Autoimmune CAR T Has Hit A Critical Moment. Are We Asking The Right Questions?
By Erin Harris, Editor-In-Chief, Cell & Gene
Follow Me On Twitter @ErinHarris_1
The promise of CAR T in autoimmune disease has never been more compelling. The field is moving from intriguing clinical signals toward the possibility of durable, drug-free remission in diseases that have historically required lifelong immunosuppression.
But this week brought a sobering reminder that autoimmune CAR T is not simply oncology CAR T in a different patient population.
Novartis has paused eight clinical studies of its CD19-directed CAR T, rap-cel, in autoimmune and neurological diseases following three patient deaths associated with immune effector cell-associated hemophagocytic syndrome (IEC-HS). The company is reviewing the safety data with regulators. Its oncology studies of rap-cel are not affected.
Bristol Myers Squibb has also voluntarily paused enrollment in autoimmune studies of its CD19 CAR T, zola-cel, after observing what it described as transient and reversible inflammatory events.
These developments do not erase the remarkable clinical potential of autoimmune CAR T. But they do raise an important question for the industry. Are we evaluating these therapies through the right lens? That is exactly why the recent episode of Cell & Gene: The Podcast featuring Dr. Panteli Theocharous, FIBMS, M.S., Ph.D., FRCPath, is so timely.
Autoimmune CAR T Has a Different Risk-Benefit Equation
Dr. Theocharous brings more than three decades of experience across clinical medicine, cell therapy development, and clinical strategy. He argues that one of the industry’s biggest mistakes is carrying the risk tolerance established in relapsed or refractory oncology directly into autoimmune disease, as the patient sitting across from the clinician may be very different.
A patient with lupus, myasthenia gravis, or another autoimmune disease may be working, caring for a family, and maintaining reasonable function on an imperfect but established treatment. That changes the benefit-risk calculation. The potential upside of CAR T may be enormous, but so is the responsibility to understand what patients are being asked to accept in exchange for that potential benefit.
The recent Novartis and BMS developments make that distinction particularly important.
The pauses are not evidence that autoimmune CAR T does not work. They are a reminder that the bar for safety, durability, patient selection, trial design, and ultimately commercial adoption must be appropriate for the diseases being treated.
The Endpoint May Matter as Much as the CAR
One of Dr. Theocharous’ most interesting observations is that autoimmune CAR T developers need to think carefully about what constitutes meaningful clinical benefit.
In oncology, a reduction in tumor burden or progression-free survival can represent an enormous clinical benefit because the underlying disease may be rapidly progressive and fatal.
Autoimmune disease is different. The comparator may be a chronic condition that is being reasonably controlled with existing therapies. That means developers have an opportunity to demonstrate something much more meaningful than a biomarker shift or an incremental change in disease activity. He points to the emerging importance of durable remission and the ability for patients to potentially move away from long-term immunosuppression.
That distinction could ultimately influence how these therapies are evaluated by physicians, patients, payers, and regulators. And it could help determine which CAR T programs change the treatment paradigm rather than simply add another option to it.
The Bottleneck May Not Be Manufacturing
For the CGT industry, we are accustomed to talking about manufacturing as one of the biggest obstacles to CAR T access. Dr. Theocharous offers a different perspective for autoimmune disease.
He identifies referral and screening as an underappreciated bottleneck. Rheumatology, neurology, and nephrology do not have the same longstanding referral infrastructure connected to certified cell therapy centers that oncology has developed. Closing that gap will require deliberate investment in clinical education and coordination across sponsors, sites, CROs, and referring physicians. That is an important shift in thinking for biotech leaders.
A therapy can be scientifically successful and still fail to reach the patients who need it if the healthcare infrastructure around it is not ready.
And that brings us to a much bigger issue, which is that operational feasibility cannot be something companies figure out after the clinical science is established.
Dr. Theocharous argues that developers need to work backward from real-world cost, access, delivery infrastructure, manufacturing, and logistics much earlier in development.
The Industry Is Beginning to Test the Limits of the Model
This is where the current landscape gets particularly interesting. On one track, conventional autologous CAR T is producing increasingly compelling evidence that immune reset may be possible in autoimmune disease. On another, developers are exploring approaches that could fundamentally change how these therapies are delivered.
Dr. Theocharous discusses both trajectories in the podcast, including emerging approaches that could potentially address some of the logistical challenges built into today's autologous model. But he is also careful about distinguishing exciting early science from an established clinical pathway. That distinction matters now more than ever.
The Novartis and BMS pauses are a reminder that the field still has important safety questions to answer. At the same time, the clinical promise is strong enough that companies continue to pursue the modality aggressively.
For CGT developers, the lesson may be that the next generation of autoimmune therapies cannot be judged solely on whether the CAR works. They will need to work for the patient, the clinical site, the manufacturing organization, the healthcare system, and ultimately the payer.
The Patient Must Be the North Star
The most important takeaway from my conversation with Dr. Theocharous is that the patient journey does not begin with infusion and end with discharge. It includes referral, eligibility, apheresis, manufacturing, bridging, conditioning, monitoring, recovery, long-term follow-up, and the emotional and practical burden carried by patients and caregivers along the way.
As autoimmune CAR T moves closer to becoming a real treatment option, developers have an opportunity to learn from the successes and challenges of oncology while recognizing that they cannot simply replicate the oncology model. And with two major companies now pausing autoimmune CAR T studies for safety reviews, that conversation has become even more urgent.
I explore these issues and much more with Dr. Theocharous on the latest episode of Cell & Gene: The Podcast. Listen to the full episode to hear his insightful perspective on the patient journey, trial design, safety, manufacturing, emerging delivery approaches, and what autoimmune CAR T could teach the broader CGT industry.