After three patient deaths and the indefinite pause of several clinical trials, questions are swirling over the future of chimeric antigen receptor (CAR) T-cell research for autoimmune diseases.
“I think this is an important moment in time for us,” Sayeef Mirza, MD, MPH, a hematologist/oncologist and cellular immunotherapy investigator at H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, told Medscape Medical News. “I think we are very excited with the advent and the discoveries of how beneficial CAR T is for lupus and scleroderma and multiple sclerosis, which are kind of the first poster children of autoimmune disease, being successfully treated with CAR T-cell therapy. But with these types of toxic and fatal events, it's a moment for pause to figure out what we can do as cellular therapists and hematologists and disease specialists. How can we work together to prevent this from happening?”
On August 24, Novartis announced it had suspended eight phase 2 and phase 1/2 trials of an autologous CD19-targeting product called rap-cel, developed to address autoimmune and neurologic diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis, systemic sclerosis (SSc), and Sjögren disease. The pause was triggered by three cases of immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), all of which were fatal.
In a statement to Medscape Medical News, Novartis said the trials were on hold for the foreseeable future as the Swiss drugmaker worked with stakeholders to find answers.
“Novartis has temporarily paused rap-cel trials in immunology and neuroscience, following notification of serious IEC-HS events — a well-known [adverse event] in patients receiving CAR T-cell therapy,” the statement read. “We are engaging with the respective independent data monitoring and steering committees and actively sharing information with global health authorities. The safety and well-being of patients is of paramount importance to Novartis, and we remain committed to addressing the needs of these patient populations.”
Bristol Myers Squibb (BMS) subsequently implemented its own voluntary pause on studies for a rival CAR T-cell product, zola-cel, “out of an abundance of caution,” according to a report from Reuters. BMS did not respond to messages seeking additional comment.
The pauses stunned the research community, as CAR T-cells were hailed earlier this year as a potential game-changing therapy for autoimmune conditions. For example, a study published in January in Nature Medicine enrolled 24 patients (10 with SLE, nine with SSc, and five with idiopathic inflammatory myopathies), all of whom received a single infusion of zorpo-cel, a CAR T-cell product similar to zola-cel and rap-cel but that was not a part of the paused trials, after they stopped immunosuppressive treatments.
Potentially serious adverse events — cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) — were moderate or did not occur at all, respectively. Regarding efficacy, 22 of the participants achieved predefined efficacy endpoints, with nine of 10 patients with SLE reaching remission, all nine patients with SSc showing no disease progression, and four of five patients with idiopathic inflammatory myopathies reaching major or moderate response.
“[The study] suggests the feasibility, safety, and efficacy of zorpo-cel in three different autoimmune diseases and paves the way for conducting a pivotal study,” the study authors concluded.
The Root of the Problem
While originally identified as an oncology complication, IEC-HS has now become a focal point in rheumatology research. IEC-HS is generally defined as a pathologic immune reaction with features of secondary hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome, occurring independently from or as a worsening continuation of CRS.
“IEC-HS is a state of usually sterile inflammation where you have to intervene with immunosuppressive treatment regimens,” Georg Schett, MD, vice president of research and head of the department of medicine 3 at Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany, told Medscape Medical News. “IEC-HS is rare in cancer patients treated with CAR T cells — less than 5% — and it’s also rare in autoimmunity. It does not seem that there is an intrinsically higher risk for IEC-HS in autoimmune diseases.”
A real-world study published in May in Cancers examined 301 adults with hematologic malignancies treated with commercial CAR T-cell products. IEC-HS was identified in 14 individuals, representing an overall incidence of 4.7%. The complication developed across multiple hematologic malignancies, with onset occurring at a median of 10 days following infusion, emerging either during ongoing CRS or shortly after its resolution.
Still, the two conditions are clinically distinct. CRS is a direct outcome of infused CAR T cells engaging their target antigen, leading to the large-scale activation of interleukin (IL)-6, IL-10, and TNF-alpha. IEC-HS involves a pathologic feedback loop between CAR T cells and host macrophages.
Further, CRS usually peaks in the first week post-infusion, while IEC-HS typically manifests after CRS has crested or resolved. According to guidelines from the American Society for Transplantation and Cellular Therapy, although CRS is a primary risk factor for IEC-HS, the latter condition operates as a distinct phenomenon rather than simply “severe CRS.”
According to Daniel Lee, MD, associate professor and director of pediatric hematopoietic stem cell transplantation and cellular therapy at the University of Virginia (UVA) School of Medicine and the UVA Comprehensive Cancer Center, Charlottesville, Virginia, “we simply do not know enough about T-cell biology and its interplay with the rest of the immune system, particularly when it has been previously exposed to other immuno- or chemotherapies, to be able to predict [CAR T-cell] expansion for a particular patient.”
“This is not to say that the approach should be abandoned, just that we need to dive deeper to understand more,” Lee told Medscape Medical News. “What we do know when it comes to CAR T-cell toxicities, including IEC-HS, is that they result from an uncontrolled, supraphysiologic activation of multiple components of the immune system. Macrophages and other myeloid-derived cells are implicated in particular. The more [CAR T-cell] activation and expansion that occurs, the more the bystander immune system is activated, which can then perpetuate the process by further activating CAR T cells. The lack of our ability to control CAR T cells once infused is at the root of the problem.”
Seeking Answers
That uncertainty is leading to questions over what, if anything, can or should change in autoimmune CAR T-cell trials moving forward. Both Novartis and BMS used rapid manufacturing platforms to generate more CAR T cells more quickly. This approach has emerged as an early potential explanation for the adverse events.
“Faster production methods shift the proliferation of therapeutic cells from ex vivo to in vivo, which may precipitate a hyperinflammatory state,” Schett said. “Hence, modifying the production process or administering lower cell numbers may be critical.”
This is easier said than done, Schett added, particularly in light of the serious and highly time-sensitive oncologic indications the cell products are in part designed to combat.
“Fast CAR T-cell production is important in acute lymphoblastic leukemia because this disease is rapidly progressing and kills the patient,” Schett explained. “In autoimmunity, you don't have such hurry. It’s usually not a matter of a few weeks. And so, I think it is obviously better to have a rather safe product with low risk of inflammatory toxicities.”
Experts cautioned, however, that it was too early to speculate on a reason behind the toxicities and that the causes are likely multifactorial.
“Rapid manufacturing has been shown to increase the proliferative capacity and cytokine production of CAR T cells, which may lead to higher efficacy but also incidence of side effects,” Aimee Payne, MD, PhD, Herbert and Florence Irving Professor and Chair of Dermatology at Columbia University Vagelos College of Physicians and Surgeons, New York, told Medscape Medical News.
“But we need more details to know all the contributing factors,” she said. “For example, what disease indication did the IEC-HS cases occur in, was diagnosis delayed, were there any other contributing factors such as fever, occult infection or viral reactivation, or possibly rare genetic mutations that may have increased the risk of IEC-HS occurring? These are the data we hope to learn as soon as possible so that the field can advance safely.”
Patient selection as well as issues like dosage considerations could also be pieces of the puzzle, experts noted.
“With three deaths due to IEC-HS, one must re-examine the eligibility criteria, among many other factors, for these autoimmune trials,” Lee said. “No doubt the companies are doing that. Equally as important is to reassess the product being given, starting with dose. Analyzing expansion kinetics in patients … and partnering this with CAR T phenotype (before and after infusion), [and analyzing] cytokine/chemokine and toxicity data may reveal some important correlates for enhanced toxicity risk. The protocol and/or product can then be modified accordingly.”
Researchers pointed to the complex relationship between the disease and the treatment.
The state of hyper-inflammation present in patients with rheumatologic or other autoimmune diseases has the potential to convey a “higher risk of HLH, but the CAR T cells that we give them are also requiring expansion, and there might be some interplay between the host immune system and the new CAR T cells that are being put in, whether they’re allogeneic or autologous,” Mirza said. “And if they're rapidly manufactured and they’re super-robust and super-potent type of immune cells going into a hyper-inflamed environment, you have all the stars aligned for a very toxic outcome. And so, the treatment for that is more immune suppression to calm the immune system down.”
Schett emphasized that cross-functional teamwork was essential in identifying and responding to any problems that emerge in patients undergoing CAR T-cell therapy.
“I think is very important to have good monitoring and a skilled team,” Schett said. “I think at the end, such complications may be avoided when there is a rigid patient selection. So, if one is not sure if there is concomitant infection or the inflammation level due to autoimmune disease is high or the patient has fever, just take your time, evaluate the patient carefully before you start. I think these considerations are important to avoid such reactions. CAR T-cell treatment can be life-changing — a single infusion can stop the disease. But of course, this treatment is not like an aspirin. It’s actually something you have to give into the hands of a skilled team, and I think that’s very important for consideration in the future.”
Mirza reported consultancy/advisory/honoraria support from BMS, Gilead Sciences, Guidepoint, Prime Education, Curio Science, and OncLive, and he is part of the BMS speaker’s bureau. Schett disclosed financial relationships with BMS, Cabaletta Bio, Janssen Biotech, Kyverna, and Novartis. Lee holds a patent related to mitigating CAR T-cell toxicities. Payne is co-founder of Cabaletta Bio.
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