Janet Macpherson, PhD
Senior Editor
Cytiva
Australia
As the editorial team discussed the September issue of Telegraft, I proposed CAR T-cells for autoimmune disease as the topic of my editorial. Imagine my surprise, when reviewing the submitted content just days before publication, to realise that our incoming ISCT president had penned his inaugural “from the President’s desk” and touched on this very topic! What to do? Do I change topic? Do I ignore the content from our esteemed President? No, I decided to bend the lens and present my view.
In the years since CD19 CAR T showed promise for treating B-cell malignancies, and culminated in the first FDA-approved product in 2017 for relapsed refractory diffuse large B-cell lymphoma in adults, our global cell therapy community has looked to expand the clinical application of CAR T-cell therapy to provide life changing therapies to more patients. We now have multiple CD19 CAR T-cell products approved across multiple jurisdictions, for a range of B-cell malignancies, including earlier line treatment, and we have also seen the approval of CAR T-cell products that target BCMA. To date all approvals have been for haematologic malignancies, predominantly those with low incidence (rare indications) and with accelerated approval pathways. Academic and clinical researchers alike have been focussed on how to improve safety and efficacy of CAR T-cells, at the same time looking to widen the therapeutic window. As discussed in this issue by our incoming ISCT President, CD-19 directed CAR T cells have already started to show clinical benefit outside B-cell malignancy.
Early efforts to identify and target antigens present on cells in solid malignancy have met limited success, due to challenges in delivery. Similar to gene therapy approaches to correcting defects in tissues, delivery remains a hurdle to clinical benefit.
Over the past few years, a number of efforts have been made to target B-cells that are mediating the clinical manifestations of auto-immune disorders, initially for patients with severe Systemic Lupus Erythematosus (SLE). We have known for many years that auto-immune conditions are associated with specific profiles of self antigen directed antibodies and therefore that B-cells play a role in disease phenotype. While the management of autoimmune diseases has improved substantially, owing largely to the emergence of targeted biologic therapies, these treatments are disease-suppressive rather than curative and lifelong treatment is required in most cases. The potential to eliminate auto-antibody producing B-cells (including plasma cells), sparing “good” B-cells and even to reset the immune response is very attractive. Other auto-immune conditions with early clinical indicators include Systemic scleroris, refractory antisynthetase syndrome and myasthenia gravis.
As we move from life threatening indications like hematologic malignancies to those with a low mortality but high morbidity, the risk benefit profile requires reassessment. Conditions such as refractory SLE are amenable to CAR T-treatment, especially for younger patients with a lifetime of participation in the workforce ahead. However, conditions like rheumatoid arthritis with variable clinical manifestation, high patient numbers, and symptomatic treatment options might offer such a clear risk benefit.
I am appreciative of the efforts of my cell therapy colleagues to explore all options to find treatment options that can make a difference to patient lives. I reflect back to 2001 when our field was faced with the realisation that insertional mutagenesis was no longer just a theoretical risk. We saw a number of children diagnosed with X-linked severe combined immunodeficiency, treated with CD34+ gene modified to express the IL2 R gamma chain, who following improved immune function presented with lymphoproliferative disease. While the new diagnosis was life threatening, it was heartening to hear that the parents would still have chosen the potentially curative genetically modified cell therapy even with the oncogenic risk. As researchers and product developers we need to always include patients and their families in our product development plans to ensure that we address their needs.
I have an auto-immune condition, not classified by traditional autoantibody profiles, and with minor clinical symptoms. For now I don’t see CAR T-cell therapy in my future but I hope that others with debilitating symptoms will benefit soon.
#CommunityFeature
#feature4
#fromtheeditors