Landscape of Advanced cell therapyLentivirus Protocol Download
Cell therapy is a kind of medicine aiming to cure disease or alleviate disease symptoms via direct infusion or transplantation of cells, which can be autologous or allogeneic. With several decades’ development and optimization, immuno-oncology cells (such as T cells, nature killer cells, etc.), stem cells (embryonic stem cells, induced pluripotent stem cells, progenitor cells, etc.) or other genetic re-engineered cells have been widely applied for cell therapy. Numerous cell types have been translated into clinical trials and promising cell therapy outcomes have been achieved from Phase I, Phase II and Phase III trials for a great number of diseases.
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Landscape of Advanced cell therapy -Index
- 1. Immuno-oncology cell therapy
- 2. Stem Cell Therapy
- 3. Genetic re-engineering cell therapy
- 4. Reference
Immuno-oncology cell therapy
In the past several decades, great progress has been made in the field of anti-tumor therapy, but there are also multiple strategies for tumors to evade the recognition and efficient suppression by the immune system. Therefore, a variety of immunotherapeutic targets (Fig. 1) and strategies have been developed to reactivate and reorganize the human immune system, such as CAR-T, TCR-T, CAR-NK, DC-CIK, oncolytic virus and so on.
Figure 1 Immunosuppressive targets for tumor therapy .
Chimeric antigen receptor (CAR)-modified T cells (CAR-T) are T cells genetically engineered to express CAR (Fig. 2A) [2,3], which can specifically recognize their target antigen via the scFv binding domain of CAR, resulting in T cell activation to specifically target and destroy tumor cells [3-5]. To date, four generations of CAR have been developed according to the structure of the endodomain (Fig. 2B) . Due to little ability to generate enough interleukin-2 (IL-2), the 1st generation CAR-T cells (such as Ag-specific CD3ζ (MFEζ)-CAR-T cells, alpha-folate receptor (FR) -CAR-T cells, CE7R-CAR-T cells, scFv(G250)-CAR-T cells, GD2- CAR-T cells and CD10- CAR-T cells) benefitted substantially from the combination of cytokines , and were used for the treatment of different tumors [7-10]. However, most of the studies using the 1st generation CAR-T cells did not show very satisfactory results because of the inadequate proliferation, cytotoxicity, and insufficient secreted cytokines in vivo. To overcome these shortcomings, the 2nd generation CAR-T cells were designed by adding intracellular signaling domains from various co-stimulatory protein receptors to the cytoplasmic tail of the CARs, [11-13]. The 2nd generation CAR-T cells, such as scFvCD19-CD137-CD3-CAR-T cells, MOv19-BBζ-CAR-T cells and scFvCD19-CD28-CD3ζ-CAR-T cells displayed better curative effects on B cell malignancies [12,14]. On the basis of the 2nd generation CAR-T cells, the 3rd generation CAR-T cells were produced with the addition of multiple signaling domains, such as CD3ζ-CD28-OX40 or CD3ζ-CD28-41BB, to promote cytokine production and killing ability. The 3rd generation CAR-T cells, such as CD20-CD28-CD137-CD3ζ-CAR-T cells and HER2-CAR-T cells were applied for the treatment of lymphoma and colon cancer, but with no better outcomes than the 2nd generation CAR-T cells, and the reasons need to be further studied [15,16]. Based on the 2nd generation CAR-T cells, the 4th generation CAR-T cells were obtained with the addition of IL-12, and can mediate T cell redirected for universal cytokine-mediated killing (TRUCKs). TRUCK T cells show great outcomes in disease therapy by augmenting T-cell activation, and also activating and recruiting innate immune cells to destroy the antigen-negative cancer cells in the targeted lesion, and can also be used for the therapy of viral infections, metabolic disorders and auto-immune diseases . Overall, these successive generations of CAR-T cells have yielded remarkable efficacy in several types of cancer or tumor therapy, and some of them have been translated into clinical trials with few side effects (Table 1) .
Figure 2 Structures of chimeric antigen receptor (CAR) . (A) CAR structure: The CAR contains antigen recognition domain of thesingle-chain Fragment variant (scFv) derived from an antibody, transmembrane domain and an intracellular T cell activation domain of CD3ζ. (B) Evolution of CAR. ITAM: immunoreceptor tyrosine-based activation motifs. CM1: costimulatory molecule.
|Antigen||Disease||In vitro, in vivo, in preclinical or in clinical trials||NCT/Reference|
|CD19||haematologic malignancies||clinical trials||[19-22]|
|CD20||haematologic malignancies||clinical trials||[23,24]|
|TRAIL receptor 1||Lymphoma||In vitro|||
|CD22||follicular lymphoma, non-Hodgkin’s lymphoma||clinical trials||NCT02315612|
|HA-1 H||Leukaemia||In vitro|||
|FAP||B cell chronic lymphocytic leukaemia||clinical trials||NCT01722149|
|ROR1||chronic lymphocytic leukaemia||clinical trials||NCT02194374|
|CD138||multiple myeloma||clinical trials||NCT01886976|
|NY-ESO-1||multiple myeloma||In vitro|||
|Lewis Y||multiple myeloma||clinical trials||NCT01716364|
|HER2||Breast cancer||In vitro|||
|HER2||Metastatic cancer||Clinical trial||NCT00924287|
|HER2||Solid tumors||Clinical trial||NCT01935843|
|CEA||Colorectal cancer||In vivo|||
|CEA||Colorectal cancer||Clinical trial||NCT00673322|
|CEA||Breast cancer||Clinical trial||NCT00673829|
|CEA||Liver metastases||Clinical trial||NCT01373047|
|CEA||Metastatic cancers||Clinical trial||NCT01723306|
|CSPG4||Melanoma, breast carcinoma||In vivo|||
|FR||Ovarian cancer||In vivo|||
|IL-13Rα2||Malignant glioma||Clinical trial||NCT02208362|
|EGFR||Advanced EGFR-positive solid tumors||Clinical trial||NCT01869166|
|EGFR||Advanced glioma||Clinical trial||NCT02331693|
T-cell receptor (TCR)–engineered T-cell therapy (TCR-T) is one potentially powerful treatment that utilizes genetically modified natural T cells to specifically target tumors and destroy tumors with greater potentials . Unlike CARs, TCRs rely on their interactions with peptide-major histocompatibility complex (pMHC), formed by peptide [38,39], generated from intracellular antigen proteolysis, bound with MHC (Fig. 3) . Besides TCR, additional costimulatory or co-inhibitory signals are also required for TCR-T function. For example, CD4 on the surface of helper T cells, which binds to class II MHC complex, and CD8 on the surface of cytotoxic T cells, which binds to class I MHC complex, activates the TCR-T mediated cell destruction , while cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are responsible for T cell signaling extinguisher . Given that only ~28% antigens are expressed on the cell surface, it is difficult for most of the antigens to be recognized by CAR . Therefore, compared to CAR-T, TCR-T cell therapy shows remarkable advantages over the destruction of tumor cells with intracellular antigens . To date, TCR-T mediated cell therapy has achieved many promising curative potency in both solid tumors and hematological cancers, and some of them have been applied in clinic trials (Table 2).
Figure 3 Diagrams of CAR-T and TCR-T-cell therapy . Unlike CAR, TCR is a heterodimer containing 2 different transmembrane polypeptide chains: α chain and β chain. The α chain and β chain each consist of a constant region and a variable region, the former anchoring the chain inside the T-cell surface membrane and the latter recognizing and binding to the antigen presented by MHCs .
|Antigen||Disease||Phase of clinical trials||NCT/Reference|
|PRAME||Acute myeloid leukemia, myelodysplastic syndrome||Phase I||NCT02743611|
|Unknown||Head and neck squamous cell carcinoma, squamous cell NSCLC||Phase I||NCT03139370|
|MAGE-A10||Non-small cell lung carcinoma||Phase I||NCT02592577|
|NY-ESO-1||Synovial sarcoma||Phase I/II||NCT01343043|
|NY-ESO-1||Multiple myeloma||Phase I/II||NCT01892293|
|NY-ESO-1||Multiple myeloma||Phase I/II||NCT01352286|
|NY-ESO-1||Ovarian cancer||Phase I/II||NCT01567891|
|NY-ESO-1||Non-small cell lung carcinoma||Phase I/II||NCT02588612|
|AFP||Hepatocellular cancer||Phase I||NCT03132792|
|NY-ESO-1||Refractory multiple myeloma||Phase I||NCT03168438|
|MAGE-A10||Urinary bladder cancer, head and neck cancer, melanoma||Phase I||NCT02989064|
CAR-T vs TCR-T
CAR-T and TCR-T both are gene-engineered technologies targeted for the destruction of tumors by improving the recognition and destroy potentials of T cells, thus called “T cell receptor redirection” technologies. However, there are also some differences in the two technologies: 1) CAR-T recognizes their target antigen via the scFv binding domain of CAR, while TCR-T relies on the interactions with peptide-major histocompatibility complex (pMHC) and requires co-stimulatory od co-inhibitory signals; 2) CAR-T recognizes and targets cell surface antigens, while TCR-T can target both cell surface antigens and intracellular antigens; 3) CAR-T shows great therapy outcomes in the treatment of hematological cancers but little effects on solid tumors, while TCR-T displays encouraging curative outcomes in the therapy of solid tumors.
Although CAR-T has been applied in clinic, quite a lot of side effects, such as off-target, cytokine release syndrome (CRS) etc., pose a great restriction in their further clinical application . Based on natural killer (NK) cells, CAR-NK cell therapy is much safer than CAR-T therapy and becomes a good candidate for targeting and combating solid tumors [48,49]. Based on the four generation of CAR, CARs in CAR-NK are designed with the addition of personalized proteins, such as DNAX-activation protein (DAP) 12 and NKG2 member D (NKG2D), which show great anti-tumor activity in acute myeloid leukemia (ALL), osteosarcoma, and prostate tumors [50-52]. Therefore, CAR-NK cells not only have the ability of CAR to specifically recognize antigen-expressing tumors, but also can destroy tumors via NK cell receptors. To date, numerous CAR-NK cell therapies have been used for anti-tumor therapy in clinical trials (Table 3).
Figure 4 Schematic of CAR-NK cell therapy . Gene engineered natural killer (NK) cells are infused into patients to destroy tumor cells. PBMC, peripheral blood mononuclear cell; UCB, umbilical cord blood; ESCs, human embryonic stem cells; iPSCs, human induced pluripotent stem cells.
|Antigen||Disease||NK source||Phase of clinical trials||NCT/Reference|
|CD33||Acute myeloid leukemia||NK-92||Phase I/II (complete)||NCT02944162|
|MUC1||Solid tumors||NK-92||Phase I/II||NCT02839954|
|NR||Non-small cell lung carcinoma||NK-92||Phase I||NCT03656705|
|HER2||Glioblastoma multiforme||NK-92||Phase I||NCT03383978|
|CD19||B-acute lymphocytic leukaemia||PB-NK||Phase II||NCT01974479|
|CD19||B-acute lymphocytic leukaemia||PB-NK||Phase I (complete)||NCT00995137|
Viral vectors used in CAR-T, TCR-T and CAR-NK
The broad application of gene engineered adoptive cell therapy, such as CAR-T, TCR-T and CAR-NK, in clinical trials for the therapy of cancers led to the development of safety-enhanced self-inactivating (SIN) vectors, such as γ-retroviral (gRV), lentiviral (LV) vectors, adenovirus, and AAV vectors. Scalable manufacturing processes for the production of gRV vectors (Fig. 5) and LV vectors using transfection in closed-system bioreactors in compliance with current good manufacturing practices (cGMP) for clinical applications have been developed and optimized [54,55].
Figure 5 Clinical manufacturing process flow chart of γ-retroviral vectors based on adherent cells .
Cytokine-induced killer cells (CD3+ CD56+ cells, CIK cells)  are non-major histocompatibility complex-restricted natural killer T lymphocytes and exhibit stronger anti-tumor and cytolytic activities than lymphokine-activated killer cells [57-59]. Co-cultured with dendritic cells (DCs) or Ag-DC cells, the selective cytotoxicity and anti-tumor immunity of CIK cells would be significantly enhanced, i.e. DC-CIK therapy [60,61]. Compared with traditional treatment, DC-CIK immunotherapy not only improves the clinical indices, but also shows mild adverse and reduces mortality .
Figure 6 Schematic of DC-CIK cell therapy . Co-cultured dendritic cells (DCs) and cytokine-induced killer cells (CIKs) (DC-CIK) are infused into patients for anti-tumor therapy.
Oncolytic virotherapy is a novel therapeutic modality utilizing oncolytic viruses (such as herpes simplex-, pox-, parvo-, or adenoviruses), which selectively replicate in cancer cells, to directly induce tumor cell lysis or indirectly reactivate human immune system to mediate tumor destruction (Fig. 7) . Through decades’ optimization, a great number of oncolytic virus therapies have been put into clinical trials, such as ONYX-015 (E1B-deleted adenovirus) , DNX-2401 (Ad5) , CG0070 (Ad5 carrying GM-CSF gene) , OBP-301 (Ad5-hTERT-E1A/B) , G207 (a conditionally-replicative HSV-1 with ICP34.5 deletion and UL39 disruption) , and JX-594 (Pexa-Vec, GM-CSF-enhanced vaccinia virus with TK gene disruption) . Among them, Amgen's T-VEC (a modified HSV-1 with expression of GM-CSF but deletions in ICP34.5 and ICP47 genes) was the first oncolytic virus approved by America Food and Drug Administration (FDA) for the treatment of melanoma in 2015 . Moreover, when combined with the other therapy, such as Anti-PD-1 immunotherapy, oncolytic virus can significantly promote immune recognition of cancer cell as well as T cell infiltration, and lead to high response rate in patients with advanced melanoma .
Figure 7 Oncolytic viruses-induced anti-tumor immunity . Oncolytic viruses mediate direct cancer lysis and indirect activation of anti-tumor immune responses.
|Adenovirus||Hepatic carcinoma||Golgi protein 73 (GP73) needed|||
|Adenovirus||Pancreatic carcinoma, prostate cancer||Tat-PTD modified hexon and Ad5/35|||
|Adenovirus||Gastric cancer||Acetylcholinesterase (AChE)|||
|Adenovirus||Gastric cancer||OBP-301, telomerase-specific|||
|Herpes simplex virus 2||Colon cancer||No virus modification or co-therapies|||
|Vaccinia||Colon cancer||Viral Thymidine kinase (TK) deficiency|||
|Measles virus||Hepatocellular carcinoma, colon cancer||Retargeted to CD133|||
|Herpes simplex virus||Ovarian cancer||Interleukin−12|||
|ONYX-015 (adenovirus)||Malignant mesothelioma cells||EB1 gene deletion|||
|DNX-2401 (adenovirus)||Glioblastoma and gliosarcoma||NCT02197169|
|CG0070 (adenovirus)||Bladder cancer||carrying CM-CSF gene||NCT02143804, NCT02365818|
|OBP-301 (adenovirus)||carrying hTERT-E1A/B||NCT0229385|
|HF10 (Herpes simplex virus)||Solid superficial malignant tumors||deletions in neurolatency genes UL43, UL49.5, UL55, and UL56||NCT02428036|
|G207 (Herpes simplex virus)||Glioblastoma||a conditionally-replicative HSV-1 with ICP34.5 deletion and UL39 disruption||NCT00157703|
|JX-594 (Vaccinia Virus)||Hepatocellular Carcinoma, colorectal cancer||GM-CSF-enhanced vaccinia virus with TK gene disruption||NCT02562755|
|GL-ONC1 (Vaccinia Virus)||Head and neck cancer||TK-inactivated||NCT01443260|
|Reolysin (Retrovirus)||Metastatic melanoma or pancreatic cancer||NCT02514382, NCT02444546|
|Cavatak™ (Coxsackievirus A21)||Melanoma||Overexpress ICAM-1 and DAF||NCT02565992, NCT02316171|
Taken together, different kinds of immune-oncology cell therapy show great variety in their curative effects. Although promising therapeutic outcomes in acute lymphocytic leukemia (ALL) and large B cell lymphomas have been achieved by CAR-T [80,81], little therapeutic effects were acquired in solid tumors as well as tumors with intracellular antigens, and multiple side effects, such as cytokine release syndrome, prohibited the broad application of CAR-T [82-84]. TCR-T displays better effects for the treatment of hematopoietic cancers and solid tumors, but requires MHC and co-stimulatory or co-inhibitory signals to combat tumors . Without the drawback of CAR-T, CAR-NK is safer than CAR-T and presents excellent tumor elimination ability in both hematopoietic cancers and solid tumors via CAR-dependent and NK receptor-dependent mechanisms . DC-CIK immunotherapy shows improved immunologic function, reduced mortality, and mild adverse effects in both hematologic malignancies and solid tumors, and may be suitable for patients that are intolerance to radiotherapy and chemotherapy [62,85]. Without the need of defined antigens included in the vectors, oncolytic viruses show a durable anti-tumor effects by directly infecting and lysing tumor cells in situ and also activating the host immune response to eliminate tumor cells, thus displaying curative effects on both hematopoietic cancers [86,87] and solid tumors . Moreover, these immune-oncology cell therapies can also be combined with programmed cell death protein 1 (PD-1) antibody or PD-1 inhibitor, showing reduced drug toxicity and enhanced the tumor cytotoxicity . For example, CD19-CAR-T cell carrying the single-chain variable fragment (scFv) of antibody against PD-1 exhibited potent therapeutic effects superior to those of conventional CAR-T cells ; oncolytic Herpes Simplex Virus Type 2 encoding an antibody against PD-1 presented an enhanced therapeutic efficacy with a durable antitumor response both in the tumor microenvironment and in the systemic immune system .
Stem Cell Therapy
Cell therapy based on stem cells is a kind of regenerative medicine with great potential for the treatment of diseases via the differentiation ability or the paracrine effects of stem cells as well as their derivatives. To date, a great number of cell types, have been applied from bench to bedside to treat diseases, such as cardiovascular diseases, neurodegenerative diseases and cancers. The cell types can be classified into three generations (Fig. 8): the 1st generation consists of skeletal myoblasts, bone marrow mononuclear cells (BMMNCs) and adipose-derived regenerative cells (ADRCs), mesenchymal stem cells (MSCs) and hematopoietic stem cells (CD34+/CD133+); the 2nd generation mainly utilizes embryonic stem cells (ESCs), induced pluripotent stem cells (iPS), cardiac stem cells (CSC) etc.; the next generation focuses on the combination therapy (CCT) of specific cell types, such as cell mixtures of cardiomyocytes, endothelial cells and smooth muscle cells.
Figure 8 Advance in stem cell therapy . Three generations of cell types have been applied for disease therapy.
Mesenchymal stromal/stem cells (MSC) are stromal cells in almost all the tissues or organs, identified by the expression of a specific panel of cell surface markers (CD1051, CD731, CD901, CD34-, CD14-, or CD11b-, CD79- or CD19-, HLA-DR-) and the differentiation potentials into at least osteogenic, adipogenic, and chondrogenic lineages . Although MSCs exist in almost all the human tissues, most of the MSCs used for clinical trials are isolated from bone marrow, adipose tissue and umbilical cord blood. And MSCs may have different biological characteristics and differentiation tendency according to their tissue sources as well as the isolation and culture procedures [93,94]. Based on the strong immunomodulatory, anti-inflammatory, and proregenerative capacities (Fig. 9) , MSCs have been promising candidates for the treatment of neurodegenerative diseases, Graft-versus-host disease (GvHD) and so on (Table 5) .
Figure 9 The regulatory effects of MSC on immune cells . MSC can secret cytokines, such as IL-6, IL-8 and GM-CSF, promoting neutrophil migration to the infection/injury site and enhancing their activation and phagocytosis; MSC can also secrete other cytokines, like PGE2, IDO, HGF, CPG, IL-2, IL-4, IL-10, TGF-β1, adjusting the proliferation, differentiation, maturation and function of other immune cells.
|Disease||Delivery route||Clinical trials||Outcome||Reference|
|Disease||Delivery route||Clinical trials||Outcome||Reference|
|Amyotrophic lateral sclerosis (ALS)||Intrathecally||Phase I||No adverse effects|||
|Amyotrophic lateral sclerosis (ALS)||Intramuscularly, intrathecally||Phase I/II||No adverse effects|||
|Amyotrophic lateral sclerosis (ALS)||Intrathecally||Phase I||No adverse effects|||
|Amyotrophic lateral sclerosis (ALS)||Intrathecally||Phase I/IIa||No adverse effects|||
|Multiple sclerosis (MS)||Intravenously||Phase I/II||Intial safety profile and feasibility of the intervention|||
|Multiple sclerosis (MS)||Intravenously||Phase I/IIa||Improvement of visual acuity|||
|Multiple sclerosis (MS)||Intravenously||Phase I/IIa||Reduction in inflammation|||
|ALS/MS||Intrathecally, intravenously||Phase I/II||Induces rapid immunomodulatory effects|||
|Spinal cord injury||Intravenously||Phase I||No tumor development|||
|Spinal cord injury||Locally injection||Phase III||Variable improvements in tactile sensitivity|||
|Spinal cord injury||intramedullary, subdurally||Phase III||Weak therapeutic effect|||
|Osteoarthritis||Intraarticulary||Phase I||Improvement of function and pain in high dose group|||
|Osteoarthritis||Intraarticulary||Phase I||Improvement in pain levels in low dose group|||
|Graft-versus-host disease (GvHD)||Intravenously||Phase I/II||No adverse effects|||
|Graft-versus-host disease (GvHD)||Intravenously||Phase I||Immunosuppressive therapy damaged intestinal epithelium|||
|Graft-versus-host disease (GvHD)||Intravenously||Phase I/II||Clinical responses|||
|Crohn's disease||Intravenously||Phase I||No adverse effects|||
|Crohn's disease||Intravenously||Phase II||Reduce Crohn's disease activity index|||
|Liver failure||Intravenously||Phase I/II||Reduce Model for End-stage Liver Disease (MELD) score|||
|Liver cirrhosis||Intravenously||Phase I||Improvement in MELD score|||
|Kidney disease||Intravenously||Phase I||Systemic immunosuppression|||
|Acute myocardial infarction||Infarcted sites||Phase I/II||No adverse effects|||
|Acute myocardial infarction||Infarct-related artery||Phase II/III||Modest improvement in left ventricular ejection fraction (LVEF) at 6-month follow-up|||
ESCs/iPSCs or their derived cells
With the ability to self-renewal and differentiation into three germ layer derived lineages, embryonic stem cells (ESCs) [120-122] and induced pluripotent stem cells (iPSCs) [123,124] were thought to be invaluable candidates for disease regenerative therapy, especially iPSCs with no or mild immunological rejection (Fig. 10). However, their tumorigenicity greatly limits the direct transplantation of ESCs/iPSCs to treat disease . Then lineage directed progenitor cells, such as neural progenitor/stem cells  and cardiac progenitor/stem cells , or terminally differentiated cells, such as cardiomyocytes [128,129], endothelial cells , smooth muscle cells , and retinal pigment epithelium have been widely used in the therapy of a variety of diseases (Table 6).
Figure 10 Schematic for the generation and medical applications of induced pluripotent stem cells (iPSCs) .
|Disease||Cell types||Phase of clinical trials||Delivery route||Outcome||Reference|
|Ischemic Cardiomyopathy||CSCs||Phase I||intracoronary||LVEF increased, scar size reduced, life quality improved|||
|Ischemic Cardiomyopathy||cardiosphere-derived cells (CDCs)||Phase I||intracoronary||Scar size reduced|||
|Ischemic Cardiomyopathy||Cardiopoietic cells||Phase II||transendocardial stem cell injection||No significance|||
|Nonischemic Cardiomyopathy||CD34+ stem cell||Phase II||intracoronary||LVEF increased, function capacity improved||, |
|Macular degeneration||hESC-derived retinal pigment epithelium||Phase I/II||subretinal injection||increase in subretinal pigmentation, vision-related life quality improved||, NCT01344993|
|Stargardt's macular dystrophy||hESC-derived retinal pigment epithelium||Phase I/II||subretinal injection||increase in subretinal pigmentation, vision-related life quality improved||, NCT01345006|
|Amyotrophic lateral sclerosis (ALS)||neural stem cells||Phase I||intraspinal||well tolerated|||
|Amyotrophic lateral sclerosis (ALS)||neural stem cells||Phase I||intraspinal||well-tolerated|||
|Amyotrophic lateral sclerosis (ALS)||neural stem cells||Phase I||intraspinal||safe|||
|Parkinson's disease||human parthenogenetic stem cell-derived NSCs (hpNSCs)||Phase I||striatum||dopamine levels increase|||
|Stroke||neural stem cells||Phase I||stereotactic ipsilateral putamen injection||neurological function improved|||
Other Cell Therapy
Cell Combination Therapy (CCT) is also a promising therapy with the combination of several cell types, resulting in better therapy outcomes covering the advantages of different cell types. The combination of autologous CSCs and MSCs displayed better cardioreparative effects on swine ischemic cardiomyopathy model than that of MSCs [144,145]. Tri-lineage cell transplantation (cardiomyocytes, endothelial cells, and smooth muscle cells) displayed significant cardiac repair effects in the porcine acute myocardial infarction model by improving left ventricular function, myocardial metabolism, and arteriole density, as well as reducing infarct size and cardiomyocyte apoptosis . Moreover, numerous biocompatible scaffolds, such as hydrogels , were used to facilitate the grafts integration in the compromised disease microenvironment and improve the survival of transplanted cells , which might significantly promote the clinical application of cell therapy.
Genetic re-engineering cell therapy
Besides the immune-oncology therapy and stem cell derived therapy, gene replacement therapy via lentivirus, adenovirus and adenovirus associated virus (AAV) as well as genetic engineered strategies via CRISPR, ZLN, TALEN have been widely applied in the field of cell therapy [149,150]. For example, PCSK9 gene can be disrupted to prevent cardiovascular disease , and PRKAG2 allele (with H530R mutation) can be disrupted to restore the heart morphology and function in Wolff-Parkinson-White syndrome with the wild-type PRKAG2 allele left , while pathogenic mutation in the MYBPC3 gene can be corrected in human embryo for the prevention of hypertrophic cardiomyopathy . Besides cardiovascular disease, the mutation in hemoglobin β (HBB) gene was also be seamlessly corrected for the therapy of β-thalassemia , and the point mutation in exon 14 of the JAK3 gene in severe combined immunodeficiency (SCID) was corrected to restore the development and maturation ability of T cells . On the basis of the impressive and encouraging outcomes of genetic re-engineering cell therapy, a great number of clinical trials have been carried out to translate the basic scientific achievements into medicines for disease therapy.
Figure 11 Schematic of gene and cell therapy . a. Cell therapy; b. gene therapy based on plasmid or viral vectors; c. genetic re-engineering cell therapy; d. cellular changes.
Beta-thalassemia and re-engineering cell therapy
Beta-thalassemia (β-thalassemia), also known as Cooley’s anemia, is a hereditary monogenic hematological disease caused by mutations in the human hemoglobin b (HBB) gene and thus lack of the β-globin chain synthesis . There are two traditional therapeutic methods for the treatment of β-thalassemia: 1) frequent iron chelation therapy, which is easy to cause iron overload and cannot sustain throughout a lifetime ; 2) allogeneic hematopoietic stem cell (HSC) transplantation, which is difficult to find a fully-matched donor . Re-engineering cell therapy is a novel therapy without the above drawbacks that utilizes gene editing technology, such as CRISPR, to correct the mutated HBB gene or supplement a functional copy of HBB gene thus restore the synthesis ability of β-globin and cure β-thalassemia (Fig. 12) . Gene therapy by autologous CD34+ cells transduced with the lentiviral BB305 vector, i.e. LentiGlobin, revealed increased hemoglobin levels in patients with no serious adverse effects or no need for long-term red-cell transfusions . To date, LentiGlobin in bluebird bio has been approved to follow the fastest assessment of an advanced therapy medicinal product (ATMP) as part of the European Medicines Agency’s Priority Medicines (PRIME) program.
Figure 12 Schematic of gene therapy for beta-thalassemia .
GSK's Strimvelis for ADA-SCID treatment
Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID) is a rare, autosomal recessive immunodeficiency, caused by deleterious mutations in ADA gene, for the production of T lymphocytes. There are three therapeutic methods for the treatment of ADA-SCID [162-164]: 1) allogeneic hematopoietic stem cell transplantation, which is difficult to find a fully-matched donor; 2) enzyme replacement therapy (ERT) with polyethylene glycol-conjugated adenosine deaminase, which needs long-term medication as well as high cost (approx. $200,000–400,000 per year) and exhibits great variable availability in different countries [165,166]; 3) autologous HSCT with gene correction of the hematopoietic stem cells, which can avoid the above drawbacks and shows excellent clinical safety and efficacy over the past 15 years [167-170]. In 2016, Strimvelis (also known as GSK2696273, autologous CD34+ cells re-engineered to express ADA) in GlaxoSmithKline was approved by European Commission for the therapy of ADA-SCID.
Figure 13 Schematic of gene therapy for ADA-SCID .
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