Stem Cell Clinic

Role of Stem-Cell Transplantation in Leukemia Treatment

Stem Cells Cloning. 2020; 13: 6777.

1Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia

1Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia

1Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia

2Department of Immunology and Molecular Biology, School of Biomedical and Laboratory, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia

1Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia

2Department of Immunology and Molecular Biology, School of Biomedical and Laboratory, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia

Correspondence: Gashaw Dessie Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia, Phone: Tel +251-97-515-2796, Email dessiegashaw@yahoo.com

Received 2020 May 15; Accepted 2020 Jul 25.

Stem cells (SCs) play a major role in advanced fields of regenerative medicine and other research areas. They are involved in the regeneration of damaged tissue or cells, due to their self-renewal characteristics. Tissue or cells can be damaged through a variety of diseases, including hematologic and nonhematologic malignancies. In regard to this, stem-cell transplantation is a cellular therapeutic approach to restore those impaired cells, tissue, or organs. SCs have a therapeutic potential in the application of stem-cell transplantation. Research has been focused mainly on the application of hematopoietic SCs for transplantation. Cord blood cells and human leukocyte antigenhaploidentical donors are considered optional sources of hematopoietic stemcell transplantation. On the other hand, pluripotent embryonic SCs and induced pluripotent SCs hold promise for advancement of stem-cell transplantation. In addition, nonhematopoietic mesenchymal SCs play their own significant role as a functional bone-marrow niche and in the management of graft-vs-host disease effects during the posttransplantation process. In this review, the role of different types of SCs is presented with regard to their application in SC transplantation. In addition to this, the therapeutic value of autologous and allogeneic hematopoietic stemcell transplantation is assessed with respect to different types of leukemia. Highly advanced and progressive scientific research has focused on the application of stem-cell transplantation on specific leukemia types. We evaluated and compared the therapeutic potential of SC transplantation with various forms of leukemia. This review aimed to focus on the application of SCs in the treatment of leukemia.

Keywords: stem cell, leukemia, transplantation

Stem cells (SCs) are undifferentiated cells that can be differentiated into other types of cell andalso have the potential to proliferate and self-renew to producenew SCs. In mammals, there are two broad type of SC. Embryonic SCs (ESCs) are present in the early life of the embryo and isolated from the inner cell massor morula of the blastocyst (future germ layer, such as endoderm, ectoderm, or mesoderm of the embryo).14 The surrounding section of the morula is known as the trophoblast, which can develop to the future placenta. Adult SCs (ASCs) are found in various tissue types of developed mammals.5 ASCs are useful for tissue regeneration and repair after severe injuries.1,6

SC populations may behave abnormally or be altered by genetic or environmental factor, resulting in the development of cancer. Leukemia comprises a group of hematologic disorders that usually begin in the bone marrow and resultin a high number of abnormal blood cells. It is the result of deregulation of normal hematopoietic SC (HSC) development by genetic mutation that produces a cell population known as leukemic SCs (LSCs). The generation of blood cells depends on the regulation of differentiation and proliferation characteristics of HSCs.7 Deregulated differentiation and proliferation activity of HSCs, including chromosomal translocation and somatic mutation, leads to different hematologic disorders. There are four major abnormalities identified under LSCs: such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL),8 chronic LL (CLL) and chronic ML (CML).4 Leukemia and lymphoma (Hodgkins lymphoma [HL] and non-HL [NHL]) are the two major types of blood cancers that result from uncontrolled proliferation of white blood cells, and were the first to be treated clinically using HSC transplantation (HSCT).1,9-11 In addition, HSCT is used as a therapeutic option for many nonhematopoietic malignancies, aplastic anemia, and certain inherited disorders like severe thalassemia, sickle-cell disease, and other inherited metabolic disorders. Historically, HSCs were obtained only from bone marrow, but are now mostly harvested from peripheral blood after mobilization through administration of hemaTtopoietic growth factor and from the umbilical cord blood (UCB) of newborns.4,9

SC-based therapies become the major concern of researchers after the first effective bone-marrow transplant in 1968.12 Globally, food and drug administrations design regulations on the application of SC therapies. An increase in scientific knowledge of cell-differentiation pathways has promoted the application of SC therapy.12 Since the application of SC therapy emerged as a new insight into cellular therapeutic potential, food and drug administrations have continuously driven awareness and designed regulation with regard to SC therapies. SCs serve as a novel cellular therapeutic approach in the field of regenerative medicine to treat various disorders.13 In addition to renewing and proliferating themselves, they are capable of differentiation to specialized functional cells.14 This enables them to substitute various injured cells, such as cardiomyocytes, fibroblasts, and endothelial cells.15 In addition, regenerative medicine has significant therapeutic potential through the application of SCT to restore impaired blood cells.16

HSCT has broad application in treating different malignant and nonmalignant hematologic disorders. Researchers have noted that >40,000 HSCTs are performed every year to treat these disorders.17 In this context, autologous SCT (auto-SCT) and allogeneic SCT (allo-SCT) are the best known and most applicable.18 There are SC types that have the capability of being the source for SCTs. Bone-marrow SCs are the major sources for treating hematologic and nonhematologic disorders.19 Similarly, peripheral blood CD34+ cell have hematopoiesis potential for HSCT.20 With respect to recent scientific advancement,HSCs are generated from pluripotent ESCs that require the transition state from endothelial to hematopoietic progenitor cells to resolve HLA-mismatched problem.21 The recent investigation done by Serap et al (2019) and his colleagues hypothesized that achievement of effective HSCT may also associate with non-hematopoietic progenitor cells, very small embryonic-like SCs (VSELSCs).22 They differentiate into HSCs in vitro.23 With specific forward reprogramming protocols, induced pluripotent SCs (iPSCs) have therapeutic potential to generate hemato-endothelial progenitor (HEP) cells.

Co-administration of chemotherapy along with auto-SCT leads to a decrease in the level of regulatory T-cells. In response to the dysregulated immune system, biological characteristics of mesenchymal SCs (MSCs) contribute to hematopoietic reconstitution and an efficient HSC engraftment.24,25 On the other hand, bone marrow derived MSCs are other components of hematopoietic niche.26 Therefore, this review assessed different types of SCs that are utilized as the source and as support of SC transplantation. In addition, we also summarized the role of allogeneic and auto-SCT in the treatment of various types of leukemia.

The involvement of ESCs is the new therapeutic insights having a regenerative potential to restore impaired tissue or cells.27 ESCs are the source of SCs for cellular transplantation therapies; however, they may also lead to uncontrolled cell proliferation which also results in the development of cancers.28 The challenges of using these cells are their characteristic features of chromosomal abnormality and mutation during in vitro.29 Regard to this, c-MYC oncogene may be expressed that results in cancer cells than their cellular therapeutic significant.29 They require a safety concern due to their teratoma formation.30 Although they have teratoma effect, ESCs have a significant role in the transplantation process.28 Human ESCs (hESCs) serve as the source of development of cellular lineages through signaling pathways.13 Recently, protocols have been on the way to be designed to generate HSCs from pluripotent ESCs in vitro. The generation of HSCs from those pluripotent ESCs requires a transition from endothelial to hematopoietic progenitor cells to resolve HLAmismatching.21 The hematopoietic transcription factor Runx1 promotes the commitment of hematopoietic cellular lineages by activating the expression of Runx1a. NOTCH signaling enhances the transition state, while the TGF-signaling pathway inhibit it.31 Recently, generation of HSCs was achieved by Wang et al from hESCs andhumaniPSCs (). The commitment stages that had been examined by those scientists confirmed the synthesis of hematopoietic cells from hESCs.32 In support of this, recently the ESC gene SLL4was identified and used as a therapeutic target for leukemia. Because of its importance in the ESC fate, SALL4 expression need to be reactivated during the reprogramming process of mouse embryonic fibroblasts to be converted into iPSCs. Under normal condition, SALL4 is expressed highly in CD34+CD38 HSCs and llittle in CD34+CD38 + hematopoietic progenitor cells. Therefore, the main application behind this ESC gene product is as key player in hematopoietic differentiation. Consequently, downregulation of this gene could be considered a therapeutic option for leukemia.33

Role of different types of SCs in SC transplantation. MSCs were the nonhematopoietic source utilized to reduce GVHD (reduce risk of graft failure by secreting soluble factors with anti-inflammatory properties), efficient HSCs support to engraftment of transplant, hematologic reconstitution, and to improve the HSCT outcome. HSCs can be generated from the hematoendothelial transition process from HESCs to HiPSCs, and commonly from bone-marrow SCs, PBSCs, and umbilical cord blood. The pluripotent potential of VSELSCs also enables to generate HSCs.

Abbreviations: GVHD, graft-vs-host disease; HESCs, human embryonic SCs; HSCs, hematopoietic SCs; HSCT, hematopoietic SC transplantation; HiPSCs, human induced pluripotent SCs; MSCs, mesenchymal SCs; PBSC, peripheral blood SC; VSELSCs, very small embryonic-like SCs.

iPSCs were introduced as an alternative SC-based therapy method in 2006, by Takahashi and Yamanaka.34 Reprogramming of SCs through the integration of viruses with these cells induces differentiation capability in various tissue types.35 These are pSCs, which are generated from adult somatic cells through in vitro experimental investigation.36 They are synthesized in vitro by reprogramming mature mouse fibroblast cells through epigenetic modification.34 In human beings, production of iPSCs was started through the introduction of four genes SOX2, MYC, OCT4, and KLF4 into matured somatic fibroblasts37 and other human somatic cells.38 The genes are induced in these cells through the encoded retrovirus.39 The ability of iPSCs to expand into multicellular lineages enables them to be a potential SC-therapy method. Various types of patient-specific SCs have been synthesized from their expansion process in vitro.40 Research has revealed their cellular therapeutic significance in various hematologic malignancies, such as CML, MDS, AML,22 and BCR-ABLmyeloproliferative neoplasms.41 Donor blood cells are reprogrammed to iPSCs to generate patient-specific SCs.40 With specific forward-reprogramming protocols, iPSCs have the therapeutic potential to generate hematoendothelial progenitor cells. Lange et al demonstrate the possible generation of hematopoietic progenitor cells by combinatorial expression of transcription factors SCL, LMO2, GATA2, and ETV242 (). Moreover, researchers have been trying to generate hematopoietic progenitor cells from PSCs. Shan et al described possible strategies for generation of HSCs from human mesenchymal cells with hematopoietic potential (). They revealed the derivation or generation of hematopoietic progenitor cells from mouse PSCs using in vitro induction methods. Therefore, iPSCs can be have possible therapeutic potential in SCT; however, they present safety concerns, due to their teratoma formation.30 Allogeneic transplantation of bone marrow or umbilical cord reveals rejection, due to the effect of graft-vs-host disease (GVHD) and disease relapse, which restricts its applicability. In cases of auto-HSCT, there is no risk of rejection, but there remain leukemic cells that induce disease relapse. Collectively, these disadvantages of bone-marrow HSCT mandate alternative sources of HSCs aiming to reduce GVHD, disease relapse, and bone marrowfailure syndrome. Considering this, iPSCs represent a suitable source to generate HSCs in vitro with limited immunogenicity.43 These have a major advantage over bone-marrow and cord types, since their autologous transplantation from iPSCs does not induce GVHD.44

Bhartiya et al characterized VSELSCs as the true SCs and the subset of different SC population, such as HSCs, ovarian SCs and MSCs. They express the OCT4A antigenic marker in their nucleus.30 The pluripotency features of VSELSCs enhance their expansion in vitro using the pyrimidoindole-derivative molecule UM171,45 and in turn are utilized for expansion of CD34+ HSCs.46 VSELSCs are involved in homeostatic processes, because they are found in quiescent stage, and later they differentiate into ASCs. They differentiate into HSCs in vitro.23 VSELSCs can be generated from primordial germ cells and undergo further differentiation into HSCs47 (). Bone marrowderived VSELSCs may not have features characteristic of hematopoietic progenitor SCs, but they can retain hematopoietic features through external-stress growth factors.48 The transcriptional factors Oct4A), Nanog, and Rex1 are found in VSELSCs, but they are not expressed in HSCs.22 Treatment of immunocompromised ALL8 patients with granulocyte colonystimulating factorincreases mobilization of VSELSCs to the peripheral circulation.49 Dissemination of VSELSCs to the circulation promotes the regeneration of tissue.49 A recent investigation done by Serap et al hypothesized that achievement of effectiveHSCT may be associated with nonhematopoietic progenitor cells VSELSCs.22 The expression of transcription factors and pluripotent markers may contribute to their therapeutic potential in SC transplantation. Demonstrations on immunocompromised mice have shown that VSELSCs have a lower teratoma effect.47 Similarly, an investigation done on animal models showed that they have the capability to differentiate into HSCs.46

Bone marrowderived MSCs are important to regenerate injured tissue.50 Recently, MSCs have served as a new cellular therapy method in the field of regenerative medicine.13 They inhibit cancer-cell proliferation through secretion and inhibition of Dkk1- and Wnt-signaling pathways, respectively.51 Besides this, MSCs alter the immune system to regenerate damaged tissue and decrease inflammation.52 GVHD is one of the complications of both auto-SCT and allo-SCT during treatment.53 This posttransplantation complication is associated with immunologic intolerance.53 Indeed, MSCs have been shown to support the engraftment of autologously or allogeneically transplanted HSCs by secreting soluble factors or immunomodulators, such as TGF1 and HGF which inhibit the proliferation of CD4+ TH1, TH17, CD8+ T, and natural-killer cells, leading to prevention of GVHD.6,24,26 Therefore, GVHD that occurs after HSCT can be treated by coinfusion with MSCs.54 Bone marrowderived MSCs are components of the hematopoietic niche. Additionally, they have the capability to regulate the hematopoiesis process through interactionand communicating with HSCs and progenitor cells55 ().

Donor availability is a very important issue, particularly in patients from ethnic minorities. A haploidentical donor and CB allow allo-HSCT in the majority of transplant-eligible patients.UCB is a well-established cellular product source for hematopoietic reconstitution and transplantation.37 It is derived from fetal tissue and acts as a potential source of progenitor SCs to synthesize matured HSCs16 (). The lower complication rate of GVHD and less stringent HLA-matching requirements make it a valuable source of HSCs.56 It is more highly enriched with HSCs/progenitor cells than peripheral blood with regard to colony-forming unitgranulocyte/macrophage progenitors and CD34+-cell content.57

The effect of HLA mismatching is less severe in mismatched UCB transplantation than unrelated peripheral and bone marrowblood transplantation;58 therefore, higher numbers of mismatched donors may donate to save lives. Compatibility at the DRB1-allele and HLA-A and -B antigen level is better for UCB transplantation to be selected traditionally without consideration of HLA-C.59 UCB has significance for allo-HSCT transplantation, because it requires lower HLA matching than for unrelated donors.59 In AML, unrelated CB transplantation has failed, due to nonrelapse mortality.60 However, the cost of CB delaying engraftment and risk of infection are still challenges in its application for hematologic diseases, including leukemia.61,62

In cases of rapid requirement of allograft and absence of an HLA-matched donor, HLA-haploidentical SC transplantation is considered a therapeutic option.63 Peripheral and bone-marrow SCs can be donated from these family members if they have one common haplotype.64 HLA-haploidentical cells are considered an optional source for HSCT.65 In haploidentical transplantation, the graft contains lower of T-cell content to diminish GVHD.66 Outcomes of haploidentical HSCT may be affected by innate immune cells like T cells and natural-killer cells.67 In high-risk acute leukemia, the applicabilion of HLA-haploidentical HSCT is elevated.65 However, outcomes of nonrelapse mortality and GVHD may be increased from haploidentical HSCT with higher HLA mismatching including from partially related donors, as the content of T-cell is replete.68

A soft, gelatinous tissue, bone marrow is used as the source of peripheral HSCs.69 Researchers have argued that both bone marrow and peripheral blood are major sources of SCs. SCASCs generated from bone marrow are known as bone-marrow SCs,37 having clinical significance in restoring damaged cardiac tissue through gene therapy.70 Also, they can be a potential source for auto-HSCT..37 There is an improvement in GVHD in patients with bone-marrow SC transplantation compared to peripheral blood SCs (PBSCs).19 Bone marrowSC transplantation is utilized in various hematologic malignancies, such as AML, ALL, and CML. The use of bone-marrow transplantation from compatible donors is the most effective treatment for CML.71 Allogenic bone-marrow transplantation is an effective alternative treatment option for patients who are resistant to chemoradiation therapy and have a higher probability of relapse.72 The physician removes marrow from the donors hip bone using surgical procedures, including anesthesia, sterile needles, and syringes, and replaces the donated bone marrow within 46 weeks. As the level of T cell compare in both bone-marrow transplantation and PBSCs, the concentration of T cells is reduced in bone-marrow transplantation.19

Recent SC-transplantation protocols state that mobilization of HSCs from bone marrow to peripheral blood is an effective treatment method in the majority of transplanted patients.73 Although bone marrow is major source of SCs, a hematopoietic growth factor found in PBSCs showed that these are also another possible source of SCs.74 PBSCs from bone marrow are a valuable source in restoring hematologic disorders.69 The potential effect of PBSCs depends on hematopoietic development and enhancement of immunologic profiles, and hence they are a valuable source of HSCs to treat hematologic disorders. Peripheral blood CD34+ cells have hematopoietic potential for SCT.20 Javarappa et alpurified hematopoietic progenitor cells from CD4+ peripheral blood cellsafter which the cells differentiated into megakaryocytes and myeloid-lineage cells75 (). PBSCs serve as a valuable SC source if mobilization is supported by granulocyte colonystimulating factor.19 They are applicable in autolo-SCT in the treatment of multiple myeloma.76 The utilization of peripheral SCs as a source of SCs may induce the occurrence of GVHD.77 Even if they have such effects, the immune system has been enhanced, due to elevation of T-cell secretion. On the contrary, the elevation of T cells may also cause GVHD development;19 however, PBSC collection in children may expose them to metabolic complications, including hypocalcemia and hypoglycemia.78

The tight control in proliferation and differentiation of HSCs has significant value for the synthesis of blood cells.7 Multipotent HSCs are responsible for cell division and proliferation.79 Somatic mutation of T cells during DNA methylation and posttransplantation alteration are risk factors for ALL.8,80 CML is a hematologic disorder induced by reverse chromosomal translocation on t(9;22)(q34;q11)81 and BCRABL oncogene effects on proliferative myelogenous cells.82 Mutated gene BCRABL, has a tyrosine-kinase effect and induces the release of highly proliferative myelogenous cells from bone marrow.81 The MYC gene is another oncogene that induces gene expression and has a proliferative effect on hematopoietic progenitor cells.83 In addition to this gene, BCL2 is another mutated gene that inhibits programmed cell death. As such, cancerous cells proceed with their continued proliferation and leukemic cells are released from the tissue where they were generated.84 Hitzler et al reported that a mutation of the GATA1 gene in acute megakaryoblastic leukemia affects hematopoietic transcriptional factor. On the other hand, chromosomal translocation of t(7;11)(p15;p15) HSCs lead to the integration of genes, including HOXA9 and NUP98, which also leads to distortion in the transcriptional process of hematopoietic precursor cells.85 Aberration of the transcriptional process in these cells induces abnormal cell proliferation, which may lead to AML.85 Overproliferation of lymphoblasts within bone marrow can also result in the pathogenesis of ALL.8,49

Emphasis on the eradication of hematologic malignancies has shifted from cytotoxic chemotherapy to donors immune cells.86 HSCT is utilized by 20,000 people in the US every year.87 It is applicable in treating patients with rare diseases, such as AML,22 ALL,8 CML, Burkitts lymphoma, HL, and NHL,11 and other hematologic malignancies.88 Although it serves as an alternative treatment method, HSCT still has a relapse risk among 40%80% of recipients.89 Both auto-HSCT and allo-HSCTare the main alternative cellular therapeutic methods to treat leukemia. Auto-HSCT is the appropriate and applicable therapeutic option for multiple myeloma1,18 and HL.11 Charles et al explained that auto-HSCT was more frequently utilized by European and North American countries than allo-HSCT to treat myeloma. A lower mortality rate for myeloma is seen with auto-HSCT. Auto-HSCT is an established treatment approach if myeloma is at an acute stage, but for older patients it requires extra improvement.90 The occurrence of GVHD among myeloma patients who undergo allo-HSCT is 50% compared to 5%20% of occurrence of auto-SCTpatients91 (). As such, fewer GVHD effects have been seen in auto-SCT n treating multiple myeloma and HL.11 Furthermore, in HIV-related lymphoma, auto-HSCT is considered an applicable therapeutic option in both relapsed HL1 and relapsed NHL patients.18,92

Comparison of allogeneic and autologous stem-cell transplantation with hematologic disorders. Autologous stem-cell transplantation has been utilized as a treatment protocol to treat MM and HL, due to its initial response, low relapse sensitivity, and positive positron-emission tomography (+PET). Patients at higher risk or progress of AML are treated with allo-HSCT. Chronic phase 1 (CP1), TKI intolerance, and blast crisis enables allo-HSCT to be a standard treatment option for the treatment of CML. Allo-HSCT is also a treatment option for NHL patients presenting with complete remission 1 and 2 (CR1 and CR2) indications and also relapse after auto-HSCT. Although they have graft-vs-leukemic toxic effects, they are a significant alternative cell-based therapy to treat hematologic malignancies.

Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukaemia; HL, Hodgkins lymphoma; MM, multiple myeloma; NHL, non-HL.

On the other hand, allo-HSCT is a curative treatment approach for severe AML93 It has been confirmed that hematologic toxicity is lower in these recipient patients. Allo-HSCT has also been used as a treatment option for acute lymphoid leukemia and multiple myeloma.1,23,94 Though alternative treatments remain undefined, it is a valuable treatment tool for hematologic malignancies. Reduced-intensity conditioning after allo-HSCT has been seen in Spain.95 The toxic effect of allo-HSCT is associated with graft-vs-leukemia reactions. Chronic myelogenous leukemia patients show lower relapse rate than other allogeneically transplanted leukemia patients.96 The therapeutic landscape of CML has shifted dramatically with developments tyrosine-kinase inhibitors (TKIs), which target the BCRABL1 hybrid oncoprotein and block the constitutive activity of tyrosine kinase. The course of CML is typically triphasic, with an early indolent chronic phase (CP), followed by an accelerated phase and a blast (crisis phase (BP).97,98 For selection of appropriate TKIs, of CML patients should be tested for BCRABL1 kinasedomain mutation (mutation profile), disease phase, and patient comorbidities. For example, if the patient has such mutations as Y253H, E255K/V, or F359C, physicians recommend dasatinib or bosutinib as TKI. On the other hand, if patients are in an advanced disease phase (BP) or CML-CP (with T315I mutation), third-generation ponatinib is preferred over imatinib.99103 However, allo-HSCT remains a therapeutic option for patients in CML-CP whose CML has progressed after at least two TKIs and after trialing ponatinib therapy (for T315I mutation) to reduce the CML burden, and for the effectiveness of the transplantation.99,100,102 An improvement in immunologic tolerance and lowered GVHD effect mean allo-HSCT is the only curative treatment option for CML-BP104 (). Similarly to CML, highly complicated and severe AML is effectively treated with allo-HSCT.22 Complications of AML may lead to higher mortality and morbidity rates, which may be due to chronic GVHD among patients >50 years old.105 Pediatric ALL patients presenting with indications of higher relapse risk are treated (10% of treatment) with allo-HSCT.106

ALL patients who develop high relapse risk are indications for treatment with allo-HSCT.107 Allo-HSCT is a standard treatment method for ALL patients who are at higher risk.108 The use of allo-HSCT has lower toxicity in young patients.86 Allo-HSCT has lower relapse risk than auto-HSCT in multiple myeloma.18 Graft-vs-tumor reactions in hematologic malignancies depend on the donors T cells and donor lymphocyte infusions. The decision to perform allo-HSCT depends mainly on reduced intensity conditioning.109 Researchers haverecommended that the use of allo-HSCT should depend on strong clinical data; however, 28%49% of allo-HSCT patients develop relapse risks for disease.110 Moreover, allo-HSCT has been widely applied as a therapeutic option in both HL and NHL.11

SCs play a major role in cell-based therapy to treat both hematologic and nonhematologic malignant disorders. They are mainly involved in the application of transplantation. Adult SCs (bone-marrow SCs), PBSCs, and UCB are the major potential sources of HSCs used during SC transplantation. Similarly, apart from ethical issues associated with disruption of inner cell mass, ESCs and ELSCs are also sources of HSCs as a therapeutic option to be utilized in SC transplantation. The generation of HSCs from iPSCs through hematopoieticendothelial transition will be therapeutic options during times of inadequate availability of compatible donors. On the other hand, non-HSCs and MSCs are possible to use as coinfusion to support engraftment of transplants, hematologic reconstitution, and manage GVHD posttransplantation. Auto-HSCT and allo-HSCT are the major cellular therapeutic options to treat leukemia. The lower relapse risk, blast crisis, TKI-intolerant patients in the CP and at higher risk of disease, and higher relapse risk are indications to utilize allo-HSCT rather than auto-HSCT to treat different types of leukemia. Likewise, primary refractory sensitivity to relapse and positive PET are basic indications to prefer auto-HSCT to allo-HSCT in treating both multiple myeloma and HL. Therefore, allo-HSCT is a more applicable standard cellular therapeutic option than auto-HSCT for many classes of leukemia.

The authors acknowledge Mrs Yonas Akalu for proofreading, language editing, and grammatical corrections to improve this review article.

Allo-HSCT, allogeneic hematopoietic stemcell transplantation; auto-HSCT, autologous HSCT; CML, chronic myeloid leukemia; GVHD, graft-versus-host disease; ESCs, embryonic SCs; iPSCs, induced pluripotent SCs;MSCs, mesenchymal SCs; PBSCs, peripheral blood SCsVSELSCs, very small embryonic-like SCs.

All authors made a significant contribution to the work reported, whether in conception, study design, execution, acquisition of data, analysis, interpretation, or all those areas; took part in drafting, revising, or critically reviewing the article; gave final approval to the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

The authors declare that they have no competing interests.

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Role of Stem-Cell Transplantation in Leukemia Treatment

Nano-Improvements to Rheumatoid Arthritis Stem Cell Therapy Show Success – AZoNano

An article published in the journal Biomaterials shows that [emailprotected]2 nanoparticles (NPs) synthesized with a short bacteriophage-selected mesenchymal stem cell(MSC) targeting peptide allowed the MSCs to take up these NPs. NP-modified MSCs produced greatly improved therapy of Rheumatoid Arthritis(RA) using stem cells.

Study:Highly effective rheumatoid arthritis therapy by peptide-promoted nanomodification of mesenchymal stem cells. Image Credit:Emily frost/Shutterstock.com

RA, which is marked by progressive joint degeneration andsynovial inflammation, is one ofthe primary widespread inflammatory arthritis thataffectsaround 1 % of the global population, however, it currently lacks an effective treatment.

Glucocorticoids (GCs), disease-modifying anti-rheumatic drugs (DMARDs) and non-steroidal anti-inflammatory drugs (NSAIDs)are the three maintypes of medicationscurrently used in clinical practice.

GCs and NSAIDscan help with joint pain and stiffness, but they may cause side effects such asheart problems, osteoporosis, infections andgastric ulcers.

Standard DMARDs, like methotrexate (MTX), can lessen swelling by inhibiting the synthesis of pro-inflammatory cytokines and have little effect on cartilage degeneration. MTX, on the other hand, has a short plasma half-lifeand a poor concentration of the drug in the inflammatory region of the body.

Other side effects may also include liver and kidney damage, bone marrow depletion, and gastrointestinal problems. Biological DMARDs have been rapidly developed in recent years, thoughtheir action slows the progression of structural damage by reducing inflammation and have issues including drug resistance and the potential to cause significant infections and malignant tumors.

Multilineage differentiation, inflammatory site and immunomodulationhoming are all features of MSCs. These distinctivecharacteristicsallowMSCs to become apotential treatmentfora variety ofinflammatory and degenerativediseases, including the treatment of RA,through cell therapy. Unfortunately, over 50 % of patients do not react to MSC treatment, and the therapeutic benefit of MSCs is only temporary.

Firstly, MSCs are susceptible to the inflammatory milieu and so lose their functions of immune-regulationwhen disclosed in an inflamed joint. Reactive oxygen species (ROS) are thought to be engaged in the inflammation development of RA and hence damaging to MSCs, as seen by the gradualdecline in the quantity of MSCs in RA patients' synovial fluid.

Secondly, while the direct impacts of MSCs on tissue regeneration in RA are unknown, an evidentclinical experiment found that MSC injections increased hyaline cartilage regeneration in RA patients. Nevertheless, the unregulated distinction of MSCs can alsoresult in the development of tumors andthe inability of cartilage repair.

As a result, it is important for an optimal stem cell strategy to include MSCs that have the ability to preserve their bio functions and chondrogenically develop to regenerate cartilage under the oxidative stress caused by RA.

According to thisstudy, RA therapy could be enhanced byshort targeting peptide-promoted nanomodification of MSCs. To begin with, [emailprotected]2 NPs wereproduced due to some of theirelements' appealing features. Mn and Cu both are critical trace components in the human body, and they play a keyrole in the production of natural Mnsuperoxide dismutase (SOD) and Cu-ZnSOD, respectively.

Cu and Mn can also encourage stem cell chondrogenesis. The study further explains the modification of [emailprotected]2 NPs with MSC-targeting peptides to increase the passage of the nanoparticles into MSCs since transporting nanomaterials into modifications of MSCs is still a difficult task.

To make [emailprotected]2/MET NPs, [emailprotected]2 NPs were injected with metformin. Lastly, MSCs were allowedto take up these NPs and utilizethem to effectively limit synovial inflammation and maintain cartilage structure, alleviating arthritic symptoms greatly.

This study demonstrates that VCMM-MCSs werecreated by engineering MSCs with catalase (CAT) and superoxide dismutase (SOD)- like activity using dynamically MSC-targeting [emailprotected]2/MET NPs.

The biological features of these cells required in stem cell treatment, such as chondrogenesis, anti-inflammation, cell migration, and increased survival under oxidative stress, were improved by VCMM-MCSs.

Consequently, the VCMM-MSCs injections reduced cartilage damage andsynovial hyperplasiain adjuvant-induced arthritis (AIA) as well as collagen-induced arthritis (CIA) models, substantially reducing arthritic symptoms. Since oxidative stress is present in numerous degenerative and inflammatory disorders, this strategy of altering MSCs with NPs could be applied to treat a number of other disorders as well as to achieve faster tissue healing using stem cell therapy.

Lu, Y., Li, Z. et al. (2022). Highly effective rheumatoid arthritis therapy by peptide-promoted nanomodification of mesenchymal stem cells. Biomaterials. Available at: https://www.sciencedirect.com/science/article/pii/S0142961222001132?via%3Dihub

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Nano-Improvements to Rheumatoid Arthritis Stem Cell Therapy Show Success - AZoNano

SQZ Biotechnologies Announces $2 Million Grant From the National Institutes of Health to Develop a Novel, Scalable Cell Replacement Therapy for…

WATERTOWN, Mass.--(BUSINESS WIRE)--SQZ Biotechnologies (NYSE: SQZ), focused on unlocking the full potential of cell therapies for multiple therapeutic areas, today announced that it has been awarded a $2 million SBIR Phase II grant from the National Institute of General Medical Sciences, a division of the National Institutes of Health. Awarded through a competitive process, the two-year grant will support the development of cell engineering methods that are designed to reprogram a patients own immune cells directly into dopamine-producing neurons, a potential novel therapeutic approach for the treatment of Parkinsons disease.

Directly creating dopamine-producing neurons by reprogramming a patients own immune cells would be a major breakthrough and could support a new Parkinsons disease treatment paradigm, said Jonathan Gilbert, Ph.D., Vice President and Head of Exploratory Research at SQZ Biotechnologies. Unlike alternative allogeneic cell replacement approaches in development for Parkinsons disease, by using a patients own cells, treatment might not require chronic immunosuppression. Moreover, in altering cell fate with RNA-based cell engineering methods, no changes to the genome are likely to occur that could carry long-term risks.

Reprogramming a patients cells to replace lost or diseased cells has significant therapeutic potential. Beyond Parkinsons Disease, applications for cell replacement therapies include Multiple Sclerosis and Type 1 diabetes. However, traditional expensive, time-intensive, and inefficient cell reprogramming methods has hindered clinical progress and patient impact.

At the 2021 International Society for Stem Cell Research annual meeting, the company presented preclinical data showing that proprietary Cell Squeeze technology can be used to generate neurons from induced human pluripotent stem cells through the delivery of an mRNA encoding for a fate-specifying transcription factor.

With the support of the NIH grant, and building upon our experience in multiplex engineering of immune cells, SQZ researchers will attempt to generate dopaminergic neurons directly from somatic cells. The Cell Squeeze technology may allow for a unique complex combination of transcription factors, dosing, and timing.

About SQZ Biotechnologies SQZ Biotechnologies Company is a clinical-stage biotechnology company focused on unlocking the full potential of cell therapies for patients around the world and has active programs in Oncology, Autoimmune and Infectious Diseases, as well as additional exploratory initiatives to support future pipeline growth. The companys proprietary Cell Squeeze technology offers the unique ability to deliver multiple biological materials into many cell types to engineer what we believe can be a broad range of potential therapeutics. With demonstrated production timelines under 24 hours and the opportunity to eliminate preconditioning and lengthy hospital stays, our approach could significantly broaden the therapeutic range and accessibility of cell therapies. The companys first therapeutic applications seek to generate target-specific immune responses, both in activation for the treatment of solid tumors and infectious diseases, and in immune tolerance for the treatment of autoimmune diseases. For more information, please visit http://www.sqzbiotech.com.

Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements relating to events our platform development, our product candidates, project funding, preclinical and clinical activities, progress and outcomes, development plans, manufacturing, clinical safety and efficacy results, therapeutic potential, market opportunities and disease prevalence. These forward-looking statements are based on management's current expectations. Actual results could differ from those projected in any forward-looking statements due to several risk factors. Such factors include, among others, risks and uncertainties related to our limited operating history; our significant losses incurred since inception and expectation to incur significant additional losses for the foreseeable future; the development of our initial product candidates, upon which our business is highly dependent; the impact of the COVID-19 pandemic on our operations and clinical activities; our need for additional funding and our cash runway; the lengthy, expensive, and uncertain process of clinical drug development, including uncertain outcomes of clinical trials and potential delays in regulatory approval; our ability to maintain our relationships with our third party vendors and strategic collaborators; and protection of our proprietary technology, intellectual property portfolio and the confidentiality of our trade secrets. These and other important factors discussed under the caption "Risk Factors" in our Annual Report on Form 10-K, as updated by our Quarterly Report on Form 10-Q for the quarterly period ended September 30, 2021 and other filings with the U.S. Securities and Exchange Commission could cause actual results to differ materially from those indicated by the forward-looking statements. Any forward-looking statements represent management's estimates as of this date and we undertake no duty to update these forward-looking statements, whether as a result of new information, the occurrence of current events, or otherwise, unless required by law.

Certain information contained in this press release relates to or is based on studies, publications, surveys and other data obtained from third-party sources and our own internal estimates and research. While we believe these third-party sources to be reliable as of the date of this press release, we have not independently verified, and we make no representation as to the adequacy, fairness, accuracy or completeness of any information obtained from third-party sources.

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SQZ Biotechnologies Announces $2 Million Grant From the National Institutes of Health to Develop a Novel, Scalable Cell Replacement Therapy for...

Lineage Announces Pipeline Expansion to Include Auditory Neuronal Cell Therapy for Treatment of Hearing Loss – Yahoo Finance

Expansion of Pipeline Into a Third Neuronal Cell Type Builds on Existing Capabilities

Intellectual Property Has Been Filed Covering Composition and Methods for Generating Auditory Neuronal Progenitors

Hearing Loss Afflicts More Than 5% of the Population; More Than 430 Million People

CARLSBAD, Calif., March 21, 2022--(BUSINESS WIRE)--Lineage Cell Therapeutics, Inc. (NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing allogeneic cell therapies for unmet medical needs, today announced that the Company is expanding its novel cell therapy pipeline to include a new investigational product candidate, an auditory neuronal cell transplant for the treatment of hearing loss, with an initial focus on the treatment of auditory neuropathy spectrum disorders. To support this new therapeutic effort, Lineage has filed for intellectual property covering the composition and methods for generating auditory neuronal progenitors which may be capable of functioning as sensory neurons and the connecting neuronal ganglion cells of the ear, and to methods of treatment that employ these cells for the potential treatment of auditory neuropathy. According to the World Health Organization, hearing loss currently afflicts over 5% of the worlds population, or more than 430 million people, and by 2050 it is estimated that one in every ten people, or more than 700 million people, will have disabling hearing loss.

"Hearing loss is a major sensory deficit which affects an enormous number of individuals worldwide, yet current approaches leave much room for improvement. I am pleased to be advising Lineage and providing insights and experience in the launch of this new endeavor and working toward developing cell-based solutions for this condition," stated Stefan Heller, Ph.D., Edward C. and Amy H. Sewall Professor, Stanford University School of Medicine, Department of Otolaryngology Head & Neck Surgery and Institute for Stem Cell Biology and Regenerative Medicine ISCBRM.

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"We are excited to announce this new, internally-developed initiative for Lineage, and to do it so quickly following the partnership we announced with Roche and Genentech for our lead program, OpRegen, in a deal worth up to $670M USD," added Brian Culley, Lineage CEO. "Many patients with sensorineural hearing loss are poorly addressed, cannot benefit from cochlear implants, and/or have no FDA-approved treatment options. Similar to OpRegen, which has demonstrated to be able to replace and restore retinal pigment epithelium cells in patients with vision loss, and OPC1, which similarly replaces oligodendrocytes for the treatment of spinal cord injury, replacing auditory neurons or augmenting an existing but damaged auditory neuron population may provide a benefit beyond the reach of alternate approaches such as prostheses. We believe auditory neuronal transplants represent a unique opportunity to leverage our knowhow and capabilities in cellular differentiation into a fourth indication with a large unmet need. In addition to the speed with which the team created this new program from our internal technology, we have done so with a modest investment of capital so far, because we were able to take advantage of our established manufacturing infrastructure and broad knowhow in the expansion and differentiation of pluripotent cells. This is another example of the efficiency and versatility of our technology platform, which is gaining broader awareness, and which offers us a favorable competitive position in the emerging fields of regenerative medicine and anti-aging technologies."

Auditory neuropathy is a hearing disorder in which the inner ear successfully detects sound but has a problem with sending signals from the ear to the brain. Current state of the art medical knowledge suggests that auditory neuropathies play a substantial role in hearing impairments and deafness. Hearing depends on a series of complex steps that change sound waves in the air into electrical signals. The auditory nerve then carries these signals to the brain. Outer hair cells help amplify sound vibrations entering the inner ear from the middle ear. When hearing is working normally, the inner hair cells convert these vibrations into electrical signals that travel as nerve impulses to the brain, where the brain interprets the impulses as sound. Auditory neuropathy can be caused by a number of factors including: (i) damage to the auditory neurons that transmit sound information from the inner hair cells specialized sensory cells in the inner ear to the brain; (ii) damage to the inner hair cells themselves; (iii) inherited genes with mutations or suffering damage to the auditory system, either of which may result in faulty connections between the inner hair cells and the auditory nerve, which leads from the inner ear to the brain; or (iv) damage to the auditory nerve itself. Researchers are still seeking effective treatments for those affected with auditory neuropathy.

About Lineage Cell Therapeutics, Inc.

Lineage Cell Therapeutics is a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs. Lineages programs are based on its robust proprietary cell-based therapy platform and associated in-house development and manufacturing capabilities. With this platform Lineage develops and manufactures specialized, terminally differentiated human cells from its pluripotent and progenitor cell starting materials. These differentiated cells are developed to either replace or support cells that are dysfunctional or absent due to degenerative disease or traumatic injury or administered as a means of helping the body mount an effective immune response to cancer. Lineages clinical programs are in markets with billion dollar opportunities and include four allogeneic ("off-the-shelf") product candidates: (i) OpRegen, a retinal pigment epithelium transplant therapy in Phase 1/2a development for the treatment of dry age-related macular degeneration, which is now being developed under a worldwide collaboration with Roche and Genentech, a member of the Roche Group; (ii) OPC1, an oligodendrocyte progenitor cell therapy in Phase 1/2a development for the treatment of acute spinal cord injuries; (iii) VAC2, a dendritic cell therapy produced from Lineages VAC technology platform for immuno-oncology and infectious disease, currently in Phase 1 clinical development for the treatment of non-small cell lung cancer and (iv) ANP1, an auditory neuronal progenitor cell therapy for the potential treatment of auditory neuropathy. For more information, please visit http://www.lineagecell.com or follow the Company on Twitter @LineageCell.

Forward-Looking Statements

Lineage cautions you that all statements, other than statements of historical facts, contained in this press release, are forward-looking statements. Forward-looking statements, in some cases, can be identified by terms such as "believe," "aim," "may," "will," "estimate," "continue," "anticipate," "design," "intend," "expect," "could," "can," "plan," "potential," "predict," "seek," "should," "would," "contemplate," "project," "target," "tend to," or the negative version of these words and similar expressions. Such statements include, but are not limited to, statements relating to the collaboration and license agreement with Roche and Genentech and activities expected to occur thereunder, the upfront, milestone and royalty consideration payable to Lineage and Lineages planned use of proceeds therefrom; the potential benefits of treatment with OpRegen, the potential success of other existing partnerships and collaborations, the broad potential for Lineages regenerative medicine platform and Lineages ability to expand the same; Lineages plans to advance its spinal cord injury, oncology and auditory neuron programs and announce new disease settings where it plans to deploy its technology; the projected timing of milestones of future studies, including their initiation and completion, the projected timing of interactions with the FDA to discuss product designation, manufacturing plans and improvements, and later-stage clinical development; the potential opportunities for the establishment or expansion of strategic partnerships and collaborations and the timing thereof, and the potential for Lineages investigational allogeneic cell therapies to generate clinical outcomes beyond the reach of traditional methods and provide safe and effective treatment for multiple, diverse serious or life threatening conditions. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Lineages actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by the forward-looking statements in this press release, including, but not limited to, the risk that competing alternative therapies may adversely impact the commercial potential of OpRegen, which could materially adversely affect the milestone and royalty payments payable to Lineage under the collaboration and license agreement, the risk that Roche and Genentech may not be successful in completing further clinical trials for OpRegen and/or obtaining regulatory approval for OpRegen in any particular jurisdiction, the risk that Lineage might not succeed in developing products and technologies that are useful in medicine and demonstrate the requisite safety and efficacy to achieve regulatory approval in accordance with its projected timing, or at all; the risk that Lineage may not be able to manufacture sufficient clinical and, if approved, commercial quantities of its product candidates in accordance with current good manufacturing practice; the risks related to Lineages dependence on other third parties, and Lineages ability to establish and maintain its collaborations with these third parties; the risk that government-imposed bans or restrictions and religious, moral, and ethical concerns about the use of hES cells could prevent Lineage or its partners from developing and successfully marketing its stem cell product candidates; the risk that Lineages intellectual property may be insufficient to protect its products; the risk that the COVID-19 pandemic or geopolitical events may directly or indirectly cause significant delays in and substantially increase the cost of development of Lineages product candidates, as well as heighten other risks and uncertainties related to Lineages business and operations; risks and uncertainties inherent in Lineages business and other risks discussed in Lineages filings with the Securities and Exchange Commission (SEC). Lineages forward-looking statements are based upon its current expectations and involve assumptions that may never materialize or may prove to be incorrect. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. Further information regarding these and other risks is included under the heading "Risk Factors" in Lineages periodic reports with the SEC, including Lineages most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q filed with the SEC and its other reports, which are available from the SECs website. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Lineage undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

View source version on businesswire.com: https://www.businesswire.com/news/home/20220321005294/en/

Contacts

Lineage Cell Therapeutics, Inc. IR Ioana C. Hone (ir@lineagecell.com) (442) 287-8963

Solebury Trout IR Mike Biega (Mbiega@soleburytrout.com) (617) 221-9660

Russo Partners Media Relations Nic Johnson or David Schull Nic.johnson@russopartnersllc.com David.schull@russopartnersllc.com (212) 845-4242

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Lineage Announces Pipeline Expansion to Include Auditory Neuronal Cell Therapy for Treatment of Hearing Loss - Yahoo Finance

Impact of maintenance therapy post autologous stem cell transplantation for multiple myeloma in early and delayed transplant – Newswise

Based on phase 3 trials, maintenance therapy after autologous stem cell transplantation (ASCT) has become the standard of care in multiple myeloma (MM). We examined the trends in maintenance therapy in a large group of patients (2530) transplanted at a single institution over two decades. Majority (n=1958; 77%) had an ASCT within 12 months of diagnosis (early ASCT). Maintenance was employed in 39% of the patients; 42% among early ASCT and 30.5% among delayed ASCT. Most common maintenance approach was an IMiD (61%), followed by a PI (31%), or a PI+IMiD (4%). Patients with high-risk FISH received PI-based maintenance more frequently. The PFS was superior with maintenance (36 vs. 22 months,p<0.001); 37 vs. 25 months for early ASCT (p<0.001) and 29 vs. 17 months for delayed ASCT (p=0.0008). OS from ASCT was higher with maintenance for the whole cohort at 93 vs. 73 months (p<0.001). OS from diagnosis was also better for the whole cohort with maintenance therapy, 112 vs. 93 months (p<0.001). The improvement in PFS and OS was seen in high-risk and standard risk disease. The experience with maintenance therapy post ASCT for myeloma in a non-clinical trial setting confirms the findings from the phase 3 trials.

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Impact of maintenance therapy post autologous stem cell transplantation for multiple myeloma in early and delayed transplant - Newswise

iTolerance, Inc. Closes $17.1 Million Convertible Note Financing to Advance Development of Innovative Regenerative Medicines for Transplantation…

The Company's proprietary biotechnology-derived Strepavidin-FasL fusion protein/biotin-PEG microgel platform technology, iTOL-100, has demonstrated in animal models of Type 1 Diabetes the ability to induce local immune tolerance and allow long-term engraftment of insulin-producing allogenic pancreatic islet cells without the need for chronic life-long immunosuppression

Lead program, iTOL-101, being developed as a potential breakthrough in curing Type 1 Diabetes

Second lead program, iTOL-102, is also being developed as another potential breakthrough in curing Type 1 Diabetes leveraging stem cell derived pancreatic islet

MIAMI, FL / ACCESSWIRE / March 21, 2022 / iTolerance, Inc. ("iTolerance" or the "Company"), an early stage regenerative medicine company developing technology to enable tissue, organoid or cell therapy without the need for life-long immunosuppression, today announced the closing of its convertible note financing in which the Company raised a total of approximately $17.1 million in gross proceeds. The Company plans to use proceeds from the financing to translate the production of iTOL-100 from the academic labs to commercial manufacturing for use in its planned pre-clinical and clinical trials and for other general corporate purposes.

"As a start-up life sciences company, raising $17.1 million is a noteworthy endorsement from investors and bolsters our confidence in the potential of our proprietary platform technology. With this capital in hand, we are focused on executing next steps in de-risking our manufacturing processes and positioning ourselves to successfully advance into and through pre-clinical studies to support a Phase 1/2 clinical study for iTOL-101," commented Dr. Anthony Japour, Chief Executive Officer of iTolerance. "We believe our platform technology is a potential game changer for patients with Type 1 Diabetes and the physicians who treat them. Additionally, this technology can be applied to a number of cellular therapies for chronic conditions."

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The Company's iTOL-100 platform technology is a biotechnology-derived Strepavidin-FasL fusion protein, a synthetic form of the naturally occurring protein FasL, mixed with a biotin-PEG microgel (SA-FasL microgel) that potentially allows convenient and effective co-administration with implanted cells or organoids to induce local immune tolerance without the need for life-long immunosuppression. In pre-clinical studies, iTOL-100 has been shown to establish durable, localized immune tolerance, allowing the implanted tissue, organoid or cell therapy to function as a replacement for damaged native cells.

iTolerance's lead program iTOL-101 is being developed as a potential cure for Type 1 Diabetes. Using the iTOL-100 platform technology, allogenic pancreatic islets are co-implanted and in pre-clinical studies have shown immune acceptance and long-term function of the graft with control of blood glucose levels and restoration of insulin secretion without the need for immunosuppression. The Company is moving forward with pre-clinical studies to support a Phase 1/2 study in Type 1 Diabetes.

The Company's second lead program, iTOL-102, utilizes the iTOL-100 platform technology to induce local immune tolerance and leverages significant advancements in stem cell-derived pancreatic islets which allows an inexhaustible supply of insulin-producing cells as a potential cure for Type 1 Diabetes without the need for life-long immunosuppression.

About iTolerance, Inc.

iTolerance is an early stage privately held regenerative medicine company developing technology to enable tissue, organoid or cell therapy without the need for life-long immunosuppression. Leveraging its proprietary biotechnology-derived Strepavidin-FasL fusion protein/biotin-PEG microgel (SA-FasL microgel) platform technology, iTOL-100, iTolerance is advancing a pipeline of programs using both allogenic pancreatic islets and stem cells that have the potential to cure diseases. The Company's lead program, iTOL-101 is being developed for Type 1 Diabetes and in a pre-clinical non-human primate study, pancreatic islet cells co-implanted with iTOL-101 exhibited long-term function with control of blood glucose levels and restoration of insulin secretion without the use of chronic immune suppression. The Company's second lead candidate, iTOL-102, is leveraging significant advancements in stem cells to derive pancreatic islets which allows an inexhaustible supply of insulin-producing cells. Utilizing iTOL-100 to induce local immune tolerance, iTOL-102 has the potential to be a cure for Type 1 Diabetes without the need for life-long immunosuppression. Additionally, the Company is developing iTOL-201 for liver failure and iTOL-301 as a potential regenerative protein and cell therapy that leverages stem cell sources to produce proteins or hormones in the body in conditions of high unmet need without the need for life-long immunosuppression. For more information, please visit itolerance.com.

Investor Contact Jenene Thomas Chief Executive Officer JTC Team, LLC T: 833.475.8247 iTolerance@jtcir.com

SOURCE: iTolerance, Inc.

View source version on accesswire.com: https://www.accesswire.com/693757/iTolerance-Inc-Closes-171-Million-Convertible-Note-Financing-to-Advance-Development-of-Innovative-Regenerative-Medicines-for-Transplantation-Without-the-Need-for-Life-Long-Immunosuppression

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iTolerance, Inc. Closes $17.1 Million Convertible Note Financing to Advance Development of Innovative Regenerative Medicines for Transplantation...

‘Without you there is no cure’ – Teenager’s call for stem cell donors in mission to support Anthony Nolan Trust – Shields Gazette

Abbie Young was 16 when she was given the devastating news that her body was suffering from severe Aplastic Anaemia.

With her bone marrow failing, medics at Newcastles Royal Victoria Infirmary Ward 3 were in a race against time to find a stem cell donor who could give her a fighting chance.

Abbie, now 18, is on the road to recovery thanks to the Anthony Nolan Trust.

To say thank you for saving her life, the Harton Academy pupil is aiming to help boost the charitys work by hosting a fundraising day at school on Friday, April 8.

Abbie, who hopes to become an Anthony Nolan youth ambassador, is aiming to encourage others to sign up as stem cell donors and help save lives.

She said: I just feel really grateful that someone out there took the time to sign up to the stem cell register and that one choice someone made, has saved my life.

I know some kids die waiting for a donor, so I will always be forever grateful for what my donors did and to the Anthony Nolan Trust.

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The teenager discovered her bone marrow was failing her after her mum became concerned over the number of bruises her daughter had. Abbie was diagnosed in January 2020.

Mum Caroline, 49, said: We went to the doctors who sent Abbie to South Tyneside Hospital for blood tests.

Abbie was at the hospital on the Friday (January 10), then by Saturday morning we had a knock on the door and there was an ambulance outside, they had come for Abbie.

They took us to Sunderland hospital and her dad followed up in the car, where they did more tests, they thought she had leukaemia, so we were transferred straight to the RVI.

According to information from Great Ormond Street Hospital, severe Aplastic Anaemia only affects around 30 to 40 children in the UK each year.

After Abbies older siblings, brother Sam, 26, and sister Kate, 21, were found not to be matches, a donor from Germany was found with the charitys help.

Abbies first transplant was in May 2020, but with the country in Covid lockdown, the stem cells had to be frozen due to restrictions.

The first transplant failed, believed in part due to the stem cells having been frozen.

The Anthony Nolan Trust stepped in and a second donor was found, but the cells were not frozen this time at the request of the hospital.

Caroline added: It is so hard when it's your child's life is suddenly put into the hands of a stranger. You're waiting for someone you don't know to come forward and help save your child's life.

The teenager underwent her second transplant in July 2020 and following a number of blood transfusions, the treatment started to work.

But due to complexities, she needed to have a top-up from her second donor at a later date.

Throughout Abbies treatment, which also included several doses of chemotherapy, radiotherapy and the top-up donation dose, she needed to stay confined in a bubble with only Caroline, dad Karl and nursing staff for company.

Abbie, of Beacon Glade, told the Gazette she felt like shed lost her purpose while receiving treatment and that losing her hair felt like the worst day of my life.

She explained: I was in denial about the whole thing. I knew I was bruising easily, but I didn't want to do anything about it. I was in denial about everything.

"I knew people lost their hair with treatment but I thought I'd be the one who didn't. Then I did and I was devastated.

I just felt like I had lost my purpose. When I lost my hair, it felt like the worst day of my life, I had had also put on quite a bit of weight.

Following her treatment and a number of blood and platelet transfusions, Abbie was finally able to ring the bell on leaving Ward 3 in August 2020; but she still needed to shield to give her body the best chance of survival.

Now, shes studying Biology, Chemistry and Psychology at A-Level and focusing on supporting the life-saving charity with her fundraising mission.

At time of writing and with weeks to go until her fundraising day at school more than 1,500 has been donated to her JustGiving page.

On her page, she said: Without you there is no cure. For someone with blood cancer, a stem cell transplant could be their last chance of survival.

Mum Caroline added: The hospital, the staff on Ward 3, were brilliant and the nurses were amazing. They were more like friends than medical professionals.

"At the time, you couldn't mix with anyone, so they were a good support to us as a family and to Abbie.

Abbie's school has also been supportive. Sir Ken, who is the school's executive head teacher, would call every day and ask how she was.

When it happened, teachers would drop off books for Abbie and they were even talking about a teacher going into a bubble, so that they could invigilate her for her GCSE exams. But the exams never happened because of Covid.

"We will be forever grateful for everyone's support.

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'Without you there is no cure' - Teenager's call for stem cell donors in mission to support Anthony Nolan Trust - Shields Gazette

Radical increase in the effectiveness of breast cancer immunotherapy – EurekAlert

Discovered the essential role of a new factor, LCOR, in enabling cancer cells to present tumour antigens on their surfaces

A study published in the journal Nature Cancer, carried out within the Cancer Programme at the Hospital del Mar Medical Research Institute (IMIM-Hospital del Mar) by the Cancer Stem Cells and Metastasis Dynamics Laboratory, led by Dr. Toni Celi-Terrassa, and the Laboratory of Molecular Cancer Therapy, coordinated by Dr. Joan Albanell, with the participation of international centres, has discovered an approach that radically increases the success of immunotherapy in one of the most aggressive types of tumours, triple-negative breast cancer. This subtype, although accounting for only 15% of cases, is one of the most rapidly progressing and affects younger patients. In this work, researchers found that tumour stem cells are the main cause of immunotherapy resistance in this subtype of breast cancer. The reason is that these cells are invisible to the immune system, making immunotherapy ineffective. In addition, the study offers a promising solution to this situation by using a new therapeutic approach in preclinical models that makes cancer stem cells visible to the immune system so that it can then eliminate the tumour.

This subpopulation of more aggressive cells may represent between 5% and 50% of the entire tumour population in triple-negative breast cancer. They have low levels of LCOR factor, which plays a key but previously unknown role in allowing cells to present antigens on their surface, molecules that enable the immune system to differentiate normal cells from tumour cells and attack the latter. Consequently, in the case of tumour stem cells, the low presence of this LCOR factor makes them invisible to the body's defences. As a result, these cells are resistant to breast cancer immunotherapy, which has a relatively low success rate in current clinical practice.

A mechanism that provokes treatment resistance

This ability of tumour stem cells to remain invisible to the immune system allows them to withstand immunotherapy treatment. As Dr. Toni Celi-Terrassa explains, "We have seen how, despite immunotherapy treatment, these cells survive and have the ability to generate resistance, which is linked to their ability to hide from the immune system, allowing them to evade immunotherapy."

Using mouse models, the researchers have demonstrated how this situation is reversed when the LCOR gene is activated in this type of cell, setting in motion the machinery that allows the immune system to detect the tumour. It involves reconfiguring the tumour to make it completely visible and, therefore, sensitive to immunotherapy, transforming it from invisible to visible, says Ivn Prez-Nez, a pre-doctoral researcher in the Cancer Stem Cells and Metastasis Dynamics Laboratory and first author of the study. The researchers were able to see how, by combining this approach with immunotherapy, the treatment response rate was total, and all tumours were eliminated, curing the mice in the long term. This prevents both the recurrence of cancer and the generation of resistance.

Pioneering study on the use of messenger-RNA therapy in cancer and immunotherapy

Inspired by the technology used in the design of messenger-RNA vaccines for COVID-19, the researchers decided to use a similar strategy to transport and deliver LCOR gene RNA into tumour cells and trigger its function. Biological nanovesicles, small bag-like structures formed in the cells, were developed to carry this information and were shown to do so successfully, preventing the tumour stem cells from remaining invisible.

"What we are doing is making the immune system see the tumour cell better. Unlike healthy cells, malignant cells have a much higher load of recognised 'foreign' antigens, which are not inherent to the immune system. In this way, the bodys natural defences will recognise, attack and eliminate the malignant cells, explains Dr. Celi-Terrassa. In this sense, he points out that We have discovered how to make this type of breast cancer respond to immunotherapy in preclinical models, making these cells visible thanks to the use of the antigen-presenting mechanism, thereby boosting the immunotherapy response and its efficiency.

This strategy may be applicable to other types of breast cancer tumours and other tumour types, although safety studies and clinical trials in humans are needed first. Even so, according to Dr. Joan Albanell, co-leader of the study, director of the Cancer Research Programme at IMIM-Hospital del Mar and head of the Oncology Department at Hospital del Mar, this approach does open up new possibilities. "What is important is that the experimental results demonstrate an unprecedented sensitisation of triple-negative breast cancer to immunotherapy, making resistant tumours virtually curable", says Dr Albanell, also a professor at the UPF. This unequivocally motivates us to investigate therapeutic strategies that may culminate in clinical trials, and to explore whether it could be applicable to other tumours, he concludes.

The use of LCOR in combination with immunotherapy has generated a patent and a spin-off company will be created to develop this. "The project led by Dr. Celi-Terrassa and Dr. Albanell is a paradigmatic example of research in immune therapies that will be boosted in the near future by the new Immuno-oncology Division that we are creating at the IMIM", explains Dr. Joaqun Arribas, director of the IMIM-Hospital del Mar and author of the study.

The study was made possible thanks to a CLIP grant from the US Cancer Research Institute and funding from the Carlos III Health Institute (ISCIII). Thanks also go to the Spanish Association Against Cancer (Asociacin Espaola contra el Cncer; AECC), the Fero Foundation and CIBERONC, a centre to which the two researchers who led the study also belong.

Immunotherapy in cancer and breast cancer

Immunotherapy is one of the most promising treatments for eradicating tumours and curing cancer. Unfortunately, for breast cancers it is only approved in the triple-negative breast cancer subtype, where the outcomes are still far from what is expected from immunotherapy. Making immunotherapy work in breast cancer would be a great therapeutic opportunity for the breast cancer population, making it a very good option for more advanced and metastatic cases. It should be remembered that metastatic breast cancer, despite significant and continuous advances, is still not curable in the majority of patients.

Precision diagnosis, immunotherapy, personalised medicine and cutting-edge cancer research at Hospital del Mar

At Hospital del Mar, cancer is addressed through the diagnostic tools necessary to achieve a precision diagnosis that makes it possible to plan and offer patients personalised and individualised therapeutic options according to their particular circumstances. At the same time, there is a commitment to a patient-centred care model through pioneering and benchmark work in multidisciplinary functional units specific to each type of tumour. The units, comprising professionals specialising in each cancer type, offer the best therapeutic options in a model of shared decision-making with the patient. Nurse managers guide patients through the diagnostic and therapeutic process. This quality care is combined with groundbreaking cancer research at the Hospital del Mar Medical Research Institute (IMIM) and an extensive programme of clinical trials. The research areas focus on furthering immunotherapy and liquid biopsy, searching for biomarkers and new therapeutic targets, and developing new surgery and radiotherapy strategies to improve efficacy and the quality of life of patients. This research generates almost 200 articles in scientific publications each year, two out of three of which are in high-impact journals. This state-of-the-art care and research are the basis for teaching excellence at the Hospital del Mar Campus.

Reference article

Prez-Nez I, Rozaln C, Palomeque JA, Sangrador I, Dalmau M, Comerma L, Hernndez-Prat A, Casadevall D, Menendez S, Liu DD, Shen M, Berenguer J, Rius Ruiz I, Pea R, Montas JC, Alb MM, Bonnin S, Ponomarenko J, Gomis RR, Cejalvo JM, Servitja S, Marzese DM, Morey Ll, Voorwerk L, Arribas J, Bermejo B, Kok M, Pusztai L, Kang Y, Albanell J, Celi-Terrassa T. LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple negative breast cancer. Nature Cancer (2022)https://doi.org/10.1038/s43018-022-00339-4

LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple negative breast cancer

17-Mar-2022

Original post:
Radical increase in the effectiveness of breast cancer immunotherapy - EurekAlert