CATCR-T cell therapy may aid in antiphospholipid syndrome through selective B-cell depletion
Click Here to Manage Email Alerts
PHILADELPHIA — Upcoming T-cell therapies may treat antiphospholipid syndrome and other autoimmune diseases without compromising a patient’s defenses against infection, according to data presented at ACR Convergence 2022.
“We have heard a lot about the promise of precision medicine over the last few days,” Maximilian F. Konig, MD, an assistant professor of medicine at the Johns Hopkins University School of Medicine, told attendees. “But we currently do not have any precision therapies for rheumatic diseases. In fact, all immunosuppressive therapies that are currently used in clinical practice are indiscriminate.”
To develop an autoantigen-specific T-cell therapy for the treatment of antiphospholipid syndrome, Konig and colleagues used a genome-editing platform to introduce the relevant antigen to the T-cell receptor complex in humans. Partial and full sequences of the correct ribonucleoprotein were introduced to the activated T cells in question. The thought process, Konig explained, was that T cells may be redirectable to kill B2GPI cells in patients with antiphospholipid syndrome.
The researchers engineered T cells to “express chimeric autoantigen-TCRs (CATCRs),” which binded to specific B-cell receptors and stop the functioning of autoreactive B cells, Konig said.
During tests, the B2GPI-CATCR-T cells “efficiently and selectively” eliminated anti-B2GPI DI B cells, while control cells did not, according to Konig. The test therapy eliminated anti-B2GPI D1 B cells while sparing normally functioning B cells. The test cells succeeded in abolishing autoantibody production. Additionally, researchers observed target cell elimination at relevant effector-to-target ratios.
“CATCR-T cells are precision cellular therapies designed to selectively deplete autoreactive B cells,” Konig said. “This technology will be applicable to many other autoimmune diseases.”
Perspective
Back to Top
David A. McLain, MD, MACR, FACP, FRCP
In this study presented by Maximilian F. Konig, MD, of Johns Hopkins, the investigators noted that CD19-targeted chimeric antigen receptor-T (CAR-T) cells hold promise for the treatment of refractory autoimmune diseases, but that indiscriminate depletion of all B cells can lead to infection.
The present study used targeted chimeric autoantigen-T cell receptor-T (CATCR-T) cells to selectively kill anti-Beta-2 Glycoprotein I (B2GPI) B cells in antiphospholipid syndrome (APS). The authors described a precision cellular immunotherapy approach for the autoantigen-specific depletion of autoreactive B cells in autoimmune disease that holds promise of treating autoimmunity without increasing the risk of infection. Although this was a “bench” study, it demonstrates what may be the future of rheumatology.
Immunotherapy of cancer and autoimmune diseases is a very dynamic area of research. The present study uses T-cell receptor (TCR) technology, which is a more recent development. CAR-T therapy is mainly being used in leukemia, lymphoma and multiple myeloma. Solid tumors have been more resistant to CAR-T therapy, but new strategies are showing promise.
Cancer cells, perhaps unlike autoimmune targets, can have an immune suppressive tumor microenvironment, lineage switching, loss of tumor antigen, immunomodulation of the host immune cells to escape from surveillances, T-cell exhaustion and epigenomic landscape modulation. Tumor cells also evolve under immune surveillance by constantly changing their surface proteins or intracellular signaling molecules to avoid their recognition from cell-mediated immunity.
Complications of CAR-T therapy include cytokine release syndrome (CRS), which has been treated with steroids and tocilizumab (Actemra, Genentech) and immune effector cell-associated neurotoxicity syndrome (ICANS). ICANS can include severe confusion, seizure-like activity and impaired speech. Although it’s effective for treating CRS, tocilizumab doesn’t work with ICANS. Another type of cellular therapy involves engineering T cells to express a specific TCR, like was done in this study.
Unlike CARs, which use portions of synthetic antibodies that can recognize specific antigens only on the surface of cells, TCRs can also recognize antigens that are inside tumor cells. Much work has been done in this area, but much work remains. This is an exciting development in oncology and now rheumatology.
Collapse
Konig M. Abstract 1677. Presented at: ACR Convergence 2022; Nov. 11-14, 2022; Philadelphia (hybrid meeting).
Click Here to Manage Email Alerts