February 26, 2024

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Emerging immunomodulatory strategies for cell therapy

Emerging immunomodulatory strategies for cell therapy


Emerging immunomodulatory strategies for cell therapy

Cell therapy promises to transform the field of medicine by repairing dysfunctional tissues and treating a variety of diseases in a dynamic manner not possible with traditional pharmaceuticals.

Cell therapy spans a variety of therapeutic areas including cancer, regenerative medicine, and immune disorders, and involves stem or non-stem cells from a variety of sources .

Although many clinical approvals or trials are in progress, the host immune response is a key obstacle to the widespread adoption and success of cell therapies.

Here, current research and clinical advances in immunomodulatory strategies to attenuate immune rejection or promote immune tolerance to cell therapies are reviewed. T

he potential of these immunomodulatory interventions to accelerate translation or maximize the prospect of clinically successful cell therapy outcomes is discussed .


· Cell therapy promises to change the field of medicine.

· These therapies may have potential impact on cancer, regenerative medicine and immune diseases.

· Cell therapy includes stem cells or non-stem cells from autologous, allogeneic or xenogeneic sources.

A new generation of innovative immunomodulatory interventions may accelerate translation or maximize cell therapy outcomes for long-term clinical success.





Modulating the immune response for successful cell therapy


The convergence of bioengineering innovations and advances in immunology has greatly expanded the landscape of cell therapy. Cell therapy aims to treat or manage disease by introducing living cells that will integrate into the host to restore or eliminate dysfunctional tissues.

They typically include stem cells (SCs) or non-SCs from autologous, allogeneic or xenogeneic sources, whether unaltered or genetically engineered. Currently, hematopoietic stem cells and chimeric antigen receptor T (CAR-T) cells are the main clinically approved products for the treatment of blood diseases and cancers.

As of August 2022, there are more than 3,000 ongoing clinical trials of cell therapy. These trials primarily use stem cells and blood cells (white blood cells, red blood cells and platelets) to treat a range of therapeutic indications such as cancer, blood disorders as well as autoimmune, cardiovascular, degenerative and infectious diseases.


Despite an expanding pipeline, host immune responses to cell therapies remain a challenge that may fundamentally hinder clinical adoption and desirable outcomes.

Even cells of HLA-matched allogeneic origin can undergo host immune rejection due to mismatched minor alleles.

Systemic immunosuppression with immunosuppressive drugs is routine to reduce rejection.


Immunosuppressive therapy is divided into “induction” (intensive immunosuppression immediately after treatment), “maintenance” (long-term immunosuppression to prevent chronic rejection), and “rejection therapy” (used to treat acute rejection).

These immunosuppressants include calcineurin inhibitors (such as tacrolimus and cyclosporine), corticosteroids (prednisone), monoclonal antibodies (such as basiliximab, adalizumab, and rituximab ), inosine monophosphate dehydrogenase inhibitors (mycophenolate mofetil), inhibitors of rapamycin (mTOR), and depleting antibodies (antithymocyte globulin).

In general, immunosuppressants target T and B cells, which are key to immune rejection. However, systemic immunosuppression is not advisable because of the increased risk of infection, cancer, and organ damage.


Therefore, clinical success of cell therapy requires innovations in promoting and maintaining immune receptivity for favorable long-term therapeutic outcomes.

Emerging immunomodulatory strategies to alleviate immune rejection or promote resistance to cell therapy are highlighted here and local specific immunomodulatory measures are discussed (Fig. 1) .

Solid organ transplants and tissue transplants were excluded. Provides the opportunity to accelerate the translation of innovative immunomodulatory strategies that work synergistically with cell therapies to achieve broad clinical success.


Emerging immunomodulatory strategies for cell therapy
● Figure 1 Cell therapy, drug delivery, and immunomodulatory strategies . There are various types of cell therapy (A) and different methods and sites of administration (B), and accordingly, different ways to modulate the immune response (C) for maximum therapeutic benefit. Cell therapy includes stem cell (SC) or non-stem cell sources.

Stem cell therapy includes embryonic stem cells (ESC), mesenchymal stem cells (MSC) or pluripotent stem cells (PSC). Non-stem cell therapies include blood cells such as dendritic cells (DCs), regulatory T cells (Tregs), CAR-T cells, and tissue-specific cells.

Depending on the type of cell therapy and the indications for treatment, there are different options for administration methods and sites. These sites may have different immune components and require different immune modulation strategies for optimal results.

As immune rejection is a key hurdle in cell therapy, many immunomodulatory interventions have emerged to improve clinical success.

CRISPR/Cas9 technology is used to interfere with immunogenic cell surface markers such as HLA, T cell receptor (TCR) and co-stimulatory molecules (such as CD40) at the genomic level, leading to immune avoidance or T cell anergy.

Likewise, RNA therapeutics, such as RNAi technology for targeted gene silencing or mRNA technology for transient protein expression, using nanoparticles (NPs) as delivery vehicles, have been used to modulate immune activity.

Immunosuppressants can be used in combination with cell therapy to create a local immunosuppressive microenvironment. Likewise, stem cells or cells derived from stem cells can be used to induce tolerance or avoid host immune responses.




CRISPR-Cas9 genome editing

Genome editing technologies, such as the clustered regularly interspaced short palindromic repeat-related protein 9 (CRISPR-Cas9) system, have led to the development of off-the-shelf or universally engineered cell therapies with little immunogenicity. The CRISPR-Cas9 system generates directed double-strand breaks (DSBs) in the genome.

It can be repaired by cells. For repair, cells can use non-homologous end joining (NHEJ), which efficiently knocks out the gene of interest.

Alternatively, if a donor DNA template is provided, homology-directed repair (HDR) can occur, allowing targeted insertion of foreign genes.

Depending on the application, gene editing to avoid immune recognition has focused on eliminating genes encoding immunogenic surface markers, such as HLAs and T-cell receptors (TCRs).

For regenerative therapies using iPSCs, the focus has been on deleting the B2M and CIITA genes required for the expression of HLAI and class II genes, respectively, which often drive allogeneic immune responses (Fig. 2) .

While complete HLA knockout helps avoid recognition by host CD4+ and CD8+ T cells, HLA-1 deficiency leads to activation of recipient NK cells and graft rejection .

Use of allele-specific editing polymorphic HLA-1 to express common HLA-C alleles that match more than 90% of the world’s population, and to generate suppressed NK and T in addition to eliminating HLA-II Cell-recognized iPSCs.

Alternatively, overexpression of non-polymorphic HLA-1 molecules, such as HLA-E, in stem and progenitor cells can also inhibit the lytic activity of NK cells.

Finally, iPSCs can be edited to simultaneously interfere with the expression of HLA-1 and overexpress CD47, a “don’t eat me” signal that can effectively inhibit phagocytosis, thus preventing macrophage and NK cell-mediated transplant rejection reaction.



Emerging immunomodulatory strategies for cell therapy

● Figure 2 Immunomodulation technology based on CRISPR and RNA .

These techniques can be used to (AC) reduce the immunogenicity of cell therapy or (D) induce resistance to cell therapy by the host immune system. Strategies to reduce donor immunogenicity include (A) CRISPR-Cas9 editing of donor cells to express common or non-polymorphic HLA, or knockdown of immunostimulatory genes by CRISPR-Cas9 or RNAi therapy.

In addition, donor cells can be genetically engineered to (B) overexpress immunosuppressive surface markers such as CD47 or (C) secrete anti-inflammatory cytokines such as IL-10 to modulate the local immune environment. (D) Furthermore, recipient tolerance to allogeneic cell therapy can be achieved by targeting activation of Tregs using mRNA-based IL-2 production or tolerance vaccines.


To generate “off-the-shelf” CAR-T cells, human T cells have been edited to eliminate CD7 and TRAC , whose absence prevents TCR-mediated signaling that leads to graft-versus-host disease (GVHD). These double-edited CAR-T cells efficiently killed T-cell acute lymphoblastic leukemia (T-ALL) in vivo without evidence of heterogeneous GVHD .

Furthermore, CAR-T cells edited to lack TCR and HLA-1 reduced cell therapy-associated alloreactivity and GVHD, while a third edit deleted PD1 .

PD1 inhibitory pathway can attenuate CAR-T cell-mediated antitumor activity. Therefore, abrogation of the PD1 inhibitory pathway improves the antitumor effect .


In addition, Cas9 was also used to confer immunomodulatory functions on the rat insulin-secreting β-cell line INS-1E.

INS-1E is precisely designed to continuously produce the IL-10 cytokine in a glucose-responsive manner because the knock-in site is located in the C-peptide region.

Sustained local secretion of IL-10 attenuates fibrosis and protects β cells from pro-inflammatory cytokine-induced cell death with minimal systemic effects on the host immune system.


The generation and use of genetically engineered cell therapies with minimal immunogenicity comes with safety concerns that must be considered.

Gene editing by CRISPR-Cas systems often involves double-strand breaks in the genome, which, if not carefully monitored and addressed, can lead to unintended large-scale deletions, complex genome rearrangements, or aneuploidy leading to deleterious pathology.

These risks are especially of concern in cell therapies designed to avoid immune recognition, since malignant transformation of engineered cells may escape perception by host immune cells.

Therefore, there is growing interest in using gene editing tools that do not cause DSBs, such as base editing and initiation editing, or even epigenome editing tools, to reduce the immunogenicity of cell therapies .


RNA therapy for immune tolerance

RNA therapy, such as RNAi technology for targeted silencing of genes or in vitro transcription of mRNA for transient expression of encoding polypeptides or proteins, has great potential in promoting immune tolerance to cell therapy.

Similar to CRISPR-Cas9, RNAi can silence the expression of immunogenic alloantigens through mRNA transcriptional degradation or translational repression .

This is achieved by using short double-stranded RNA (dsRNA) in combination with the endogenous effector RNA-induced silencing complex to promote homology-directed gene silencing at the post-transcriptional level.

Thus, elimination of surface MHC molecules can be achieved by RNAi without the risks associated with gene editing as mentioned in the previous section (Fig. 2).


For vascularized cell therapy, host immune responses to graft endothelial cells (ECs) expressing mismatched HLA can lead to graft rejection.

In vitro pretreatment of donor vessels with siRNA against CIITA abolished HLA-II expression in endothelial cells and prevented rejection of donor arteries by adoptive transfer of allogeneic PBMCs from immunodeficient mice.

While siRNA holds promise for temporarily knocking down HLA, which may help promote initial immune tolerance, permanent ablation may be preferable to improve the likelihood of long-term survival of cell therapy.

Lentiviral delivery of short hairpin RNA (shRNA) targeting B2M can stabilize the expression of interfering RNA for more durable knockdown of HLA-1 .

This approach has been used to generate knockdown HLA-1 cells to prevent CD8+ T cell responses, while residual HLA-1 expression prevents NK cell lysis.

Stably expressed shRNA targeting B2M was also used to generate iPSCs suppressed by knockdown of HLA-1, which could be derived into platelet-producing megakaryocytes after transfusion into a mouse model of platelet instability.


With the approval of two mRNA vaccines against SARS-CoV-2 and more mRNA therapeutics in clinical trials, there has been growing interest in using mRNA to increase immune tolerance of cell therapies .

The focus of mRNA therapy in this field has been on the activation and expansion of regulatory T cells (Tregs), which play important roles in immunosuppression and prevention of GVHD.

The mRNA encoding the human IL-2 mutein is designed to preferentially bind to the IL-2 receptor alpha (IL-2Rα) on DCs and avoid activation of proinflammatory T cells.

This mRNA can activate and expand Treg in mice and non-human primate models, and effectively reduces acute GVHD in mice.

However, the dual role of IL-2 in promoting Tregs and proinflammatory T cells requires careful monitoring of T cell responses to avoid exacerbating the immunogenicity of cell therapy .


Alternatively, tolerizing mRNA vaccines are used to induce alloantigen-specific tolerance.

The vaccine is engineered using chemically modified mRNA that has been carefully purified to remove dsRNA contaminants.

The resulting non-inflammatory mRNA vaccine can induce tolerance to the encoded antigen when presented to T cells in the absence of co-stimulatory molecules.

Currently, the use of tolerogenic mRNA vaccines in mouse models of multiple sclerosis is limited to the induction of autoantigen-specific Treg responses to prevent autoimmune disease onset.

It is envisaged that a prophylactic tolerogenic mRNA vaccine encoding donor HLA could induce resistance to HLA-mismatched cell therapy mediated by donor HLA-specific Tregs.




Immunomodulators or immunoregulatory cells alter the local immune microenvironment

Local delivery of immunomodulators is an intervention that alters the immune microenvironment to favor cell therapy, as an alternative to systemic delivery (Figure 3) .

Furthermore, in situ co-deployment of immune regulatory cells including tolerogenic dendritic cells (tolDCs) and Tregs has also shown promise.

Mesenchymal stem cells (MSCs) can also be used in a topical setting.



Emerging immunomodulatory strategies for cell therapy
● Fig. 3 Alteration of the local immune microenvironment by immunomodulators or immunomodulatory cells .

The local immune microenvironment of cell therapy plays a critical role in the success of implantation. Various strategies have emerged to modulate local immune responses, including drug-eluting biomaterials such as hydrogels (microgels), micelles, and graphene scaffolds.

These drug-eluting biomaterials are functionalized to allow localized release of immunosuppressants and co-delivery with cell therapy, creating an immunosuppressive environment.

Local Immunomodulation The subcutaneous implant NICHE allows simultaneous elution of cells with immunosuppressants, favoring a physically immune protected microenvironment of the implant.

Other strategies include the co-delivery of tolerogenic dendritic cells (tolDC) with cell therapy to induce and maintain immunosuppression by promoting Tregs or T cell anergy to maintain immune self-tolerance and thereby protect transplanted cells.



Locally delivered immunomodulators

Hydrogels and micelles are biomaterials increasingly used for immunomodulation, including cell therapy, because of their tunability, biocompatibility, and flexibility. Likewise, biomaterial-based scaffolds have been used as niches for local immune modulation.

The Fas receptor/Fas ligand (FasL) pathway produces immune immunity and tolerance to self-antigens by initiating apoptosis of infiltrating lymphocytes and inflammatory cells.

When allogeneic islets were co-transplanted with FasL-modified microgels or scaffolds, islets engrafted long-term in diabetic mice and in euglycemic and nonhuman primates, implying that systemic tolerance induction is a viable alternative.

Likewise, immune checkpoint regulators, whose blockade has proliferated in the oncology setting, could be used for transplant immune regulation.

The PD-1/PD-L1 pathway regulates CD8+ T cell anergy and induces Tregs, which are critical for both alloimmune responses and transplant tolerance.

Consistent with this, PD-L1-eluting microgels combined with transient rapamycin treatment created a microenvironment enriched for tolerant, immunosuppressive cells for islet transplantation.


Alternatively, using dexamethasone-eluting micelles combined with local release of CTLA4Ig reduced pro-inflammatory cytokines such as IL-10, IL-1β, and IFNγ within the graft and improved allogeneic islet survival in diabetic mice.

Likewise, islet engraftment was achieved via a dexamethasone-eluted graphene scaffold, which provided a local immunosuppressive microenvironment for co-implantation of islets with adipose tissue-derived MSCs.

Graphene is a novel biomaterial whose research focuses on functionalization as a scaffold for localized drug delivery, tissue engineering, or regenerative medicine.

Consistent with the local immunosuppressive approach, the neovascular implantable cell homing and encapsulation (NICHE) implant features a drug reservoir for continuous elution of immunosuppressants directly into interconnected cell graft lumens.

CTLA4Ig and/or immunosuppressant elution with antilymphocyte serum creates a local immune-protective NICHE environment where host vessels provide engraftment support for long-term mesenchymal cells or islet transplantation.

In addition, co-transplantation of islets with bone marrow-derived mesenchymal stem cells further provided local immune modulation, supporting long-term graft acceptance.


Co-delivery of TolDC

TolDCs, also known as DCregs, are immature, immunosuppressive DC subtypes. TolDCs can induce and maintain immune tolerance by promoting T cell anergy, apoptosis, and hyposensitivity, and are beneficial to the generation of Tregs. Because of this, TolDCs that can be targeted in vivo or generated in vitro are expected to be valuable in promoting graft tolerance and survival.


Tacrolimus microspheres and clodronic acid liposomes were used together to generate tolDC in situ during subcutaneous islet xenograft transplantation in rats.

The expression of CD40, CD80, CD86 and MHCII molecules on the surface of DC cells was significantly down-regulated, suggesting that the polarization tends to the tolDC phenotype.

At 520 days after transplantation, the antigen presentation ability and T cell activation ability of TolDCs decreased, and the generation and maintenance of Tregs meant the long-term maintenance of immune tolerance.

TolDCs can be cultured in vitro from bone marrow or blood-derived DCs in the presence of cytokines such as GM-CSF, TGFβ, IL-4, IL-10 or IL-3, as well as rapamycin, vitamin D3 or dexamethasone.

A study in which autologous BM-derived tolDCs were co-transplanted with rat islets under the renal capsule achieved prolonged xenograft survival in the absence of immunosuppressants.

Although promising, there are concerns about low migratory activity or elimination of NK cells, and the risk of TolDC maturation and promoting alloimmunity rather than tolerance.



Co-transplantation with Tregs

Tregs (CD4+CD25+FoxP3+) are a long-lived, immunosuppressive T cell subset that is essential for maintaining autoimmune tolerance.

There are many ongoing clinical trials investigating Treg cell therapy. Notably, the safety and feasibility of simultaneous portal vein infusion of autologous Treg and allogeneic islets has been demonstrated (NCT04820270).

Other studies include Treg infusions 6 weeks after islet transplantation (NCT03444064), hoping to reduce the need for immunosuppressants.

Although Tregs are promising in achieving immune tolerance, the source, isolation, and manufacturing procedures of Tregs, especially for long-term use of immunosuppressive drugs, need further development.


Co-transplantation with Sertoli cells

Sertoli cell support cells are involved in the generation of the immune evasion microenvironment in the testis.

They play a major role in the blood-testis barrier, which hinders the transport of lymphocytes and antibodies.

Given that Sertoli cells can secrete immunomodulatory molecules to inhibit the production of IL-2 and the proliferation of B and T lymphocytes, Sertoli cells have been explored for co-transplantation with exogenous cell grafts.

For example, co-transplantation with allogeneic islets in a type 1 diabetes (T1D) model, use of midbrain tissue in a Parkinson’s disease model, and skin transplantation, among others.



Stem Cell-Derived Immunomodulatory Therapies

SCs can be bioengineered and differentiated into specific cell lines, or used as active drugs for immune regulation in cell therapy.

In cell transplantation, SCs provide an unlimited source of cells, eliminating the problem of limited donor tissue availability.



iPSC-derived cells

Human stem cell (hPSC)-based therapies, including human embryonic stem cells (HESCs) and hiPSCs, are widely studied for the treatment of various diseases, such as neurodegenerative and cardiovascular diseases, T1D, and spinal cord injuries.

However, hPSC-derived cells can undergo immune rejection, which hinders clinical application. In addition, the high cost of personalized cell production for individual patients may pose a barrier to clinical development.

Furthermore, autoimmunity, as in the case of T1D, remains a clinically significant disorder.


To this end, advances in immune engineering have paved the way for the generation of hypoimmune (HIP) cells. demonstrated in a T1D mouse model that deletion of the Rnls gene by CRISPR rendered iPSC-derived β cells resistant to autoimmunity without affecting cell function.

In another study, lentiviral manipulation of hiPSCs to achieve PD-L1 overexpression protected islet-like xenografts from immune rejection and restored normoglycemia in T1D immunocompetent mice.

To explore applications in cardiovascular regeneration, HIP-iPSCs were engineered to lack expression of MHC class I and class II and overexpression of CD47.

HIP-iPSCs were differentiated into iPSC-derived ECs (HIP-iECs) and injected into the infarct region of an allogeneic mouse myocardial infarction model.

These cells were transplanted into the heart and significantly increased cardiac output, but there was no measurable immune response to the graft.

Taken together, these studies highlight the promise of genetic manipulation of PSCs to abrogate autoimmune and alloimmune rejection of cell therapy .



DC-like cells

Stem cell-derived dendritic cells (DC-like, DCL) is a way to induce tolerance. CTLA4-Ig/PD-L1-derived DCL cells expressing hESCs.

DCL cells induce long-term tolerance to hPSC-derived smooth muscle and cardiomyocyte allografts by maintaining an immature tolerance state similar to tolDC.

Uniquely, only T cells specific to the alloantigen expressing DCL are immunotolerant, thereby avoiding systemic immunosuppression and its associated toxicity and risks.




MSCs secrete cytokines, chemokines, and growth factors responsible for regulating inflammatory and immune responses.

MCSs suppress allogeneic T cell responses, promote Tregs, trigger DCs to differentiate into tolDCs, convert pro-inflammatory M1 macrophages to an anti-inflammatory M2 phenotype, and inhibit NK cell proliferation.

These immunosuppressive properties of MSCs make them attractive in cell therapy, including for islet therapy (NCT02384018).


In a mouse model of retinal degenerative disease, co-transplantation of MSCs with fetal retinal pigment epithelial (RPE) cells suppressed host immune responses, thereby prolonging graft survival and preserving retinal function.

In a mouse model of acute liver failure, coencapsulation of MSCs with high expression of hepatocyte nuclear factor-4α (HNF4α) with hepatocytes promoted M2 macrophage polarization and reduced inflammation.

It was shown that syngeneic MSCs induced immune tolerance to iPSC-derived cardiomyocytes by promoting Tregs and triggering CD8+ T cell apoptosis.

In a mouse model of myocardial infarction, the combination of iPSC-derived cardiomyocytes and MSCs produced improved cardiac function compared with transplantation of single-cell populations alone.

In the diabetic context, co-transplantation of human umbilical cord perivascular MSCs in accordance with good manufacturing practice and islets from diabetic mice achieved T cell suppression and maintained tight glycemic control.

Furthermore, PD-L1/CTLA4-Ig-expressing MSCs (eMSCs) can induce local immunosuppression and support allogeneic rat islet transplantation without systemic immunosuppression.


Despite the promise of SCs, challenges include achieving full functional maturity, unclear long-term fate, immunogenicity, and cost and complexity of large-scale production .

In this regard, quality control between different SC sources, ease of procurement, and scaling up while maintaining a stable phenotype are important criteria for clinical translation.


Site-specific immune regulation by cell delivery

Immune surveillance is inherently suppressed in certain organs or tissues, making these immune-privileged spaces ideal for cell therapy .

Typically, these anatomical niches have limited or slow regenerative capacity, such as the eye, central nervous system (CNS), testis, and placenta. Stem cell niches including hematopoietic cells or hair follicles are also known as immune privileged sites.

However, immune immunity often does not extend to all tissues within an organ. The blood-ocular barrier protects the inner compartments of the eye (anterior chamber, vitreous cavity, and subretinal space), while the blood-brain barrier immune-shields the parenchyma.

Therefore, cell replacement therapy is often investigated at these immunodominant sites to prevent rejection.


iPSC-derived dopamine neural progenitor cells

Transplantation of autologous or allogeneic iPSC-derived dopamine neural progenitors into the brain parenchyma of a Parkinson’s disease macaque model.

Despite the transplantation at an immune-privileged site, only autologous transplantation produced signs of locomotor and depression recovery without immunosuppression during the two-year study period.

This study highlights that even in immune-privileged sites, successful cell therapy using non-autologous transplantation still requires immunosuppression.

In this regard, in a first-of-its-kind study, a patient with progressive idiopathic Parkinson’s disease underwent intracerebral injection of autologous iPSC-derived dopamine neural progenitors. Improvements were noted during the 24-month follow-up period, suggesting successful engraftment of the cell therapy without immunosuppression throughout the course of treatment.


hESC-derived RPE

Research into cell replacement therapy for retinal diseases is widespread due to the retinal immune barrier. Allogeneic hESC-RPE (OpRegen) Retinal Transplants Show Improved Vision Over 15 Months in Legally Blind Patients With Dry Age-Related Macular Degeneration (AMD) and Geographic Atrophy in a Phase 1/2 Study Improvement and maintenance (NCT02286089).

In another study, hESC-derived RPE (MA09-hRPE) were transplanted into the retina of patients with advanced Stargardt disease for macular repair (NCT01344993). During the 12-month follow-up period, subretinal pigmentation developed, indicating survival of transplanted cells.

Although both transplantation studies were performed at immune-privileged sites, systemic immunosuppression was used to reduce the risk of rejection.

Retinal transplantation using hESC-RPE-containing patches improves vision in AMD patients. In this study, local immunosuppression was implemented by intravitreal implantation of fluoroquinolones.

In addition, human retinal progenitor cells (hRPCs) have been studied clinically for the treatment of retinitis pigmentosa by intravitreal or retinal injection without immunosuppression (NCT02464436, NCT03073733).


Application of islet or β cell transplantation in the anterior chamber

In a study of T1D, allogeneic intraocular islet transplantation was not immunosuppressive in mice, whereas transient immune intervention was required in a baboon model. The results of this study led to a clinical trial of islet transplantation into the anterior chamber (ACE) of legally blind T1D patients (NCT02846571).

Islet revascularization in revascularization breaks down the immune barrier because of the vascular network extending from the iris. Consistent with this, maintenance immunosuppressive drugs were administered to trial participants for 2 years.

To avoid systemic immunosuppression, studies have investigated local protection, including a study utilizing slow-release rapamycin microparticles that improved survival of islet allografts in mice with ACE.




Site-specific immunomodulatory effects of endothelial cells

Various studies have highlighted the ability of endothelial cells to exert immunomodulatory roles in immune cell recruitment, immune tolerance, and alloimmunity.

Specifically, tissue-specific subsets of endothelial cells serve immune activities and exhibit characteristics typical of immune cells, such as the ability to induce apoptosis in other cells, secrete cytokines, and express co-inhibitory or co-stimulatory receptors.

Their fundamental role in maintaining tissue-specific immunity is manifested at the blood-brain barrier, where ECs express low levels of adhesion molecules and low levels of cytokines, ultimately impairing immune cell migration. As new discoveries elucidate the tissue-specific immune functions of EC subpopulations, new opportunities may arise to exploit these cells for immunomodulatory therapies. However, this field is still in its infancy.



Summary and  Outlook

Extensive research in this area is reflected in numerous clinical trials exploring immunomodulatory strategies for cell therapy, some of which are listed in Table 1 .

The first open-label clinical trial (NCT04817774) of CAR-Tregs for the induction and maintenance of immune tolerance in kidney transplantation was initiated in 2021.

Recently, a clinical trial in Japan showed that cord blood transplantation combined with intramedullary injection of MSCs could prevent GVHD without inhibiting engraftment.

In addition, several innovative immunomodulatory interventions including CRISPR-Cas9 and mRNA-based therapies are under clinical investigation to alleviate immune rejection or promote tolerance (NCT05210530).



● Table 1 Some clinical trials of regenerative therapy involving cell therapy and immune regulation

Emerging immunomodulatory strategies for cell therapy


As with all new biomedical technologies, safety and ethical aspects must be addressed before clinical translation .

Additionally , key considerations for cell therapy translation include reproducibility, large-scale production, and standardization and quality control protocols .

To address these challenges, various public and private projects have established basic guidelines for good manufacturing processes in the biomanufacturing industry.

A relevant example of these efforts is the BioFabUSA program established at ARMI. BioFabUSA is a public-private partnership comprised of industry, academia, government and nonprofit organizations.

This unique partnership is focused on directing scientific and engineering resources to enable scalable, consistent and cost-effective manufacturing of cell therapies.

In this regard, advances in robotics, information technology, computing science, and artificial intelligence infrastructure will be fundamental to making cell therapies more personalized, accessible, and affordable.

Furthermore, since cell therapies are inherently living drugs, mastery of the supply chain from proper temperature-controlled shipping logistics and storage to proper thawing and management is important for widespread implementation in a reproducible manner .


Another major challenge is to develop safe and effective delivery strategies for cell therapies.

Transplantation of islets or β-cells derived from stem cells provides a clear example of the importance of the delivery method for graft viability and function.

Despite more than 70 years of research and development in this field, the ideal technical solution for delivering these cells remains to be determined.

To this end, new discoveries in biomaterials and nanomedicine will continue to support these efforts, providing new molecular and cellular engineering tools.


Finally, new research opportunities lie in the development of effective strategies to follow cell therapies as they are delivered in vivo, non-invasively monitor their viability and function, and specifically modulate immune responses.

Here, innovative real-time imaging techniques and optogenetics methods for manipulating cells with light stimulation of specific wavelengths may pave the way for new discoveries.


These translational challenges are enormous and require a blend of multidisciplinary expertise and capabilities.

As demonstrated by the global response to the SARS-CoV-2 pandemic through collective action by academia and industry, leading to ultra-rapid vaccine development and regulatory approval, working together can enable cell therapies to reach their full potential .








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Emerging immunomodulatory strategies for cell therapy

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