Cell Therapy Expands Into Autoimmune Disease

A powerful treatment modality expands beyond the initial disease condition it was developed to impact. Monoclonal antibodies first found favor as immunosuppressants before revolutionizing immuno-oncology. While adoptive immune cell transfer therapies (e.g., CAR-T) are currently approved only in certain blood cancers, we may be witnessing the repurposing of the technology to treat autoimmune diseases.


Adopting Autoimmune Disease

Millions of people worldwide are affected by one of 80+ autoimmune diseases. Continued adoption of a Western lifestyle is expected to swell these ranks to the tune of a ~$190 billion autoimmune therapeutics market by 2029. The curative potential and enormous capital investment in adoptive cell transfer therapies have many leaders in the biotechnology industry asking whether CAR-T-like medicines can provide similar, targeted benefits for patients with inflammatory conditions.

As the name implies, cell therapies purposed for autoimmune conditions involve engineering the immune cells of the patient (autologous) or a healthy donor (allogeneic) to temper the underlying inflammation responsible for the disease. Like their more established cancer immunotherapy brethren, autoimmune cell therapies require copious mononuclear immune cells for research and development programs. Whether they represent the engineered targets themselves or sources for clinical and translational biomarkers, T cells, B cells, and natural killer (NK) cells are in high demand across the R&D pipeline.

Researchers frequently choose leukapheresis products to obtain up to 10 billion peripheral mononuclear cells (PBMCs) from the same donor. These “leukopak” specimens reduce inter-donor and specimen handling variability in fueling assay, analytical, and process development pipelines. Scientists can control costs and timelines by stocking up on cells collected in one sitting and linked to specific donor metadata such as medical records, demographics, and HLA typing. Obtaining leukopaks directly from individuals with a confirmed diagnosis of the indication under investigation provides valuable context and relevance to the eventual cell product given to patients. For instance, specific immune cell distributions and lineages often deviate when comparing disease and healthy states.


Repurposing CD19 CAR-T for Lupus

All five approved CAR-T therapies are engineered to eliminate B-cell malignancies. Since B cells are the antibody-producing cells, CD19-seeking CAR-Ts represent an attractive avenue to tackle autoantibody-linked conditions like systemic lupus erythematosus (SLE). As autoantibodies attack their healthy tissues, patients with SLE have no disease-modifying treatment options and can only hope to control symptoms and flare-ups. In September 2022, a German team reported that five SLE patients who were refractory to immunosuppressants were in complete remission after receiving autologous CD19 CAR-T therapy [1]. Noteworthy, the remission was durable even after B cell reappearance, and no severe cytokine release syndrome was observed, a typical adverse event associated with CAR-T for cancer.

The possibility of a relatively safe and effective one-time treatment for patients with SLE has cell therapy leaders and therapeutics companies thinking the autoimmune space is a good match for CAR-T. Kymriah developer Novartis has been busy fine-tuning its CD19 targeting CAR-T and this year launched a Phase I/II study in SLE patients. Similarly, Kyverna Therapeutics is developing a CD19 CAR-T optimized for autoimmune indications, including lupus. Lastly, Cabaletta Therapeutics has developed a suite of CAR-T candidates that seek CD19-bearing B cell subsets believed to be responsible for producing disease-causing autoantibodies, and the company has announced early clinical trials in several autoimmune conditions, including SLE. The race is on to develop a CAR-T that depletes the autoantibody-producing culprits.


Beyond CD19

Another approach to autoimmune adoptive cell therapy is to engineer regulatory T cells (Tregs), a type of immune cell that plays a critical role in maintaining immune tolerance. In contrast to the SWAT team-like effector T cells utilized in oncology cell therapies, Tregs act more like firefighters, controlling inflammation and returning immune homeostasis. Tregs expressing the transcription factor FoxP3 can be isolated from leukopaks and expanded in culture to create a concentrated and purified product that can treat autoimmune diseases such as type 1 diabetes (T1D) and multiple sclerosis (MS).

In T1D, effector T cells eliminate a patient’s insulin-producing beta islet cells. Antigen-specific Tregs explicitly directed to the pancreas to mediate effector T cell activity are desirable but exceedingly difficult to isolate and expand. Using gene editing and adoptive transfer techniques, a Seattle-based team combined engineered FoxP3 expression and T cell receptors from T1D patients into a strategy for turning autologous T cells into pancreas-specific Tregs. In a mouse model, the therapy suppressed T cells from attacking islet beta cells, preserving their insulin-producing function [2]. Seattle Children’s spinout GentiBio is commercializing the strategy for treating T1D using a patient’s own engineered Tregs.

Adoptive cell therapy programs abound for treating multiple sclerosis, a CNS condition characterized by inflammation that leads to demyelination, axonal loss, and gliosis. Lower numbers of circulating Tregs and reduced immunomodulatory function of CNS-resident Tregs have been described in patients with MS [3]. In a small Phase 1/2 trial of a FoxP3+ autologous Treg therapy, disease progression was halted in patients receiving intrathecal injection, while relapsing was reported in those receiving the therapy intravenously [4]. While no serious adverse events were reported in either group, the results suggest the blood-brain barrier may pose an additional hurdle in delivering an effective Treg adoptive cell therapy.

Finally, tolerogenic dendritic cells (tolDCs) are a subset of the antigen-presenting DCs that can suppress immunogenic T cell responses and promote immune tolerance, making them attractive targets in MS, rheumatoid arthritis, and T1D. While DCs represent only 1-2% of PBMCs, they can be autologously collected by leukapheresis and induced into tolDCs through co-stimulatory and genetic engineering approaches [5]. In a Phase 1 study in patients with MS, engineered tolDCs were loaded with myelin peptides to promote a tolerogenic response in the nervous system. The cell therapy elicited no significant adverse events while increasing circulating levels of the immunomodulatory cytokine IL-10, supporting further clinical development [6].


Disease-State Leukopaks for Research

Adoptive cell therapies have shown positive, early-stage clinical evidence for treating several autoimmune diseases. Companies are applying the vast immune cell engineering toolbox built
on CAR-T development, such as employing leukopaks across their R&D pipelines. By offering leukopaks directly from patients with confirmed disease, Sanguine Biosciences equips autoimmune cell therapy researchers with a unique biospecimen that more closely resembles the eventual therapeutic product under development. Obtaining a large volume of PBMCs from a recallable, and representative individual donor supports discovery, translational, and manufacturing goals while reducing inter-donor and handling variability. Access to patient medical records, HLA typing, and demographics provide donor specificity. Engaged and recallable donors join Sanguine’s 70,000+ participant community to facilitate the delivery of potentially life-altering therapies impacting their autoimmune condition.


Please contact us to learn whether leukopaks can support your advanced therapy program.



[1] Mackensen, A., Müller, F., Mougiakakos, D. et al. (2022) Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 28: 2124–2132. https://doi.org/10.1038/s41591-022-02017-5.
[2] Soo Jung Yang, et al. (2022) Pancreatic islet-specific engineered Tregs exhibit robust antigen- specific and bystander immune suppression in type 1 diabetes models. Sci Transl Med. 14:
eabn1716. https://doi.org/10.1126/scitranslmed.abn1716.
[3] Verreycken J, Baeten P, Broux B. (2022) Regulatory T cell therapy for multiple sclerosis: Breaching (blood-brain) barriers. Hum Vaccin Immunother. 18(7): 2153534.
[4] Chwojnicki, K., Iwaszkiewicz-Grześ, D., Jankowska, A. et al. (2021) Administration of CD4+CD25highCD127−FoxP3+ Regulatory T Cells for Relapsing-Remitting Multiple Sclerosis: A
Phase 1 Study. BioDrugs. 35: 47–60. https://doi.org/10.1007/s40259-020-00462-7.
[5] Mansilla, M.J., Presas-Rodríguez, S., Teniente-Serra, A. et al. (2021) Paving the way towards an effective treatment for multiple sclerosis: advances in cell therapy. Cell Mol Immunol. 18:
1353–1374. https://doi.org/10.1038/s41423-020-00618-z.

[6] Zubizarreta I, et al. (2019) Immune tolerance in multiple sclerosis and neuromyelitis optica with peptide-loaded tolerogenic dendritic cells in a phase 1b trial. Proc Natl Acad Sci USA. 116(17): 8463-8470. https://doi.org/10.1073/pnas.1820039116.


By Geoffrey Feld, Ph.D. Geocyte