NEW YORK – Autologous B-cell maturation antigen (BCMA)-directed CAR T-cell therapy could present a safe and effective treatment option for patients with light chain amyloidosis, interim results presented during the American Society of Gene & Cell Therapy's annual meeting suggest.
On Friday, Nathalie Asherie, a senior researcher at the Hadassah Medical Center in Israel, presented data from a Phase I study involving eight patients with the rare disease who received BCMA CAR T-cell therapy.
As Asherie explained, light chain amyloidosis is a rare disease in which immunoglobulin light chains aggregate to form insoluble fibrils. These fibrils gather in various tissues and organs and can cause them to fail, resulting in severe health implications for patients if the affected organ is the heart, for example. Although the condition is exceedingly rare, with around 4,000 patients being diagnosed with it in the US each year, light chain amyloidosis tends to show up in multiple myeloma patients. Up to 15 percent of patients with this type of bone marrow cancer develop amyloidosis, but still little is known about how to treat it.
This is partially because light chain amyloidosis affects five in 1 million people, which is 10 times less common than multiple myeloma, Asherie pointed out. "And due to the rarity and extreme frailty of this patient population, amyloidosis patients are invariably excluded from clinical trials." This results in a situation where available treatments for amyloidosis are mostly extrapolations of multiple myeloma treatments.
Sometimes existing multiple myeloma treatment strategies work in amyloidosis patients since the two conditions share common biological origins; they're both plasma cell dyscrasia disorders. "However, due to their frail condition, amyloidosis patients may suffer from toxicity from this treatment, and many of these patients are left without alternative therapeutic options." This presents a significant unmet need, she continued. "There is an urgent need to stop or significantly reduce fibril accumulation so as to prevent irreversible organ damage," Asherie said, adding that in amyloidosis, "time is truly of the essence," as is inducing deep and sustained organ response.
This is why a one-time infusion with BCMA-targeted CAR T-cell therapy presents a promising option. Indeed, the two BCMA-targeting CAR T-cell therapies approved for refractory multiple myeloma patients — Bristol Myers Squibb's Abecma (idecabtagene vicleucel) and Janssen and Legend Biotech's Carvykti (ciltacabtagene autoleucel) — have produced deep and durable responses.
The treatments aren't approved for amyloidosis, however, and given the safety concerns in this setting, Asherie said "it is not surprising" that there has only been one previous case report to date of BCMA CAR T cells being administered to a multiple myeloma patient presenting with amyloidosis.
The Phase Ia/b study that Asherie presented at the meeting involves HBI0101, an autologous BCMA-directed CAR T-cell therapy developed at the Hadassah Medical Center. Investigators are evaluating the therapy for both multiple myeloma and amyloidosis patients in the trial and have treated more than 70 patients so far.
Immix Biopharma subsidiary Nexcella licensed HBI0101 from Hadassah Medical Organization last year and renamed it NXC-201. "The recent in-licensing of our therapy should help to extend the accessibility of BCMA CAR T cells worldwide," Asherie said.
While only eight out of 70 patients enrolled in the trial have been amyloidosis patients, Asherie said it represents the largest amyloidosis patient cohort to receive CAR T-cell therapy to date. These eight patients were in very poor condition when they entered the trial, she noted. All but one had signs of cardiac failure; three had overlapping multiple myeloma; and two patients were treated on a compassionate use basis. All had been refractory to three or more treatments.
The toxicity profile of the CAR T-cell therapy in amyloidosis patients was manageable. Patients had low-grade cytotoxic release syndrome and none experienced immune effector cell-associated neurotoxicity syndrome. The hematologic toxicity with the treatment was similar to what had been previously reported in multiple myeloma patients in the trial.
In terms of efficacy, all eight amyloidosis patients responded to the therapy, and five patients experienced a complete response with negative minimal residual disease. Two other patients experienced a "very good" partial response, and one patient had a partial response.
"The efficacy results are very encouraging," Asherie said. "These fast and deep hematologic responses translated into organ responses in the majority of patients." Four patients achieved fast, deep, and prolonged responses that lasted more than eight months. One of these patients is still in remission 15 months post-infusion with NXC-201, and four patients still have ongoing responses.
When looking at the difference in involved versus uninvolved free light chain levels, which Asherie said is the "most indicative parameter to assess response to therapy" in amyloidosis patients, investigators observed a rapid decrease following CAR T-cell infusion. Light chain levels continued to decrease in parallel with CAR T-cell expansion in the peripheral blood.
"Our results suggest that the treatment is safe and may induce fast, deep, and sustained responses in amyloidosis patients," Asherie said, acknowledging that larger cohorts with longer-term follow-up will be needed to confirm these findings.
"While amyloidosis remains incurable, BCMA CAR T-cell therapy represents a promising and potentially transformative approach to treating this disease," she said.
In April, Nexcella announced it will submit data to the US Food and Drug Administration on the activity of its CAR T-cell therapy in amyloidosis once 30 to 40 patients have been treated. The Los Angeles-based firm will also file a biologics licensing application for the multiple myeloma indication once 100 patients have been treated with the CAR T-cell therapy.
In multiple myeloma, Nexcella's BCMA-targeted drug would compete with Abecma and Carvykti. However, Nexcella has maintained that NXC-201 has an advantage in that its safety profile may allow it to be infused in an outpatient setting, and therefore, it may be more easily accessed than CAR T-cell therapies on the market.
"Ninety-five percent of US medical centers cannot offer CAR T today due to their severe side effect profile," Nexcella Executive Chairman Ilya Rachman said in the April statement. "Favorable NXC-201 tolerability could result in not only a three-day hospital stay instead of the CAR T standard 14-day hospital stay, but also enable NXC-201 to be delivered in the 95 percent of US medical centers that cannot offer CAR Ts today, potentially reducing hospitalization costs by up to 80 percent."