Lupus Research Alliance grants inaugural awards to 11 researchers focused on engineered cell therapies for. Lupus

(Press-News.org) The Lupus Research Alliance (LRA) is proud to announce the inaugural recipients of the new Targeted Research Program on Engineered Cell Therapies for Lupus (TRP-ECT) to support the development and mechanistic understanding of safe and accessible next-generation engineered cell therapies for people with lupus. Engineered cell therapies, such as CD19-targeted chimeric antigen receptor (CAR) T cells, involve reengineering a patient’s own T cells to recognize and attack cells that cause disease.

The LRA established this program to build upon the promise already shown for engineered cell therapies in treating and potentially curing lupus, including a clinical trial showing complete remission (no clinical evidence of active disease) among participants treated with CD19 CAR T cells who had not responded to previous treatments.

The TRP-ECT provides funding for two types of studies: preclinical studies, including discovery and translational projects, each of which will be supported with up to $300,000 over two years, and ancillary studies to ongoing or completed clinical trials, which will each receive up to $600,000 over two years.

"The establishment of the TRP-ECT marks a significant milestone in our mission to advance innovative treatments for lupus,” noted LRA Chief Scientific Officer Teodora Staeva, PhD. “By supporting cutting-edge research in engineered cell therapies, we are paving the way for breakthroughs that could significantly improve the lives of those affected by this challenging disease.”

Below are the 2024 TRP-ECT awardees who will conduct a preclinical study:

Reuben Benjamin, MBBS, FRCPath, PhD, King's College London
Despite recent successes with CD19-targeted CAR T cell therapy, several barriers limit their widespread use, including high costs, lengthy manufacturing times, and the need to reduce a patient’s medications (including steroids) prior to treatment. Dr. Benjamin, along with his collaborator Dr Chris Wincup, will test the effectiveness of a newly developed CAR T cell therapy that takes only three days to produce. His study could result in a quicker, safer, and more effective cell therapy option more widely available to people with lupus.

Vijay Bhoj, MD, PhD, University of Pennsylvania, Perelman School of Medicine
While it appears to be a promising treatment option, one drawback to CD19-targeted CAR T cell therapy is its broad targeting of all B cells (including those that protect us from infections), potentially resulting in the individual becoming immunocompromised. Dr. Bhoj will develop a more selective approach that targets only age-associated B cells (ABCs), an autoreactive B cell population (that mistakenly recognizes the patient’s own body), potentially inducing lasting remission (decrease or absence of symptoms) with minimal side effects.

Leslie Kean, MD, PhD, Boston Children's Hospital
Regulatory T cells (Tregs) are cells that suppress autoimmunity (autoimmunity occurs when a patient’s immune system attacks their own cells and tissues). Phase 1 clinical studies have shown Treg therapies to have an excellent safety profile, highlighting their therapeutic potential. Dr. Kean has engineered Tregs with CARs that recognize OX40L, a molecule on the surface of immune cells in people with active lupus. She will now test these “OX40L-CAR-Tregs" in human cells and mouse models, potentially paving the way for rapid translation to the clinic for people with lupus.

Richard O’Neil, PhD, Medical University of South Carolina
CAR T cell therapy typically requires lymphodepletion—a chemotherapy treatment that kills T cells and other immune cells—prior to treatment. This creates a “blank slate” that gives the CAR T cells more room to expand. However, lymphodepletion can cause severe side effects, including increasing the likelihood of infections. Dr. O’Neil will test a novel method that does not require lymphodepletion, potentially offering a safer and more effective process to simplify CAR T patient management.

Joshua Ooi, PhD, Monash University
Dr. Ooi previously engineered Tregs that specifically recognize a protein called Sm, which is a key target in lupus. These engineered Tregs (called Sm-Tregs) showed therapeutic promise, dampening the inflammatory response in blood from individuals with lupus and halting the progression of kidney injury in a mouse model. Dr. Ooi will now transfer the creation of Sm-Tregs from a small-scale to large-scale manufacturing process, potentially demonstrating that Sm-Tregs can be manufactured at a high enough quality to conduct a clinical trial.

Reshmi Parameswaran, PhD, Case Western Reserve University School of Medicine
T cells are not the only white blood cells that can be leveraged to treat autoimmune diseases. Dr. Parameswaran will engineer natural killer (NK) cells, another type of white blood cell, to target three molecules on the surface of autoreactive B cells: BAFF-R, BCMA, and TACI. These “BAFF-CAR NK” cells will be generated from NK cells from healthy donors, making them a potentially less expensive and safer option that could be offered as an “off-the-shelf" therapy.

Stanley Riddell, MD, Fred Hutchinson Cancer Center
While CAR T cell therapy has shown immense promise, it does not come without side effects, including fever, blood pressure changes, and the elimination of protective B cells that leave the patient at risk of infection. Dr. Riddell has designed new, sensitive receptors called chimeric T cell receptors (ChTCRs) that do not trigger the production of cytokines, which can cause toxicity after CAR T cell therapy. He will test this approach in an animal model to advance new concepts that could improve the safety and efficacy of T cell immunotherapy for lupus.

Mark Shlomchik, MD, PhD, University of Pittsburgh
Dr. Shlomchik is testing a novel CAR T cell therapy in lupus mouse models to selectively eliminate ABCs, a type of B cell that may be pathogenic in lupus and which is linked to lupus severity. His research aims to develop a precise and safer treatment for lupus by targeting these specific harmful B cells while sparing protective ones.

Below are the 2024 TRP-ECT awardees who will conduct an ancillary study to an ongoing or complete clinical trial:

Ricardo Grieshaber-Bouyer, MD, PhD, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Since 2020, the team at FAU has successfully treated more than 15 patients with refractory lupus (for whom no other treatments have worked) with CD19 CAR T cells, all of whom reached drug-free remission. Dr. Grieshaber-Bouyer will perform a comprehensive study of the blood and tissue of treated individuals to determine the mechanisms by which CAR T cell therapy resets the immune system and leads to lasting, drug-free remission.

Shaun Jackson, MD, PhD, Seattle Children's Hospital
While C19 CAR T cell therapy has shown profound effects, it has only been tested in adults with lupus. The Reversing Autoimmunity through Cell Therapy (REACT-01) clinical trial is the first clinical trial in the U.S. evaluating the safety and feasibility of this treatment for children with lupus. Dr. Jackson’s study will analyze samples from pediatric patients to understand which patients respond best to therapy and why they do or do not respond. This could inform future treatment strategies and revolutionize care for pediatric and young adult patients with SLE.

Ignacio Sanz, MD, Emory University
After B cells are eliminated by CAR T cell therapy, they eventually return, healthy and in a naive state (not yet exposed to their targets). This “resetting” of the B cells has been proposed as the main reason for the lasting efficacy of CAR T cell therapy. Dr. Sanz will conduct detailed analyses of CAR T cell-induced B cell depletion in patients treated at Emory University to understand what determines a successful response, helping to select patients more likely to respond for future studies.

For people living with lupus, innovative research in engineered cell therapies can open doors to treatments that were once unimaginable. These treatments aim to reset the immune system to restore balance and health, reducing the burden of lupus and improving quality of life.

About Lupus
Lupus is a chronic, complex autoimmune disease that affects millions of people worldwide. In lupus, the immune system, meant to defend against infections, produces autoantibodies that mistake the body’s own cells as foreign, causing other immune cells to attack organs such as the kidneys, brain, heart, lungs and skin, as well as blood and joints. Ninety percent of people with lupus are women, most often diagnosed between the ages of 15-45. Black, Latinx, Indigenous, Asian and Pacific Islander people are disproportionately affected by lupus and more likely to experience severe lupus symptoms.

About the Lupus Research Alliance
The Lupus Research Alliance is the largest non-governmental, non-profit funder of lupus research worldwide. The organization aims to transform treatment by funding the most innovative lupus research, fostering diverse scientific talent, and driving discovery toward better diagnostics, improved treatments and ultimately a cure for lupus. Because the Lupus Research Alliance’s Board of Directors funds all administrative and fundraising costs, 100% of all donations goes to support lupus research programs. For more information or to donate to lupus research, visit the LRA at LupusResearch.org and on social media at:  X, Facebook, LinkedIn, and Instagram.

 

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