Autoimmunity: Exploring New Horizons for Cell Therapies

Introduction to autoimmunity

The human immune system is an extensive and sophisticated network of both innate and adaptive signals that, to function properly, rely on a delicate balance between regulation and activation. Specific disease syndromes occur when this balance is skewed toward activation and an inappropriate response ensues, resulting in tissue damage and dysfunction. Collectively, this pathogenic state can be subdivided based on the underlying cells involved in the dysregulated immune response.  Autoimmunity occurs when the adaptive immune system, including autoantibodies from pathogenic B cell populations and antigen-specific T cells targeting self-antigens, will destroy otherwise healthy and normally functioning tissues.¹ Diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and rheumatoid arthritis all fall within this classification Autoinflammatory disorders cause tissue damage due to self-directed inflammation from the aberrant activation of innate immune cells like macrophages and neutrophils.¹ PFAPA syndrome, Behcet’s disease, Still’s disease, and gout are a few examples of autoinflammatory disease syndromes.²

Though the origin of autoimmunity can be multifactorial, the overall prevalence of autoimmune disease is thought to impact approximately 3-5% of the general population with increasing rates of diagnosis of specific disease subsets noted over the past few decades.^3–5 The traditional clinical management of these autoimmune conditions have focused on suppressing the immune response using systemic steroids and other immune modulating strategies.⁶ More targeted biologics and small molecules, including mAbs and signal transduction inhibitors, have also been successful in modulating disease progression and thus preventing further organ damage.^7,8 However, even though the management of these complex disease states have improved over the years, nontargeted global immune suppression of the immune system or targeting general pathways of inflammation is the primary strategy to treat autoimmunity.

 

Autoimmunity is the next frontier for proven cell therapies

Autoimmune conditions and cancer share a common thread in that the source of disease are rogue cell populations that, if left unabated, can cause significant damage to healthy tissues and disrupt the normal function of target organs. Although global immune suppression does improve symptoms for autoimmune patients, it lacks the specificity to explicitly target the problematic cell populations and thus offer a potential cure. The emergence of cell therapy in oncology has gained tremendous traction due to the unrivaled potency and specificity of this approach.

 

B-cell targeted and other autologous cell therapies in autoimmune diseases

Autologous chimeric antigen receptor (CAR) T cells have demonstrated impressive efficacy with acceptable safety profiles against B cell malignancies.⁹ A related approach utilizes engineered variants of the T cell receptor, enabling T cells to be reprogrammed to target intracellular antigens and hence expand the engineered T cell repertoire to address solid tumors as well.¹⁰ This approach received recent validation through the approval of Adaptimmune’s afami-cel, an engineered TCR-modified T-cell therapy for advanced synovial sarcoma.¹¹ Collectively, the clinical data generated thus far suggests that engineered T cells exhibit the desired specificity, potency, and safety profiles that warrants additional investigation into autoimmunity given the high unmet medical need.

Read this pre-print article to learn more about a vein-to vein approach to accelerate CAR-T therapies for autoimmune indications

Systemic Lupus Erythematosus, a proving ground for autologous CAR-T therapies

Targets utilized in B cell malignancies, such as CD19 and BCMA, have offered unique opportunities to leverage known pharmacokinetics generated in oncology trials to evaluate these CARs in autoimmune conditions. To date, the use of autologous CAR-T cells directed against the B cell CD19 antigen have proven to be highly effective in refractory SLE.^12–14 Both preclinical and clinical studies demonstrated that CD19 CAR-T cells are able to sufficiently deplete B cell populations, including the autoreactive clone stimulated by autoantigens.¹⁴ As expected, with B cell depletion, serological and clinical remission of the SLE was observed.¹³

Autologous CAR-T cells in other autoimmune syndromes

The promising results observed in SLE are not an isolated event as utilization of both antiCD19 and BCMA CARs have also been clinically evaluated and found to be feasible in anti-synthetase antibody syndrome, idiopathic inflammatory myopathy, systemic sclerosis, neuromyelitis optica spectrum, myasthenia gravis and MS.^15–20 Further, preclinical studies investigating other antigens, such as carcino-embryonic antigen (CEA) in murine models of colitis and Myelin oligodendrocyte glycoprotein (MOG) in murine models of MS, have provided positive results in animal models.^21,22   Taken together, this data suggests that targeting problematic autoreactive cell lineages with engineered T cells for long term B cell depletion is an effective clinical strategy for the management of autoimmune diseases.

 

Regulatory T cells as therapeutics in autoimmunity

Although the sustained ablation of B cells may be effective in some autoimmune diseases, additional cell therapy-based approaches utilize long-term tolerance to self-antigens as the primary mechanism of action. Foxp3+ CD4+ regulatory T cells (Tregs) are central in the maintenance of peripheral self-tolerance and are critical for moderating the immune response.²³  As such, these cells have exhibited initial success in the management of Type 1 Diabetes, SLE, and inflammatory bowel disease through the induction of long-term tolerance of self-antigens and a return of homeostasis to the immune system. Through preclinical evaluation of this cell type, it was determined that although antigen-specific T regs are more potent than polyclonal T regs, generating adequate cell numbers for an effective dose is extremely inefficient.²⁴ Further improvements have been realized through the introduction of CARs into Tregs as a strategy to further enhance their potency.^24,25

As both targeted autoreactive clone ablation using cytotoxic CARs or induction of self-tolerance via Tregs continue to make clinical advancements for patients living with autoimmune conditions, ongoing improvements can further enhance these living medicines. The conversion of autologous-based treatments through cell engineering as well as investigation of alternative cell sources, such as induced pluripotent stem cells, to create allogeneic versions of these therapies can facilitate the accessibility and lower costs.²⁶ The engineering of cells to prevent the mounting of a response to the host involves the elimination of select domains of the TCR.²⁶ Alternate strategies to disrupt the TCR function also include modifications to impede antigen recognition function.²⁶ Preclinical studies demonstrated that although these TCR-deficient T cells were able to control tumor growth in vivo, these cells exhibited lower long-term persistence.²⁷ Thus, additional strategies are required to prevent host immune rejection of these cells to enhance the in vivo persistence, especially important in the context of a chronic autoimmunity.²⁸ Studies have demonstrated that engineered cells can exhibit a hypoimmune phenotype through the disruption of the B2M, CIITA, and the TRAC genes, which are the most important determinants of allorejection.²⁹ These hypoimmune (HIP) CAR-T cells have the potential to overcome the limitations associated with the poor persistence of allogeneic CAR-T cells.³⁰

 

Challenges in designing and using cell therapies for autoimmune indication

The advantages demonstrated in specificity and potency of cell-based therapies compared to less specific global immune suppression have translated to encouraging early clinical readouts in multiple autoimmune conditions. In the context of CD19 CARs, the scientific rationale is the deep depletion of B cells, including the autoreactive clones, induces an immune reset with a concurrent elimination of symptoms of the disease.¹⁷ However, much remains to be defined in the context of chronic autoimmune syndromes to assess the true efficacy of a cell therapy. Comprehensive long-term data on the effectiveness of CAR-T, which is currently lacking in autoimmune disease management, needs to be generated.¹⁶ Long term efficacy evaluation would be crucial to inform future avenues of autoimmune-specific cell therapy development.

Further, the optimal target selection and targeting moiety design must be identified and validated clinically.  Single antigen specificity may not elicit a complete response due to the heterogeneity of the pathogenic cell population. In the context of B-cell driven autoimmune syndromes such as SLE, a subgroup of pathogenic B cells do not express the signature CD19 target that is required for CAR-T-mediated cytotoxicity, resulting in incomplete disease treatment.³¹ This phenomenon is similar to the noted antigen-escape mechanism that has proven problematic in oncology applications as the disease has significant potential for relapse.³² For Tregs, antigen-specific clones have demonstrated considerably better inhibitory activity compared to polyclonal Tregs but offer significant manufacturing hurdles for commercial implementation. Improvements in CAR designs, such as bispecifics and logic-gated CAR constructs, can serve as additional strategies to enhance potency of cell therapy products as well as to target heterogeneous populations safely.³³ Indeed, improvements in genetic engineering techniques, such as high fidelity CRISPR/Cas systems, can overcome construct size and complexity limitations encountered in the development of earlier generation cell therapeutics.³⁴

 

Current progress and future directions

Though the inception and development of CAR-T cells initially started with the intent of treating cancer, the early success of this strategy has catapulted their application into autoimmune diseases given the similarities of disease etiology between the two conditions. Given some of the early success with CD19 and BCMA CARs as well as Tregs, autoimmunity is the next great frontier for CAR-T therapy.³⁵ Currently, the pipeline is expanding from well characterized anti-CD19 and BCMA-directed CAR T treatments in B cell-driven diseases such as SLE and MS to exploring novel antigens associated with the progression of different autoimmune diseases. Further, evaluation of other cell types, such as T regulatory cells, is beginning to merge with CAR-T construct engineering and design. Collectively, this incremental progression in the application of these novel cell types and construct designs will only further our understanding of the clinical potential these cells are capable of. More importantly, these cell therapies will offer the hope of effective and safe management for chronic autoimmune disorders and the patients who desperately need these lifesaving medicines.

To learn more about CAR-engineered Tregs in autoimmune therapies, watch this on-demand webinar

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