Clinical Trial Halts for Rapid-Manufactured CAR T-Cell Therapies in Autoimmune Diseases Following Patient Fatalities

Overview and Clinical Background

Comparison of Impacted Investigational Cellular Therapies

Expert Commentary and Mechanistic Considerations

“Three deaths have to be taken seriously, and pausing was the only call. This is not a verdict, though. It is the system doing exactly what it should in a young field that is still learning its own risk profile.”

“What deserves the field’s attention is what the two products share. Rap-cel and zola-cel are both made on rapid manufacturing platforms, and the working hypothesis is that faster production yields fitter T cells that expand greater in the patient, with immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) sitting at the severe end of that inflammation.”

Risk-Benefit Profile: Autoimmune vs Oncology Populations

“The autoimmune setting also changes the risk calculus. Unlike our oncology patients, people with lupus, myositis, scleroderma or other autoimmune diseases are often younger, are not facing imminent death and increasingly have other options.”

“I would not read this as the end of cellular therapy in autoimmunity. The durable, drug-free remissions we have seen in people who had run out of options are real, and the work now is to learn who actually needs autologous CAR T and build the tools to intercept or better yet predict these events before they turn catastrophic.”

Disclosures and Contact Information

• Contact: Alfred Kim, MD, PhD (akim@wustl.edu).
• Financial Disclosures: Dr Kim reported receiving research funding from AstraZeneca, Bristol Myers Squibb, CRISPR Therapeutics, and Novartis, as well as consulting fees from AstraZeneca, Hinge Bio, Kymera Therapeutics, and Miltenyi Biomedicine.

“Despite contemporary guideline-directed medical therapy, we still lack an effective treatment for patients with heart failure associated with pulmonary hypertension. With understanding the central role of sympathetic and RAS activation in the heart failure development, so the PADN technology emerges. It was designed to interrupt sympathetic nerves surrounding the pulmonary artery. The consistent findings from prior studies included improvements in hemodynamics and exercise capacity, and many fewer clinical events. Unfortunately, neither of these studies provided definitively very strong power of the clinical benefit. So a large clinical trial was therefore required.”

“Also PADN improved the outcomes directly relevant to the patient, including 6-minute walk distance, [Kansas City Cardiomyopathy Questionnaire score] and [N-terminal pro-B-type natriuretic peptide]. At 6 months of follow-up, echocardiography confirmed the PADN plus GDMT led to significant improvements in left and right heart function, notably [right ventricular] systolic pressure decreased by 13 mm Hg and the ratio of [tricuspid annular plane systolic excursion] to [systolic pulmonary artery pressure] increased by 15 in the PADN plus GDMT group.”

“Our trial has several limitations. No. 1 is the trial was unblinded to the operators, research personnel and patients. Secondly, secondary endpoints were not powered or adjusted for multiplicity. No. 3, we need long-term clinical follow-up, particularly beyond 3 years of follow-up, to identify the real difference in all-cause deaths or rehospitalization between two groups. Finally, all patients were in rural China. However, the generalizability and the impact of blinding are being assessed in the ongoing international sham control trial PULSE-LHD.”

“when looking more closely at the primary endpoint, the picture becomes somewhat more nuanced. Only 67 patients experienced the first primary event. There was no significant difference in death, and although the numbers were lower for heart failure hospitalization, the difference was not statistically significant. So indeed, no individual conventional component of this clinical composite was significantly improved with pulmonary denervation. But most important for me, the most relevant limitation of this trial is the lack of sham control. The physicians and patients were aware of treatment allocation. And we have learned from other trials that invasive placebos can be quite powerful.”

“We have a compelling efficacy signal, [but] we require further confirmation with sham-controlled, larger trials, international with hard endpoints, and longer follow-up duration with careful phenotype selection before final conclusions can be drawn with respect to pulmonary denervation.”

“What really motivated the study is the known impact of chemotherapy on the brain, particularly in a region of the brain called the hippocampus, which is critical for memory formation and specifically for episodic memory formation.”

“There’s really a lack of understanding.”

“Verbal Paired Associates is used as a measure of episodic memory. It’s a gold standard test. But it taps into a different kind of episodic memory.”

“The standardized measures, while well validated, just may not be picking up on the subtypes of memory where deficits in that kind of everyday memory actually lie.”

“Listen to what your patients are telling you they’re experiencing. These standardized tests may not be picking up the objective evidence of their cognitive impairment despite the fact that they’re experiencing this fuzziness.”

“An easy thing that clinicians can do is listen and take the subjective cognitive reports of their patients seriously.”

“When they do actually exhibit a deficit, it may not be detectable at clinical levels. They feel that they’ve lost a lot compared to their pre-treatment selves.”

“That’s an easy one. Even if they don’t perceive hearing loss, it may in fact be contributing to their cognitive performance, and even just increasing cognitive workload. If you’re not hearing quite as well as you could be, it does take more cognitive effort.”

“We can actually visualize the brain network activation, as they recall this, and see specifically how the hippocampus is impacted at a structural and functional level.”

“Possibly, the brain is less able to recruit these regions important for memory. There’s a lack of clarity specifically of how these brain networks are impacted, so that is something that we’re currently looking at.”

“When Oregon voters passed a ballot initiative in 2020 to permit state-licensed access to psilocybin services, our group of interdisciplinary researchers talked about the need to learn about the safety and outcomes of this first-in-the-nation initiative.”

Study Cohort and Intervention Design

Psychiatric Symptom Trajectories and Well-Being

Participant Satisfaction, Perceptions, and Safety Signals

“We were struck by the low incidence of serious adverse reactions.”

“Oregon-regulated psilocybin services appear to be safe and associated with improved mental health and wellbeing. While promising, these early results need to be confirmed by comparing groups receiving psilocybin services with a control group of people who don’t access state psilocybin services.”

Invited Commentary: Diagnostic Validity and Selection Bias

• Absence of Formal Psychiatric Diagnoses: Participants were not verified through formal diagnostic evaluations. Reductions on screening scales (such as PHQ-9 or PCL-5) do not confirm DSM-defined major depressive disorder or PTSD. The clearest indicators of formal psychiatric illness were restricted to the 4 patients who developed acute behavioral reactions (two of whom were prescribed psychotropic drugs). If the broader cohort comprised largely non-clinical individuals seeking wellness, reported safety and efficacy metrics cannot be extrapolated directly to psychiatric cohorts.
• Positive Selection Bias via Prior Exposure: More than half of participants had prior psychedelic experience. Individuals who have had severe, frightening, or destabilizing reactions to psychedelics in the past are unlikely to voluntarily pay for state-licensed sessions. Consequently, the cohort was enriched with individuals preselected for biological and psychological tolerability.
• Recommendations for Future Studies: Future evaluations must systematically stratify clinical endpoints based on baseline diagnostic verification and psychedelic-naïve versus psychedelic-experienced status.