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. Author manuscript; available in PMC: 2023 Feb 28.
Published in final edited form as: Nat Metab. 2022 Feb 28;4(2):163–169. doi: 10.1038/s42255-022-00537-5

CAR-based therapies: opportunities for immuno-medicine beyond cancer

Haig Aghajanian 1,*, Joel G Rurik 1, Jonathan A Epstein 1,2,*
PMCID: PMC9947862  NIHMSID: NIHMS1869804  PMID: 35228742

Abstract

One of the most exciting new therapies for cancer involves the use of autologous T cells that are engineered to recognize and destroy cancerous cells. Patients with previously untreatable B cell leukemias and lymphomas have been cured and efforts are underway to extend this success to other tumors. Here, we discuss recent studies and emerging research aimed to extend this approach beyond oncology, in areas such as cardiometabolic disorders, autoimmunity, fibrosis, and senescence. We also summarize new technologies that may help to reduce the cost and increase access to related forms of immunotherapy.

Introduction

The use of redirected T cells and Chimeric Antigen Receptors (CARs) in therapeutic applications has a long history that has recently culminated in the extraordinary success of these interventions and several FDA approved therapies for cancer. While the use of CAR T cells didn’t start out targeting neoplastic cells, the therapeutic applications gained traction with the success of CART cell therapy for B cell malignancies. In 2017, the first of several CAR T cell therapies against B cell cancer was approved by the US FDA 1, which sparked hundreds of clinical trials and countless preclinical programs, solidifying cell therapies as the “third pillar” of medicine along with small-molecule drugs and biologies 2.

More recently, a number of studies have built on the success of CAR T cell therapy in cancer to branch out to other disease areas such as cardiometabolic disorders, autoimmune disease, fibrosis, and cellular senescence. Further, infectious pathologies, which were some of the earliest targets of CAR therapy, are being revisited with an enhanced understanding of immune responses and improved tools. These include several generations of CAR constructs, improved manufacturing, the ability to target various subsets of immune cells including Tregs and macrophages 3, and improvements in clinical practice.

The dramatic successes of CAR T cell therapy in oncology have spurred enormous recent interest and investment, but the first CAR T treatments date back decades and were focused on targeting infectious disease; specifically human immunodeficiency virus (HIV). These first-generation CAR constructs consisted of a CD4 extracellular domain fused by a hinge to an intercellular CD3ζ signaling domain (CD4ζCAR). This CD4ζCAR was able to redirect T cells to HIV infected CD4+ cells in vitro and in vivo, resulting in numerous clinical trials beginning in the late 90s 4. These initial studies demonstrated the safety and feasibility of this concept 5 but were ultimately unable to durably control infection or lower viral burden. Since that time, there have been many generations of CAR design, such as the inclusion of a co-stimulatory domain like CD28 or 4-1BB, to improve function and persistence 6. Recently there have been significant advances in the the treatment of HIV with CAR T cells, including various antigen targeting strategies (HIV envelope protein moieties, broadly neutralizing antibodies, bispecific targeting, and others) and methods to overcome challenges such as virus escape and host antigen down-regulation 7–9, which have been recently reviewed 10. Similar CAR T cell approaches are ongoing for other infectious diseases such as infections due to cytomegalovirus 11,12, Hepatitis B virus 13–16, Hepatitis C virus 17, invasive aspergillus 18, and tuberculosis 19. CAR T therapy is now poised to impact a host of disease areas beyond oncology and infectious disease, including autoimmunity, cardiometabolic disease, fibrosis and senescence.

CAR T cell therapy beyond cancer

a). Autoimmune disease

Recent advances suggest that CAR T therapy may hold enormous promise for the treatement of many types of autoimmune diseases, which occur when the immune system abnormally attacks host cells or tissues. In some cases, individuals produce autoantibodies against a non-pathogenic endogenous protein through B cells. There are dozens of described autoimmune conditions, only some of which are due to autoantibodies, and in most of these cases the specific antigenic targets of the autoantibodies are unknown. In other cases, autoimmune disease is thought to be due to abnormal T cell responses (which may also be dependent on B cells through antigen presentation) or other aspects of the immune system. A common strategy for treatment is immunosuppression, however this is not curative and can have safety concerns and side effects.

i). CAART

One example of an autoimmune disorder where the target of autoantibodies is understood in many cases is pemphigus vulgaris (PV). This is a skin blistering condition that is life-threatening, frequently caused by the production of autoantibodies against desmoglein 3 (Dsg3). Clinical trials attempting to non-specifically deplete the source of these antibodies, B cells, using the anti-CD20 monoclonal antibody Rituximab saw short term remission in almost all patients, but very high levels of relapse and significant safety concerns 20. In 2016, Payne and colleagues published a report that cleverly re-engineered the chimeric antigen receptor to selectively deplete Dsg3 autoreactive B cells to avoid the risks of non-specific B cell aplasia 21. This construct came to be known as a chimeric autoantibody receptor (CAAR). Instead of a scFv specific against and antigen as in a traditional CAR, CAARs instead have the target of the autoantibodies, in this case recombinant Dsg3, fused to CD137-CD3ζ signaling domains (CD137 is also known as 4-1BB). Dsg3 CAAR T cells selectively ablated only B cells that expressed B cell receptors against Dsg3 while sparing the rest (Fig. 1). This therapy ameliorated the skin phenotype in a mouse model of PV without off-target toxicity. A phase 1 clinical trial in humans is currently underway (NCT04422912).

Figure 1 – Chimeric antigen receptor (CAR) and chimeric autoantigen receptor (CAAR) T cell therapies to treat diseases beyond cancer.

Figure 1 –

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Second generation CARs consist of a single-chain variable fragment (scFv) fused to a costimulatory domain (CS, e.g. CD28 or 4-1BB) and a CD3ζ signaling domain, while CAARs substitute a recombinant autoantigen in place of the scFv. Pictured are examples of therapy for fibrotic diseases (anti-fibroblast activation protein – FAP – CAR), autoimmune diseases (anti-CD19 CAR and autoantigen CAAR), and diseases arising from cell senescence (anti-uPAR CAR). TM – transmembrane.

A similar approach was reported in a study targeting factor VIII (FVIII) autoantibody producing B cells 22. A significant portion of hemophiliacs develop anti-FVIII antibodies during the course of FVIII infusions making treatment difficult. In what is essentially the same concept as a CAAR, which the authors term B-cell antibody receptors (BAR), the FVIII domain is fused to CD28- CD3ζ and expressed on cytotoxic CD8+ T cells. Adoptive transfer of these cells into hemophilic mice leads to significantly reduced anti-FVIII antibodies. Success of this CAAR/BAR strategy would suggest that this type of cell therapy can be applied to additional autoimmune disorders where the autoantibody target is known.

ii). Anti-B cell CAR T

In most cases of autoimmune disorders, the autoantibody target is not known, and other strategies need to be utilized. Non-specific depletion of B cells is one such strategy, although two separate clinical trials using Rituximab for the treatment of systemic lupus erythematosus failed in achieving efficacy 23,24. In both cases, this was most likely due to the incomplete depletion of B cells and failure to ablate the autoantibody producing clones. However, unlike monoclonal antibodies, anti-B cell CAR T cells have been shown to result in complete and sustained depletion of B cells, as is the case with CD19 CARs (Fig. 1). B cell ablation by CD19 CAR T cells in mouse models of SLE was effective in both preventing the symptoms of the disorder, but also in the treatment of established disease and increasing lifespan 25,26. CD19 CAR T cells have already been approved by the FDA for treatment of B cell malignancies, making this an attractive approach for SLE, and clinical trials are currently underway (NCT03030976). Promising results from a patient with SLE receiving this therapy have recently been reported 27. A similar approach of whole B cell depletion is being taken to treat myasthenia gravis, a neuromuscular disorder, by using anti B cell maturation antigens (BCMA) CAR T cells, which is also in clinical trials (NCT04146051). More targeted approaches, such as those targeting MuSK (Muscle Associated Receptor Tyrosine Kinase), are currently in preclinical development 28.

iii). CAR Tregs

Until this point we have been discussing redirecting cytotoxic T cells using CARs or modified CAR constructs to target and ablate specific cells. An alternative approach with great therapeutic potential is the targeting of regulatory T (Treg) cells to areas affected by autoreactive immunity to locally suppress the immune response. Three examples of preclinical work in autoimmune disorders using CAR Tregs are in colitis 29,30, multiple sclerosis 31, and type 1 diabetes 32. Additinally, HLA-targeted CAR Tregs have been proposed to help prevent immune rejection of a transplanted organ 33–37, which is discussed further below.

iv). Tissue transplantation

Tissue rejection and graft-versus-host disease are serious immunologic complications following organ transplantation. Regulatory T cells, engineered with a CAR to recognize the donor tissue, may have the potential to locally suppress host immunologic response to a transplant. Administration of Tregs expressing a CAR against HLA antigen A*02 (A2-CAR) administered prior to human skin xenograft improved mouse tolerance to the transplant and avoided GVHD 34,37. Similar benefits were observed following co-injection of A2-CAR Tregs with HLA-mismatched peripheral blood monoculear cells 35. A2-CAR Tregs can be further engineered to constitutively express interleukin 10, which helps maintain their immunosuppressive phenotype over time 36. These preclinical data suggest exciting opportunities for future application of CAR T cell technology to augment transplantaion, which may especially benefit patients with complex HLA types.

b). Metabolic disease

CAR T cell therapy is emerging as a potential approach for a number of metabolic disorders, including those with an underlying autoimmune pathogenesis and those due to hyperactivity of a specific cell type that could be targeted and depleted by cytotoxic T cells. Type 1 diabetes (T1D) is an autoimmune condition resulting in the destruction of insulin producing beta cells in the pancreas, necessitating lifelong insulin treatment. There are currently no approved therapies for the prevention or reversal of T1D. Here we explore two potential CAR T cell strategies for the treatment of T1D. First, it may be possible to target and destroy the autoimmune cells responsible for beta cell destruction. A 2019 study described a CAR T cell against an insulin peptide-MHC class II complex on the antigen presenting cells (Fig. 1a) in NOD mice that are responsible for development of diabetes in a mouse model 38. When adoptively transferred, this CAR T cell treatment significantly delayed the onset of T1D; however, the cells were not long lived and were undetectable by fifteen weeks. In 2020, a group developed a novel first-generation biomimetic five-module chimeric antigen receptor (5MCAR) targeting autoimmune CD4+ T cells in a mouse model of diabetes 39. 5MCAR CTLs were capable of eliminating pathogenic autoimmune T cells (Fig. 1a), and were able to both prevent and treat T1D in mice. Persistance of these cells was seen in a subset of treated mice for up to a year.

A second strategy employed has been the use of Tregs to suppress the immune system in the context of T1D. Because of the known Treg dysfunction in T1D patients, cell therapy to increase the number or function of Tregs have been explored. There have been at least 2 clinical trials transferring polyclonal Tregs into patients with T1D with mixed results (40–42. There are several possible reasons for modest efficacy seen in these trials, but one important factor may be that antigen specific Tregs, which have been shown to be effective in autoimmunity, were not utilized. To overcome this, a group has attempted to localize Tregs to the pancreas (Fig. 2b) by engineering them to express a CAR against insulin. Co-expression of FoxP3 with the CAR in T effector cells was used to transform them into functional T regulatory cells. These Tregs were successfully localized, suppressive, and long-lived in vivo, but this localization was not able to delay progression of T1D in a mouse model 32.

Figure 2 – Preclinical strategies using CAR T cells for the treatment of diabetes.

Figure 2 –

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(a) CAR T cells can be used to ablate insulin autoantigen presenting cells (APCs) by targeting the insulin peptide:MHC class II complex, and pathogenic CD4+ T cells responsible for beta cell destruction by using a biomimetic five-module chimeric antigen receptor (5MCAR). (b) CAR Tregs can be targeted to the pancreas to locally suppress the immune system and prevent type 1 diabetes. (c) Anti-beta cell CAR T cells can potentially be used to deplete insulin producing cells in congenital hyperinsulinemism.

Additional cardiometabolic indications for T cell therapy that have been proposed include treatments for atherosclerosis using Tregs 43 or by targeting senescent cells within the vessel wall 44. Investigators are also exploring whether targeting of oxidized LDL may be beneficial in atherosclerosis, as has been suggested by studies using anti-oxidized LDL antibodies 45. Furthermore, Congenital Hyperinsulinism (HI) may be amenable to CAR T therapy. HI is a rare genetic disorder (caused by mutation of at least 11 different genes) characterized by inappropriate secretion of insulin by beta cells in the pancreas of affected infants resulting in debilitating hypoglycemia. Current strategies to control blood sugar and insulin production include partial or total pancreatectomy. In theory, a cytotoxic CAR T cell directed against beta cells (Fig 2c) could have a similar effect without sacrificing the entire pancreas (including its important exocrine functions). It may also be possible to titrate the dose of transient cytotoxic CAR T cells based on need, thus preserving some endocrine function as well.

c). Fibrosis

Another area of enormous medical need that may be possible to address with engineered T cell therapy is fibrosis, which can affect every organ and tissue and underlies a wide range of human diseases. Fibrosis is characterized by the activation and proliferation of fibroblasts and the accumulation of excess extracellular matrix in response to injury, infection, or other known or unknown disease processes. Despite the enormous medical burden of fibrotic diseases, anti-fibrotic therapies have been limited.

A pair of papers in 2016 found that inducible genetic ablation of activated cardiac fibroblasts in mice after injury resulted in significant resolution of cardiac fibrosis and, importantly, improvement of cardiac function 46,47. Several studies had successfully targeted and ablated activated fibroblast in the tumor stroma of desmoplastic tumors with CAR T cells 48,49. Thus, we adapted this approach to target activated fibroblasts in the heart after cardiac injury 50. By comparing the gene expression profiles in human transplant patients with either hypertrophic or dilated cardiomyopathies to healthy donor hearts, we were able to identify a target protein, fibroblast activation protein (FAP), that was significantly upregulated in the diseased hearts and is expressed at low levels, if at all, in healthy human hearts. FAP is a good target for CAR T cell targeting because it is a cell surface molecule that is only expressed during pathology and is not expressed at high levels elsewhere in the body under normal conditions. By using a mouse model of hypertensive heart disease, we were able to induce cardiac fibrosis with resultant impairment of cardiac function to test whether CAR T cells directed against FAP could target and ablate activated cardiac fibroblasts. We found that FAP CAR T cell immunotherapy significantly reduced fibrosis in these hearts compared with injured controls and rescued both systolic and diastolic function. This proof-of-concept of using CAR T cells to target cardiac fibrosis is important as it not only opens the door to targeting other forms of cardiac fibrosis, but potentially many fibrotic conditions outside of the heart.

d). Cellular senescence

Cellular senescence, first described by Leonard Hayflick in 1961, is a state of permanent cell cycle arrest, distinct from quiescent cells, which are capable of re-entering the cell cycle, and terminally differentiated cells. In addition, these cells undergo marked changes in chromatin structure, metabolic activity, and transcription resulting in a pro-inflammatory phenotype known as senescence-associated secretory phenotype (SASP) 51. Senescent cells are normally cleared from the body by the immune system; however, accumulation of senescent cells in organs and tissues has been shown to contribute to many age-related pathologies including inflammatory diseases, tissue degeneration, and cancer. Previous reports demonstrate that removal of senescent cells in mice via diphtheria toxin mediated ablation results in the amelioration of several age-related pathologies 52. Building on these findings, Lowe and colleagues identified a cell surface molecule, urokinase-type plasminogen activator receptor (uPAR), that is widely expressed in senescent cells, and designed a CAR against this antigen 44. Adoptive transfer of uPAR CAR T cells was able to efficiently ablate senescent cells in vitro and in vivo, resulting in prolonged survival of a mouse model of lung adenocarcinoma. Additionally, in both carbon tetrachloride-induced and NASH mouse models of liver fibrosis, uPAR CAR T cell adoptive transfer resulted in therapeutic efficacy. This report suggests that CAR T cells are a promising senolytic that can be utilized to treat many age-related conditions such as tissue fibrosis, osteoarthritis, diabetes, and atherosclerosis, although much work will need to be done to assess whether targeting uPAR will be safe and effective in humans.

Future applications

The growing body of preclinical evidence for the effectiveness of CAR T cell therapy in non oncologic conditions indicates a rapidly expanding field that holds much promise. Many of the proof-of concept studies in cardiometabolic disorders, autoimmunity, fibrosis and senescence can potentially be applied to a wide array of disease processes that would benefit from the removal of pathogenic cells. As mentioned before, fibrosis can negatively affect nearly every organ system in the body and is an important factor in disease progression. Target organs for antifibrotic CAR T cell therapy include the heart (hypertrophic cardiomyopathy, COVID-19 myocarditis, ischemic cardiomyopathies 47), liver (cirrhosis, nonalcoholic steatohepatitis - NASH, hepatitis C induced liver fibrosis, primary biliary cholangitis), lung (idiopathic pulmonary fibrosis, infectious pulmonary fibrosis including COVID-19), kidney (diabetic and hypertensive nephropathy, polycystic kidney disease), skin (keloids, wound healing) 53, joints54,55, skeletal muscle fibrosis (Duchenne and other muscular dystrophies), and others (strictures, myelofibrosis, radiation-induced fibrosis, sarcoidosis).

Muscular dystrophies such as Duchenne are an especially attractive target for this type of antifibrotic CAR T cell therapy. This monogenic disorder is comprised of a relatively homogeneous population of affect patients (X-linked, males affected) with a well defined natural history of disease. Duchenne muscular dystrophy affects both skeletal muscle, with loss of ambulation usually within the first decade, and the heart, with cardiac fibrosis and impaired function usually by the teens. Mortality is frequently the result of cardiopulmonary failure. Antifibrotic CAR T cell therapy in these patients has the potential to “kill two birds with one stone” by addressing both skeletal and cardiac muscle fibrosis. Additionally, studies have suggested that anti-fibrotic therapies in Duchenne muscular dystrophy patients may not only improve muscle function, but promote muscle regeneration 56. While this approach would not address the underlying genetic disorder, one can conceive of utilizing a CAR T approach to address existing fibrosis combined with a gene-therapy approach to restore dystrophin expression in muscle.

Additionally, there are several autoimmune diseases that result in fibrosis that could benefit from both ablation of autoantibody producing B cells as well as activated fibroblasts. There are many factors to be considered with this type of dual targeting approach including stage of disease and level of fibrosis. An example of this type of therapy could be for treating the autoimmune disease rheumatoid arthritis (RA) 57. The anti-B cell monoclonal antibody Rituximab has shown clinical efficacy in the treatment of RA 58, suggesting that targeting B cell with either non-specific B cell ablation (eg. CD19 CAR) or specific depletion of autoreactive B cells (eg. CAAR/BARs) may be an effective approach to addressing the underlying cause of disease. A recent in vitro study has demonstrated the feasibility of using CAR T cells agains RA autoreactive B cells 59. However, depending on the stage of disease, there may be significant joint fibrosis and potentially interstilial lung fibrosis associated with RA. Recently, Buckley, Croft, and collegues identified a subpopulation of destructive fibroblasts in RA that are characterized by FAP expression and lack of Thy1 60. By genetically ablating FAP+ fibroblasts in a mouse model of arthritis, they were able to inhibit bone erosion and inflammation in the joints. Given the proof of concept evidence for using FAP CAR T cells to target and elimate pathogenic cardiac fibroblasts 50, it is logical to conclude that this approach may also be effective to elminate FAP+ bone-destructive fibroblast populations in RA. Similar approaches might be applied to autoimmune induced fibrotic conditions where FAP overexpression has been noted, such as systemic sclerosis 61, idiopathic pulmonary fibrosis 62,63, and Crohn’s disease 64. This dual CAR targeting strategy offers an innovative way to both tackle the underlying cause of autoimmune disease and also address the cumulative insults that have already resulted from prior disease.

Arising Technologies

The potential for CAR T therapies as treatments for a wide range of common disorder is exciting, but also presents new challenges. Present CAR T approaches, such as those approved for B cell leukemia and lymphoma, are appropriate for relatively few patients. Potential indications such as cardiac or liver fibrosis affect millions in the Unites States alone. One of the major hurdles for this kind of therapy is the manufacturing, scaling, and costs of autologous cell products. Significant efforts are being undertaken to produce “off the shelf” cell therapy products to address some of these issues. Examples include allogeneic CAR T cells (gene editing, iPSC derived, γδ T cells), CAR NK (natural killer) cells, and CAR invariant natural killer T (iNKT) cells 65,66. Efforts to automate, streamline and shorten the time required for manufacture of autologous cells are also underway, which could lower the cost and improve availability.

a). In situ reprogramming

A potentially disruptive technology that could be transformative to reduce cost and improve access is the emerging field of in situ cell reprogramming 67. This entails targeting and reprogramming T cells in the body to express a CAR, obviating the need to perform any ex vivo manufacturing, thereby dramatically reducing costs and simplifying logistics while increasing scalability and access. The success of modified mRNA lipid nanoparticle (LNP) COVID-19 vaccines has validated the potential of mRNA therapies. Whereas the mRNA LNPs in the COVID-19 vaccines from Moderna and BioNTech/Pfizer are untargeted, mainly delivering mRNA cargo to the liver, Weissman and colleagues have recently published a report describing conjugation of a CD4 antibody to LNPs loaded with mRNA that specifically and efficiently targets T cells upon intravenous injection in mice 68. Similarly, CD3 targeted nanocarriers loaded with anti-CD19 CAR mRNA resulted in the expression of the CAR on T cells after injection with resultant amelioration of B cell leukemia in a mouse model 69. In collaboration with the Weissman group, we have recently shown that T cell-targeted LNPs can deliver mRNA encoding an anti-activated fibroblast CAR in mice, producing functional CAR T cells in vivo 70. In this study we demonstrate that a single injection of an off-the-shelf, dosable product effectively reprograms the immune system and significantly improves heart function and reduces cardiac fibrosis. These technologies hold the promise of a drug-like delivery of CAR T cell therapy and a step towards scalability, lower cost, and increased access (Fig. 3).

Figure 3. Tarteted lipid nanoparticle (tLNP) reprogramming of T cells in vivo.

Figure 3

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tLNPs loaded with modified mRNAs encoding a CAR are decorated with antibodies targeted to T cells and when bound will be endocytosed and release their cargo. mRNA is subsequently directly translated in the cytoplasm and CAR proteins are localized to the cell membrane, thus producing a CAR T cell in the body.

Conclusions

CAR T therapy has had enormous impact in some areas of oncology and significant efforts are underway to extend the success to additional forms of cancer. However, the use of engineered T cells may be even more attractive for disorders other than cancer for several reasons. First, for a cancer therapy to be effective, every neoplastic cell must by elimated to avoid recurrence. In contrast, lowering the fibrotic burden in diseases characterized by fibrosis would likely have significant clinical benefits. Additionally, B cell malignancies and other cancers can consist of multiple pounds of tumor cells; the lysis of which is a major contributor of cytokine release syndrome (CRS). In many fibrotic indications the number of pathogenic cells can be orders of magnitude fewer, therby decreasing the risk of adverse effects like CRS after cytotoxicity. Because of the need to avoid recurrence and the enormous number of neoplastic cells, CAR T cells in cancer therapy are required to expand in vivo and to be long-lasting, necessitating the use of viral transduction. This poses risks such as insertional mutagenesis, overactivation, and the need for lymphodepletion. Most non-cancer indications that could benefit from CAR T cell therapy do not have these requirements and are able to utilize safer approaches, like transient mRNA CAR T cells, that negate the safety risks associated with viral transduction. Such “transient” CAR T cells could also be delivered in multiple doses over time in order to titrate the necessary effect while reducing side effects.

The appreciation of the power and potential for engineering the immune system to combat disease is among the most exciting advances in modern medicine. The challenge lies ahead of us to extend these advances to a wider range of human afflications and to utilize developing technologies to make these approaches safe, effective, widely available and affordable. The pace of advance is breathtaking, and early studies already predict the possibility of utilizing CAR T cells, or related products, to treat autoimmune disorders, infections, and the enormous unmet need of tissue fibrosis. Strategies for developing effective immune therapies for non-ongologic disease may diverge from those used to treat cancer and may benefit from advances in mRNA and nanodelivery advances. These are still the early days of the “immuno-revolution” in medicine.

Acknowledgments

This work was supported supported by a grant from the Leducq Foundation, NIH R35 HL140018, the Cotswold Foundation, and the WW Smith endowed chair to J.A.E.

Footnotes

Conflict of Interest

H.A. and J.A.E. are co-founders and hold equity in Capstan Therapeutics, which develops therapeutics to reprogram immune cells in vivo. J.G.R. declares no competing interests.

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