neuroinflammatory settings rather than demonstrated in ICANS tissue. The article carries one named reviewer, and the authors disclose that generative AI was used to produce the figures.
No financial support was received for the work. The senior author reports unlicensed patents in cellular immunotherapy held by Moffitt Cancer Center and a consultancy with Kite Pharma, whose axicabtagene ciloleucel carries the prophylactic dexamethasone schedule this line of work would eventually seek to displace. The remaining authors declare no competing interests.
Zahedi A, Ifejeokwu OV, Griffin SP, Dean EA. Repurposing mitochondrial-targeting drugs for management of ICANS in CAR T-cell therapy: a novel steroid-sparing approach. Frontiers in Pharmacology, volume 17, published 28 July 2026.