Dual-target CAR T-cell therapy shows promise for SLE in small trial

Treatment safely leads to medication-free remission for lupus patients

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by Lindsey Shapiro |

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Two hands, a stethoscope, and a handful of oral medications surround a graph labeled 'CLINICAL TRIAL' that shows positively trending results.

A dual-target CAR T-cell therapy from iCell Gene Therapeutics safely led to medication-free disease remission for systemic lupus erythematosus (SLE) patients in a small Phase 1 study.

For patients with lupus nephritis (LN), a common and serious SLE manifestation involving the kidneys, renal function also was improved.

Based on these positive results, iCell now is planning to seek permission from regulators in the U.S. and China to conduct additional clinical studies in the two countries.

“iCell first envisioned the potential for CAR treatments in autoimmune diseases more than 10 years ago and … nearly five years ago, we were the first company worldwide to treat an autoimmune patient with a CAR,” Greg Deener, iCell’s CEO, said in a company press release. “We look forward to receiving further follow-up data confirming the promising results to date.”

Findings from the trial were detailed in “BCMA-CD19 compound CAR T cells for systemic lupus erythematosus: a phase 1 open-label clinical trial,” a study published in the Annals of the Rheumatic Diseases.

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iCell’s CAR T-cell therapy targets 2 different proteins: CD19 and BCMA

SLE is an autoimmune disease in which the immune system attacks the body’s own healthy tissues. Lupus nephritis, or simply LN, is a serious manifestation of SLE where the waste-filtering units of the kidneys are damaged.

These attacks are mediated by self-reactive antibodies, or autoantibodies, that mistakenly target the body’s own tissues. Such antibodies are produced by activated immune B-cells and a type of their progeny, called plasma cells.

CAR T-cell therapies aim to kill off autoantibody-producing cells by engineering a person’s own immune T-cells — which are capable of launching potent immune attacks against a target — to specifically seek out and destroy the problematic cells.

To do that, T-cells are isolated from the body and equipped with a chimeric antigen receptor, or CAR, that specifically binds to a protein on the surface of the target cells. With it, T-cells gain the means to specifically bind to those cells and kill them off once returned to the body. That’s expected to lower the production of autoantibodies, thereby easing disease symptoms.

Several CAR T-cell therapies that are now in development use the CAR-targeting CD19, a protein found on the surface of B-cells. However, long-lived plasma cells don’t always contain CD19. They might thus be missed by standard CAR T-cell therapies, and instead continue to produce harmful antibodies that drive disease symptoms and prevent remission.

Other standard SLE therapies also don’t effectively target long-lived plasma cells, according to these researchers.

iCell’s therapy is what the team calls a compound CAR T-cell therapy (cCAR). It’s designed to include two different CARs: one that targets CD19 and another targeting BCMA, a protein found on both B-cells and long-lived plasma cells. As such, it is expected to offer more complete depletion of disease-driving antibodies.

The Phase 1 trial (NCT04162353/NCT05474885), conducted in China, evaluated the safety and proof-of-concept efficacy of the therapy in 13 SLE patients. Two patients had lymphoma, a type of B-cell mediated blood cancer, and 11 people had LN with active disease and an inadequate response to at least two prior lines of therapy.

Patients in the study stopped all other lupus medications before receiving the therapy. All but one received the treatment at its target dose of 3 million cells per kilogram of body weight.

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CAR T-cell therapy shown to drive long-term remission in SLE patients

Trial provides proof-of-concept evidence dual therapy can reset immune system

The trial showed proof-of-concept evidence that this dual-target therapy could reset the immune system and enable long-term disease remission — with a follow-up of up to nearly four years in the longest-treated patient.

Mean scores on the SLE Disease Activity Index 2000 (SLEDAI-2K), a measure of disease activity, dropped from 10.6 points at the study’s start (baseline) to 2.7 points three months after the start of treatment among LN patients.

Most patients achieved disease remission — an SLEDAI-2K score of zero — without the need for other medications. The company noted that there are no approved therapies currently capable of achieving this in SLE or LN patients who are at a high risk of sustaining long-term organ damage and requiring a kidney transplant.

For LN patients, kidney function also significantly improved and both lymphoma patients experienced complete cancer remission.

Treated patients were negative for all self-reactive antibodies associated with SLE, including the ones produced by long-lived plasma cells. Levels of proteins associated with the immune system’s complement cascade, which is implicated in SLE autoimmune attacks, also returned to normal.

B-cells were depleted from the blood within 10 days of treatment, and recovered between months two and six without signs of disease relapse. Other lab tests indicated the immune system was reset without compromised immune function.

This study demonstrates … that long-term medication-free remission is achievable [for SLE patients].

The therapy was well tolerated and cases of cytokine release syndrome, a type of serious immune response that’s common with these therapies, were mild and resolved with supportive care. No neurotoxicity was observed.

These early findings demonstrate the “promise” of the CAR T-cell therapy for achieving SLE remission, according to the researchers.

“Larger study cohorts as well as additional longitudinal follow-up data are required to better contextualize the results of this study,” the team wrote.

According to Yupo Ma, MD, PhD, chief scientific officer and founder of iCell, “this study demonstrates … that long-term medication-free remission is achievable” for SLE patients.