NEW YORK – After seeing how autologous CAR T-cell therapies have revolutionized cancer treatment, biopharmaceutical companies are eager to emulate their success in other disease settings.
But even as companies take lessons from oncology in testing CAR T cells in other diseases, the industry must contend with intensive treatment protocols, high costs, and risks that patients, unlike those with a terminal cancer diagnosis, may not want to take.
Autologous CAR T-cell therapies require a patient's own immune T cells to be extracted and engineered to target antigens expressed on other cells that are involved in a particular disease. This is done by inserting a chimeric antigen receptor (CAR) gene that can recognize target cell-surface proteins. For example, CAR T-cell therapies on the market for certain blood cancers, such as leukemia, lymphoma, and multiple myeloma, are designed to target B cells, the immune cells that become abnormal in these malignancies.
The first such therapy, Novartis Pharmaceuticals' Kymriah (tisagenlecleucel), was approved by the US Food and Drug Administration in 2017 as a treatment for B-cell acute lymphoblastic leukemia. Since then, the FDA has approved six other CAR T-cell therapies for various hematologic cancer indications, and there are nearly 1,000 active clinical trials evaluating these cell therapies in cancer and other diseases.
It took three decades from when the first CARs were conceptualized in cancer to the approval of the first CAR T-cell therapy product, noted Saad Kenderian, a hematologist-oncologist at the Mayo Clinic in Rochester, Minnesota, who leads a translational research program studying T-cell biology and engineering. Researchers and drug companies now investing R&D budgets into developing and repurposing CAR T-cell therapies in other settings have the benefit of that foundational work and the market experience of the first products.
"We continue to learn how to make CAR T better, more effective, and safer," Kenderian said.
Still, drugmakers pursuing CAR T-cell development in non-cancer indications will have to be strategic when deciding what indications to start with and prove not only their safety and efficacy, but also that the benefits are worth the risk and the likely high cost of treatment — a calculation that might be very different than in cancer.
Accepting risk
Numerous approaches to CAR T-cell therapies are being tested to treat autoimmune conditions, eliminate viruses, and more. But unlike cancer, many of these conditions are not fatal and have other medication options, which means there's a different risk-benefit calculus for patients and physicians when prescribing CAR T-cell therapies or enrolling in clinical trials of such treatments.
While the gold standard when evaluating the efficacy and safety of a new cancer treatment is whether it extends a patient's life compared to standard care, plenty of therapies come to market having shown the ability in single-arm trials to shrink tumors or stave off disease progression for a while. Cancer patients facing death, especially if they have aggressive and advanced tumors that aren't responding to existing treatments or if they have few, if any, options left, are often willing to take their chances even if the benefits are limited, the side effects dire, and the financial costs enormous.
For example, more than 80 percent of blood cancer patients on CAR T-cell therapies achieve complete remission, but after a year or two, many relapse. Cancer patients considering CAR T-cell therapy, typically after a recurrence or because they've stopped responding to other first- or second-line treatments, have a high threshold for tolerating the risks and toxicities, Kenderian said. "Patients who have relapsed, refractory cancer don't have other options," he said.
Just last week, the FDA approved Autolus' Aucatzyl (obecabtagene autoleucel) for treating refractory B-cell precursor acute lymphoblastic leukemia (ALL) based on data from a single-arm trial, in which 27 out 65 patients achieved a complete response after three months of receiving the CAR T-cell therapy and these complete responses lasted a median 14.1 months. "Adult ALL is an extremely aggressive cancer, and there is a high unmet medical need that exists in the treatment of patients with this disease once they relapse, where historically they suffer from poor outcomes," Elias Jabbour, lead investigator of the trial that led to Aucatzyl's approval and ALL section chief at MD Anderson Cancer Center, said in a statement.
For the chance to benefit from CAR T-cell therapy, patients undergo an intense treatment process. To extract and collect the T cells needed to create a CAR T-cell therapy, patients undergo a multi-hour process known as leukapheresis. The collected cells are engineered into CAR T cells at a lab, a process that can take multiple weeks. The engineered CAR T cells then have to be shipped back to the hospital for reinfusion into the patient. But before the patient can receive them, the physician might recommend chemotherapy to deplete other T cells in the body so that there's room for the new cells. After treatment, patients can have serious side effects such as cytokine release syndrome (CRS) or neurological issues that require them to remain hospitalized for days or even weeks.
After factoring in the cost of the treatment and hospital stays, CAR T-cell therapies are some of the priciest on the market. The average total cost of care for patients with relapsed or refractory B-cell non-Hodgkin lymphoma who receive CAR T-cell therapy, for example, is more than $600,000 based on an analysis of private insurance claims published in 2022, and insurance coverage varies.
That's likely one reason why a sizeable chunk of patients who are eligible for CAR T-cell therapy don't get it, though the demand remains high. Despite the risks and high cost, drugmakers have struggled to keep up with demand for CAR T-cell therapies in oncology. At some hospitals, cancer patients are waiting months to receive them and many die waiting for their shot at CAR T-cell therapy.
Outside of cancer, however, all of these considerations could make CAR T-cell therapy a tough sell for patients suffering from diseases where there are generally effective, if imperfect, treatments on the market. This means drugmakers will have to figure out how to cut down those risks for CAR T-cell therapy in these other settings.
Autolus, for example, has launched a Phase I study in the UK to test Aucatzyl in patients with lupus, a chronic autoimmune disease that can have mild to severe symptoms. In the trial, however, researchers at the University College London Hospitals (UCLH) and UCL are focusing on patients with a severe form of the disease who have stopped responding to existing medications. "We have seen the effectiveness of CAR T in cancer, particularly blood cancers, and hope we can replicate this in autoimmune diseases, starting with lupus," Maria Leandro, a consultant rheumatologist at UCLH, said in statement announcing the start of the lupus study.
In the FDA-approved label for Aucatzyl, there is a boxed warning for CRS and neurological toxicities, which occurred in 75 percent and 64 percent of patients, respectively. However, only 3 percent had grade 3 CRS and 12 percent experienced grade 3 or higher neurological toxicities. Autolus has highlighted the low rate of higher-grade toxicities and that Aucatzyl is the first CAR T-cell therapy the FDA has approved without a Risk Evaluation Mitigation Strategy program.
A more manageable safety profile can be a particularly attractive feature for Aucatzyl as Autolus tries to expand its use into lupus, and researchers currently enrolling patients into the lupus trial of the cell therapy are already highlighting this fact. "It is fantastic to be involved in the wider development of the UCL-innovated, 'low toxicity' CAR-T therapeutic … for patients with refractory lupus," Claire Roddie, a UCLH consultant hematologist and UCL Cancer Institute researcher, said in a statement. "In early-phase trials of patients with blood cancers we showed that [Autolus' CAR T-cell therapy] was well tolerated and resulted in durable remissions in substantial numbers of patients. We are hopeful that [it] will have a similarly transformational impact in patients suffering the debilitating symptoms of refractory lupus."
Managing cost
Autolus has set a list price of $525,000 for Aucatzyl, which the company believes "reflects the clinical evidence and benefit we have observed to date as well as the differentiated safety profile," Autolus COO Christopher Vann said on a call with investors and market analysts this week.
It's unclear how the firm would price Aucatzyl for an indication in lupus, a condition in which patients likely will have a different threshold for risks and benefits, if the product continues to advance to late-stage clinical trials and regulatory approval. A company spokesperson said that Autolus expects to present initial clinical data from the Phase I trial in lupus in Q1 2025, but that the company does not comment on pricing at this stage.
There are many factors to consider in a cost-effectiveness analysis, said Dan Ollendorf, an assistant professor at Tufts University School of Medicine and director of value measurement and global health initiatives at Tuft's Center for the Evaluation of Value and Risk in Health. If a CAR T-cell therapy is expected to be a one-time, durable treatment, a cost-effectiveness analysis should assess its price against other healthcare services and chronic medications that the patient may have otherwise needed, many of which are also expensive.
"Certainly, a big difference in thinking about the economic argument for CAR Ts in cancer, versus something like autoimmune disease, is in cancer there's also the potential to increase survival by a pretty significant amount … which also makes the cost-effectiveness argument more favorable," Ollendorf said. "That is going to be somewhat different when we move into these other indications."
In autoimmune diseases, drugmakers are typically aiming to significantly improve patients' daily functions and quality of life, but not necessarily extend survival, since these illnesses aren't fatal for most.
If CAR T-cell therapies prove their efficacy and ability to provide long-term remission in late-stage clinical trials, there may be a larger, younger, and potentially healthier population that could also benefit from these products, said Denise Chambley, head of global medical solutions at Amplity Health, a contract sales and commercial organization that works with pharmaceutical and biotech companies. "In this situation, payors will have the challenge of identifying and implementing payment models and prior authorization processes to address the high upfront costs and administration needs of a therapy, relative to the enduring benefits it offers a larger population."
Last-ditch effort
Autoimmune conditions like lupus, in which a person's immune system erroneously attacks healthy tissues, are among the most active areas for autologous CAR T-cell therapy development outside of cancer. While these autoimmune conditions are chronic but typically not fatal diseases, with many patients living normal lifespans, they are mediated by B cells like the blood cancers for which CAR T-cell therapies have been developed and launched on the market.
Drugmakers are hoping that infrequent CAR T-cell therapy infusions every few years, or potentially even as a one-time treatment, could take patients with these chronic conditions into clinical remission, precluding the need for other drugs that some would need to take for their entire lives. Taking lessons from oncology, however, companies investigating CAR T-cell therapies for autoimmune diseases, including Bristol Myers Squibb, Iaso Biotherapeutics, and Kyverna Therapeutics, are initially testing CAR T-cell therapy in patients with severe disease who aren't responding to standard treatment.
The strategy has yielded some promising results. In a study out of Germany, for example, 15 patients with refractory systemic lupus erythematosus, idiopathic inflammatory myositis, or systemic sclerosis treated with a CAR T-cell therapy achieved drug-free remission. It's too early to say if the CAR T-cell therapy has permanently cured patients, since researchers have only followed them for a median of 15 months post-treatment.
It makes sense to start testing within a relapsed and refractory population, since there are existing effective treatments on the market, in Kenderian's view. "It's the ethical thing to do," he said. Kenderian noted that CAR T-cell therapies on the market were initially approved as third-line treatments for advanced cancers, but the FDA has begun approving them as earlier, second-line treatments, and researchers are now starting to investigate them in the first-line setting.
Assessing whether CAR T-cell therapy can be moved up in the line of treatment is something Christopher Blosser, a kidney transplant specialist and director of Fred Hutchinson Cancer Center's cancer and organ transplant clinic in Seattle, is interested in investigating in post-transplant lymphoproliferative disorder (PTLD), a rare complication of solid organ transplants.
PTLD describes a group of potentially fatal conditions, most frequently caused by the oncogenic Epstein-Barr virus, which commonly infects patients whose immune systems are weakened due to pre-transplant immunosuppression therapy. The virus can infect B cells that multiply, leading patients to develop lymphomas.
In a paper published in Bone Marrow Transplantation last year, Blosser and colleagues reported outcomes from a patient who developed PTLD after receiving a kidney transplant. The patient had achieved only a partial remission after first- and second-line therapy, including R-CHOP, a cocktail comprising Genentech and Biogen's monoclonal antibody Rituxan (rituximab) and chemotherapy, as well as other second-line chemotherapy. The patient was so sick that he wasn't a candidate for a stem cell transplant, since he wouldn't be able to tolerate its toxicities and infection risks, Blosser said.
The patient was only the 17th person in the world to receive a CAR T-cell therapy for PTLD. "At the point that he was considered for CAR T therapy, it was because there was no other option," Blosser said. "It was our last-ditch effort."
Since CAR T-cell therapy, this patient has recovered and achieved remission. Blosser has been working with other physicians in the US looking to use CAR T-cell therapy to treat patients with PTLD and said he's interested in studying whether CAR T-cell therapy can be used in patients who are refractory to R-CHOP but haven't yet failed other salvage therapies.
Less intensive treatment
One of the companies furthest along in advancing autologous CAR T-cell therapy for autoimmune conditions, Cartesian Therapeutics, is testing its lead candidate Descartes-08 as a treatment for lupus and generalized myasthenia gravis (gMG) in Phase II trials, aiming to bring it to patients with less severe disease. Its strategy for making CAR T-cell therapy attractive to a broader population is to make the treatment process less intensive.
As part of the standard of care for autoimmune diseases today, many patients will take chronic immunosuppressants and other lifelong medications to relieve disease symptoms. Patients with lupus, for example, might take Sanofi's antimalarial drug Plaquenil (hydroxychloroquine), corticosteroids, or biologics. Patients with gMG might take cholinesterase inhibitors to improve muscle strength and complement inhibitors to block portions of the immune system. It can take years to find the right combination of treatments, and even then, patients may stop responding and need to switch medications.
Cartesian is testing Descartes-08 as a treatment that's administered in six weekly outpatient infusions. Unlike other CAR T-cell therapies, it doesn't require preconditioning chemotherapy, which reduces the likelihood of toxicities like CRS and the need for inpatient monitoring. Also, unlike standard CAR T-cell therapies, Descartes-08 relies on modifying mRNA, rather than DNA. Since mRNA doesn't replicate with cell division, there also aren't permanent changes to the genome. The CAR protein is only expressed for about a week, and an exponential increase of CAR T cells after infusion hasn't been seen in patients as it has been with DNA-based CAR T-cell therapy.
That may open the door to using CAR T-cell therapy more broadly in autoimmune diseases and treating less severe conditions. "If you're giving chemotherapy, if you need inpatient monitoring, it really restricts the indications to the most severe phenotypes where there are really no other options," said Cartesian Chief Medical Officer Miloš Miljković.
Cartesian recently completed testing Descartes-08 in a randomized, controlled Phase IIb trial of patients with gMG, which met its primary endpoint of improvement on a scale of disease severity. Cartesian is in the midst of planning a Phase III trial of the mRNA-based CAR T-cell therapy, in which it will test the treatment in a larger cohort of gMG patients.
In a previous open-label Phase IIa trial of Descartes-08 in seven patients with gMG, all patients sustained clinical improvements through nine months post-treatment, Miljković said. In a small number of cases, patients stopped responding a year or longer after receiving Descartes-08, but they've been retreated and have since experienced durable remission.
Promise of a cure
Drugmakers advancing CAR T-cell therapies in disease settings where there are other treatment options are touting that these advanced cell therapies won't just treat the symptoms of the conditions but could cure them. For example, Caring Cross, a Gaithersburg, Maryland-based nonprofit, is developing a CAR T-cell therapy for HIV, the virus that causes AIDS. While there are existing treatments that keep HIV at bay, "our goal is to cure the disease with a single treatment," so patients no longer have to take chronic medications, said Caring Cross Cofounder and Executive Director Boro Dropulić.
The HIV treatment is Caring Cross' first therapeutic candidate, which it refers to as a duoCAR T-cell therapy because the CAR T cells, derived from a patient's own T cells and engineered to express anti-HIV CAR proteins on their surface, are designed to target and eliminate HIV-infected cells and to protect T cells from HIV infection. This dual mechanism, Caring Cross is betting, will allow its duoCAR T-cell therapy to be a one-time HIV treatment.
"We're at the early stages of an exciting developmental pathway," Dropulić said.
HIV is largely considered a manageable disease today with the advent of antiretroviral therapy (ART), which aims to keep the HIV viral load low enough to perpetually delay disease. These drugs are effective for the vast majority of patients who take them as prescribed, but efficacy dwindles unless patients commit to taking them daily for the rest of their lives. Moreover, like all medications, these drugs come with the risk of side effects and long-term toxicities, like nausea, depression, and high cholesterol. These side effects plus the emotional toll of having HIV can make it difficult to remain adherent to ART, a challenge for nearly one-quarter of patients across 25 countries.
Caring Cross in 2022 launched a first-in-human open-label Phase I/IIa trial to evaluate the safety and efficacy of the duoCAR T-cell therapy. In the study, Caring Cross is testing the investigational treatment in patients who are HIV-positive but have been on continuous ART with undetectable HIV viral load for at least a year.
But the organization's larger goal is to develop technologies and methods so the treatments it is advancing can be manufactured on-site at hospitals. Dropulić cofounded Caring Cross with a vision of developing cutting-edge medicines that are more affordable to manufacture. He previously founded Lentigen, a company that developed the lentiviral vector used in Novartis' cancer CAR T-cell therapy Kymriah. Lentigen was acquired by Miltenyi Biotec in 2014.
Manufacturing CAR T cells closer to patients could lower their development costs potentially by ten-fold, Dropulić asserted. "It's not just about making a therapy that works," he said. "It's making it affordable and ultimately accessible to those people who really need it, both in this country and around the world."
A widening field
Those developing CAR T-cell therapies in new indications benefit from decades of efficacy and safety research and from tried and tested management processes in oncology. "For autologous T-cell therapy, the biggest argument for it is: We know that it works," said Cartesian's Miljković, referring to the vast body of evidence generated over the years showing that CAR T cells can target B cells.
CAR T-cell therapy is a promising treatment approach for any B-cell pathology, agreed Martha Gadd, a senior scientist in the regenerative immunotherapy and CAR T translational research program at Mayo Clinic's Florida campus, which aims to expand these treatments beyond blood cancers. She's one of the coauthors of a recent paper in Kidney International, describing the use of CAR T cells to improve organ transplants.
While the results reported in the paper are from a preclinical proof-of-concept study, Mayo Clinic is preparing to test the experimental CAR T-cell therapy in an early-stage clinical trial. "I'm encouraging our team to view targeting of B cells as not just a cancer therapy, but as a target for any B-cell pathology," she said. "That really widens the field for us."
A subset of patients in need of organ transplants struggle to find an appropriately matched kidney donor on account of overactive autoantibodies — antibodies that are produced by B cells — that make them susceptible to organ rejection. By attacking these B cells with CAR T-cell therapy, investigators believe they can potentially prevent organ rejection and ultimately reduce wait times for patients in need of organ transplants.
The researchers worked with Mohamed Kharfan-Dabaja, a hematologist-oncologist at the Mayo Clinic with experience treating patients with CAR T-cell therapies, to develop the treatment. Once the therapy is ready for clinical testing, he will be the one administering it in collaboration with other members of the transplant and rheumatology teams who are managing these patients.
Other drugmakers aren't just taking lessons from oncology but are also testing therapies initially developed for cancer indications in other disease settings.
Autolus' Aucatzyl, which was recently approved by the FDA in B-ALL and is under investigation for lupus, is a prime example. Similarly, Kyverna's lead CAR T-cell candidate under development for multiple rheumatological and neurological autoimmune conditions, KYV-101, was originally developed by the US National Institutes of Health and initially safety tested in 20 patients with B-cell lymphoma, before the construct was licensed to Kyverna. ImmPact Bio, too, is assessing a CAR T-cell therapy for lupus, which has the same CAR construct as a cell therapy that it is developing for aggressive B-cell lymphoma.
Seattle Children's Therapeutics, the nonprofit therapeutics arm of Seattle Children's Hospital that develops cell and gene therapies for pediatric patients, this year received regulatory permission to begin a clinical trial for its first CAR T-cell therapy in a non-cancer indication, refractory lupus. Since researchers had originally tested this cell therapy in leukemia and lymphoma patients, they already had safety data on the treatment and experience developing study protocols with it.
This allowed researchers to design a clinical trial and get FDA clearance for an investigational new drug application for the CAR T-cell therapy in lupus after only about a year, said Colleen Annesley, medical director of Seattle Children's Therapeutics. "We already had all those pieces ready to go," she said. "We had a lot of the building blocks necessary to move forward with this fairly quickly."
Annesley said the Seattle Children's team had been discussing conducting a CAR T-cell therapy trial in the autoimmune setting for several years, and seeing promising results from other organizations testing such treatments in adults gave them confidence to kick off the first US trial of such a therapy in children with lupus. If the treatment shows promising activity in this Phase I trial, the team may consider testing it in other diseases, such as other B-cell mediated autoimmune conditions. Investigators will also monitor patients' side effects and compare them to those experienced by leukemia and lymphoma patients.
"We really want to see how this trial goes, and then talk about where we would go next," Annesley said.