Effector cells having enhanced target cell recognition

Abstract

Provided are methods and compositions for obtaining functionally enhanced immune cells, and derivative effector cells obtained from directed differentiation of genomically engineered iPSCs. Also provided are derivative cells having stable and functional genome editing that delivers improved or enhanced therapeutic effects. Further provided are therapeutic compositions and the use thereof comprising the functionally enhanced derivative effector cells alone, or with antibodies or checkpoint inhibitors in combination therapies.

Description

EFFECTOR CELLS HAVING ENHANCED TARGET CELL RECOGNITIONRELATED APPLICATIONS

[0001] The present application claims priority to U. S. Provisional Application Serial No.63 / 718,504, filed November 8, 2024, the disclosure of which is hereby incorporated by reference in its entirety.INCORPORATED BY REFERENCE OF SEQUENCE LISTING

[0002] The Sequence Listing titled 184143-657601_SL.xml, which was created on November 5, 2025, and is 69,286 bytes in size, is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION

[0003] The present disclosure is broadly concerned with the field of off-the-shelf immunocellular products. More particularly, the present disclosure is concerned with strategies for developing multifunctional effector cells capable of delivering therapeutically relevant properties in vivo. Cell products developed under the present disclosure address critical limitations of patient-sourced cell therapies.BACKGROUND OF THE INVENTION

[0004] The field of adoptive cell therapy is currently focused on using patient- and donor-sourced cells, which makes it particularly difficult to achieve consistent manufacturing of cancer immunotherapies and to deliver therapies to all patients who may benefit therefrom. There is also a need to improve the efficacy and persistence of adoptively transferred lymphocytes to promote favorable patient outcomes. Lymphocytes such as T cells and natural killer (NK) cells are potent anti-tumor effectors that play an important role in innate and adaptive immunity. However, the use of these immune cells for adoptive cell therapies remains challenging and has unmet needs for improvement. Therefore, there remain significant opportunities to harness the full potential of T and NK cells, or other immune effector cells in adoptive immunotherapy.SUMMARY OF THE INVENTION

[0005] There is a need for functionally improved effector cells that address issues ranging from response rate, cell exhaustion, loss of transfused cells (survival and / or persistence), tumor escape through target loss or lineage switch, tumor targeting precision, off-target toxicity, off-tumor effect, to efficacy against solid tumors, e.g., tumor microenvironment and related immune suppression, recruiting, trafficking and infiltration.

[0006] It is an object of embodiments of the present invention to provide methods and compositions to generate derivative non-pluripotent cells differentiated from a single cell derived iPSC (induced pluripotent stem cell) clonal line, which iPSC line comprises one or several genetic modifications in its genome. In some embodiments, the one or several genetic modifications include one or more of DNA insertion, deletion, and substitution, and which modifications are retained and remain functional in subsequently derived cells after differentiation, expansion, passaging and / or transplantation.

[0007] The iPSC derived non-pluripotent cells of the present application include, but are not limited to, CD34+cells, hemogenic endothelium cells, HSCs (hematopoietic stem and progenitor cells), hematopoietic multipotent progenitor cells, T cell progenitors, NK cell progenitors, T cells, NKT cells, NK cells, and B cells. The iPSC-derived non-pluripotent cells of the present application comprise one or several genetic modifications in their genome through differentiation from an iPSC comprising the same genetic modifications. In some embodiments, the engineered clonal iPSC differentiation strategy for obtaining genetically engineered derivative cells benefits from the developmental potential of the iPSC in a directed differentiation that is not significantly adversely impacted by the engineered modality in the iPSC, and also that the engineered modality functions as intended in the derivative cell. Further, this strategy overcomes the present barrier in engineering primary lymphocytes, such as T cells or NK cells obtained from peripheral blood, as such cells are difficult to engineer, with engineering of such cells often lacking reproducibility and uniformity, resulting in cells exhibiting poor cell persistence with high cell death and low cell expansion. Moreover, this strategy avoids production of a heterogenous effector cell population otherwise obtained using primary cell sources which are heterogenous to start with.

[0008] In general, this application provides compositions and methods for generating a Master Cell Bank (MCB) having at least three targeted integration sites hosting multiplex configured edits via multiple MCB intermediaries (pre-MCBs). One aspect of the present application provides compositions and methods to generate iPSCs and derivative effector cells comprising, in addition to edits comprising a CAR and an avidity-enhancing receptor (AvER). Optionally, the iPSCs and derivative effector cells thereof further comprise one or more edits comprising an TCR promoter-driven ADR and / or a cytokine, a constitutively expressed TCE, a TGFP-SRR, a C-X-C-motif chemokine receptor or a variant thereof, a CD 16 variant, and / or a CD38 knockout, among other modifications as provided herein.

[0009] In one aspect, the present disclosure provides a cell or population thereof, wherein the cell is (a) an immune cell; (b) an induced pluripotent cell (iPSC); or (c) a derivative effector cell obtained from differentiating the iPSC; and wherein the cell comprises a polynucleotide encoding a chimeric antigen receptor (CAR), wherein the CAR comprises a first target binding region, a first transmembrane domain, and an endodomain; and a polynucleotide encoding an avidity-enhancing receptor (AvER), wherein the AvER comprises a second target binding region, a second transmembrane domain, but not an endodomain. In some of the embodiments, the first target binding region and the second target binding region recognize a same or different antigen; wherein the first target binding region and the second target binding region target the same or different epitope of a same antigen. In some embodiments of the cell or population thereof, the cell comprises a construct comprising at least one of: (i) a polynucleotide encoding an allo-immune defense receptor (ADR); and (ii) a polynucleotide encoding IL2, IL 18, or a IL7RF, and said construct is inserted into a T cell receptor (TCR) locus, thereby knocking out the TCR; and wherein the construct is expressed under control of an endogenous TCR promoter.

[0010] In some embodiments, the cell or population thereof further comprises a construct at a first integration site (site 1), wherein the site 1 construct comprises two or more of: (a) a polynucleotide encoding a TGFP signaling redirector receptor (TGFP-SRR) comprising a partial or full peptide of the extracellular domain (ECD) of transforming growth factor beta receptor (TGFpR); (b) a polynucleotide encoding a C-X-C motif chemokine receptor or a variant thereof; and (c) a polynucleotide encoding an exogenous CD 16 or a variant thereof; and wherein the site 1 construct comprises an exogenous promoter that regulates expression of the polynucleotides in the site 1 construct. In some embodiments, the cell or population thereof further comprises a construct at a second integration site (site 2), wherein the site 2 construct comprises one or more of: (a) a polynucleotide encoding a chimeric antigen receptor; (b) a polynucleotide encoding a T cell enhancer (TCE); and (c) a polynucleotide encoding a cytokine; wherein the site 2 differs from the site 1; and wherein the site 2 construct comprises an exogenous promoter that regulates expression of the polynucleotides in the site 2 construct.

[0011] In some embodiments of the cell or population thereof, wherein the site 1 comprises one of AAVS1, CCR5, ROSA26, collagen, HTRP, Hll, PH12, GAPDH, TCR constant region, RUNX1, B2M, TAPI, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR a or p constant region (TRAC or TRBC), NKG2A, NKG2D, CD38, CD25, CD69, CD71, CD44, CD54, CD56, CD58, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, or TIGIT. In some other embodiments, the site 1 comprises one of CD38, CD54, CD56, CD58, TIM3, TIGIT, Hl 1 or PH12; and integration of the site 1 construct at any of CD38, CD54, CD56, CD58, TIM3, or TIGIT knocks out an endogenous gene at the site 1.

[0012] In some embodiments of the cell or population thereof, wherein the site 2 comprises one of AAVS1, CCR5, ROSA26, collagen, HTRP, Hll, PH12, GAPDH, TCR constant region, RUNX1, B2M, TAPI, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR a or p constant region (TRAC or TRBC), NKG2A, NKG2D, CD38, CD25, CD69, CD71, CD44, CD54, CD56, CD58, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, or TIGIT. In some further embodiments, the site 2 comprises one of CD38, CD54, CD56, CD58, TIM3, TIGIT, Hl 1 or PH12; and integration of the site 2 construct at any of CD38, CD54, CD56, CD58, TIM3, or TIGIT knocks out an endogenous gene at the site 2.

[0013] In some embodiments of the cell or population thereof, wherein the TCR locus is a constant region of TCR alpha (TRAC) or TCR beta (TRBC), wherein the gene at the TCR locus is TCRa or TCRP, and wherein the endogenous TCR promoter is a TRAC promoter or a TRBC promoter.

[0014] In some embodiments of the cell of population thereof, wherein the ADR is specific to 41BB. In some embodiments of the cell of population thereof, wherein the TGFP-SRR further comprises a partial or full peptide of the intracellular domain (ICD) of a cytokine receptor comprising an IL2R, IL12R, IL18R, IL21R, or any combination thereof; wherein the C-X-C motif chemokine receptor comprises CXCR2 or CXCR3; or wherein the exogenous CD 16 or variant thereof comprises at least one of: (a) a high affinity non-cleavable CD16 (hnCD16); (b) Fl 76V and S197P in ectodomain domain of CD 16; (c) a full or partial ectodomain originated from CD64; (d) a non-native (or non-CD16) transmembrane domain; (e) a non-native (or nonCD 16) intracellular domain; (f) a non-native (or non-CD16) signaling domain; (g) a non-native stimulatory domain; and (h) transmembrane, signaling, and stimulatory domains that are not originated from CD 16, and are originated from a same or different polypeptide.

[0015] In some embodiments of the cell or population thereof, the first target binding region and the second target binding region are specific to the same antigen, and wherein the antigen comprises ADGRE2, B7H3, carbonic anhydrase IX (CAIX), CCR1, CCR4, carcinoembryonic antigen (CEA), CD3, CD5, CD7, CD8, CD10, CD20, CD22, CD30, CD33, CD34, CD38, CD41, CD44, CD44V6, CD49f, CD56, CD70, CD74, CD79b, CD99, CD123, CD133, CD138, CDS, CLEC12A, an antigen of a cytomegalovirus (CMV) infected cell, epithelial glycoprotein-2 (EGP-2), epithelial glycoprotein-40 (EGP-40), epithelial cell adhesion molecule (EpCAM), EGFRvIII, receptor tyrosine-protein kinases erb- B2,3,4, EGFIR, EGFR-VIII, ERBB folate-binding protein (FBP), fetal acetylcholine receptor (AChR), folate receptor-a, Ganglioside G2 (GD2), Ganglioside G3 (GD3), GPRC5D, human Epidermal Growth Factor Receptor 2 (HER2), human telomerase reverse transcriptase (hTERT), ICAM-1, Integrin B7, Interleukin- 13 receptor subunit alpha-2 (IL-13Ra2), K-light chain, kinase insert domain receptor(KDR), KLK2, Lewis A (CA19.9), Lewis Y (LeY), LI cell adhesion molecule (Ll-CAM), LILRB2, melanoma antigen family A 1 (MAGE-A1), MICA / B, Mucin 1 (Muc-1), Mucin 16 (Muc-16), Mesothelin (MSLN), NKCSI, NKG2D ligands, c-Met, cancer-testis antigen NY-ESO-1, oncofetal antigen (h5T4), PRAME, prostate stem cell antigen (PSCA), PRAME prostatespecific membrane antigen (PSMA), tumor-associated glycoprotein 72 (TAG-72), TIM-3, TRBCI, TRBC2, vascular endothelial growth factor R2 (VEGF-R2), Wilms tumor protein (WT-1), and a pathogen antigen. In some other embodiments, the first target binding region and the second target binding region are specific to the same antigen comprising B7H3, BCMA, CD19, CD20, CD22, CD38, CD52, CD79b, CD 123, EGFR, EGP2 / EpCAM, GD2, GPRC5D, HER2, KLK2, MICA / B, MSLN, VEGF-R2, PSMA or PDLL

[0016] In some embodiments of the cell or population thereof, the first target binding region comprises an amino acid sequence that has at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identity to any of SEQ ID NOs: 6, 7, 14-25, and 32-34. In some embodiments of the cell or population thereof, the TCE is TCF1 or CD27. In some embodiments of the cell or population thereof, wherein the site 1 is CD38, TIM3, TIGIT, or PH12; and wherein the site 2 is one of CD58, TIM3, TIGIT, or PH12.

[0017] In some embodiments, wherein the cell or population thereof are iPSC, and the iPSC is a clonal iPSC, a single cell dissociated iPSC, an iPSC cell line cell, or an iPSC master cell bank (MCB) cell. In some other embodiments, wherein the cell or population thereof are derivative cell, and the derivative cell comprises a derivative CD34+cell, a derivative hematopoietic stem and progenitor cell, a derivative hematopoietic multipotent progenitor cell, a derivative T cell progenitor, a derivative NK cell progenitor, a derivative T lineage cell, a derivative NKT lineage cell, a derivative NK lineage cell, or a derivative B lineage cell. In some embodiments, the derivative cell comprises a derivative effector cell having one or more functional features that are not present in a counterpart primary T, NK, NKT, and / or B cell.

[0018] Another aspect of the present disclosure provides a composition comprising the cell or population thereof as described herein. In some embodiments, said composition further comprises one or more therapeutic agents. In some embodiments, the one or more therapeutic agents comprise a peptide, a cytokine, a checkpoint inhibitor, a mitogen, a growth factor, a small RNA, a dsRNA (double stranded RNA), mononuclear blood cells, feeder cells, feeder cell components or replacement factors thereof, a vector comprising one or more polynucleic acids of interest, an antibody, an engager, a chemotherapeutic agent or a radioactive moiety, or an immunomodulatory drug (IMiD). In some embodiments, the antibody in said composition comprises an anti-CD20 antibody, an anti-HER2 antibody, an anti-CD52 antibody, an anti-EGFR antibody, an anti-CD123 antibody, an anti-GD2 antibody, an anti-PDLl antibody, or an anti-CD38 antibody; or one or more of rituximab, veltuzumab, ofatumumab, ublituximab, ocaratuzumab, obinutuzumab, trastuzumab, pertuzumab, alemtuzumab, cetuximab, dinutuximab, avelumab, daclizumab, basiliximab, M-A251, 2A3, BC69, 24204, 22722, 24212, MAB23591, FN50, 298614, AF2359, CY1G4, DF1513, bivatuzumab, RG7356, G44-26, 7G3, CSL362, elotuzumab, daratumumab, isatuximab, MOR202, and their humanized or Fc modified variants or fragments and their functional equivalents and biosimilars thereof. In some embodiments of said composition, the engager comprises: (i) a bispecific T cell engager (BiTE); (ii) a bispecific killer cell engager (BiKE); or (iii) a tri-specific killer cell engager (TriKE); or the engager comprises: (a) a first binding domain recognizing an extracellular portion of CD3, CD28, CD5, CD16, CD64, CD32, CD33, CD89, NKG2C, NKG2D, or any functional variants thereof of the cell or a by-stander immune effector cell; and (b) a second binding domain specific to an antigen comprising any one of: B7H3, CD10, CD19, CD20, CD22, CD24, CD30, CD33, CD34, CD38, CD44, CD52, CD79a, CD79b, CD 123, CD 138, CD 179b, CEA, CLEC12A, CS-1, DLL3, EGFR, EGFRvIII, EpCAM, FLT-3, FOLR1, FOLR3, GD2, gpA33, HER2, HM1.24, LGR5, MSLN, MCSP, MICA / B, Mucl, Mucl6, PDL1, PSMA, PAMA, P-cadherin, ROR1, or VEGF-R2.

[0019] A further aspect of the present disclosure provides a master cell bank (MCB) comprising the iPSC as described herein.

[0020] The present disclosure also provides therapeutic use of said composition by introducing the composition to a subject in need of an adoptive cell therapy, wherein the subject has an autoimmune disorder, a hematological malignancy, a solid tumor, cancer, or a virus infection.

[0021] Yet another aspect of the present disclosure provides a method of treating a subject in need of an adoptive cell therapy, wherein the method comprises infusing the subject with effector cells, wherein the effector cells comprise the derivative cell or population thereof. In some embodiments of the method, the effector cells comprise a CAR specific to an antigen expressed on a cancer cell, wherein the antigen comprises at least one of B7H3, BCMA, CD19, CD20, CD22, CD38, CD52, CD79b, CD 123, EGFR, EGP2 / EpCAM, GD2, GPRC5D, HER2, KLK2, MICA / B, MSLN, VEGF-R2, PSMA and PDL1. In some other embodiments of the method, the method further comprises administering one or more therapeutic agents to the subject, wherein the one or more therapeutic agents comprise: (i) a cytokine, an antibody, an engager, a checkpoint inhibitor, a chemotherapeutic agent or a radioactive moiety, or an immunomodulatory drug (IMiD); (ii) an anti-CD38 antibody comprising daratumumab, isatuximab, or MOR202; (iii) an engager comprising a BiTE (bi-specific T cell engager) or a TriKE (tri-specific Killer cell engager); (iv) a checkpoint inhibitor comprising atezolizumab, avelumab, durvalumab, ipilimumab, IPH4102, IPH43, IPH33, lirimumab, monalizumab,nivolumab, or pembrolizumab; and / or (v) a chemotherapeutic agent comprising cyclophosphamide and fludarabine (Cy / Flu). In some embodiments of the method, the effector cells comprise a CD38 knockout, a TCR knockout, and an ADR; wherein the method comprises administering to the subject an anti-CD38 antibody; and wherein the method does not require, or requires minimal, lymphodepletion comprising administering Cy / Flu to the subject. In yet other embodiments of the method, the effector cells are allogeneic, and wherein infusing the subject with effector cells is in an out-patient setting. In some embodiments of the method, the derivative cells are T lineage cells.

[0022] Various objects and advantages of the compositions and methods as provided herein will become apparent from the following description taken in conjunction with the accompanying drawings wherein are set forth, by way of illustration and example, certain embodiments of this invention.BRIEF DESCRIPTION OF THE DRAWINGS

[0023] FIGS. 1 A-1D show co-expression of CAR and AvER in Jurkat cells: (FIG. 1 A) design and structure of CAR and AvER; (FIG. IB) CAR and AvER expression on Jurkat cell surface; (FIG. 1C) CAR MFI changes; (FIG. ID) relative avidity of CAR+AvER Jurkat cells.

[0024] FIGS. 2A-2F show co-expression of CAR and AvER in primary T cells: (FIG. 2A) transduction efficacy of CAR and AvER in primary T cells; (FIG. 2B) T cell population with CAR and AvER co-expression; (FIG. 2C) surface scFv detection on CAR, AvER and CAR+AvER expressing primary T cells; (FIG. 2D) % cytolysis of target tumor cell (E: T 1: 1); (FIG. 2E) % CAR+ cells before and after the presence of target tumor cells; (FIG. 2F) IFN-y and TNF-a secretion of indicated effector cells with or without the target tumor cells.

[0025] FIGS. 3 A-3D show iPSC-derived T cells expressing CAR and AvER function through (FIG. 3 A) % cytolysis, (FIG. 3B) fold expansion, (FIG. 3C) CAR MFI and (FIG. 3D) cytokine IFN-y and TNF-a secretion of iT cells after co-culture with OVCAR8 and MS751 tumor cells in a serial stimulation assay.

[0026] FIG. 4 shows that co-expression of CAR and AvER on iPSC-derived T cells enhances tumor growth inhibition in vivo.DETAILED DESCRIPTION OF THE INVENTION

[0027] Genomic modification of iPSCs (induced pluripotent stem cells) can include one or more of polynucleotide insertion, deletion, and substitution. Exogenous gene expression in genome-engineered iPSCs often encounters problems such as gene silencing or reduced gene expression after prolonged clonal expansion of the original genome-engineered iPSCs, after celldifferentiation, and in dedifferentiated cell types from the cells derived from the genome-engineered iPSCs. On the other hand, direct engineering of primary immune cells such as T or NK cells is challenging and presents a hurdle to the preparation and delivery of engineered immune cells for adoptive cell therapy. In various embodiments, the present invention provides an efficient, reliable, and targeted approach for stably integrating one or more exogenous genes, including suicide genes and other functional modalities, which provide improved therapeutic properties relating to engraftment, trafficking, homing, migration, cytotoxicity, viability, maintenance, expansion, longevity, self-renewal, persistence, and / or survival, into iPSC derivative cells, including but not limited to HSCs (hematopoietic stem and progenitor cells), T cell progenitor cells, NK cell progenitor cells, T lineage cells, NKT lineage cells, and NK lineage cells.

[0028] Definitions

[0029] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0030] It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such may vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims.

[0031] As used herein, the articles “a,” “an,” and “the” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0032] The use of the alternative (e.g., “or”) should be understood to mean either one, both, or any combination thereof of the alternatives.

[0033] The term “and / or” should be understood to mean either one, or both of the alternatives.

[0034] As used herein, the term “about” or “approximately” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% compared to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. In one embodiment, the term “about” or “approximately” refers a range of quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, or ± 1% of a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.

[0035] As used herein, the term “substantially” or “essentially” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that is about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or higher compared to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. In one embodiment, the terms “essentially the same” or “substantially the same” refer a range of quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that is about the same as a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.

[0036] As used herein, the terms “substantially free of’ and “essentially free of’ are used interchangeably, and when used to describe a composition, such as a cell population or culture media, refer to a composition that is free of a specified substance or its source thereof, such as, 95% free, 96% free, 97% free, 98% free, 99% free of the specified substance or its source thereof, or is undetectable as measured by conventional means. The term “free of’ or “essentially free of’ a certain ingredient or substance in a composition also means that no such ingredient or substance is (1) included in the composition at any concentration, or (2) included in the composition at a functionally inert, low concentration. Similar meaning can be applied to the term “absence of,” where referring to the absence of a particular substance or its source thereof of a composition.

[0037] Throughout this specification, unless the context requires otherwise, the words “comprise,” “comprises” and “comprising” will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements. In particular embodiments, the terms “include,” “has,” “contains,” and “comprise” are used synonymously.

[0038] By “consisting of’ is meant including, and limited to, whatever follows the phrase “consisting of.” Thus, the phrase “consisting of’ indicates that the listed elements are required or mandatory, and that no other elements may be present.

[0039] By “consisting essentially of’ is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase “consisting essentially of’ indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements.

[0040] Reference throughout this specification to “one embodiment,” “an embodiment,” “a particular embodiment,” “a related embodiment,” “a certain embodiment,” “an additional embodiment,” or “a further embodiment” or combinations thereof means that a particular feature,structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the foregoing phrases in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0041] The term “ex vivo" refers generally to activities that take place outside an organism, such as experimentation or measurements done in or on living tissue in an artificial environment outside the organism, preferably with minimum alteration of the natural conditions. In particular embodiments, “ex vivo" procedures involve living cells or tissues taken from an organism and cultured in a laboratory apparatus, usually under sterile conditions, and typically for a few hours or up to about 24 hours, but including up to 48 or 72 hours or longer, depending on the circumstances. In certain embodiments, such tissues or cells can be collected and frozen, and later thawed for ex vivo treatment. Tissue culture experiments or procedures lasting longer than a few days using living cells or tissue are typically considered to be “zzz vitro" though in certain embodiments, this term can be used interchangeably with ex vivo.

[0042] The term “zzz vivo" refers generally to activities that take place inside an organism.

[0043] As used herein, the terms “reprogramming” or “dedifferentiation” or “increasing cell potency” or “increasing developmental potency” refer to a method of increasing the potency of a cell or dedifferentiating the cell to a less differentiated state. For example, a cell that has an increased cell potency has more developmental plasticity (i.e., can differentiate into more cell types) compared to the same cell in the non-reprogrammed state. In other words, a reprogrammed cell is one that is in a less differentiated state than the same cell in a nonreprogrammed state.

[0044] As used herein, the term “differentiation” is the process by which an unspecialized (“uncommitted”) or less specialized cell acquires the features of a specialized cell such as, for example, a blood cell or a muscle cell. A differentiated or differentiation- induced cell is one that has taken on a more specialized (“committed”) position within the lineage of a cell. The term “committed”, when applied to the process of differentiation, refers to a cell that has proceeded in the differentiation pathway to a point where, under normal circumstances, it will continue to differentiate into a specific cell type or subset of cell types, and cannot, under normal circumstances, differentiate into a different cell type or revert to a less differentiated cell type. As used herein, the term “pluripotent” refers to the ability of a cell to form all lineages of the body or soma (i.e., the embryo proper). For example, embryonic stem cells are a type of pluripotent stem cells that are able to form cells from each of the three germs layers, the ectoderm, the mesoderm, and the endoderm. Pluripotency is a continuum of developmental potencies rangingfrom the incompletely or partially pluripotent cell (e.g., an epiblast stem cell or EpiSC), which is unable to give rise to a complete organism to the more primitive, more pluripotent cell, which is able to give rise to a complete organism (e.g., an embryonic stem cell).

[0045] As used herein, the term “induced pluripotent stem cells” or “iPSCs”, refers to stem cells that are produced in vitro from differentiated adult, neonatal or fetal cells that have been induced or changed, i.e., reprogrammed into cells capable of differentiating into tissues of all three germ or dermal layers: mesoderm, endoderm, and ectoderm. In some embodiments, the reprogramming process uses reprogramming factors and / or small molecule chemical driven methods. The iPSCs produced do not refer to cells as they are found in nature.

[0046] As used herein, the term “embryonic stem cell” refers to naturally occurring pluripotent stem cells of the inner cell mass of the embryonic blastocyst. Embryonic stem cells are pluripotent and give rise during development to all derivatives of the three primary germ layers: ectoderm, endoderm and mesoderm. They do not contribute to the extra-embryonic membranes or the placenta (i.e., are not totipotent).

[0047] As used herein, the term “multipotent stem cell” refers to a cell that has the developmental potential to differentiate into cells of one or more germ layers (i.e., ectoderm, mesoderm and endoderm), but not all three. Thus, a multipotent cell can also be termed a “partially differentiated cell.” Multipotent cells are known in the art, and examples of multipotent cells include adult stem cells, such as for example, hematopoietic stem cells and neural stem cells. “Multipotent” indicates that a cell may form many types of cells in a given lineage, but not cells of other lineages. For example, a multipotent hematopoietic cell can form the many different types of blood cells (red, white, platelets, etc.), but it cannot form neurons. Accordingly, the term “multipotency” refers to the state of a cell with a degree of developmental potential that is less than totipotent and pluripotent.

[0048] Pluripotency can be determined, in part, by assessing pluripotency characteristics of the cells. Pluripotency characteristics include, but are not limited to: (i) pluripotent stem cell morphology; (ii) the potential for unlimited self-renewal; (iii) expression of pluripotent stem cell markers including, but not limited to SSEA1 (mouse only), SSEA3 / 4, SSEA5, TRA1 -60 / 81, TRA1-85, TRA2-54, GCTM-2, TG343, TG30, CD9, CD29, CD133 / prominin, CD140a, CD56, CD73, CD90, CD105, OCT4, NANOG, SOX2, CD30 and / or CD50; (iv) the ability to differentiate to all three somatic lineages (ectoderm, mesoderm and endoderm); (v) teratoma formation consisting of the three somatic lineages; and (vi) formation of embryoid bodies consisting of cells from the three somatic lineages.

[0049] Two types of pluripotency have previously been described: the “primed” or “metastable” state of pluripotency akin to the epiblast stem cells (EpiSC) of the late blastocyst,and the “naive” or “ground” state of pluripotency akin to the inner cell mass of the early / preimplantation blastocyst. While both pluripotent states exhibit the characteristics as described above, the naive or ground state further exhibits: (i) pre-inactivation or reactivation of the X-chromosome in female cells; (ii) improved clonality and survival during single-cell culturing; (iii) global reduction in DNA methylation; (iv) reduction of H3K27me3 repressive chromatin mark deposition on developmental regulatory gene promoters; and (v) reduced expression of differentiation markers relative to primed state pluripotent cells. Standard methodologies of cellular reprogramming in which exogenous pluripotency genes are introduced to a somatic cell, expressed, and then either silenced or removed from the resulting pluripotent cells are generally seen to have characteristics of the primed state of pluripotency. Under standard pluripotent cell culture conditions such cells remain in the primed state unless the exogenous transgene expression is maintained, wherein characteristics of the ground state are observed.

[0050] As used herein, the term “pluripotent stem cell morphology” refers to the classical morphological features of an embryonic stem cell. Normal embryonic stem cell morphology is characterized by being round and small in shape, with a high nucleus-to-cytoplasm ratio, the notable presence of nucleoli, and typical inter-cell spacing.

[0051] As used herein, the term “subject” refers to any animal, preferably a human patient, livestock, or other domesticated animal.

[0052] A “pluripotency factor,” or “reprogramming factor,” refers to an agent capable of increasing the developmental potency of a cell, either alone or in combination with other agents. Pluripotency factors include, without limitation, polynucleotides, polypeptides, and small molecules capable of increasing the developmental potency of a cell. Exemplary pluripotency factors include, for example, transcription factors and small molecule reprogramming agents.

[0053] Culture” or “cell culture” refers to the maintenance, growth and / or differentiation of cells in an in vitro environment. “Cell culture media,” “culture media” (singular “medium” in each case), “supplement” and “media supplement” refer to nutritive compositions that cultivate cell cultures.

[0054] Cultivate” or “maintain” refers to the sustaining, propagating (growing) and / or differentiating of cells outside of tissue or the body, for example in a sterile plastic (or coated plastic) cell culture dish or flask. “Cultivation” or “maintaining” may utilize a culture medium as a source of nutrients, hormones and / or other factors helpful to propagate and / or sustain the cells.

[0055] As used herein, the term “mesoderm” refers to one of the three germinal layers that appears during early embryogenesis and which gives rise to various specialized cell typesincluding blood cells of the circulatory system, muscles, the heart, the dermis, skeleton, and other supportive and connective tissues.

[0056] As used herein, the term “definitive hemogenic endothelium” (HE) or “pluripotent stem cell-derived definitive hemogenic endothelium” (iHE) refers to a subset of endothelial cells that give rise to hematopoietic stem and progenitor cells in a process called endothelial-to-hematopoietic transition. The development of hematopoietic cells in the embryo proceeds sequentially from lateral plate mesoderm through the hemangioblast to the definitive hemogenic endothelium and hematopoietic progenitors.

[0057] The term “hematopoietic stem and progenitor cells,” “hematopoietic stem cells,” “hematopoietic progenitor cells,” or “hematopoietic precursor cells” refers to cells which are committed to a hematopoietic lineage but are capable of further hematopoietic differentiation and include, multipotent hematopoietic stem cells (hematoblasts), myeloid progenitors, megakaryocyte progenitors, erythrocyte progenitors, and lymphoid progenitors. Hematopoietic stem and progenitor cells (HSCs) are multipotent stem cells that give rise to all the blood cell types including myeloid (monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes / platelets, dendritic cells), and lymphoid lineages (T cells, B cells, NK cells). The term “definitive hematopoietic stem cell” as used herein, refers to CD34+hematopoietic cells capable of giving rise to both mature myeloid and lymphoid cell types including T lineage cells, NK lineage cells and B lineage cells. Hematopoietic cells also include various subsets of primitive hematopoietic cells that give rise to primitive erythrocytes, megakarocytes and macrophages.

[0058] As used herein, the terms “T lymphocyte” and “T cell” are used interchangeably and refer to a principal type of white blood cell that completes maturation in the thymus and that has various roles in the immune system, including the identification of specific foreign antigens in the body and the activation and deactivation of other immune cells in an MHC class I-restricted manner. A T cell can be any T cell, such as a cultured T cell, e.g., a primary T cell, or a T cell from a cultured T cell line, e.g., Jurkat, SupTl, etc., or a T cell obtained from a mammal. The T cell can be a CD3+cell. The T cell can be any type of T cell and can be of any developmental stage, including but not limited to, CD4+ / CD8+double positive T cells, CD4+helper T cells (e.g., Thl and Th2 cells), CD8+T cells (e.g., cytotoxic T cells), peripheral blood mononuclear cells (PBMCs), peripheral blood leukocytes (PBLs), tumor infiltrating lymphocytes (TILs), memory T cells, naive T cells, regulator T cells, gamma delta T cells (y5 T cells), and the like. Additional types of helper T cells include cells such as Th3 (Treg), Thl7, Th9, or Tfh cells. Additional types of memory T cells include cells such as central memory T cells (Tcm cells), effector memory T cells (Tern cells and TEMRA cells). The term “T cell” can also refer to agenetically engineered T cell, such as a T cell modified to express a T cell receptor (TCR) or a chimeric antigen receptor (CAR). A T cell or T cell like effector cell can also be differentiated from a stem cell or progenitor cell (“a derived T cell” or “a derived T cell like effector cell”, or collectively, “a derivative T lineage cell”). A derived T cell like effector cell may have a T cell lineage in some respects, but at the same time has one or more functional features that are not present in a primary T cell. In this application, a T cell, a T cell like effector cell, a derived T cell, a derived T cell like effector cell, or a derivative T lineage cell, are collectively termed as “a T lineage cell”.

[0059] CD4+T cells” refers to a subset of T cells that express CD4 on their surface and are associated with cell-mediated immune response. They are characterized by secretion profiles following stimulation, which may include secretion of cytokines such as IFN-gamma, TNF-alpha, IL2, IL4 and IL10. “CD4” molecules are 55-kD glycoproteins originally defined as differentiation antigens on T-lymphocytes, but also found on other cells including monocytes / macrophages. CD4 antigens are members of the immunoglobulin supergene family and are implicated as associative recognition elements in MHC (major histocompatibility complex) class Il-restricted immune responses. On T-lymphocytes they define the helper / inducer subset.

[0060] CD8+T cells” refers to a subset of T cells which express CD8 on their surface, are MHC class I-restricted, and function as cytotoxic T cells. “CD8” molecules are differentiation antigens found on thymocytes and on cytotoxic and suppressor T-lymphocytes. CD8 antigens are members of the immunoglobulin supergene family and are associative recognition elements in major histocompatibility complex class I-restricted interactions.

[0061] As used herein, the term “NK cell” or “Natural Killer cell” refer to a subset of peripheral blood lymphocytes defined by the expression of CD56 or CD 16 and the absence of the T cell receptor (CD3). An NK cell can be any NK cell, such as a cultured NK cell, e.g., a primary NK cell, or an NK cell from a cultured or expanded NK cell or a cell-line NK cell, e.g., NK-92, or an NK cell obtained from a mammal that is healthy or with a disease condition. As used herein, the terms “adaptive NK cell” and “memory NK cell” are interchangeable and refer to a subset of NK cells that are phenotypically CD3-and CD56+, expressing at least one of NKG2C and CD57, and optionally, CD 16, but lack expression of one or more of the following: PLZF, SYK, FceRy, and EAT-2. In some embodiments, isolated subpopulations of CD56+NK cells comprise expression of CD16, NKG2C, CD57, NKG2D, NCR ligands, NKp30, NKp40, NKp46, activating and inhibitory KIRs, NKG2A and / or DNAM-1. CD56+can be dim or bright expression. An NK cell, or an NK cell like effector cell may be differentiated from a stem cell or progenitor cell (“a derived NK cell” or “a derived NK cell like effector cell”, or collectively, “aderivative NEC lineage cell”). A derivative NEC cell like effector cell may have an NEC cell lineage in some respects, but at the same time has one or more functional features that are not present in a primary NEC cell. In this application, an NEC cell, an NEC cell like effector cell, a derived NEC cell, a derived NEC cell like effector cell, or a derivative NEC lineage cell, are collectively termed as “an NEC lineage cell”.

[0062] As used herein, the term “NECT cells” or “natural killer T cells” or “NECT lineage cells” refers to CD Id-restricted T cells, which express a T cell receptor (TCR). Unlike conventional T cells that detect peptide antigens presented by conventional major histocompatibility (MHC) molecules, NECT cells recognize lipid antigens presented by CD Id, a non-classical MHC molecule. Two types of NECT cells are recognized. Invariant or type I NECT cells express a very limited TCR repertoire - a canonical a-chain (Va24-Jal8 in humans) associated with a limited spectrum of P chains (Vpil in humans). The second population of NECT cells, called non-classical or non-invariant type II NECT cells, display a more heterogeneous TCR aP usage. Type I NECT cells are considered suitable for immunotherapy. Adaptive or invariant (type I) NECT cells can be identified by the expression of one or more of the following markers: TCR Va24-Jal8, Vbll, CDld, CD3, CD4, CD8, aGalCer, CD161 and CD56.

[0063] The term “effector cell” generally is applied to certain cells in the immune system that carry out a specific activity in response to stimulation and / or activation, or to cells that effect a specific function upon activation. As used herein, the term “effector cell” includes, and in some contexts is interchangeable with, immune cells, “differentiated immune cells,” and primary or differentiated cells that are edited and / or modulated to carry out a specific activity in response to stimulation and / or activation. Non-limiting examples of effector cells include primary-sourced or iPSC-derived T cells, NEC cells, NECT cells, B cells, macrophages, and neutrophils.

[0064] As used herein, the term “isolated” or the like refers to a cell, or a population of cells, which has been separated from its original environment, i.e., the environment of the isolated cells is substantially free of at least one component as found in the environment in which the “un-isolated” reference cells exist. The term includes a cell that is removed from some or all components as it is found in its natural environment, for example, isolated from a tissue or biopsy sample. The term also includes a cell that is removed from at least one, some or all components as the cell is found in non-naturally occurring environments, for example, isolated form a cell culture or cell suspension. Therefore, an “isolated cell” is partly or completely separated from at least one component, including other substances, cells or cell populations, as it is found in nature or as it is grown, stored or subsisted in non-naturally occurring environments. Specific examples of isolated cells include partially pure cell compositions, substantially pure cell compositions and cells cultured in a medium that is non-naturally occurring. Isolated cellsmay be obtained by separating the desired cells, or populations thereof, from other substances or cells in the environment, or by removing one or more other cell populations or subpopulations from the environment.

[0065] As used herein, the term “purify” or the like refers to increasing purity. For example, the purity can be increased to at least 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%.

[0066] As used herein, the term “encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or a mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (e.g., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as “encoding” the protein or other product of that gene or cDNA.

[0067] A “construct” refers to a macromolecule or complex of molecules comprising a polynucleotide to be delivered to a host cell, either in vitro or in vivo. A “vector,” as used herein refers to any nucleic acid construct capable of directing the delivery or transfer of a foreign genetic material to target cells, where it can be replicated and / or expressed. Thus, the term “vector” comprises the construct to be delivered. A vector can be a linear or a circular molecule. A vector can be integrating or non-integrating. The major types of vectors include, but are not limited to, plasmids, episomal vectors, viral vectors, cosmids, and artificial chromosomes. Viral vectors include, but are not limited to, adenovirus vectors, adeno-associated virus vectors, retrovirus vectors, lentivirus vectors, Sendai virus vectors, and the like.

[0068] As used from time to time throughout the application, the expression of “TRAC_[construct]”, with “[construct]” being a variable expression construct having components and arrangement thereof specified in a given context, means that the expression construct is inserted at the TRAC locus to knock out TCR and with the component(s) of the expression construct expressed or co-expressed under the control of the endogenous TCR promoter.

[0069] As used from time to time throughout the application, the expression of “CD38_[construct]”, with “[construct]” being a variable expression construct having components and arrangement thereof specified in a given context, means that the expression construct is inserted at the CD38 locus to knock out CD38 and with the component(s) of theexpression construct expressed or co-expressed, whether under control of the endogenous CD38 promoter or under an exogenous promoter in the construct.

[0070] By “integration” it is meant that one or more nucleotides of a construct is stably inserted into the cellular genome, i.e., covalently linked to the nucleic acid sequence within the cell’s chromosomal DNA. By “targeted integration” it is meant that the nucleotide(s) of a construct is inserted into the cell's chromosomal or mitochondrial DNA at a pre-selected site or “integration site”. The term “integration” as used herein further refers to a process involving insertion of one or more exogenous sequences or nucleotides of the construct, with or without deletion of an endogenous sequence or nucleotide at the integration site. In the case, where there is a deletion at the insertion site, “integration” may further comprise replacement of the endogenous sequence or a nucleotide that is deleted with the one or more inserted nucleotides.

[0071] As used herein, the term “exogenous” is intended to mean that the referenced molecule or the referenced activity is introduced into, or is non-native to, the host cell. The molecule can be introduced, for example, by introduction of an encoding nucleic acid into the host genetic material such as by integration into a host chromosome or as non-chromosomal genetic material such as a plasmid. Therefore, the term as it is used in reference to expression of an encoding nucleic acid refers to introduction of the encoding nucleic acid in an expressible form into the cell. The term “endogenous” refers to a referenced molecule or activity that is present in the host cell. Similarly, the term when used in reference to expression of an encoding nucleic acid refers to expression of an encoding nucleic acid contained within the cell and not exogenously introduced.

[0072] As used herein, a “gene of interest” or “a polynucleotide sequence of interest” is a DNA sequence that is transcribed into RNA and in some instances translated into a polypeptide in vivo when placed under the control of appropriate regulatory sequences. A gene or polynucleotide of interest can include, but is not limited to, prokaryotic sequences, cDNA from eukaryotic mRNA, genomic DNA sequences from eukaryotic (e.g., mammalian) DNA, and synthetic DNA sequences. For example, a gene of interest may encode an miRNA, an shRNA, a native polypeptide (i.e., a polypeptide found in nature) or fragment thereof; a variant polypeptide (i.e., a mutant of the native polypeptide having less than 100% sequence identity with the native polypeptide) or fragment thereof; an engineered polypeptide or peptide fragment, a therapeutic peptide or polypeptide, an imaging marker, a selectable marker, and the like.

[0073] As used herein, the term “polynucleotide” refers to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides or analogs thereof. The sequence of a polynucleotide is composed of four nucleotide bases: adenine (A); cytosine (C); guanine (G); thymine (T); and uracil (U) for thymine when the polynucleotide is RNA. A polynucleotide caninclude a gene or gene fragment (for example, a probe, primer, EST or SAGE tag), exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes and primers. “Polynucleotide” also refers to both double- and single-stranded molecules.

[0074] As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably and refer to a molecule having amino acid residues covalently linked by peptide bonds. A polypeptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids of a polypeptide. As used herein, the terms refer to both short chains, which are also commonly referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as polypeptides or proteins. “Polypeptides” include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. The polypeptides include natural polypeptides, recombinant polypeptides, synthetic polypeptides, or a combination thereof.

[0075] As used herein, the term “subunit” refers to each separate polypeptide chain of a protein complex, where each separate polypeptide chain can form a stable folded structure by itself. Many protein molecules are composed of more than one subunit, where the amino acid sequences can either be identical for each subunit, or similar, or completely different. For example, CD3 complex is composed of CD3a, CD3s, CD36, CD3y, and CD3ζ subunits, which form the CD3s / CD3y, CD3s / CD36, and CD3ζ / CD3ζ dimers. Within a single subunit, contiguous portions of the polypeptide chain frequently fold into compact, local, semi-independent units that are called “domains”. Many protein domains may further comprise independent “structural subunits”, also called subdomains, contributing to a common function of the domain. As such, the term “subdomain” as used herein refers to a protein domain inside of a larger domain, for example, a binding domain within an ectodomain of a cell surface receptor; or a stimulatory domain or a signaling domain of an endodomain of a cell surface receptor.

[0076] “Operably-linked” or “operatively linked,” interchangeable with “operably connected” or “operatively connected,” refers to the association of nucleic acid sequences on a single nucleic acid fragment (or amino acids in a polypeptide with multiple domains) so that the function of one is affected by the other. For example, a promoter is operably-linked with a coding sequence or functional RNA when it is capable of affecting the expression of that coding sequence or functional RNA (i.e., the coding sequence or functional RNA is under the transcriptional control of the promoter). Coding sequences can be operably-linked to regulatorysequences in sense or antisense orientation. As a further example, a receptor-binding domain can be operatively connected to an intracellular signaling domain, such that binding of the receptor to a ligand transduces a signal responsive to said binding.

[0077] “Fusion proteins” or “chimeric proteins”, as used herein, are proteins created through genetic engineering to join two or more partial or whole polynucleotide coding sequences encoding separate proteins, and the expression of these joined polynucleotides results in a single peptide or multiple polypeptides with functional properties derived from each of the original proteins or fragments thereof. Between two neighboring polypeptides of different sources in the fusion protein, a linker (or spacer) peptide can be added.

[0078] As used herein, the term “genetic imprint” refers to genetic or epigenetic information that contributes to preferential therapeutic attributes in a source cell or an iPSC, and is retainable in the source cell derived iPSCs, and / or the iPSC-derived hematopoietic lineage cells. As used herein, “a source cell” is a non-pluripotent cell that may be used for generating iPSCs through reprogramming, and the source cell derived iPSCs may be further differentiated to specific cell types including any hematopoietic lineage cells. The source cell derived iPSCs, and differentiated cells therefrom are sometimes collectively called “derived” or “derivative” cells depending on the context. For example, derivative effector cells, or derivative NK cells or derivative T cells, as used throughout this application are cells differentiated from an iPSC, as compared to their primary counterpart obtained from natural / native sources such as peripheral blood, umbilical cord blood, or other donor tissues. As used herein, the genetic imprint(s) conferring a preferential therapeutic attribute is incorporated into the iPSCs either through reprogramming a selected source cell that is donor-, disease-, or treatment response- specific, or through introducing genetically modified modalities to iPSCs using genomic editing. In the aspect of a source cell obtained from a specifically selected donor, disease or treatment context, the genetic imprint contributing to preferential therapeutic attributes may include any contextspecific genetic or epigenetic modifications which manifest a retainable phenotype, e.g., a preferential therapeutic attribute, that is passed on to derivative cells of the selected source cell, irrespective of the underlying molecular events being identified or not. Donor-, disease-, or treatment response- specific source cells may comprise genetic imprints that are retainable in iPSCs and derived hematopoietic lineage cells, which genetic imprints include but are not limited to, prearranged monospecific TCR, for example, from a viral specific T cell or invariant natural killer T (iNKT) cell; trackable and desirable genetic polymorphisms, for example, homozygous for a point mutation that encodes for the high-affinity CD 16 receptor in selected donors; and predetermined HLA requirements, e.g., selected HLA-matched donor cells exhibiting a haplotype with increased population. As used herein, preferential therapeuticattributes include improved engraftment, trafficking, homing, viability, self-renewal, persistence, immune response regulation and modulation, survival, and cytotoxicity of a derived cell. A preferential therapeutic attribute may also relate to antigen targeting receptor expression; HLA presentation or lack thereof; resistance to tumor microenvironment; induction of bystander immune cells and immune modulations; improved on-target specificity with reduced off-tumor effect; and / or resistance to treatment such as chemotherapy. When derivative cells having one or more therapeutic attributes are obtained from differentiating an iPSC that has genetic imprint(s) conferring a preferential therapeutic attribute incorporated thereto, such derivative cells are also called “synthetic cells”. In general, a synthetic cell possesses one or more non-native cell functions when compared to its closest counterpart primary cell, whether the synthetic cell is differentiated from engineered pluripotent cells or obtained by engineering a primary cell from natural / native sources, such as peripheral blood, umbilical cord blood, or other donor tissues. For example, synthetic effector cells, or synthetic NK cells or synthetic T cells, as used throughout this application are cells differentiated from a genomically modified iPSC, as compared to their primary counterpart obtained from natural / native sources such as peripheral blood, umbilical cord blood, or other donor tissues. In some embodiments, the synthetic cell possesses one or more non-native cell functions when compared to its closest counterpart primary cell.

[0079] The term “enhanced therapeutic property” as used herein, refers to a therapeutic property of a cell that is enhanced as compared to a typical immune cell of the same general cell type. For example, an NK cell with an “enhanced therapeutic property” will possess an enhanced, improved, and / or augmented therapeutic property as compared to a typical, unmodified, and / or naturally occurring NK cell. Therapeutic properties of an immune cell may include, but are not limited to, cell engraftment, trafficking, homing, viability, self-renewal, persistence, immune response regulation and modulation, survival, and cytotoxicity. Therapeutic properties of an immune cell are also manifested by antigen targeting receptor expression; HLA presentation or lack thereof; resistance to tumor microenvironment; induction of bystander immune cells and immune modulations; improved on-target specificity with reduced off-tumor effect; and / or resistance to treatment such as chemotherapy.

[0080] As used herein, the term “engager” refers to a molecule, e.g., a fusion polypeptide, which is capable of forming a link between an immune cell (e.g., a T cell, a NK cell, a NKT cell, a B cell, a macrophage, a neutrophil), and a tumor cell; and activating the immune cell.Examples of engagers include, but are not limited to, bi-specific T cell engagers (BiTEs), bispecific killer cell engagers (BiKEs), tri-specific killer cell engagers (TriKEs), or multi-specific killer cell engagers, or universal engagers compatible with multiple immune cell types.

[0081] As used herein, the term “surface triggering receptor” refers to a receptor capable of triggering or initiating an immune response, e.g., a cytotoxic response. Surface triggering receptors may be engineered, and may be expressed on effector cells, e.g., a T cell, a NK cell, a NKT cell, a B cell, a macrophage, or a neutrophil. In some embodiments, the surface triggering receptor facilitates bi- or multi- specific antibody engagement between the effector cells and a specific target cell (e.g., a tumor cell) independent of the effector cells’ natural receptors and cell types. Using this approach, one may generate iPSCs comprising a universal surface triggering receptor, and then differentiate such iPSCs into populations of various effector cell types that express the universal surface triggering receptor. By “universal”, it is meant that the surface triggering receptor can be expressed in, and activate, any effector cells irrespective of the cell type, and all effector cells expressing the universal receptor can be coupled or linked to the engagers recognizable by the surface triggering receptor, regardless of the engager’s tumor binding specificities. In some embodiments, engagers having the same tumor targeting specificity are used to couple with the universal surface triggering receptor. In some embodiments, engagers having different tumor targeting specificity are used to couple with the universal surface triggering receptor. As such, one or multiple effector cell types can be engaged to kill one specific type of tumor cells in some cases, and to kill two or more types of tumors in other cases. A surface triggering receptor generally comprises a co-stimulatory domain for effector cell activation and an anti-epitope that is specific to the epitope of an engager. A bispecific engager is specific to the anti-epitope of a surface triggering receptor on one end, and is specific to a tumor antigen on the other end.

[0082] As used herein, the term “safety switch protein” refers to an engineered protein designed to prevent potential toxicity or otherwise adverse effects of a cell therapy. In some instances, the safety switch protein expression is conditionally controlled to address safety concerns for transplanted engineered cells that have permanently incorporated the gene encoding the safety switch protein into its genome. This conditional regulation could be variable and might include control through a small molecule-mediated post-translational activation and tissuespecific and / or temporal transcriptional regulation. The safety switch protein could mediate induction of apoptosis, inhibition of protein synthesis, DNA replication, growth arrest, transcriptional and post-transcriptional genetic regulation and / or antibody-mediated depletion. In some instance, the safety switch protein is activated by an exogenous molecule, e.g., a prodrug, that when activated, triggers apoptosis and / or cell death of a therapeutic cell. Examples of safety switch proteins include, but are not limited to, suicide genes such as caspase 9 (or caspase 3 or 7), thymidine kinase, cytosine deaminase, B cell CD20, modified EGFR, and any combinationthereof. In this strategy, a prodrug that is administered in the event of an adverse event is activated by the suicide-gene product and kills the transduced cell.

[0083] As used herein, the term “pharmaceutically active proteins or peptides” refers to proteins or peptides that are capable of achieving a biological and / or pharmaceutical effect on an organism. A pharmaceutically active protein has healing, curative or palliative properties against a disease and may be administered to ameliorate, relieve, alleviate, reverse or lessen the severity of a disease. A pharmaceutically active protein also has prophylactic properties and is used to prevent the onset of a disease or to lessen the severity of such disease or pathological condition when it does emerge. “Pharmaceutically active proteins” include an entire protein or peptide or pharmaceutically active fragments thereof. The term also includes pharmaceutically active analogs of the protein or peptide or analogs of fragments of the protein or peptide. The term pharmaceutically active protein also refers to a plurality of proteins or peptides that act cooperatively or synergistically to provide a therapeutic benefit. Examples of pharmaceutically active proteins or peptides include, but are not limited to, receptors, binding proteins, transcription and translation factors, tumor growth suppressing proteins, antibodies or fragments thereof, growth factors, and / or cytokines.

[0084] As used herein, the term “signaling molecule” refers to any molecule that modulates, participates in, inhibits, activates, reduces, or increases, cellular signal transduction. “Signal transduction” refers to the transmission of a molecular signal in the form of chemical modification by recruitment of protein complexes along a pathway that ultimately triggers a biochemical event in the cell. Examples of signal transduction pathways are known in the art, and include, but are not limited to, G protein coupled receptor signaling, tyrosine kinase receptor signaling, integrin signaling, toll gate signaling, ligand-gated ion channel signaling, ERK / MAPK signaling pathway, Wnt signaling pathway, cAMP-dependent pathway, and IP3 / DAG signaling pathway.

[0085] As used herein, the term “targeting modality” refers to a molecule, e.g., a polypeptide, that is genetically incorporated into a cell to promote antigen and / or epitope specificity that includes, but is not limited to, i) antigen specificity as it relates to a unique chimeric antigen receptor (CAR) or T cell receptor (TCR), ii) engager specificity as it relates to monoclonal antibodies or bispecific engagers, iii) targeting of transformed cells, iv) targeting of cancer stem cells, and v) other targeting strategies in the absence of a specific antigen or surface molecule.

[0086] As used herein, the term “specific” or “specificity” can be used to refer to the ability of a molecule, e.g., a receptor or an engager, to selectively bind to a target molecule, in contrast to non-specific or non-selective binding.

[0087] The term “adoptive cell therapy” as used herein refers to a cell-based immunotherapy that relates to the transfusion of autologous or allogeneic lymphocytes, whether the immune cells are isolated from a human donor, or effector cells obtained from in vitro differentiation of a pluripotent cell; whether they are genetically modified or not; or whether they are primary donor cells or cells that have been passaged, expanded, or immortalized, ex vivo, after isolation from a donor.

[0088] As used herein, “radiation” refers to the emission or transmission of energy in the form of waves or particles. Exemplary forms of radiation include, but are not limited to, electromagnetic radiation (e.g., radio waves, microwaves, infrared, visible light, ultraviolet, x-rays, and gamma radiation), particle radiation (e.g., alpha radiation, beta radiation, proton radiation and neutron radiation), and acoustic radiation (e.g., ultrasound, sound and seismic waves). In various embodiments, the amount of radiation is measured as a Gray (Gy), which is defined as the absorption of one joule of radiation energy per kilogram of matter. In radiation therapy, the amount of radiation applied varies depending on the type and stage of cancer being treated. For curative cases, the typical dose for a solid epithelial tumor ranges from 60 to 80 Gy, while lymphomas are typically treated with 20 to 40 Gy. Preventive (adjuvant) doses are typically around 45-60 Gy in 1.8-2 Gy fractions (for, e.g., breast, head, and neck cancers). In various embodiments, radiation may be used as a sensitizing agent as disclosed herein.

[0089] As used herein, “radiation therapy” or “radiotherapy” are used interchangeably to refer to a type of cancer treatment that involves use of radiation to damage cells by destroying the genetic material that controls how cells grow and divide. While both healthy and cancerous cells are damaged by radiation therapy, the goal of radiation therapy is to destroy as few normal, healthy cells as possible. The term “radiation therapy” often refers to external beam radiation therapy, wherein high-energy beams (e.g., x-rays, gamma rays, photons, protons, neutrons, ions, and any other forms of energy applicable to such treatments) are produced by a machine outside of the subject being treated, and are aimed at a precise point on the subject’s body. However, the term “radiation therapy” also includes brachytherapy, wherein seeds, ribbons, or capsules that contain or are otherwise linked to a radiation source are placed inside the subject’s body in or near a tumor or cancer cell. Included in brachytherapy are low-dose rate implants, high-dose rate implants, and permanent implants. Also included in the term “radiation therapy” is systemic radiation therapy, wherein radioactive drugs (e.g., radiopharmaceuticals or radionuclides, including radiopeptides) are given to the subject orally or intravenously and collect within the subject’s body at the tumor or area where cancers cells are located. Similar to antibody-drug candidates, where an antibody that binds to a tumor antigen is linked to a toxic drug, radiopharmaceuticals incorporate a radioactive compound linked to a targeting molecule (such asan antibody) that specifically binds to a tumor antigen. Examples of radioactive compounds useful in radiopharmaceuticals include, but are not limited to calcium-47, carbon-11, carbon-14, chromium-51, cobalt-57, cobalt-58, erbium-169, fluorine-18, gallium-67, gallium-68, hydrogen-3, indium-111, iodine-123, iodine-125, iodine-131, iorn-59, krypton-81m, lutetium-177, nitrogen-13, oxygen-15, phosphorus-32, radium-223, rubidium-82, samarium-153, selenium-75, sodium-22, sodium-24, strontium-89, technetium-99m, thallium-201, xenon- 133, and yttrium-90. In various embodiments, radiation therapy may be used as a sensitizing agent as disclosed herein.

[0090] As used herein, “lymphodepletion” and “lympho-conditioning” are used interchangeably to refer to the destruction of lymphocytes and T cells, typically prior to immunotherapy. The purpose of lympho-conditioning prior to the administration of an adoptive cell therapy is to promote homeostatic proliferation of effector cells as well as to eliminate regulatory immune cells and other competing elements of the immune system that compete for homeostatic cytokines. Thus, lympho-conditioning is typically accomplished by administering one or more chemotherapeutic agents to the subject prior to a first dose of the adoptive cell therapy. In various embodiments, lympho-conditioning precedes the first dose of the adoptive cell therapy by a few hours to a few days. Exemplary chemotherapeutic agents useful for lympho-conditioning include, but are not limited to, cyclophosphamide (CY), fludarabine (FLU), and those described below. However, a sufficient lymphodepletion through anti-CD38 mAb could provide an alternative conditioning process for the present iNK cell therapy, without or with minimal need of a CY / FLU-based lympho-conditioning procedure, as further described herein.

[0091] As used herein, “homing” or “trafficking” refers to active navigation (migration) of a cell to a target site (e.g., a cell, tissue (e.g., tumor), or organ). A “homing molecule” refers to a molecule that directs cells to a target site. In some embodiments, a homing molecule functions to recognize and / or initiate interaction of a cell to a target site. In some embodiments, a homing molecule is a chemokine receptor. As used herein, “chemokine receptor” refers to a cell surface molecule that binds to a chemokine. A chemokine receptor can comprise a naturally occurring or recombinant chemokine receptor or a variant thereof. Exemplary chemokine receptors include, but are not limited to, a CXC chemokine receptor (for example, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, or CXCR7), a CC chemokine receptor (for example, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, or CCR11), a CX3C chemokine receptor (for example, CX3CR1), an XC chemokine receptor (for example, XCR1), or a variant thereof.

[0092] A “therapeutically sufficient amount”, as used herein, includes within its meaning a non-toxic, but sufficient and / or effective amount of a particular therapeutic agent and / or pharmaceutical composition to which it is referring to provide a desired therapeutic effect. The exact amount required will vary from subject to subject, depending on factors such as the patient’s general health, the patient’s age and the stage and severity of the condition being treated. In particular embodiments, a “therapeutically sufficient amount” is sufficient and / or effective to ameliorate, reduce, and / or improve at least one symptom associated with a disease or condition of the subject being treated.

[0093] Differentiation of pluripotent stem cells typically involves a change in the culture system, such as changing the stimuli agents in the culture medium or the physical state of the cells. The most conventional strategy utilizes the formation of embryoid bodies (EBs) as a common and critical intermediate to initiate lineage-specific differentiation. “Embryoid bodies” are three-dimensional clusters that have been shown to mimic embryo development as they give rise to numerous lineages within their three-dimensional area. Through the differentiation process, typically a few hours to days, simple EBs (for example, aggregated pluripotent stem cells elicited to differentiate) continue maturation and develop into a cystic EB at which time, typically days to a few weeks, they are further processed to continue differentiation. EB formation is initiated by bringing pluripotent stem cells into close proximity with one another in three-dimensional multilayered clusters of cells. Typically, this is achieved by one of several methods including allowing pluripotent cells to sediment in liquid droplets, sedimenting cells into “U” bottomed well-plates or by mechanical agitation. To promote EB development, the pluripotent stem cell aggregates may require further differentiation cues, as aggregates maintained in pluripotent culture maintenance medium do not form proper EBs. As such, the pluripotent stem cell aggregates need to be transferred to differentiation medium that provides eliciting cues towards the lineage of choice. EB-based culture of pluripotent stem cells typically results in generation of differentiated cell populations (e.g., ectoderm, mesoderm and endoderm germ layers) with modest proliferation within the EB cell cluster. Although proven to facilitate cell differentiation, EBs, however, give rise to heterogeneous cells in variable differentiation states because of the inconsistent exposure of the cells in the three-dimensional structure to the differentiation cues within the environment. In addition, EBs are laborious to create and maintain. Moreover, cell differentiation through EB formation is accompanied with modest cell expansion, which also contributes to low differentiation efficiency.

[0094] In comparison, “aggregate formation,” as distinct from “EB formation,” can be used to expand the populations of pluripotent stem cell derived cells. For example, during aggregate-based pluripotent stem cell expansion, culture media are selected to maintainproliferation and pluripotency. Cell proliferation generally increases the size of the aggregates, forming larger aggregates, which can be mechanically or enzymatically dissociated into smaller aggregates to maintain cell proliferation within the culture and increase numbers of cells. As distinct from EB culture, cells cultured within aggregates in maintenance culture media maintain markers of pluripotency. The pluripotent stem cell aggregates may require further differentiation cues to induce differentiation.

[0095] As used herein, “monolayer differentiation” is a term referring to a differentiation method distinct from differentiation through three-dimensional multilayered clusters of cells, e.g., “EB formation.” Monolayer differentiation, among other advantages disclosed herein, avoids the need for EB formation to initiate differentiation. Because monolayer culturing does not mimic embryo development such as is the case with EB formation, differentiation towards specific lineages is deemed to be minimal as compared to all three germ layer differentiation in EB formation.

[0096] As used herein, a “dissociated cell” or “single dissociated cell” refers to a cell that has been substantially separated or purified away from other cells or from a surface (e.g., a culture plate surface). For example, cells can be dissociated from an animal or tissue by mechanical or enzymatic methods. Alternatively, cells that aggregate in vitro can be enzymatically or mechanically dissociated from each other, such as by dissociation into a suspension of clusters, single cells or a mixture of single cells and clusters. In yet another alternative embodiment, adherent cells can be dissociated from a culture plate or other surface. Dissociation thus can involve breaking cell interactions with extracellular matrix (ECM) and substrates (e.g., culture surfaces), or breaking the ECM between cells.

[0097] As used herein, a “master cell bank” or “MCB” refers to a clonal master engineered iPSC line, which is a clonal population of iPSCs that have been engineered to comprise one or more therapeutic attributes, have been characterized, tested, qualified, and expanded, and have been shown to reliably serve as the starting cellular material for the production of cell-based therapeutics through directed differentiation in manufacturing settings. In various embodiments, an MCB is maintained, stored, and / or cryopreserved in multiple vessels to prevent genetic variation and / or potential contamination by reducing and / or eliminating the total number of times the iPS cell line is passaged, thawed or handled during the manufacturing processes.

[0098] As used herein, “feeder cells” or “feeders” are terms describing cells of one type that are co-cultured with cells of a second type to provide an environment in which the cells of the second type can grow, expand, or differentiate, as the feeder cells provide stimulation, growth factors and nutrients for the support of the second cell type. The feeder cells are optionally from a different species as the cells they are supporting. For example, certain types of human cells,including stem cells, can be supported by primary cultures of mouse embryonic fibroblasts, or immortalized mouse embryonic fibroblasts. In another example, peripheral blood derived cells or transformed leukemia cells support the expansion and maturation of natural killer cells. The feeder cells may typically be inactivated when being co-cultured with other cells by irradiation or treatment with an anti-mitotic agent such as mitomycin to prevent them from outgrowing the cells they are supporting. Feeder cells may include endothelial cells, stromal cells (for example, epithelial cells or fibroblasts), and leukemic cells. Without limiting the foregoing, one specific feeder cell type may be a human feeder, such as a human skin fibroblast. Another feeder cell type may be mouse embryonic fibroblasts (MEF). In general, various feeder cells can be used in part to maintain pluripotency, direct differentiation towards a certain lineage, enhance proliferation capacity and promote maturation to a specialized cell type, such as an effector cell.

[0099] As used herein, a “feeder-free” (FF) environment refers to an environment such as a culture condition, cell culture or culture media which is essentially free of feeder or stromal cells, and / or which has not been pre-conditioned by the cultivation of feeder cells. “Preconditioned” medium refers to a medium harvested after feeder cells have been cultivated within the medium for a period of time, such as for at least one day. Pre-conditioned medium contains many mediator substances, including growth factors and cytokines secreted by the feeder cells cultivated in the medium. In some embodiments, a feeder-free environment is free of both feeder or stromal cells and is also not pre-conditioned by the cultivation of feeder cells.[000100] “Functional” as used in the context of genomic editing or modification of iPSC, and derived non-pluripotent cells differentiated therefrom, or genomic editing or modification of non-pluripotent cells and derived iPSCs reprogrammed therefrom, refers to (1) at the gene level — successful knocked-in, knocked-out, knocked-down gene expression, transgenic or controlled gene expression such as inducible or temporal expression at a desired cell development stage, which is achieved through direct genomic editing or modification, or through “passing-on” via differentiation from or reprogramming of a starting cell that is initially genomically engineered; or (2) at the cell level — successful removal, addition, or alteration of a cell function / characteristic via (i) gene expression modification obtained in said cell through direct genomic editing, (ii) gene expression modification maintained in said cell through “passing-on” via differentiation from or reprogramming of a starting cell that is initially genomically engineered; (iii) down-stream gene regulation in said cell as a result of gene expression modification that only appears in an earlier development stage of said cell, or only appears in the starting cell that gives rise to said cell via differentiation or reprogramming; or (iv) enhanced or newly attained cellular function or attribute displayed within the mature cellularproduct, initially derived from the genomic editing or modification conducted at the iPSC, progenitor or dedifferentiated cellular origin.[000101] “HLA deficient”, including HLA class I deficient, HLA class II deficient, or both, refers to cells that either lack, or no longer maintain, or have a reduced level of surface expression of a complete MHC complex comprising an HLA class I protein heterodimer and / or an HLA class II heterodimer, such that the diminished or reduced level is less than the level naturally detectable by other cells or by synthetic methods.[000102] “Modified HLA deficient iPSC,” as used herein, refers to an HLA deficient iPSC that is further modified by introducing genes expressing proteins related, but not limited to improved differentiation potential, antigen targeting, antigen presentation, antibody recognition, persistence, immune evasion, resistance to suppression, proliferation, costimulation, cytokine stimulation, cytokine production (autocrine or paracrine), chemotaxis, and cellular cytotoxicity, such as non-classical HLA class I proteins (e.g., HLA-E and HLA-G), chimeric antigen receptor (CAR), T cell receptor (TCR), CD16 Fc Receptor, BCLllb, NOTCH, RUNX1, IL 15, 4- IBB, DAP10, DAP12, CD24, CD3ζ 4-1BBL, CD47, CD113, and PDL1. The cells that are “modified HLA deficient” also include cells other than iPSCs.[000103] The term “ligand” refers to a substance that forms a complex with a target molecule to produce a signal by binding to a site on the target. The ligand may be a natural or artificial substance capable of specific binding to the target. The ligand may be in the form of a protein, a peptide, an antibody, an antibody complex, a conjugate, a nucleic acid, a lipid, a polysaccharide, a monosaccharide, a small molecule, a nanoparticle, an ion, a neurotransmitter, or any other molecular entity capable of specific binding to a target. The target to which the ligand binds, may be a protein, a nucleic acid, an antigen, a receptor, a protein complex, or a cell. A ligand that binds to and alters the function of the target and triggers a signaling response is called “agonistic” or “an agonist”. A ligand that binds to a target and blocks or reduces a signaling response is “antagonistic” or “an antagonist.”[000104] The term “antibody” is used herein in the broadest sense and refers generally to an immune-response generating molecule that contains at least one binding site that specifically binds to a target, wherein the target may be an antigen, or a receptor that is capable of interacting with certain antibodies. For example, an NK cell can be activated by the binding of an antibody or the Fc region of an antibody to its Fc-gamma receptors (FcyR), thereby triggering the ADCC (antibody-dependent cellular cytotoxicity) mediated effector cell activation. A specific piece or portion of an antigen or receptor, or a target in general, to which an antibody binds is known as an epitope or an antigenic determinant. The term “antibody” includes, but is not limited to, native antibodies and variants thereof, fragments of native antibodies and variants thereof,peptibodies and variants thereof, and antibody mimetics that mimic the structure and / or function of an antibody or a specified fragment or portion thereof, including single chain antibodies and fragments thereof. An antibody may be a murine antibody, a human antibody, a humanized antibody, a camel IgG, a single variable new antigen receptor (VNAR), a shark heavy-chain antibody (Ig-NAR), a chimeric antibody, a recombinant antibody, a single-domain antibody (dAb), an anti-idiotype antibody, a bi-specific-, multi-specific- or multimeric- antibody, or antibody fragment thereof. Anti-idiotype antibodies are specific for binding to an idiotope of another antibody, wherein the idiotope is an antigenic determinant of an antibody. A bi-specific antibody may be a BiTE (bi-specific T cell engager) or a BiKE (bi-specific killer cell engager), and a multi-specific antibody may be a TriKE (tri-specific Killer cell engager). Non-limiting examples of antibody fragments include Fab, Fab', F(ab')2, F(ab')3, Fv, Fabc, pFc, Fd, single chain fragment variable (scFv), tandem scFv (scFv)2, single chain Fab (scFab), disulfide stabilized Fv (dsFv), minibody, diabody, triabody, tetrabody, single-domain antigen binding fragments (sdAb), camelid heavy-chain IgG and Nanobody® fragments, recombinant heavychain-only antibody (VHH), and other antibody fragments that maintain the binding specificity of the antibody.[000105] “Fc receptors,” abbreviated FcR, are classified based on the type of antibody that they recognize. For example, those that bind the most common class of antibody, IgG, are called Fc-gamma receptors (FcyR), those that bind IgA are called Fc-alpha receptors (FcaR) and those that bind IgE are called Fc-epsilon receptors (FcsR). The classes of FcRs are also distinguished by the cells that express them (macrophages, granulocytes, natural killer cells, T and B cells) and the signaling properties of each receptor. Fc-gamma receptors (FcyR) include several members, FcyRI (CD64), FcyRIIA (CD32), FcyRIIB (CD32), FcyRIIIA (CD16a), and FcyRIIIB (CD16b), which differ in their antibody affinities due to their different molecular structures.[000106] Chimeric Receptor” is a general term used to describe an engineered, artificial, or a hybrid receptor protein molecule that is made to comprise two or more portions of amino acid sequences that are originated from at least two different proteins. The chimeric receptor proteins have been engineered to give a cell the ability to initiate signal transduction and carry out downstream function upon binding of an agonistic ligand to the receptor. Exemplary “chimeric receptors” include, but are not limited to, chimeric antigen receptors (CARs), chimeric fusion receptors (CFRs), chimeric Fc receptors (CFcRs), as well as fusions of two or more receptors.[000107] Chimeric Fc Receptor,” abbreviated as CFcR, is a term used to describe engineered Fc receptors having their native transmembrane and / or intracellular signaling domains modified or replaced with non-native transmembrane and / or intracellular signaling domains. In some embodiments of the chimeric Fc receptor, in addition to having one of, or bothof, the transmembrane and signaling domains being non-native, one or more stimulatory domains can be introduced to the intracellular portion of the engineered Fc receptor to enhance cell activation, expansion and function upon triggering of the receptor. Unlike a chimeric antigen receptor (CAR), which contains an antigen binding domain to a target antigen, the chimeric Fc receptor binds to an Fc fragment, or the Fc region of an antibody, or the Fc region comprised in an engager or a binding molecule and activates the cell function with or without bringing the targeted cell close in vicinity. For example, a Fey receptor can be engineered to comprise selected transmembrane, stimulatory, and / or signaling domains in the intracellular region that respond to the binding of IgG at the extracellular domain, thereby generating a CFcR. In one example, a CFcR is produced by engineering CD16, a Fey receptor, by replacing its transmembrane domain and / or intracellular domain. To further improve the binding affinity of the CD 16-based CFcR, the extracellular domain of CD64 or the high-affinity variants of CD 16 (F176V, for example) can be incorporated. In some embodiments of the CFcR where a high affinity CD 16 extracellular domain is involved, the proteolytic cleavage site comprising a serine at position 197 is eliminated or is replaced such at the extracellular domain of the receptor is non-cleavable, i.e., not subject to shedding, thereby obtaining a hnCD 16-based CFcR.[000108] CD16, a FcyR receptor, has been identified to have two isoforms, Fc receptors FcyRIIIa (CD16a) and FcyRIIIb (CD16b). CD16a is a transmembrane protein expressed by NK cells, which binds monomeric IgG attached to target cells to activate NK cells and facilitate antibody-dependent cell-mediated cytotoxicity (ADCC). “High affinity CD 16,” “non-cleavable CD 16,” or “high affinity non-cleavable CD 16” (abbreviated as hnCD16), as used herein, refers to a natural or non-natural variant of CD 16. The wildtype CD 16 has low affinity and is subject to ectodomain shedding, a proteolytic cleavage process that regulates the cells surface density of various cell surface molecules on leukocytes upon NK cell activation. F176V and F158V are exemplary CD 16 polymorphic variants having high affinity. A CD 16 variant having the cleavage site (position 195-198) in the membrane-proximal region (position 189-212) altered or eliminated is not subject to shedding. The cleavage site and the membrane-proximal region are described in detail in WO2015 / 148926, the complete disclosure of which is incorporated herein by reference. The CD 16 S197P variant is an engineered non-cleavable version of CD 16. A CD16 variant comprising both F158V and S197P has high affinity and is non-cleavable. Another exemplary high affinity and non-cleavable CD 16 (hnCD16) variant is an engineered CD 16 comprising an ectodomain originated from one or more of the 3 exons of the CD64 ectodomain.[000109] In some embodiments, provided herein are cells comprising a set of engineered components that collectively complement (and in some cases synergize with) one another to enhance the activity of an effector cell, in the context of treating a tumor in general, and for asolid tumor microenvironment in particular. The selected set of engineered components are referred to herein as a “backbone;” for its compatibility with any tumor antigen binding molecule to be expressed in the effector cell, including but not limited to, a CAR, an antibody, a bispecific antibody, and a TCR. However, the term “backbone” does not require any particular physical relationship between the individual components of the set, or their location within the cell; although certain association and / or arrangements (e.g., order in a co-expression construct of two or more of the individual components) may be optimized for higher expression level or ease of processing, among other considerations in a manufacturing setting. For example, a backbone may comprise integration of two expression cassettes, each at a different location in the genome of the cell. In some embodiments, the backbone comprises a plurality of genomic modifications, such as the insertion of one or more polynucleotides and / or modification to knockout one or more genes. Modifications may be made simultaneously or sequentially. Non-limiting examples of effector cell function that may be increased by the modifications of the backbone include one or more of improving cell growth, proliferation, expansion, and / or effector function autonomously without contacting additionally supplied soluble cytokines in vitro or in vivo, as well as enhanced homing, trafficking, depletion or reduction of alloreactive host immune cells, and retention at tumor sites, in which the tumor cells could be sensitized to synergize with the functional features provided to the effector cells. A solid tumor targeting backbone of the present disclosure can be particularly beneficial in the context of an iPSC comprising the backbone, such as by providing a master cell bank providing a source of starting cells that can be modified by the simple addition of a tumor antigen binding molecule for an indication intended to be treated, and then being used as a source for differentiating enhanced effector cells with therapeutic properties for one or more intended tumor indications.I. Cells and Compositions Useful for Adoptive Cell Therapies with Enhanced Properties[000110] Provided herein is a strategy to systematically engineer the regulatory circuitry of a clonal iPSC without impacting the differentiation potency and cell development biology of the iPSC and its derivative cells, while enhancing the therapeutic properties of the derivative cells differentiated from the iPSC. The iPSC-derived cells are functionally improved and suitable for adoptive cell therapies following a combination of selective modalities being introduced to the cells at the level of iPSC through genomic engineering. It was previously unclear whether altered iPSCs comprising one or more provided genetic edits still have the capacity to enter cell development, and / or to mature and generate functional differentiated cells while retaining modified activities and / or properties. Unanticipated failures during directed cell differentiationfrom iPSCs have been attributed to aspects including, but not limited to, development stage specific gene expression or lack thereof, requirements for HLA complex presentation, protein shedding of introduced surface expressing modalities, and the need for reconfiguration of differentiation protocols enabling phenotypic and / or functional change in the cell. The present application has shown that the one or more selected genomic modifications as provided herein does not negatively impact iPSC differentiation potency, and the functional effector cells derived from the engineered iPSC have enhanced and / or acquired therapeutic properties attributable to the individual or combined genomic modifications retained in the effector cells following the iPSC differentiation. Further, all genomic modifications and combinations thereof as may be described in the context of iPSC and iPSC-derived effector cells are applicable to primary sourced cells, including primary immune cells such as T, NK, or immunregulatory cells, whether cultured or expanded, the modification of which results in engineered immune cells useful for adoptive cell therapy.[000111] Further, while CAR-T cells have been shown to be effective and potent in treating several hematologic malignancies, engineered T cell therapies have had limited success in addressing solid tumors. Unlike liquid tumors where uniformly-expressed antigens are accessible and can be effectively targeted, tumor access, lack of tumor-exclusive antigen targets, and antigen heterogeneity are significant barriers to the successful development of CAR-T cells in solid tumors. In addition, inherent genetic engineering variability seen with patient- and donor- derived immune cells limits the wide application of CAR-T cell therapy. The present application provides genomic engineering aspects in the form of a solid tumor targeting backbone, as well as other genetic modalities, to improve on-target specificity with reduced off-tumor effect in the off-the-shelf adoptive cell therapy setting using effector cells derived from engineered iPSCs, to evade allorej ection, as well as to overcome suppressive tumor microenvironment, a heightened challenge especially with solid tumors.1. Avidity-Enhancing Receptor (AvER) and Associated Chimeric Antigen Receptor (CAR)[000112] While chimeric antigen receptor (CAR) T cells have shown remarkable success in the treatment of hematologic malignancies, there is still a need to improve the efficacy and durability of CAR T-cell therapy especially for solid tumors. It is disclosed herein that coexpression of a CAR and of a second receptor binding to a same or different antigen but without the intracellular signaling domains results in improved anti-tumor activity via enhanced target cell avidity.[000113] Applicable to the genetically engineered immune cells, iPSCs and derivative effector cells thereof may be any AvER design according to this application. AvER is a fusion protein generally including an ectodomain that comprises a target binding region (for example, an antigen recognition domain), a transmembrane domain. Unlike a CAR, AvER does not comprise an endodomain. CAR generally comprises an ectodomain that comprises a target binding region (for example, an antigen recognition domain), a transmembrane domain, and an endodomain. In some embodiments, the co-expressed CAR and AvER targets different antigens. In some embodiments, the co-expressed CAR and AvER targets the same antigen. In some embodiments, the co-expressed CAR and AvER targets the same epitope of an antigen. In some embodiments, the co-expressed CAR and AvER targets different epitopes of the same antigen. In some embodiments, the co-expressed CAR and AvER comprise the same target binding region. In some embodiments, co-expressed CAR and AvER comprise the same antigen recognition domain. In some embodiments, the co-expressed CAR and AvER comprise the same ectodomain. In some embodiments, the ectodomain of an AvER can further include a signal peptide or leader sequence and / or a spacer. In some embodiments, the endodomain can further comprise a signaling peptide that activates the effector cell expressing the CAR. As used herein, the terms “co-expressed”, “co-expressing” or “co-expression”, with respect to CAR and AvER, refer to the expression of both CAR and AvER, without regard to the spatial or physical arrangement of the two elements in construct(s), vector(s) for cell engineering and / or at insertion site(s) of cell genome after genetic engineering.[000114] In some embodiments, the target binding region of an AvER is an antigen recognition domain that can specifically bind an antigen.[000115] In various embodiments, the antigen recognition region of an AvER comprises a murine antibody, a human antibody, a humanized antibody, a camel Ig, a single variable new antigen receptor (VNAR), a shark heavy-chain antibody (Ig-NAR), a chimeric antibody, a recombinant antibody, a single-domain antibody (dAb), an anti-idiotype antibody, a bi-specific-, multi-specific- or multimeric- antibody, or antibody fragment thereof. Anti-idiotype antibodies are specific for binding to an idiotope of another antibody, wherein the idiotope is an antigenic determinant of an antibody. A bi-specific antibody may be a BiTE (bi-specific T cell engager) or a BiKE (bi-specific killer cell engager), and a multi-specific antibody may be a TriKE (tri-specific Killer cell engager). Non-limiting examples of antibody fragments include Fab, Fab’, F(ab’)2, F(ab’)3, Fv, Fabc, pFc, Fd, single chain fragment variable (scFv), tandem scFv (scFv)2, single chain Fab (scFab), disulfide stabilized Fv (dsFv), minibody, diabody, triabody, tetrabody, single-domain antigen binding fragments (sdAb), camelid heavy-chain IgG and Nanobody®fragments, recombinant heavy-chain-only antibody (VHH), and other antibody fragments that maintain the binding specificity of the antibody. In some embodiments an antigen binding domain of a CAR comprises CDR1, CDR2, and CDR3 of a heavy chain (H-CDRs) of an antibody or fragments thereof. In some embodiments, the antigen binding domain of a CAR comprising the H-CDRs of an antibody further comprises the CDRs of a light chain (L-CDRs) of the antibody.[000116] In some embodiments, the antigen recognition domain of an AvER specifically binds an antigen associated with a disease or pathogen. In some embodiments, the disease-associated antigen is a tumor antigen, wherein the tumor may be a liquid or a solid tumor. In some embodiments of an AvER, the AvER binds antigens of hematological malignancies, which include, but are not limited to, acute and chronic leukemias (acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), lymphomas, non-Hodgkin lymphoma (NHL), Hodgkin’s disease, multiple myeloma, and myelodysplastic syndromes.[000117] In some embodiments of AvERs that bind solid cancer antigens, the antigens are associated with sarcomas and carcinomas. In some embodiments, the solid cancers suitable for AvER binding include, but are not limited to, bladder cancer, bone cancer, brain / CNS cancer, breast cancer, breast lung cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric / stomach cancer, head and neck cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, metastatic cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, salivary gland cancer, skin cancer, testicular tumor, thyroid tumor, urothelial cancer, and uterine / endometrial cancer. More specifically, in some embodiments, the AvER binds an antigen associated to adenocarcinoma, basal cell carcinoma, bile duct carcinoma, bladder carcinoma, bronchogenic carcinoma, cholangiocarcinoma, chondrosarcoma, choriocarcinoma, colon carcinoma, Ewing’s tumor, fibrosarcoma, gallbladder carcinoma, hepatocellular carcinoma, hepatoma, leiomyosarcoma, liposarcoma, lymphoid malignancy, medullary carcinoma, medullary thyroid carcinoma, melanoma, mesothelioma, myxosarcoma, non-small cell lung cancer, osteosarcoma, papillary adenocarcinoma, papillary carcinoma, papillary thyroid carcinoma, pheochromocytomas sebaceous gland carcinoma, peritoneal carcinoma, renal cell carcinoma, rhabdomyosarcoma, sarcoma, seminoma, squamous cell carcinoma, sweat gland carcinoma, synovial sarcoma, synovioma, and Wilms' tumor. In some embodiments, the CAR targets antigens of CNS tumors including, but not limited to, acoustic neuroma, astrocytoma, CNS lymphoma, ependymoma, hemangioblastoma, germinoma, glioma (including brainstem glioma and mixed gliomas), glioblastoma (also known as glioblastoma multiforme),medulloblastoma, menangioma, neuroblastoma, oligodendroglioma, pinealoma, retinoblastoma, Schwannoma craniopharyogioma, and brain metastases.[000118] Non-limiting examples of antigens that may be recognized by AvER include oncofetal antigen (h5T4), 8H9, 9D7, ACPP, a actinin-4 (ACTN4), ADAM12, ADRB3, ADGRE2 / EMR2, AFP, AKAP-4, ALK, ALPP, ALPPL2, Androgen receptor, ASGR1 (asialoglycoprotein receptor 1), ASGR2 (asialoglycoprotein receptor 2), AXL, B7H3, B7H6, BAGE, P-catenin, BCR, BCR-ABL, Bigh3, BING-4, BORIS, BRCA1 / 2, BST2, carbonic anhydrase IX (CAIX / CA9), CA125, C-C motif chemokine receptor 1 (CCR1), CCR4, carcinoembryonic antigen (CEA / CECAM5), Calcium-activated chloride channel 2 (CLCA4), Carbohydrates (Le), CD3, CD4, CD5, CD7, CD8, CD10, CD19, CD20, CD22, CD24, CD30, CD33, CD34, CD37, CD38, CD41, CD44, CD44V6, CD44v7 / 8, CD47, CD49f, CD52, CD56, CD70, CD72, CD74, CD79a, CD79b, CD97, CD99, CD 123, CD 133, CD 138, CD171, CD 179a, CD207, CD269 (BCMA), CD300LF, CDC127, CDH3 (p-cadherin), CDH6, cadherin 19 (CDH19), CDK4, CFC1, CLCA1, CLDN6, CLDN18.2, CLEC12A, CLL-1, c-MET, CML66, an antigen of a cytomegalovirus (CMV) infected cell (e.g., a cell surface antigen), CR1L, CS-1, CSPG4, CXCR2, CXCR5, CXORF61, CyclinBl (CCNB1), CYP1B1, DLL3, EFNA4, EGFR (or erbB-1), EGFRvIII, EGF1R, epithelial cell adhesion molecule / epithelial glycoprotein-2 (EpCAM / EGP2), epithelial glycoprotein-40 (EGP40), ELF2M, ENPP3, EphA2, EphA3, EphB2, ERBB2 (or HER2 / neu), ERBB3, ERBB4, ERG (TMPRSS2 ETS fusion gene), ETA, ETV6-AML, FAP, folate-binding protein (FBP), FCAR, FCRL5, fetal acetylcholine receptor (AChR), Fibronectin, FLT3, folate receptor-a, (FR-a / FOLRl), Folate receptor beta (FR-P / FOLR2), FOLR3, Fos-related antigen 1 (FOSL1), FRcc, FZD10, GAGE, gangliosides (GM1, FucGMl, GM2, GM3, GD2, o-acetyl-GD2, GD3), GloboH, GpA33, Gp75, GplOO, Glypican-1 (GPC1), Glypican-2 (GPC2), Glypican-3 (GPC3), GPNMB, GPR20, GPR27, GPR35, GPR119, GPRC5D, guanylate cyclase C (GC-C), GUCY2C, HAVCR1, HERV-envelope protein, HLA-A1, HM1.24, HMWMAA, HPV E6, HPV E7, human telomerase reverse transcriptase (hTERT), IGFr / IGFIR, IGLL1 (CD179b), ILllRa, Interleukin- 13 receptor subunit alpha-2 (IL13Ra2), IL13Rcc2, Immature laminin receptor (iLRP), Integrin aVp3, Integrin alpha5p, Integrin B7, intercellular adhesion molecule 1 (ICAM1), intestinal carboxyl esterase (iCE), K-light chain, kinase insert domain receptor (KDR), KIT, KISS1R, LAIR1, LAGE-la, LAMP-1, LCK, legumain, Lewis A (CA19.9), Lewis Y (LeY), LI cell adhesion molecule (Ll-CAM), LILRA2, LILRB2, LIV-1, LMP2, LRRC15, LY6K, LY75, LYPD3, MAD-CT-1, MAD-CT-2, melanoma antigen family Al (MAGE-A1), MC1R, MelanA / MARTl, MART2, melanoma-associated chondroitin sulfate proteoglycan (MCSP), c-Met, MICA / B, Mesothelin (MSLN), ML-IAP, MR1, multidrug resistance-associated protein 3 (MRP3), MS4A12, Mucin 1 (MUC1, tMUCl), MUC2,MUC5A, MUC12, MUC16, MUC17, MUC21, Mud, MUM1, MUM2, MUM3, mut hsp70-2, MYCN, NA17, NA88-1, NCAM, Nectin4, NKCSI, NKG2D ligands, NPM, NY-BR-1, cancertestis antigen NY-ESO-1, 0A1, OGT, OR51E2, OY-TES1, p53, p53 mutant, PANX3, PAP, PAX3, PAX5, PCTA-l / Galectin 8, PDGFR-beta, PDL1, periostin, PLAC1, PRAME, PRLR, Prostase (KLK2, KLK4), prostein (P501S), PRSS21, Polysialic acid (PSA), prostate stem cell antigen (PSCA), PSC1, PRAME prostate-specific membrane antigen (PSMA / FOLH1), PTK7, QRFPR, RAGE-1, RANKL, Ras, Ras mutant, RCC, RhoC, Ron Kinase, R0R1, RU1, RU2, SAGE, SAP1, sarcoma translocation breakpoints, SART3, SIGLEC-15, Sialo-epitope CA6, SLC6A3, SLC12A3, SLC13A5, SLC22A1, SLC22A7, SLC30A4, SLC30A8, SLC34A2, SLC45A3, sLe, SLITRK6, SPARC, Sperm protein 17 (SP17), S SEA-4, SSTR1, SSX2, STEAP, sTN, Survivin, tumor-associated glycoprotein 72 (TAG72), TARP, TEM1 / CD248, TEM7R, TEMs, Telomerase, TGF-B receptor, TGS5, Tie 2, Tissue Factor (TF), TIM-3, TMEFF2 (TENB2), TMEM238, TMPRSS11B, TMPRSS11E, Tn Ag, TNC, TP-3, TRAILR1, TRAILR2, TRBC1, TRBC2, TRF2, TRG, TROP2, TRP1, TRP2, TSHR, TSTA, Tyrosinase, UGT1A1, UPK1B, UPK2, VEGF, VEGFR, vascular endothelial growth factor R2 (VEGF-R2), VTCN1 (B7H4), Wilms tumor protein (WT1), XAGE1, and various pathogen antigen known in the art. Non-limiting examples of pathogens include viruses, bacteria, fungi, parasites and protozoa capable of causing diseases.[000119] Non-limiting examples of solid cancers with corresponding tumor antigens are provided in Table 1.Table 1 - Exemplary Solid Tumors and Solid Tumor Associated Antigens[000120] In some embodiments, the antigen recognition domain of an AvER comprises CDRs of the heavy chain (H-CDRs), CDRs of both the heavy and the light chains (H- and L-CDRs), the variable region of the heavy chain (VH), or a single chain of the variable regions of both the heavy and light chains (VH and VL) of the binding domains of an antibody that is specific to a tumor antigen, including those exemplified in this application. In some embodiments, the CAR is designed based on the binding domains of an antibody comprising trastuzumab, cetuximab, panitumumab, ofatumumab, belimumab, ipilimumab, pertuzumab, tremelimumab, nivolumab, pembrolizumab, atezolizumab, MDX-1105, dacetuzumab, urelumab, MPDL3280A, lambrolizumab, blinatumomab, nimotuzumab, zalutumumab, onartuzumab, patritumab, clivatuzumab, sofituzumab, edrecolomab, adecatumumab, anetumab, huDS6, lifastuzumab, sacituzumab, PR1A3, humanized PR1A3, humanized Ab2-3, claudiximab, AMG595, ABT806, sibrotuzumab, DS-8895a variant 1, DS-8895a variant 2, MEDI-547, narnatumab, RG7841, farletuzumab, mirvetuximab, J591 variant 1, J591 variant 2, rovalpituzumab, PF-06647020, ladiratuzumab, cirmtuzumab, ladiratuzumab, huLivl-14, Livl-1.7A4, huLivl-22, 4H11, 4H5, glembatumumab, oportuzumab, enfortumab, depatuxizumab, or codrituzumab.[000121] Accordingly, in some embodiments, the antigen recognition domain of an AvER specifically binds to an antigen present on bladder cancer. In some embodiments, the AvER binding a bladder cancer associated antigen specifically binds to HER2, MICA / B, CD207, EFNA4, LY6K, LYPD3, Nectin4, PTK7, SLITRK6, TIM-3, TNC, UPK1B, or UPK2. In some embodiments, the antigen recognition domain of said AvER comprises the H-CDRs, H- and L-CDRs, the VH, or a single chain of VH and VL of an antibody comprising enfortumab, trastuzumab, pertuzumab or SLITRK6.[000122] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on bone cancer. In some embodiments, the AvER recognizing a bone cancer associated antigen specifically binds to MICA / B, ADAM12, CCR1, CD99, CD248, EPHA2, GPNMB, LRRC15, or TP-3. In some embodiments, the antigen recognition domain of said CAR comprises the H-CDRs, H- and L- CDRs, the VH, or a single chain of VH and VL of an antibody comprising huM25, DS-8895a variant 1, DS-8895a variant 2, or glembatumab.[000123] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on brain cancer. In some embodiments, the CAR targeting a brain cancer associated antigen specifically binds to MICA / B, CD133, DLL3, EGFRvIII, or TNC. In some embodiments, the antigen recognition domain of said CAR comprises the H-CDRs, H- and L- CDRs, the VH, or a single chain of VH and VL of an antibody comprising AMG595, ABT806, rovalpituzumab or depatuxizumab.[000124] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on a breast cancer cell. In some embodiments, the CAR targeting a breast cancer associated antigen specifically binds to HER2, MICA / B, ADAM12, ADGRE2 / EMR2, CCR4, CD49f, CD 133, CDH3 (p-cadherin), CLDN6, c-MET, CXCR2, EFNA4, EGFR, EPCAM / EGP2, EPHA2, GPNMB, ICAM1, LAMP-1, LIV-1, LILRB2, LRRC15, LYPD3, MUC1, tMUCl, PRLR, PTK7, Sialo-epitope CA6, TNC, or TROP2. In some embodiments, the antigen recognition domain of said CAR comprises the H-CDRs, H- and L-CDRs, the VH, or a single chain of VH and VL of an antibody comprising trastuzumab, pertuzumab, sacituzumab, ladiratuzumab, huLivl-14, Livl-1.7A4, huLivl-22, huDS6, glembatumumab, PF-0664720, MEDL547, DS-8895a variant 1, or DS-08895a variant 2.[000125] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on a breast lung cancer cell. In some embodiments, the AvER recognizing a breast lung cancer associated antigen specifically binds to HER2, MICA / B, ADGRE2 / EMR2, EPCAM / EGP2, orRORl.[000126] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on cervical / uterine / endometrial cancer. In some embodiments, the AvER recognizing a cervical / uterine / endometrial cancer associated antigen specifically binds to MICA / B, EFNA4, LY6K, MUC1, MUC16, LYPD3, PTK7, SLC12A3, or SSTR1. In some embodiments, the antigen recognition domain of said AvER comprises the H-CDRs, H- and L-CDRs, the VH, or a single chain of VH and VL of an antibody comprising PF-0664720, anetumumab, 4H11, 4H5, huDS6, or sofituzumab.[000127] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on a cholangiocarcinoma cell. In some embodiments, the AvER recognizing a cholangiocarcinoma associated antigen specifically binds to MICA / B or tMUCl.[000128] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on colorectal cancer. In some embodiments, the AvER recognizing a colorectal cancer associated antigen specifically binds to HER2, MICA / B, ADAM12, CA19.9, CD3, CD49f, CD133, CEA / CECAM5, CLCA1, c-MET, EFNA4, EPHB2, GPA33, GPR35, GUCY2C, ICAM1, LGR5 / GPR49, LRRC15, MS4A12, MUC12, MUC17, TIM-3, or TMEM238. In some embodiments, the antigen recognition domain of said AvER comprises the H-CDRs, H- and L- CDRs, the VH, or a single chain of VH and VL of an antibody comprising huM25, PR1 A3, humanized PR1 A3, pantumumab, cetuximab, nimotuzumab, or zalutumumab.[000129] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on an esophageal cancer cell. In some embodiments, the AvER recognizing an esophageal cancer associated antigen specifically binds to HER2, MICA / B, CA19.9, CD10, CEA / CECAM5, EFNA4, EPHB2, MUC21, TMEM238, TMPRSS11B, or TMPRSS11E.[000130] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on a gall bladder carcinoma cell. In some embodiments, the AvER recognizing a gall bladder carcinoma associated antigen specifically binds to EPCAM / EGP2.[000131] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on gastric / stomach cancer. In some embodiments, the AvER recognizing a gastric / stomach cancer associated antigen specifically binds to HER2, MICA / B, CEA / CECAM5, CLDN18.2, c-MET, CR1L, EFNA4, EPHB2, LGR5 / GPR49, MUC17, PSCA, TIM-3, or TMEM238. In some embodiments, the antigen recognition domain of said AvER comprises the H-CDRs, H- and L- CDRs, the VH, or a single chain of VH and VL of an antibody comprising sofituzumab, anetumab, pertuzumab, trastuzumab, or humanized PR1A3.[000132] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on a glioma cancer cell. In some embodiments, the AvERrecognizing a glioma cancer associated antigen specifically binds to MICA / B, ADGRE2ZEMR2, CD49f, CD133, EGFR, EGFRvIII, EPHA2, HM1.24, or IL13-Ra2.[000133] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on head and neck cancer. In some embodiments, the AvER recognizing a head and neck cancer associated antigen specifically binds to HER2, MICA / B, ADAM12, CD3, c-MET, EFNA4, LRRC15, LY6K, LYPD3, PTK7, or TNG In some embodiments, the antigen recognition domain of said AvER comprises the H-CDRs, H- and L-CDRs, the VH, or a single chain of VH and VL of an antibody comprising cetuximab, panitumumab, nimtuzumab, PF-0664720, pantumumab, cetuximab, nimotuzumab, or zalutumumab.[000134] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on kidney cancer. In some embodiments, the AvER recognizing a kidney cancer associated antigen specifically binds to MICA / B, CD70, CDH6, c-MET, ENPP3, or HAVCR1. In some embodiments, the antigen recognition domain of said CAR comprises the H-CDRs, H- and L- CDRs, the VH, or a single chain of VH and VL of an antibody comprising AGS-16M8F, AGS-16C3, the antibody of CDX-014, or onartuzumab.[000135] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on liver cancer. In some embodiments, the AvER recognizing a liver cancer associated antigen specifically binds to MICA / B, ASGR1, ASGR2, C9 (CAIX), CA19.9, CEA / CECAM5, CCR1, CD3, CD133, EPCAM / EGP2, GPC3, ICAM1, LGR5 / GPR49, SLC13A5, SLC22A1, SLC22A7, TIM-3, TRF2, or UGT1A1. In some embodiments, the antigen recognition domain of said AvER comprises the H-CDRs, H- and L- CDRs, the VH, or a single chain of VH and VL of an antibody comprising codrituzumab, oportuzumab, or humanized PR1A3.[000136] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on lung cancer. In some embodiments, the AvER recognizing a lung cancer associated antigen specifically binds to HER2, MICA / B, ADAM12, ADGRE2 / EMR2, CCR1, CCR4, CD56, CD133, CEA / CECAM5, CXCR2, DLL3, EFNA4, EGFR, EGFRvIII, FOLR1, GPC3, HM1.24, ICAM1, LILRB2, LRRC15, LY6K, LYPD3, MSLN, MUC1, MUC16, PDL1, PTK7, SLC34A2, or TIM-3. In some such embodiments, the antigen recognition domain of said AvER comprises the H-CDRs, H- and L- CDRs, the VH, or a single chain of VH and VL of an antibody comprising panitumumab, cetuximab, pembrolizumab, nivolumab, atezolizumab, and nimotuzumab, lifastuzumab, anetumab, PF-0664720, farletuzumab, rovalpituzumab, lifastuzumab, sofituzumab, huDS6, ABT806, AMG595, or huM25.[000137] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on a mesothelioma cell. In some embodiments, the AvER recognizing a mesothelioma associated antigen specifically binds to MICA / B, FAP, or MSLN.[000138] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on a metastatic cancer cell. In some embodiments, the CAR targeting a metastatic cancer cell associated antigen specifically binds to MICA / B, MSLN, or VEGFR-II.[000139] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on a neuroblastoma cell. In some embodiments, the AvER recognizing a neuroblastoma associated antigen specifically binds to MICA / B or GD2.[000140] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on a non-small cell lung cancer (NSCLC) cell. In some embodiments, the AvER recognizing a non-small cell lung cancer associated antigen specifically binds to MICA / B, c-MET, or EGFR.[000141] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on ovarian cancer. In some embodiments, the AvER recognizing an ovarian cancer associated antigen specifically binds to HER2, MICA / B, CCR1, CD3, CD133, CLDN6, c-MET, EFNA4, EPCAM / EGP2, FAP, FOLR1, FOLR3, FR-a, FZD10, GPR27, GPR119, LRRC15, MSLN, MUC1, MUC16, PTK7, SLC34A2, sTN, TMEM238, or VTCN1. In some embodiments, the antigen recognition domain of said CAR comprises the H-CDRs, H- and L- CDRs, the VH, or a single chain of VH and VL of an antibody comprising sofituzumab, 4H11, 4H5, huDS6, farletuzumab, anetumab, trastuzumab, pertuzumab, PF-0664720, sibrotuzumab, huM25, or lifastuzumab.[000142] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on pancreatic cancer. In some embodiments, the AvER recognizing a pancreatic cancer associated antigen specifically binds to MICA / B, ADAM12, CA19.9, CFC1, EFNA4, EPCAM / EGP2, ICAM1, LILRB2, LRRC15, MSLN, MUC1, tMUCl, MUC5A, MUC16, MUC17, PSCA, PTK7, or SLC30A8. In some embodiments, the antigen recognition domain of said AvER comprises the H-CDRs, H- and L- CDRs, the VH, or a single chain of VH and VL of an antibody comprising PF-0664720, clivatuzumab, 4H11, 4H5, anetumumab, huDS6, sofituzumab, huM25, or RG7841.[000143] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on a peritoneal carconima cell. In some embodiments, the AvER recognizing a peritoneal carcinoma associated antigen specifically binds to FOLR3.[000144] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on prostate cancer. In some embodiments, the AvER recognizing aprostate cancer associated antigen specifically binds to MICA / B, ACPP, CD 10, CD49f, CD 133, EFNA4, OR51E2, PSCA, PSMA / FOLH1, PTK7, SLC30A4, SLC45A3, STEAP, TIM-3, or TMEFF2 / TENB2. In some embodiments, the antigen recognition domain of said AvER comprises the H-CDRs, H- and L- CDRs, the VH, or a single chain of VH and VL of an antibody comprising mirvetuximab, or J591 variant 1 or 2.[000145] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on a renal cancer cell. In some embodiments, the AvER recognizing a renal cancer associated antigen specifically binds to MICA / B, CD3, CD70, ICAM1, KISS1R, LILRB2, QRFPR, SLC6A3, or TIM-3.[000146] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on a sarcoma. In some embodiments, the AvER recognizing a sarcoma associated antigen specifically binds to MICA / B or LRRC15.[000147] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on a salivary gland cancer cell. In some embodiments, the AvER recognizing a salivary gland cancer associated antigen specifically binds to HER2 or MICA / B.[000148] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on skin cancer. In some embodiments, the AvER recognizing a skin cancer associated antigen specifically binds to CCR4, CD3, CD10, or ICAM1.[000149] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on a synovial sarcoma. In some embodiments, the AvER recognizing a synovial sarcoma associated antigen specifically binds to CD99.[000150] In some embodiments, an antibody specifically binds to an antigen present on a thyroid cancer / tumor cell. In some embodiments, the AvER recognizing a thyroid cancer / tumor associated antigen specifically binds to MICA / B, CD 10, c-MET, PTK7, or TSHR.[000151] In some embodiments, an antibody specifically binds to an antigen present on a urothelial cancer cell. In some embodiments, the AvER recognizing a urothelial cancer associated antigen specifically binds to MICA / B, CLDN6, EPCAMZEGP2, SIGLEC-15, TIM-3, or UPK2.[000152] In some embodiments, the antigen recognition domain of the AvER specifically binds to an antigen present on uterine / endometrial cancer cell. In some embodiments, the AvER recognizing a uterine / endometrial cancer associated antigen specifically binds to HER2, MICA / B, ALPP, ALPPL2, CCR1, CLDN6, EFNA4, EPHB2, FOLR1, LILRB2, LY6K, LYPD3, MUC1, MUC16, or PTK7. In some embodiments, the antigen recognition domain of said AvER comprises the H-CDRs, H- and L- CDRs, the VH, or a single chain of VH and VL of an antibody comprising PF-0664720, farletuzumab, sofituzumab, 4H11, or 4H5.[000153] In various embodiments, the antigen recognition domain of the AvER specifically binds to a tumor antigen known to be associated with three or more cancer types (sometimes referred to as “pan-tumor antigen”). A non-limiting set of such pan-tumor antigens comprises at least ADAM12, ADGRE2 / EMR2, CA19.9, CCR1, CCR4, CD3, CD10, CD49f, CD133, CEA / CECAM5, CLDN6, c-MET, EFNA4, EGFR, EGFRvIII, EPHA2, EPHB2, FOLR1, HER2, ICAM1, LILRB2, LRRC15, LY6K, LYPD3, MICA / B, MSLN, MUC1, tMUCl, MUC16, MUC17, PSCA, PTK7, TIM-3, TMEM238, and TNC as exemplified in Table 2.Table 2 - Exemplary Pan-Tumor Antigens and Associated Cancers[000154] In some embodiments, the antigen recognition domain of the AvER specifically binds to tumor associated HER2, wherein an effector cell comprising said AvER and a solid tumor targeting backbone as disclosed is useful for treating one or more cancers comprising at least bladder cancer, breast cancer, breast lung cancer, colorectal cancer, esophageal cancer, gastric / stomach cancer, head and neck cancer, lung cancer, ovarian cancer, or salivary gland cancer.[000155] In some embodiments, the antigen recognition domain of the AvER specifically binds to tumor associated MICA / B, wherein an effector cell comprising said AvER and CAR targeting the same antigen is useful for treating one or more cancers comprising at least bladder cancer, bone cancer, brain cancer, breast cancer, breast lung cancer, cervical cancer,cholangiocarcinoma, colorectal cancer, esophageal cancer, gastric / stomach cancer, glioma, head and neck cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, metastatic cancer, neuroblastoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma, salivary gland cancer, thyroid cancer, urothelial cancer, or uterine / endometrial cancer.[000156] In some embodiments, the antigen recognition domain of the AvER specifically binds to tumor associated MSLN, wherein an effector cell comprising said AvER and CAR targeting the same antigen is useful for treating one or more cancers comprising at least lung cancer, metastatic cancer, mesothelioma, ovarian cancer, or pancreatic cancer.[000157] In some embodiments, the antigen recognition domain of the AvER specifically binds to tumor associated MUC1, wherein an effector cell comprising said AvER and CAR targeting the same antigen is useful for treating one or more cancers comprising at least breast cancer, cervical cancer, lung cancer, ovarian cancer, pancreatic cancer, or uterine / endometrial cancer.[000158] In some embodiments, the antigen recognition domain of the AvER specifically binds to tumor associated PSCA, wherein an effector cell comprising said AvER and CAR targeting the same antigen is useful for treating one or more cancers comprising at least gastric / stomach cancer, pancreatic cancer, or prostate cancer.[000159] In various embodiments, the AvERs appliable to the cells described herein include an ectodomain and a transmembrane domain, but not an endodomain. In general, a transmembrane domain is a three-dimensional protein structure which is thermodynamically stable in a membrane such as the phospholipid bilayer of a biological membrane (e.g., a membrane of a cell or cell vesicle). Thus, in some embodiments, the transmembrane domain of the AvER applicable to the cells provided herein comprises a single alpha helix, a stable complex of several transmembrane alpha helices, a transmembrane beta barrel, a beta-helix of gramicidin A, or any combination thereof. In various embodiments, the transmembrane domain of the CER comprises all or a portion of a “transmembrane protein” or “membrane protein” that is within the membrane. As used herein, a “transmembrane protein” or “membrane protein” is a protein located at and / or within a membrane. Examples of transmembrane proteins that are suitable for providing a transmembrane domain comprised in an AvER according to some embodiments of the invention include, but are not limited to, a receptor, a ligand, an immunoglobulin, a glycophorin, or any combination thereof. In some embodiments, the transmembrane domain comprised in the AvER comprises all or a portion of a transmembrane domain of 2B4, 4-1BB, BTLA, CD2, CD36, CD3s, CD3y, CD3 CD4, CD8, CD8a, CD8b, CD 16, CD27, CD28,CD28H, CD40, CD84, CD166, CS1, CTLA-4, DNAM1, DAP10, DAP12, FcERIy, ICOS, ICAM-1, IL7, IL12, IL15, KIR2DL4, KIR2DS1, KIR2DS2, LAG3, PD1, NKp30, NKp44, NKp46, NKG2C, NKG2D, 0X40, T cell receptor polypeptide (such as TCRa and / or TCRP), a nicotinic acetylcholine receptor, a GABA receptor, or any combination thereof.[000160] In some embodiments, the endodomain of a CAR that is co-expressed with the AvER in the cell comprises at least one signaling domain that is activated upon antigen binding. In some embodiments of the CAR endodomain, one or more co-stimulation domains (oftentimes referred to as “additional signaling domain(s)”) is further included for optimized functionality. Exemplary and non-limiting signaling domains, co-stimulation domains, and / or endodomain for CARs are described for example in PCT7US2024 / 040194, which is incorporated herein by reference.[000161] In various embodiments, the CARs appliable to the cells described herein include at least an ectodomain, a transmembrane domain, and an endodomain. In some embodiments, the endodomain of the CAR comprises at least one signaling domain that is activated upon antigen binding. In some embodiments of the CAR endodomain, one or more co-stimulation domains is further included for optimized functionality. Exemplary signal transducing proteins suitable for a CAR design include, but are not limited to, 2B4, 4-1BB, CD16, CD2, CD28, CD28H, CD3 1XX (i.e., CD3i or CD3i iXX), DAP10, DAP12, DNAM1, FcERIy, IL21R, IL-2RP (IL-15RP), IL-2Ry, IL-7R, KIR2DS2, NKG2D, NKp30, NKp44, NKp46, CS1 and CD8.Transmembrane and cytoplasmic sequences of such proteins are known in the art, non-limiting examples of which are disclosed in PCT / US2024 / 040194 and incorporated herein by reference.[000162] In some embodiments of the CAR applicable to the cells provided herein, the endodomain of the CAR comprises at least a first signaling domain comprising a cytoplasmic domain, or a portion thereof, of 2B4, 4-1BB, CD16, CD2, CD28, CD28H, CD3ζ CD3i iXX, DAP10, DAP12, DNAM1, FcERIy IL21R, IL-2RP (IL-15RP), IL-2Ry, IL-7R, KIR2DS2, NKG2D, NKp30, NKp44, NKp46, CS1, or CD8. In some embodiments, the signaling domain of the CAR comprises only a portion of the cytoplasmic domain of 2B4, 4- IBB, CD 16, CD2, CD28, CD28H, CD3ζ CD3i iXX, DAP10, DAP12, DNAM1, FcERIy IL21R, IL-2RP (IL-15RP), IL-2Ry, IL-7R, KIR2DS2, NKG2D, NKp30, NKp44, NKp46, CS1, or CD8. In some embodiments, the portion of the cytoplasmic domain selected for the CAR signaling domain comprises an ITAM (immunoreceptor tyrosine-based activation motif), a YxxM motif, a TxYxxV / I motif, FcRy, hemi-ITAM, and / or an ITT-like motif.[000163] In some embodiments of the CAR as provided, the endodomain of the CAR comprising a first signaling domain further comprises a second signaling domain comprising acytoplasmic domain, or a portion thereof, of 2B4, 4-1BB, CD16, CD2, CD28, CD28H, CD3ζ, CD3qXX, DAP10, DAP12, DNAM1, FcERIy IL21R, IL-2RP (IL-15R ), IL-2RY, IL-7R, KIR2DS2, NKG2D, NKp30, NKp44, NKp46, CS1 or CD8. In some embodiments, the second signaling domain is different from the first signaling domain.[000164] In some embodiments of the CAR as provided, the endodomain of the CAR comprising a first and a second signaling domain further comprises a third signaling domain comprising a cytoplasmic domain, or a portion thereof, of 2B4, 4- IBB, CD 16, CD2, CD28, CD28H, CD3ζ CD3i iXX, DAP10, DAP12, DNAM1, FcERIy, IL21R, IL-2RP (IL-15RP), IL-2Ry, IL-7R, KIR2DS2, NKG2D, NKp30, NKp44, NKp46, CS1, or CD8. In some embodiments, the third signaling domain is different from the first and the second signaling domains. In some embodiments, signal transducing proteins suitable for designing a signaling domain of a CAR endodomain further comprise CD27, 0X40, ICOS, PD-1, LAG-3, BTLA, or CTLA-4.[000165] In some exemplary embodiments of a CAR having an endodomain comprised of only one signaling domain, said endodomain comprises a cytoplasmic domain or a portion thereof, of a protein including, but not limited to, DNAM1, CD28H, KIR2DS2, DAP12 or DAP 10. In some exemplary embodiments of a CAR having an endodomain comprised of two different signaling domains, said endodomain comprises fused cytoplasmic domains, or portions thereof, in a form including, but not limited to, 2B4-CD3iyiXX (i.e., 2B4-CD3ζ or 2B4-CD3qXX; same below), 2B4-DNAM1, 2B4-FcERIy, 2B4-DAP10, CD16-DNAM1, CD16-DAP10, CD16-DAP12, CD2-CD3 1XX, CD2-DNAM1, CD2-FcERIy, CD2-DAP10, CD28-DNAM1, CD28-FcERIy, CD28-DAP10, CD28-DAP12, CD28-CD3 1XX, CD28H-CD3 1XX, DAP10-CD3 1XX, DAP10-DAP12, DAP12-CD3 1XX, DAP12-DAP10, DNAM1-CD3 1XX, KIR2DS2-CD3 1XX, KIR2DS2-DAP10, KIR2DS2-2B4, or NKp46-2B4. In some exemplary embodiments of a CAR having an endodomain comprised of three different signaling domains, said endodomain comprises fused cytoplasmic domains, or portions thereof, in a form including, but not limited to, 2B4-DAP10-CD3 1XX, 2B4-IL21R-DAP10, 2B4-IL2RB-DAP10, 2B4-IL2RB-CD3 1XX, 2B4-41BB-DAP10, CD16-2B4-DAP10, or KIR2DS2-2B4-CD3 1XX.[000166] In some embodiments, the transmembrane domain of the CAR comprises a full length or a portion of the transmembrane region of CD2, CD36, CD3s, CD3y, CD3ζ, CD4, CD8, CD8a, CD8b, CD16, CD27, CD28, CD28H, CD40, CD84, CD166, 4-1BB, 0X40, ICOS, ICAM-1, CTLA4, PD1, LAG3, 2B4, BTLA, DNAM1, DAP10, DAP12, FcERIy, IL7, IL12, IL15, KIR2DL4, KIR2DS1, KIR2DS2, NKp30, NKp44, NKp46, NKG2C, NKG2D, CS1, or T cell receptor polypeptide. In some other embodiments, the transmembrane domain of a CAR comprises a full length or a portion of the transmembrane region of (a) 2B4, CD 16, CD2, CD28, CD28H, CD3ζ DAP10, DAP12, DNAM1, FcERIy, KIR2DS2, NKG2D, NKp30, NKp44,NKp46, CS1, or CD8; or of (b) 2B4, CD28, CD28H, DAP10, DNAM1, KIR2DS2, and NKG2D. In some embodiments of the CAR, the transmembrane domain and its immediately linked signaling domain are from the same protein. In some other embodiments of the CAR, the transmembrane domain and the signaling domain that is immediately linked are from different proteins.[000167] Non-limiting examples of CAR constructs comprising a transmembrane domain (TM) and an endodomain (labelled as: TM-(endodomain)) are NKG2D-(2B4-IL2RB-CD3Q, CD8-(41BB-CD3C1XX), CD28-(CD28-2B4-CD3Q, CD28-(CD28-CD3 1XX), CD28H-(CD28H-CD3Q, DNAM 1 -(DNA 1 -CD3 Q, DAP10-(DAP10-CD3Q, KIR2DS2-(KIR2DS2-CD3Q, KIR2DS2-(KIR2DS2-DAP10), KIR2DS2-(KIR2DS2-2B4), CD 16-(CD 16-2B4-DAP 10), CD16-(CD16-DN M1), NKp46-(NKp46-2B4), NKp46-(NKp46-2B4-CD3 Q, NKp46-(NKp46-CD2-DAP10), CD2-(CD2-CD3Q, 2B4-(2B4-CD3Q, 2B4-(2B4-FcERIV), and CS1-(CS1-CD3Q.[000168] In one example, the genetically engineered immune cells, iPSCs and derivative effector cells comprise an AvER and a CAR, both comprising an antigen recognition region specific to a tumor cell surface HER2 antigen. In some embodiments the antigen binding domain of the AvER and the co-expressed HER2-CAR comprises a single chain variable fragment (scFV) having a sequence identity of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, or any percentage in-between, when compared to the exemplary sequences represented by SEQ ID NO: 1 or SEQ ID NO: 2, wherein each of SEQ ID NOs: 1 and 2 comprise a linker that can vary in length and / or sequence. In some embodiments, the scFV comprises an amino acid sequence of at least 90% identity to SEQ ID NO: 1 or 2. In some embodiments, the scFV comprises an amino acid sequence of at least 95% identity to SEQ ID NO: 1 or 2. In some embodiments, the scFV comprises the amino acid sequence of SEQ ID NO: 1. In some embodiments, the scFV comprises the amino acid sequence of SEQ ID NO: 2.SEQ ID NO: 1 EVQLVESGGGLVQPGGSLKLSCAASGFTFSNYGMSWVRQTPDRRLELVATINNNGGGTYYPDSVKGRFTI SRDNAKNTLYLQMSSLKSEDTAMYYCTSPGLLWDAWGAGTTVTVSSGSTSGGGSGGGSGGGGSSDVVMTQ TPLTLSVSIGQPASISCKSSQSLLDSDGRTYLNWLLQRPGQSPKRLIYLVSKLDSGAPDRFTGSGSGTDF TLKI SRVEAEDLGVYYCWQGTH FPQT FGGGTKLE IKSEQ ID NO: 2 DVVMTQTPLTLSVSIGQPASISCKSSQSLLDSDGRTYLNWLLQRPGQSPKRLIYLVSKLDSGAPDRFTGS GSGTDFTLKI SRVEAEDLGVYYCWQGTH FPQT FGGGTKLE IKGSTSGGGSGGGSGGGGSSEVQLVESGGG LVQPGGSLKLSCAASGFTFSNYGMSWVRQTPDRRLELVATINNNGGGTYYPDSVKGRFTISRDNAKNTLY LQMSSLKSEDTAMYYCTSPGLLWDAWGAGTTVTVSS[000169] In one embodiment, the CAR provided herein comprises an amino acid sequence of at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identity to SEQ ID NO: 3, wherein the linker in the ectodomain and the spacer between the ectodomain and transmembrane domain may vary in length and sequence. In some embodiments, the CAR comprises an amino acid sequence of at least about 90% identity to SEQ ID NO: 3, wherein the linker in the ectodomain and the spacer between the ectodomain and transmembrane domain may vary in length and sequence. In some embodiments, the CAR comprises an amino acid sequence of at least about 95% identity to SEQ ID NO: 3, wherein the linker in the ectodomain and the spacer between the ectodomain and transmembrane domain may vary in length and sequence. In some embodiments, the CAR comprises the amino acid sequence of SEQ ID NO: 3. In some embodiments, the CAR provided herein recognizes a HER2 antigen specific to cells of solid tumors. In some embodiments, the CAR provided herein recognizes a HER2 antigen of a tumor comprising breast cancer, ovary cancer, endometrium cancer, lung cancer, esophageal cancer, salivary gland cancer, bladder cancer, gastric cancer, colorectal cancer, or head and neck cancer. In yet some other embodiments, the CAR provided herein recognizes a HER2 antigen of a tumor and does not respond, or has a low level of response, to HER2 expressed on non-cancer or normal cells.SEQ ID NO: 3 EVQLVESGGGLVQPGGSLKLSCAASGFTFSNYGMSWVRQTPDRRLELVATINNNGGGTYYPDSVKGRFTI SRDNAKNTLYLQMSSLKSEDTAMYYCTSPGLLWDAWGAGTTVTVSSGSTSGGGSGGGSGGGGSSDWMTQ TPLTLSVS I GQPAS I S CKS SQSLLDSDGRTYLNWLLQRPGQS PKRL I YLVSKLD SGAPDRFTGS GS GTDF TLKISRVEAEDLGVYYCWQGTHFPQTFGGGTKLEIKPSKyGPPCPPCPGGGSSGGGSGGppPPPppYTPP PSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSWHEAP HyTQKSPSPSPGAMFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTP RRPG PT RKH Y Q P Y AP P RD FAAY RSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMG GKPRRKNPQEGL ENEL QKDKMAEAFSEIGMKGERRRGKGHDGL FQGL S TA TKD TFDALHMQAL PPR(anti-HER2 scFV[linker]- spacer- CD28 TM- CD28 Costim-CD3^1XX activation)[000170] In another example, the genetically engineered immune cells, iPSCs and derivative effector cells comprise an AvER and a CAR, both comprising an antigen recognition region that recognize tumor antigen MICA and MICB (MICA / B). In some embodiments of the MICA / B targeting AvER and the co-expressed CAR, the antigen recognition region is a scFV that specifically binds to the conserved a3 domain of MICA and MICB. In one embodiment, the scFV comprises a variable region of the heavy chain and a variable region of the light chain, respectively represented by an amino acid sequence that is of at least about 99%, about 98%, about 96%, about 95%, about 90%, about 85%, or at least about 80% identity to SEQ ID NO: 4and 5. In one embodiment of the MICA / B scFV, the scFV is represented by an amino acid sequence that is of at least about 99%, about 98%, about 96%, about 95%, about 90%, about 85%, or at least about 80% identity to any of SEQ ID NOs: 6 and 7. In some embodiments, the scFV comprises an amino acid sequence of at least 90% identity to SEQ ID NO: 6 or 7. In some embodiments, the scFV comprises an amino acid sequence of at least 95% identity to SEQ ID NO: 6 or 7. In some embodiments, the scFV comprises the amino acid sequence of SEQ ID NO: 6 or 7.SEQ ID NO: 4 QIQLVQSGPELKKPGETVKVSCKASGYMFTNYAMNWVKQAPEKGLKWMGWINTHTGDPTYADDFKGRIAF SLETSASTAYLQINNLKNEDTATYFCVRTYGNYAMDYWGQGTSVTVSS(118AA. MICA / B scFV heavy chain (HC))SEQ ID NO: 5 DIQMTQTTSSLSASLGDRVTISCSASQDISNYLNWYQQKPDGTVKLLIYDTSILHLGVPSRFSGSGSGTD YSLTISNLEPEDIATYYCQQYSKFPRTFGGGTTLEIK(107AA. MICA / B scFV light chain (LC))SEQ ID NO: 6 MDFQVQIFSFLLISASVIMSRQIQLVQSGPELKKPGETVKVSCKASGYMFTNYAMNWVKQAPEKGLKWMG WINTHTGDPTYADDFKGRIAFSLETSASTAYLQINNLKNEDTATYFCVRTYGNYAMDYWGQGTSVTVSSG GGGSGGGGSGGGGSDIQMTQTTSSLSASLGDRVTISCSASQDISNYLNWYQQKPDGTVKLLIYDTSILHL GVPSRFSGSGSGTDYSLTISNLEPEDIATYYCQQYSKFPRTFGGGTTLEIK(MICA / B scFV; HC-Linker-LC Signal peptide / Leader - other signal peptides are also possible;Linker - other linkers are also possible)SEQ ID NO: 7 MDFQVQIFSFLLISASVIMSRDIQMTQTTSSLSASLGDRVTISCSASQDISNYLNWYQQKPDGTVKLLIY DTSILHLGVPSRFSGSGSGTDYSLTISNLEPEDIATYYCQQYSKFPRTFGGGTTLEIKGGGGSGGGGSGG GGSQIQLVQSGPELKKPGETVKVSCKASGYMFTNYAMNWVKQAPEKGLKWMGWINTHTGDPTYADDFKGR IAFSLETSASTAYLQINNLKNEDTATYFCVRTYGNYAMDYWGQGTSVTVSSSignal peptide / Leader - other signal peptides are also possible;Linker - other linkers are also possible)[000171] In another example, the genetically engineered iPSC and its derivative cell comprise an AcRE and a CAR that recognizing tumor antigen BCMA (B cell maturation antigen). Some embodiments of the BCMA antigen recognition region comprise a scFV that specifically binds to the extracellular domain of CD269. One embodiment of the BCMA scFVcomprises a VH and a VL, represented by an amino acid sequence that is of at least about 99%, about 98%, about 96%, about 95%, about 90%, about 85%, or at least about 80% identity to SEQ ID NO: 8 and SEQ ID NO: 9, respectively; or SEQ ID NO: 10 and SEQ ID NO: 11, or SEQ ID NO: 12 and SEQ ID NO: 13, respectively.[000172] In one embodiment of the BCMA scFV, the scFV is represented by an amino acid sequence that is of at least about 99%, about 98%, about 96%, about 95%, about 90%, about 85%, or at least about 80% identity to any of SEQ ID NOs: 14-19. In some embodiments, the scFV comprises an amino acid sequence of at least 90% identity to any of SEQ ID NOs: 14-19. In some embodiments, the scFV comprises an amino acid sequence of at least 95% identity to any of SEQ ID NOs: 14-19. In some embodiments, the scFV comprises an amino acid sequence of any of SEQ ID NOs: 14-19.SEQ ID NO: 8 EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWFSWVRQAPGKGLVWVGEINPSSSTINYAPSLKDKFTI SRDNAKNTLYLQMNSLRAEDTAVYYCASLYYDYGDAYDYWGQGTLVTVSS(BCMA scFV heavy chain- 1 (VH))SEQ ID NO: 9 EIVMTQSPATLSVSPGERATLSCKASQSVESNVAWYQQKPGQAPRALIYSASLRFSGIPARFSGSGSGTE FTLTISSLQSEDFAVYYCQQYNNYPLTFGAGTKLELK(BCMA scFV light chain- 1 (VL))SEQ ID NO: 10 QVQLVQSGAEVKKPGASVKVSCKASGYSFPDYYINWVRQAPGQGLEWMGWIYFASGNSEYNQKFTGRVTM TRDTSINTAYMELSSLTSEDTAVYFCASLYDYDWYFDVWGQGTMVTVSS(BCMA scFV heavy chain-2 (VH))SEQ ID NO: 11 DIVMTQTPLSLSVTPGQPASISCKSSQSLVHSNGNTYLHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGS GSGTDFTLKISRVEAEDVGIYYCSQSSIYPWTFGQGTKLEIK(BCMA scFV light chain-2 (VL))SEQ ID NO: 12 QVQLVQSGAEVKKPGASVKVSCKASGYSFPDYYINWVRQAPGQGLEWMGWIYFASGNSEYNQKFTGRVTM TRDTSSSTAYMELSSLRSEDTAVYFCASLYDYDWYFDVWGQGTMVTVSS(BCMA scFV heavy chain-3 (VH))SEQ ID NO: 13 DIVMTQTPLSLSVTPGEPASISCKSSQSLVHSNGNTYLHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGS GSGADFTLKI SRVEAEDVGVYYCAET SHVPWT FGQGTKLE IK(BCMA scFV light chain-3 (VL))SEQ ID NO: 14 MDFQVQIFSFLLISASVIMSREVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWFSWVRQAPGKGLVWVG EINPSSSTINYAPSLKDKFTISRDNAKNTLYLQMNSLRAEDTAVYYCASLYYDYGDAYDYWGQGTLVTVS S GSTSGSGKPGSGEGSTKGE I VMTQS PATL S VS PGE RATL SCKASQ S VE SNVAWYQQKPGQAPRAL I Y SA SLRFSGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNYPLTFGAGTKLELK(BCMA scFV-1; VH-Linker-VL., Signal peptide / Leader - other signal peptides are also possible;Linker - other linkers are also possible)SEQ ID NO: 15MDFQVQIFSFLLISASVIMSRE I VMTQS PATL S VS PGE RATL SCKASQ SVE SNVAWYQQKPGQAPRAL I Y SASLRFSGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNYPLTFGAGTKLELKGGGGSGGGGSGG GGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWFSWVRQAPGKGLVWVGEINPSSSTINYAPSLKDK FTISRDNAKNTLYLQMNSLRAEDTAVYYCASLYYDYGDAYDYWGQGTLVTVSS(BCMA scFV-2; N -Linker-VLL Signal peptide / Leader - other signal peptides are also possible;Linker - other linkers are also possible)SEQ ID NO: 16 MDFQVQIFSFLLISASVIMSRQVQLVQSGAEVKKPGASVKVSCKASGYSFPDYYINWVRQAPGQGLEWMG WIYFASGNSEYNQKFTGRVTMTRDTSINTAYMELSSLTSEDTAVYFCASLYDYDWYFDVWGQGTMVTVSS GSTSGSGKPGSGPGSTKGDIVMTQTPLSLSVTPGQPASISCKSSQSLVHSNGNTYLHWYLQKPGQSPQLL IYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGIYYCSQSSIYPWTFGQGTKLEIK(BCMA scFV-3; NH-Linker-VL Signal peptide / Leader - other signal peptides are also possible;Linker - other linkers are also possible)SEQ ID NO: 17 MDFQVQIFSFLLISASVIMSRDIVMTQTPLSLSVTPGQPASISCKSSQSLVHSNGNTYLHWYLQKPGQSP QLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGIYYCSQSSIYPWTFGQGTKLEIKGSTSGSG■KPGSGAGSTKGQVQLVQSGAEVKKPGASVKVSCKASGYSFPDYYINWVRQAPGQGLEWMGWIYFASGNSE YNQKFTGRVTMTRDTSINTAYMELSSLTSEDTAVYFCASLYDYDWYFDVWGQGTMVTVSS(BCMA scFV-4; N -Linker-VLL Signal peptide / Leader - other signal peptides are also possible;Linker - other linkers are also possible)SEQ ID NO: 18 MDFQVQIFSFLLISASVIMSRQVQLVQSGAEVKKPGASVKVSCKASGYSFPDYYINWVRQAPGQGLEWMG WIYFASGNSEYNQKFTGRVTMTRDTSSSTAYMELSSLRSEDTAVYFCASLYDYDWYFDVWGQGTMVTVSS GSTSGSGKPGSGPGSTKGDIVMTQTPLSLSVTPGEPASISCKSSQSLVHSNGNTYLHWYLQKPGQSPQLL IYKVSNRFSGVPDRFSGSGSGADFTLKISRVEAEDVGVYYCAETSHVPWTFGQGTKLEIK(BCMA scFV-5; NH-Linker-VL Signal peptide / Leader - other signal peptides are also possible;Linker - other linkers are also possible)SEQ ID NO: 19 MDFQVQIFSFLLISASVIMSRDIVMTQTPLSLSVTPGEPASISCKSSQSLVHSNGNTYLHWYLQKPGQSP QLLIYKVSNRFSGVPDRFSGSGSGADFTLKISRVEAEDVGVYYCAETSHVPWTFGQGTKLEIKGSTSGSGKPGSGAGSAKGQVQLVQSGAEVKKPGASVKVSCKASGYSFPDYYINWVRQAPGQGLEWMGWIYFASGNSE YNQKFTGRVTMTRDTSSSTAYMELSSLRSEDTAVYFCASLYDYDWYFDVWGQGTMVTVSS(BCMA scFV-6; VL-Zzfzfer-VH; Signal peptide / Leader - other signal peptides are also possible;Linker - other linkers are also possible)[000173] In yet another example, the genetically engineered iPSC and its derivative cell comprise a solid tumor targeting backbone as disclosed herein and a CAR that targets tumor antigen B7H3 (CD276). In various embodiments of the CAR targeting a B7H3 tumor antigen, the CAR comprises a recombinant heavy-chain-only antibody (VHH) that specifically binds to B7H3. In one embodiment, the CAR comprises a binding domain comprising an amino acid sequence that is of at least about 99%, about 98%, about 96%, about 95%, about 90%, about 85%, or at least about 80% identity to any of SEQ ID NOs: 20-25. In some embodiments, the binding domain comprises an amino acid sequence of at least about 90% identity to any of SEQ ID NOs: 20-25. In some embodiments, the binding domain comprises an amino acid sequence of at least about 95% identity to any of SEQ ID NOs: 20-25. In some embodiments, the binding domain comprises the sequence of any of SEQ ID Nos: 20-25.[000174] In certain embodiments, the CAR comprises a binding domain comprising a variant of SEQ ID NO: 20, and wherein the variant has one or more mutations at positions comprising 1, 40, 46, 79, 87, 88, 89, 97, 98, and 117 of SEQ ID NO: 20. In other embodiments, the CAR comprises an amino acid sequence represented by a variant of SEQ ID NO: 20, wherein the variant has one or more substitutions comprising Q1E, T40A, E46V, G79L, K87R, P88A, D89E, V97A, S98R, and Q117L according to SEQ ID NO: 20.SEQ ID NO: 20 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQTPGKGLEWVSTINRDGSATWYADSVKGRFTI SRDNAKNTGYLQMNSLKPDDTAVYYCVSDPDNYSSDEMVPYWGQGTQVTVSS(122 a. a. VHH camelid B7H3)SEQ ID NO: 21 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLVWVSTINRDGSATWYADSVKGRFTI SRDNAKNTLYLQMNSLRAEDTAVYYCARDPDNYSSDEMVPYWGQGTLVTVSS(122 a. a. VHH1)SEQ ID NO: 22 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLVWVSTINRDGSATWYADSVKGRFTI SRDNAKNTLYLQMNSLRAEDTAVYYCVSDPDNYSSDEMVPYWGQGTLVTVSS(122 a. a. VHH2)SEQ ID NO: 23 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQTPGKGLVWVSTINRDGSATWYADSVKGRFTI SRDNAKNTLYLQMNSLRAEDTAVYYCVSDPDNYSSDEMVPYWGQGTLVTVSS(122 a. a. VHH3)SEQ ID NO: 24 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVSTINRDGSATWYADSVKGRFTI SRDNAKNTLYLQMNSLRAEDTAVYYCVSDPDNYSSDEMVPYWGQGTLVTVSS(122 a. a. VHH4)SEQ ID NO: 25 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQTPGKGLEWVSTINRDGSATWYADSVKGRFTI SRDNAKNTGYLQMNSLRPEDTAVYYCVSDPDNYSSDEMVPYWGQGTLVTVSS(122AA. VHH5)[000175] In some embodiments, the antigen binding domain of the AvER and the coexpressed CAR comprises a VH and a VL domain having a sequence identity of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, or any percentage in-between, when compared to the exemplary sequences represented by SEQ ID NOs: 26 and 27, or SEQ ID NOs: 28 and 29, or SEQ ID NOs: 30 and 31. These VH and VL sequences are described in detail in WO2020148677 (GPRC5D binding specificity), WO2021099944 (CD79b binding specificity), and WO2021019386 (KLK2 binding specificity) respectively. In some embodiments the antigen binding domain of the CAR comprises a single chain variable fragment (scFV) having a sequence identity of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, or any percentage in-between, when compared to the exemplary sequence represented by SEQ ID NOs: 32, 33, or 34, wherein SEQ ID NOs: 32, 33, or 34 comprises a linker that can vary in length and / or sequence. In some embodiments, the scFV comprises an amino acid sequence of at least 90% identity to any of SEQ ID NOs: 32-34. In some embodiments, the scFV comprises an amino acid sequence of at least 95% identity to any of SEQ ID NOs: 32-34. In some embodiments, the scFV comprises the amino acid sequence of any of SEQ ID NOs: 32-34.SEQ ID NO: 26 QLQLQESGPGLVKPSETLSLTCTVSGGSLSSSSYWWGWTRQPPGRGLEWIGTMYYSGNFVYNPS LQSRATISVDTSKNQFSLKLSSVTAADTAVYYCARHVGYSYGRRFWYFDLWGRGTLVTVSSSEQ ID NO: 27 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIKSEQ ID NO: 28 QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSKSGAWNWIRQSPSRGLEWLGRTYYRSKWYNEYA VSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCTRVDTDFDYWGQGTLVTVSSSEQ ID NO: 29 QSALTQPPSVSEAPRQRVTISCSGSASNIGNNGVNWYQQLPGKTPKLLIYNDDLLPSGVSDRFSGS KSGTSASLAISGLQSEDEADYFCAAWDDSLNGLVFGGGTKLTVLSEQ ID NO: 30 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMTWVRQAPGKGLEWVANIKQDGSERYYVDS VKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDQNYDILTGHYGMDVWGQGTTVTVSSSEQ ID NO: 31 EIVLTQSPSFLSASVGDRVTITCRASQGISSYLSWYQQKPGKAPKLLIYATSTLQSGVPSRFSGSGS GTEFTLTISSLQPEDFATYYCQQLNSYPRTFGQGTKVEIKSEQ ID NO: 32 QLQLQESGPGLVKPSETLSLTCTVSGGSLSSSSYWWGWTRQPPGRGLEWIGTMYYSGNFYYNPS LQSRATISVDTSKNQFSLKLSSVTAADTAVYYCARHVGYSYGRRFWYFDLWGRGTLVTVSSGGS EGXSSGSGSES STGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIKSEQ ID NO: 33 QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSKSGAWNWIRQSPSRGLEWLGRTYYRSKWYNEYA VSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCTRVDTDFDYWGQGTLVTVSSGG. S' / . GA'. S'. S'G. S' G. S7.. S '. S7GG. SOSALTQPPSVSEAPRQRVTISC SGSASNIGNNGVNWYQOLPG1< TP1< LLIYNDDLLP SGVSDRFSGSKSGTSASLAISGLQSEDEADYFCAAWDDSLNGLVFGGGTKLTVLSEQ ID NO: 34 EIVLTQSPSFLSASVGDRVTITCRASQGISSYLSWYQQKPGKAPKLLIYATSTLQSGVPSRFSGSGS GTEFTLTISSLQPEDFATYYCQOLNSYPRTFGQGT1< VEI1< GGSGSGSSGSGSGSSGGSSEVQLVES GGGLVQPGGSLRLSCAASGFTFSSYWMTWVRQAPGKGLEWVANIKQDGSERYYVDSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDQNYDILTGHYGMDVWGQGTTVTVSS[000176] In some embodiments, the polynucleotide encoding an AvER and as disclosed is operatively linked to an endogenous promoter. In some embodiments, the polynucleotide encoding an AvER as disclosed is operatively linked to an exogenous promoter. The promoters may be inducible, or constitutive, and may be temporal-, tissue- or cell type- specific. Suitable constitutive promoters for methods disclosed herein include, but are not limited to, cytomegalovirus (CMV), elongation factor la (EFla), phosphoglycerate kinase (PGK), hybrid CMV enhancer / chicken P-actin (CAG) and ubiquitin C (UBC) promoters. In one embodiment, the exogenous promoter is CAG.[000177] As described herein, in some embodiments, the cells comprising an AvER and a CAR further comprise one or more additional modified modalities. Non-limiting examples of additional modified modalities are provided in PCT / US2024 / 040194, which is incorporatedherein by reference. Additionally provided in this application is a master cell bank comprising single cell sorted and expanded clonal engineered iPSCs having at least one phenotype as provided herein, including but not limited to, an AvER and a CAR, wherein the cell bank provides a platform for additional iPSC engineering and a renewable source for manufacturing off-the-shelf, engineered, homogeneous cell therapy products, including but not limited to derivative NEC and T cells, which are well-defined and uniform in composition, and can be mass produced at significant scale in a cost-effective manner.[000178] Non-limiting examples of other modalities include TCR promoter-driven ADR, and / or a cytokine, TCE, a TGFP-SRR, a C-X-C-motif chemokine receptor or a variant thereof, a CD 16 variant, a CD38 knockout, a cytokine signaling complex, among other modifications which are all described in detail in, for example, PCT7US2024 / 040194 which is incorporated herein as a reference.a. C-X-C Motif Chemokine Receptor Overexpression[000179] Chemokines are a family of homogeneous serum proteins of about 7 to about 16 kDa originally characterized by their ability to induce leukocyte migration. Most of chemokines have four characteristic cysteines (Cys) and are classified into C-X-C (or alpha, CXC), C-C (or beta), C (or gamma), and CX3C (or delta) chemokine classes, according to motifs displayed by the first two cysteines. Subfamilies of C-X-C (or alpha, CXC) are further classified, according to the presence of an ELR motif (Glu-Leu-Arg) preceding the first cysteine, into two groups: ELR-CXC chemokines and non-ELR-CXC chemokines.[000180] CXC chemokine receptor 2 (CXCR2), also known as CD128, interleukin 8 receptor beta (IL8RP), or L8 receptor type B, is a chemokine receptor mostly expressed by neutrophils, mast cells, monocytes, and macrophages. It is known that CD56 dim NK cells express CXCR2, however its expression can be downregulated upon NK cell activation. T cells typically do not express CXCR2. iPSCs and iPSC-derived T cells do not express CXCR2 without transducing exogenous polynucleotides encoding CXCR2 as disclosed in this application. The chemokine IL8 (also known as CXCL8) is secreted by mononuclear macrophages, neutrophils, eosinophils, T lymphocytes, epithelial cells, and fibroblasts, and functions as a chemotactic factor by guiding the neutrophils to the site of infection. CXCL8 is also secreted by tumor cells and promotes tumor migration, invasion, angiogenesis and metastasis. CXCL8 is one of the ligands to multiple CXC chemokine receptors including CXCR1 and CXCR2. Additional chemokines known to bind to CXCR2 include, but are not limited to, CXCL1, GROp (CXCL2), CXCL3, CXCL5, CXCL6, and CXCL7.[000181] CXC chemokine receptor 3 (CXCR3), also known as G Protein-coupled Receptor 9 (GPR9) and CD183, is a G Protein-coupled receptor that binds to the chemokines CXCL9, CXCL10, and CXCL11. CXCR3 is expressed primarily in activated T-helper type 1 (Thl) lymphocytes, but is also present in natural killer cells, macrophages, dendritic cells, and B lymphocyte subsets. The interaction of CXCR3 and its ligands is involved in guiding receptorbearing cells to specific parts of the body, especially sites of inflammation, immune impairment, and immune dysfunction.[000182] In various embodiments, the present application provides effector cells or iPSCs genetically engineered to comprise, among other editing as contemplated and described herein, a solid tumor targeting backbone comprising, among other genetic modalities, a C-X-C motif chemokine receptor. In various embodiments, the C-X-C motif chemokine receptor comprises CXCR2 or CXCR3, or variants thereof. A non-limiting example of the amino acid sequence of human CXCR2 is one registered as UniProtKB No: P25025. In one embodiment, the CXCR2 comprises an amino acid sequence of at least 75%, 80%, 85%, 90%, 95% or 99% identity to SEQ ID NO: 35. In some embodiments, the CXCR2 comprises an amino acid sequence of at least 90% identity to SEQ ID NO: 35. In some embodiments, the CXCR2 comprises an amino acid sequence of at least 95% identity to SEQ ID NO: 35. In some embodiments, the CXCR2 comprises the amino acid sequence of SEQ ID NO: 35. As used herein and throughout the application, the percent identity between two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = # of identical positions / total # of positions x 100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm recognized in the art.SEQ ID NO: 35 MEDFNMESDSFEDFWKGEDLSNYSYSSTLPPFLLDAAPCEPESLEINKYFVVIIYALVFLLSLLGNSLVM LVILYSRVGRSVTDVYLLNLALADLLFALTLPIWAASKVNGWIFGTFLCKVVSLLKEVNFYSGILLLACI SVDRYLAIVHATRTLTQKRYLVKFICLSIWGLSLLLALPVLLFRRTVYSSNVSPACYEDMGNNTANWRML LRILPQSFGFIVPLLIMLFCYGFTLRTLFKAHMGQKHRAMRVIFAVVLIFLLCWLPYNLVLLADTLMRTQ VIQETCERRNHIDRALDATEILGILHSCLNPLIYAFIGQKFRHGLLKILAIHGLISKDSLPKDSRPSFVG SSSGHTSTTL(360 a.a. CXCR2; UniProtKB No: P25025)[000183] Anon-limiting example of the amino acid sequence of human CXCR3 is one registered as UniProtKB No: P49682. In one embodiment, the CXCR3 comprises an amino acid sequence of at least 75%, 80%, 85%, 90%, 95% or 99% identity to SEQ ID NO: 36. In someembodiments, the CXCR3 comprises an amino acid sequence of at least 90% identity to SEQ ID NO: 36. In some embodiments, the CXCR3 comprises an amino acid sequence of at least 95% identity to SEQ ID NO: 36. In some embodiments, the CXCR3 comprises the amino acid sequence of SEQ ID NO: 36.SEQ ID NO: 36 MVLEVSDHQVLNDAEVAALLENFSSSYDYGENESDSCCTSPPCPQDFSLNFDRAFLPALYSLLFLLGLLG NGAVAAVLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFGSGLCKVAGALFNINFYAGAL LLACISFDRYLNIVHATQLYRRGPPARVTLTCLAVWGLCLLFALPDFIFLSAHHDERLNATHCQYNFPQV GRTALRVLQLVAGFLLPLLVMAYCYAHILAVLLVSRGQRRLRAMRLVVVVVVAFALCWTPYHLVVLVDIL MDLGALARNCGRESRVDVAKSVTSGLGYMHCCLNPLLYAFVGVKFRERMWMLLLRLGCPNQRGLQRQPSS SRRDSSWSETSEASYSGL(368 a.a. CXCR3; UniProtKB No: P49682)[000184] In various embodiments, the polynucleotide encoding the C-X-C motif chemokine receptor or variant thereof is inserted in a selected locus of a primary-sourced effector cell or an iPSC for deriving functional effector cells comprising the same genetic editing through directed differentiation. In some embodiments, the selected locus for insertion of the C-X-C motif chemokine receptor comprises a safe harbor locus, a gene locus intended to be disrupted or knocked out, a gene locus that provides an endogenous promoter that provides spacial and / or temporal control of the exogenous gene expression. In some embodiments, the selected locus for C-X-C motif chemokine receptor insertion comprises AAVS1, CCR5, ROSA26, collagen, HTRP, Hll, PH12, GAPDH, RUNX1, B2M, TAPI, TAP2, Tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR, NKG2A, NKG2D, CD38, CD25, CD69, CD44, CD58, CD54, CD56, CD71, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, or TIGIT. In one embodiment, the selected locus for C-X-C motif chemokine receptor insertion is the TCR locus. In one embodiment, the selected locus for C-X-C motif chemokine receptor insertion is the CD38 locus.[000185] In some embodiments, the C-X-C motif chemokine receptor is co-expressed with one or more exogenous polynucleotides encoding a polypeptide of interest through separate expression constructs, or a single bi- or tri- cistronic expression cassete. In some embodiments, the single bi- or tri- cistronic expression cassete comprising the C-X-C motif chemokine receptor and one or more exogenous polynucleotides encoding a polypeptide of interest comprises a 2A sequence, such that the C-X-C motif chemokine receptor and the additional polynucleotide(s) are in a single open reading frame (ORF). The bi-cistronic design allows coordinated expression of multiple polynucleotides both in timing and quantity, and under the same control mechanism that may be chosen to incorporate, for example, an inducible promoter for the expression of the single ORF. Self-cleaving peptides are found in members of the Picomaviridae virus family,including aphthoviruses such as foot-and-mouth disease virus (FMDV), equine rhinitis A virus (ERAV), Thosea asigna virus (TaV) and porcine tescho virus- 1 (PTV-I) (Donnelly, ML, et al, J. Gen. Virol, 82, 1027-101 (2001); Ryan, MD, et al., J. Gen. Virol., 72, 2727-2732 (2001)), and cardioviruses such as Theilovirus (e.g., Theiler's murine encephalomyelitis) and encephalomyocarditis viruses. The 2A peptides derived from FMDV, ERAV, PTV-I, and TaV are sometimes also referred to as “F2A”, “E2A”, “P2A”, and “T2A”, respectively. In some embodiments, the exogenous polynucleotides that could be co-expressed with the C-X-C motif chemokine receptor encode one or more polypeptides comprising a CAR, a CD 16 or a variant thereof, a cytokine, a cytokine receptor, a cytokine signaling complex, a chimeric fusion receptor, a chimeric Fc receptor, an engager, a checkpoint inhibitor, an Fc receptor, or an antibody or functional variant or fragment thereof. In one embodiment, the exogenous polynucleotides that are co-expressed with the C-X-C motif chemokine receptor in a bi-cistronic cassette do not encode a CAR. In one embodiment, at least one exogenous polynucleotide that is co-expressed in a bi-cistronic cassette with the C-X-C motif chemokine receptor encodes an exogenous CD 16. In some embodiments, the primary-sourced or derived effector cells comprising the C-X-C motif chemokine receptor or variant thereof are T lineage cells. In some embodiments, the primary-sourced or derived effector cells comprising the C-X-C motif chemokine receptor or a variant thereof are NK lineage cells.[000186] Additionally provided in this application is a master cell bank comprising single cell sorted and expanded clonal engineered iPSCs having at least one modification or phenotype as provided herein, including but not limited to, a C-X-C motif chemokine receptor or a variant thereof, wherein the cell bank provides clonal engineered iPSCs for additional engineering and a renewable source for manufacturing off-the-shelf, engineered, homogeneous cell therapy products, including but not limited to derivative NK and T cells, which are well-defined and uniform in composition, and can be mass produced at significant scale in a cost-effective manner.b. Exogenously introduced TGFfl Redirector Receptor[000187] Transforming growth factor beta (TGFP) is a multipotent immunosuppressive cytokine with complex roles in tumorigenesis including epithelial to mesenchymal transition, angiogenesis, tumor cell motility and metastasis, cancer associated fibroblast (CAF) proliferation, and immunosuppression. TGFP exists in its latent form in the tumor microenvironment, and is known to suppress T cell effector function, in part, through Smad-mediated downregulation of the target genes granzyme, perforin, and interferon. Furthermore, the detection of a TGFP gene expression signature correlates with T cell exclusion from tumors and resistance to immunotherapy. One aspect of the present application provides a multi-elementsolid tumor targeting backbone design that incorporates a synthetic transforming growth factor beta receptor (TGFpR) signaling redirector receptor, among other editing as contemplated and described herein, to equip allogeneic effector cells, including those derived from genetically engineered iPSCs for better efficacy in tumors in general, and in solid tumors in particular. In general, a “signaling (or signal) redirector receptor” or “SRR” redirects the signaling of an extracellular domain from a first receptor (e.g., a TGFP receptor) through an intracellular domain from a different receptor (e.g., a cytokine receptor) by joining the extracellular domain of the first receptor and intracellular domains of the different receptor. In the context of TGFpR, the signaling redirector receptor may be referred to as a “TGFpR redirector” or “TGFpR redirector receptor” or “TGFP signal redirector receptor” or “TGFP-SRR” throughout this application.[000188] In some embodiments, iPSCs and derivative cells therefrom comprise a polynucleotide encoding a TGFP redirector receptor (TGFP-SRR), which comprises a partial or full peptide of an extracellular domain (ECD) of TGFpR. In some embodiments, the TGFP redirector receptor comprises: (i) an extracellular domain, or a fragment thereof, of transforming growth factor beta receptor (TGFpR); and (ii) an intracellular domain (ICD), or a fragment thereof, of a cytokine receptor comprising IL2R, IL12R, IL18R, IL21R, or any combination thereof.[000189] In some embodiments, the TGFP redirector receptor comprising the ECD and ICD as described above further comprises a transmembrane domain (TM). In various embodiments, the transmembrane (TM) domain of the TGFP redirector receptor can: (i) originate from the same molecule providing the intracellular domain, (ii) originate from the same molecule providing the extracellular domain, or (iii) may be modified or replaced with a transmembrane domain of any other membrane bound proteins. In some embodiments, the cytokine receptor providing an intracellular domain or a fragment thereof of the TGFP redirector receptor comprises at least one of an IL2R (e.g, IL2RP), IL4R, IL6R, IL7R, IL9R, IL10R, IL11R, IL12R (e.g., IL12RP), IL15R, IL18R (e.g. IL18RP), and IL21R (e.g., IL21RP).[000190] In some embodiments, the extracellular domain (ECD) of TGFpR comprises an amino acid sequence having at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identity to SEQ ID NO: 37. In some embodiments, the extracellular domain (ECD) of TGFpR comprises an amino acid sequence having at least about 90% identity to SEQ ID NO: 37. In some embodiments, the extracellular domain (ECD) of TGFpR comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 37. In some embodiments, the extracellular domain (ECD) of TGFpR comprises the amino acid sequence of SEQ ID NO: 37. In some embodiments, the intracellular domain (ICD) of IL2RP comprises an amino acid sequence having at least about 85%, about 90%, about 95%, about 96%, about 97%,about 98%, or about 99% identity to SEQ ID NO: 38. In some embodiments, the intracellular domain (ICD) of IL2RP comprises an amino acid sequence having at least about 90% identity to SEQ ID NO: 38. In some embodiments, the intracellular domain (ICD) of IL2RP comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 38. In some embodiments, the intracellular domain (ICD) of IL2RP comprises the amino acid sequence of SEQ ID NO: 38. In some embodiments, the intracellular domain (ICD) of IL12RP comprises an amino acid sequence having at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identity to SEQ ID NO: 39. In some embodiments, the intracellular domain (ICD) of IL12RP comprises an amino acid sequence having at least about 90% identity to SEQ ID NO: 39. In some embodiments, the intracellular domain (ICD) of IL12RP comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 39. In some embodiments, the intracellular domain (ICD) of IL12RP comprises the amino acid sequence of SEQ ID NO: 39. In some embodiments, a fragment of the intracellular domain of IL12RP comprises an amino acid sequence having at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identity to SEQ ID NO: 40. In some embodiments, a fragment of the intracellular domain of IL12RP comprises an amino acid sequence having at least about 90% identity to SEQ ID NO: 40. In some embodiments, a fragment of the intracellular domain of IL12RP comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 40. In some embodiments, a fragment of the intracellular domain of IL12RP comprises the amino acid sequence of SEQ ID NO: 40. In some embodiments, the intracellular domain (ICD) of IL18RP comprises an amino acid sequence having at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identity to SEQ ID NO: 41. In some embodiments, the intracellular domain (ICD) of IL18RP comprises an amino acid sequence having at least about 90% identity to SEQ ID NO: 41. In some embodiments, the intracellular domain (ICD) of IL18RP comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 41. In some embodiments, the intracellular domain (ICD) of IL18RP comprises the amino acid sequence of SEQ ID NO: 41. In some embodiments, the intracellular domain (ICD) of IL21RP comprises an amino acid sequence having at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identity to SEQ ID NO: 42. In some embodiments, the intracellular domain (ICD) of IL21RP comprises an amino acid sequence having at least about 90% identity to SEQ ID NO: 42. In some embodiments, the intracellular domain (ICD) of IL21RP comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 42. In some embodiments, the intracellular domain (ICD) of IL21RP comprises the amino acid sequence of SEQ ID NO: 42.SEQ ID NO: 37 TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKND ENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLL VIFQ(ECD of TGFpR)SEQ IDNO: 38 NCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQ LLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHLPDALEIEACQVYFTYDPYSEEDPDEGVAGAPTGSSP QPLQPLSGEDDAYCTFPSRDDLLLFSPSLLGGPSPPSTAPGGSGAGEERMPPSLQERVPRDWDPQPLGPP TPGVPDLVDFQPPPELVLREAGEEVPDAGPREGVSFPWSRPPGQGEFRALNARLPLNTDAYLSLQELQGQ DPTHLV( ICD of IL2Rp )SEQ ID NO: 39 HYFQQKVFVLLAALRPQWCSREIPDPANSTCAKKYPIAEEKTQLPLDRLLIDWPTPEDPEPLVISEVLHQ VTPVFRHPPCSNWPQREKGIQGHQASEKDMMHSASSPPPPRALQAESRQLVDLYKVLESRGSDPKPENPA CPWTVLPAGDLPTHDGYLPSNIDDLPSHEAPLADSLEELEPQHISLSVFPSSSLHPLTFSCGDKLTLDQL KMRCDSLML( ICD of IL12RP )SEQ ID NO: 40SDPKPENPACPWTVLPAGDLPTHDGYLPSNIDDLPSHEAPLADSLEELEPQ(an ICD fragment of IL12Rp )SEQ IDNO: 41 YRVDLVLFYRHLTRRDETLTDGKTYDAFVSYLKECRPENGEEHTFAVEILPRVLEKHFGYKLCIFERDVV PGGAVVDEIHSLIEKSRRLIIVLSKSYMSNEVRYELESGLHEALVERKIKIILIEFTPVTDFTFLPQSLK LLKSHRVLKWKADKSLSYNSRFWKNLLYLMPAKTVKPGRDEPEVLPVLSES( ICD of IL8Rp )SEQ ID NO: 42 SLKTHPLWRLWKKIWAVPSPERFFMPLYKGCSGDFKKWVGAPFTGSSLELGPWSPEVPSTLEVYSCHPPR SPAKRLQLTELQEPAELVESDGVPKPSFWPTAQNSGGSAYSEERDRPYGLVSIDTVTVLDAEGPCTWPCS CEDDGYPALDLDAGLEPSPGLEDPLLDAGTTVLSCGCVSAGSPGLGGPLGSLLDRLKPPLADGEDWAGGL PWGGRSPGGVSESEAGSPLAGLDMDTFDSGFVGSDCSSPVECDFTSPGDEGPPRSYLRQWVVIPPPLSSP GPQAS( ICD of IL21RP )[000191] In some embodiments, the signaling receptor comprises an extracellular domain or a fragment thereof of TGFpR and an intracellular domain or a fragment thereof of the cytokine receptor IL2RP, thereby forming a TGFPR2-IL2RP signaling redirector receptor. In some embodiments, the signaling receptor comprises an extracellular domain or a fragment thereof of TGFpR and an intracellular domain or a fragment thereof of the cytokine receptor IL12RP, thereby forming a TGFPR2-IL12RP signaling redirector receptor. In some embodiments, the signaling receptor comprises an extracellular domain or a fragment thereof of TGFpR and an intracellular domain or a fragment thereof of the cytokine receptor IL18RP, thereby forming a TGFPR2-IL18RP signaling redirector receptor. In some embodiments, the signaling receptor comprises an extracellular domain or a fragment thereof of TGFpR and an intracellular domain or a fragment thereof of the cytokine receptor IL21R, thereby forming a TGFPR2-IL21R signaling redirector receptor.[000192] In some embodiments, TGFPR2-IL12RP signaling redirector receptor comprises an amino acid sequence having sequence identity of at least 80%, 85%, 90%, 95%, or 97%, 98%, or 99% to a sequence represented by SEQ ID NO: 43 (termed specifically as TGFpR2-trIL12Rp throughout the application). In some embodiments, TGFPR2-IL12RP signaling redirector receptor comprises an amino acid sequence having sequence identity of at least 90% to SEQ ID NO: 43. In some embodiments, TGFPR2-IL12RP signaling redirector receptor comprises an amino acid sequence having sequence identity of at least 95% to SEQ ID NO: 43. In some embodiments, TGFPR2-IL12RP signaling redirector receptor comprises the amino acid sequence of SEQ ID NO: 43. In some embodiments, the transmembrane domain (TM) sequence represented by SEQ ID NO: 44 that is comprised within SEQ ID NO: 43 may vary in sequence or in length, or may even be replaced with a transmembrane domain of another transmembrane protein.SEQ ID NO: 43 TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKND ENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLL VI FQ VTGTSLLPFLGVATSVTTTFyCYRVNSDPKPENPACPWTVLPAGDLPTHDGYLPSNIDDLPSHEAP LADSLEELEPQ(TGFpR2-TM-trIL12Rp )SEQ ID NO: 44VTGI SLLPPLGVAI SVI I I FYCYRVN(exemplary and variable portion of TGFpR2-trIL12Rp )[000193] As such, in various embodiments, any of the TGFP-SRRs provided herein may be introduced to iPSCs using one or more of the construct designs described above, and to their derivative cells upon iPSC differentiation. In addition to an induced pluripotent cell (iPSC), a clonal iPSC, a clonal iPS cell line, or iPSC-derived cells comprising at least one engineered modality as disclosed herein are provided. Also provided is a master cell bank comprising single cell sorted and expanded clonal engineered iPSCs having at least a TGFP-SRR as described in this section, wherein the cell bank provides a platform for additional iPSC engineering and a renewable source for manufacturing off-the-shelf, engineered, homogeneous cell therapy products, which are well-defined and uniform in composition, and can be mass produced at a significant scale in a cost-effective manner.[000194] Accordingly, in some embodiments, the present invention provides immune cells, iPSCs, and iPSC derived cells comprising a solid tumor targeting backbone comprising a polynucleotide encoding a TGFP redirector receptor, among other genetic modalities, wherein the cells, such as derivative T and NK cells, are useful for overcoming or reducing tumor microenvironment suppression associated with a tumor, and particularly, a solid tumor. In some embodiments, the iPSC and derivative cells thereof comprise a solid tumor targeting backbone comprising two or more of: a polynucleotide encoding a C-X-C motif chemokine receptor or a variant thereof, a polynucleotide encoding a TGFP redirector receptor, and and / or one or more additional genomic edits as described herein, without adversely impacting the differentiation potential of the iPSC and function of the derived effector cells, such as derivative T and NK cells.[000195] Also provided is a master cell bank comprising single cell sorted and expanded clonal engineered iPSCs having at least an exogenously introduced polynucleotide encoding a TGFP redirector receptor, and optionally a polynucleotide encoding a C-X-C motif chemokine receptor or a variant thereof, wherein the cell bank provides a platform for additional iPSC engineering and a renewable source for manufacturing off-the-shelf, engineered, homogeneous cell therapy products, which are well-defined and uniform in composition, and can be mass produced at a significant scale in a cost-effective manner.c. CD 16 knock-in[000196] CD16 has been identified as two isoforms, Fc receptors FcyRIIIa (CD16a;NM_000569.6) and FcyRIIIb (CD16b; NM_000570.4). CD16a is a transmembrane protein expressed by NK cells, which binds monomeric IgG attached to target cells to activate NK cellsand facilitate antibody-dependent cell-mediated cytotoxicity (ADCC). CD 16b is exclusively expressed by human neutrophils. “High affinity CD 16,” “non-cleavable CD 16,” or “high affinity non-cleavable CD 16” (abbreviated as hnCD16), as used herein, refers to various CD 16 variants. The wildtype CD 16 has low affinity and is subject to ectodomain shedding, a proteolytic cleavage process that regulates cell surface density of various cell surface molecules on leukocytes upon NK cell activation. F176V (also called F158V in some publications) is an exemplary CD16 polymorphic variant having high affinity; whereas S197P variant is an example of genetically engineered non-cleavable version of CD 16. An engineered CD 16 variant comprising both Fl 76V and S197P has high affinity and is non-cleavable, which was described in greater detail in WO2015 / 148926, the complete disclosure of which is incorporated herein by reference. In addition, a chimeric CD 16 receptor with the ectodomain of CD 16 essentially replaced with at least a portion of CD64 ectodomain can also achieve the desired high affinity and non-cleavable features of a CD16 receptor capable of carrying out ADCC. In some embodiments, the replacement ectodomain of a chimeric CD 16 comprises one or more of ECI, EC2, and EC3 exons of CD64 (UniPRotKB_P12314 or its isoform or polymorphic variant).[000197] As such, various embodiments of an exogenous CD 16 introduced to a cell include functional CD 16 variants and chimeric receptors thereof. In some embodiments, the functional CD 16 variant is a high-affinity non-cleavable CD 16 receptor (hnCD16). An hnCD16, in some embodiments, comprises both Fl 76V and S197P; and in some embodiments, comprises Fl 76V and with the cleavage region eliminated. In some embodiments, an hnCD16 comprises a sequence having identity of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, or any percentage in-between, when compared to any of the exemplary sequences, SEQ ID NOs. 45, 46, and 47, and each comprises at least a portion of CD64 ectodomain. In some embodiments, the hnCD16 comprises an amino acid sequence of at least 90% identity to any of SEQ ID NOs. 45-47, and optionally one or more of Fl 76V, S197P, and at least a portion of CD64 ectodomain. In some embodiments, the hnCD16 comprises an amino acid sequence of at least 95% identity to any of SEQ ID NOs. 45-47, and optionally one or more of Fl 76 V, S197P, and at least a portion of CD64 ectodomain. In some embodiments, the hnCD16 comprises the amino acid sequence of SEQ ID NO 45. In some embodiments, the hnCD16 comprises the amino acid sequence of SEQ ID NO 46. In some embodiments, the hnCD16 comprises the amino acid sequence of SEQ ID NO 47.SEQ ID NO: 45 M FLTTLLLWVPVDGQVDTTKAVITLQPPWVSVFQEETVTLHCEVLHLPGSSSTQWFLNGTATQTSTPSY RITSASVNDSGEYRCQRGLSGRSDPIQLEIHRGWLLLQVSSRVFTEGEPLALRCHAWKDKLVYNVLYYRNGKAFKFFHWNSNLTILKTNISHNGTYHCSGMGKHRYTSAGISVTVKELFPAPVLNASVTSPLLEGNLVTL SCETKLLLQRPGLQLYFSFYMGSKTLRGRNTSSEYQILTARREDSGLYWCEAATEDGNVLKRSPELELQV LGLQLPTPVWFHY Q VS FCL VMVL L FA VD TGLYFS VKTNIRSS TRDWKDHKFKWRKDPQDK( 340 a. a. CD64 domain-based construction; CD16TM; CD16ICD)SEQ ID NO: 46 M FLTTLLLWVPVDGQVDTTKAVITLQPPWVSVFQEETVTLHCEVLHLPGSSSTQWFLNGTATQTSTPSY RITSASVNDSGEYRCQRGLSGRSDPIQLEIHRGWLLLQVSSRVFTEGEPLALRCHAWKDKLVYNVLYYRN GKAFKFFHWNSNLTILKTNISHNGTYHCSGMGKHRYTSAGISVTVKELFPAPVLNASVTSPLLEGNLVTL SCETKLLLQRPGLQLYFSFYMGSKTLRGRNTSSEYQILTARREDSGLYWCEAATEDGNVLKRSPELELQV LGLFFPPGYQ VS FCL VMVLLFA VDTGL YFSVKTNIRSS TRDWKDHKFKWRKDPQDK( 336 a. a. CD64 exon-based construction; CD16TM; CD16ICD)SEQ ID NO: 47 M FLTTLLLWVPVDGQVDTTKAVITLQPPWVSVFQEETVTLHCEVLHLPGSSSTQWFLNGTATQTSTPSY RITSASVNDSGEYRCQRGLSGRSDPIQLEIHRGWLLLQVSSRVFTEGEPLALRCHAWKDKLVYNVLYYRN GKAFKFFHWNSNLTILKTNISHNGTYHCSGMGKHRYTSAGISVTVKELFPAPVLNASVTSPLLEGNLVTL SCETKLLLQRPGLQLYFSFYMGSKTLRGRNTSSEYQILTARREDSGLYWCEAATEDGNVLKRSPELELQV LGFFPPGYQ VS FCL VMVL L FAVD TGL YFSVKTNTRS S TRD WKDHKFKWRKDPQDK( 335 a. a. CD64 exon-based construction; CD16TM; CD16TCD)[000198] Accordingly, provided herein are effector cells or iPSCs genetically engineered to comprise a solid tumor targeting backbone that comprises, among other editing as contemplated and described herein, an exogenous CD 16 or a variant thereof, wherein the effector cells are cells from primary sources or derived from iPSC differentiation, or wherein the genetically engineered iPSCs are capable of differentiating into derived effector cells comprising the exogenous CD 16 or a variant thereof introduced to the iPSCs. In some embodiments, the exogenous CD 16 is a high-affinity non-cleavable CD 16 receptor (hnCD16). In some embodiments, the exogenous CD 16 comprises at least a portion of the CD64 ectodomain. In some embodiments, the exogenous CD16 is in a form of a CD16-based chimeric Fc receptor (CFcR) that comprises a transmembrane domain, a stimulatory domain and / or a signaling domain that is not derived from CD 16.[000199] In some embodiments, the primary-sourced or derived effector cells comprising the exogenous CD 16 or variant thereof are NK lineage cells. In some embodiments, the primary-sourced or derived effector cells comprising the exogenous CD 16 or variant thereof are T lineage cells. In some embodiments, the exogenous CD 16 or functional variants thereof comprised in iPSC or effector cells has high affinity in binding to a ligand that triggers downstream signaling upon such binding. Non-limiting examples of ligands binding to the exogenous CD 16 or functional variants thereof include not only ADCC antibodies or fragments thereof, but also to bi-, tri-, or multi- specific engagers or binders that recognize the CD 16 or CD64 extracellularbinding domains of the exognous CD 16. Examples of bi-, tri-, or multi- specific engagers or binders are further described below in this application. As such, at least one of the aspects of the present application provides a derivative effector cell comprising a solid tumor targeting backbone, or a cell population thereof, preloaded with one or more pre-selected ADCC antibodies through an exogenous CD 16 expressed on the derivative effector cell, in an amount sufficient for therapeutic use in a treatment of a condition, a disease, or an infection as further detailed in this application, wherein the exogenous CD 16 comprises an extracellular binding domain of CD64, or of a CD 16 having Fl 76V and S197P.[000200] In some other embodiments, an exogenous CD 16 comprises a CD16-, or variants thereof, based CFcR. A chimeric Fc receptor (CFcR) is produced to comprise a non-native transmembrane domain, a non-native stimulatory domain and / or a non-native signaling domain by modifying or replacing the native CD 16 transmembrane- and / or the intracellular-domain. The term “non-native” used herein means that the transmembrane, stimulatory or signaling domain are derived from a different receptor other than the receptor which provides the extracellular domain.[000201] The various embodiments of the CD 16-based chimeric Fc receptor as described above are capable of binding, with high affinity, to the Fc region of an antibody or fragment thereof; or to a bi-, tri-, or multi- specific engager or binder. Upon binding, the stimulatory and / or signaling domains of the chimeric receptor enable the activation and cytokine secretion of the effector cells, and the killing of the tumor cells targeted by the antibody, or the bi-, tri-, or multi- specific engager or binder having a tumor antigen binding component as well as the Fc region. Without being limited by theory, through the non-native transmembrane, stimulatory and / or signaling domains, or through an engager binding to the ectodomain, of the CD 16-based chimeric Fc receptor, the CFcR could contribute to effector cells’ killing ability while increasing the effector cells’ proliferation and / or expansion potential. The antibody and the engager can bring tumor cells expressing the antigen and the effector cells expressing the CFcR into close proximity, which also contributes to the enhanced killing of the tumor cells..[000202] In some embodiments, the present disclosure also provides a derivative NK or T cell comprising a solid tumor targeting backbone, or a cell population thereof, preloaded with one or more pre-selected ADCC antibodies in an amount sufficient for therapeutic use in a treatment of a condition, a disease, or an infection as further detailed in this application. In some embodiments, the preloaded CD38 antibody is daratumumab. In some embodiments, the derived NK or T cells comprise a solid tumor targeting backbone comprising a TCR promoter-driven ADR and / or a cytokine, and a constitutively expressed TCE, in addition to edits comprising a CAR, a TGFP-SRR, a C-X-C-motif chemokine receptor or a variant thereof, a CD 16 variant, anda CD38 knockout, among other edits as provided herein. In some embodiments, said derived NK or T cells are preloaded with one or more of an anti-HER2 antibody (e.g., trastuzumab, pertuzumab), an anti-EGFR antibody (e.g., cetuximab), or an anti-PDLl antibody (e.g., avelumab).[000203] As provided further, the cell or population thereof, comprising the solid tumor targeting backbone, and optionally a CAR, and an exogenous CD 16 or a variant thereof, may further comprise one or more additional engineered modalities described herein. Additionally provided in this application is a master cell bank comprising single cell sorted and expanded clonal engineered iPSCs having at least one phenotype as provided herein, including but not limited to, a solid tumor targeting backbone comprising, among other genetic modalities, an exogenous CD 16 or a variant thereof, wherein the cell bank provides a platform for additional iPSC engineering and a renewable source for manufacturing off-the-shelf, engineered, homogeneous cell therapy products, including but not limited to derivative NK and T cells, which are well-defined and uniform in composition, and can be mass produced at significant scale in a cost-effective manner.d. Allo-Immune Defense Receptor (ADR) expression[000204] Unwanted activation of T- and NK- cells often promotes allo-immune reactions leading to development of graft-versus-host disease (GvHD). Although some steps may be taken to reduce the reactivity of allogeneic cells in the recipient individual, such cells would still be targeted by the immune system of the recipient (primarily T- and NK-cells), which would recognize them as foreign leading to rejection and limiting therapeutic benefit. On the other hand, modulating a host immune system to reduce allo-immune reactions, for example, by lympho-conditioning using chemotherapy such as Cy / Flu (cyclophosphamide / fludarabine) often leads to associated hematologic toxicities, including increased susceptibility to severe infections, due to indiscriminative lymphodepletion and a severely compromised immune system as a result. To control pathogenic conditions due to unwanted activation of the immune system, in various embodiments, the present application provides a solid tumor targeting backbone comprising an allo-immune defense receptor (ADR), among other components. Another aspect of the application provides immune cells, iPSCs, and iPSC-derived effector cells that are genetically engineered to comprise, among other editing as contemplated and described herein, a 4- IBB or CD38 specific allo-immune defense receptor (ADR) for effector cell potentiation as well as selective depletion of alloreactive host NK cells and T cells with upregulated 4- IBB and / or CD38 expression, the latter of which include pathogenic T cells, and regulatory T cells, while sparing resting cells in the recipient.[000205] In some embodiments of the ADR that is specific to 4-1BB (CD137, also referred to as “4 IBB”), the ADR comprises an extracellular domain that targets 4- IBB upregulated on host T or NK cells when they are activated, and a signaling domain promoting effector cell activation. For example, the 41BB-ADR extracellular domain may comprise any suitable ligand for 4- IBB, including 4-1BBL, an antibody (or functional fragment thereof) that targets 4- IBB, a fusion of Fc with 4-1BBL, or functional derivatives or fragments thereof. In some embodiments, the 41BB-ADR extracellular domain comprises 4-1BBL, or a fragment thereof effective to bind 4-1BB. In some embodiments, the 41BB-ADR extracellular domain comprises an amino acid sequence with at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to SEQ ID NO: 48. In some embodiments, the 41BB-ADR extracellular domain comprises an amino acid sequence with at least about 90% sequence identity to SEQ ID NO: 48. In some embodiments, the 41BB-ADR extracellular domain comprises an amino acid sequence with at least about 95% sequence identity to SEQ ID NO: 48. In some embodiments, the 41BB-ADR extracellular domain comprises the amino acid sequence of SEQ ID NO: 48.SEQ ID NO: 48 GLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRV VAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARA RHAWQLTQGATVLGLFRVTPEIPAGLPSPRSE[000206] In one embodiment of the CD38 specific ADR, the CD38-ADR comprises an extracellular domain comprising a CD38 binding domain or fragments thereof. In some embodiments, the CD38 binding domain or fragment thereof is from an anti-CD38 antibody. In some embodiments, the anti-CD38 antibody comprises a murine antibody, a human antibody, a humanized antibody, a camel Ig, a single variable new antigen receptor (VNAR), a shark heavychain-only antibody (Ig NAR), a chimeric antibody, a recombinant antibody, or an antibody fragment thereof. Non-limiting examples of antibody binding domain or fragments thereof include Fab, Fab', F(ab')2, F(ab')3, Fv, single chain antigen binding fragment (scFv), (scFv)2, disulfide stabilized Fv (dsFv), minibody, diabody, triabody, tetrabody, single-domain antigen binding fragments (sdAb, Nanobody), recombinant heavy-chain-only antibody (VHH), and other antibody fragments that maintain the binding specificity of the whole antibody. Non-limiting examples of CD38 binding domains for an ADR are provided in PCT / US2024 / 040194, which is incorporated herein by reference.[000207] In some embodiments, the extracellular domain of the 41BB-ADR or CD38-ADR may be operably linked to one or more signaling domains that mediate downstream signaling upon effector cell activation upon the binding to the 4- IBB or CD38, respectively, of alloreactive host immune cells. In particular embodiments, the ADR comprises CD3ζ, represented by an amino acid sequence of at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to SEQ ID NO: 49 or a functional fragment thereof, or comprises a CD3ζ derivative (for example, CD3ζ1XX, represented by an amino acid sequence of at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to SEQ ID NO: 50 or a functional fragment thereof). In some embodiments, the CD3ζ comprises an amino acid sequence of at least about 90% sequence identity to SEQ ID NO: 49. In some embodiments, the CD3ζ comprises an amino acid sequence of at least about 95% sequence identity to SEQ ID NO: 49. In some embodiments, the CD3ζ comprises the amino acid sequence of SEQ ID NO: 49. In some embodiments, the CD3ζ derivative comprises an amino acid sequence of at least about 90% sequence identity to SEQ ID NO: 50. In some embodiments, the CD3ζ derivative comprises an amino acid sequence of at least about 95% sequence identity to SEQ ID NO: 50. In some embodiments, the CD3ζ derivative comprises the amino acid sequence of SEQ ID NO: 50. CD3ζ mediates downstream ITAM-derived signaling during effector T or NK cell activation. Other ITAM-containing signaling domains may include those derived from DAP 12, Fc receptors, and other CD3 subunits.SEQ ID NO: 49 RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAE AYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(CD3 )SEQ ID NO: 50 RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLFNELQKDKMAEA FSEIGMKGERRRGKGHDGLFQGLSTATKDTFDALHMQALPPR(CD3 ^1XX - containing 2 mutations in ITAM1 )[000208] In some embodiments, the intracellular domain of ADR comprising a signaling domain further comprises one, two, three, or more costimulatory domains that enhance cytokine production from the effector cells that express the ADR. The costimulatory domains may be derived from the intracellular signaling domains of costimulatory proteins including, but not limited to, CD28, CD27, 4-1BB, 0X40, ICOS, CD30, HVEM, CD40, and so forth. In some embodiments the ADR comprising CD3ζ further comprises a costimulatory domain derived from4- IBB endodomain. In some embodiments, the endodomain is represented by an amino acid sequence of at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to SEQ ID NO: 51 or a functional fragment thereof. In some embodiments, the endodomain comprises an amino acid sequence of at least about 90% sequence identity to SEQ ID NO: 51. In some embodiments, the endodomain comprises an amino acid sequence of at least about 95% sequence identity to SEQ ID NO: 51. In some embodiments, the endo-domain comprises the amino acid sequence of SEQ ID NO: 51. In one embodiment, when the ADR comprises 4-1BBL in its extracellular domain, the costimulatory domain of the ADR is not derived from 4- IBB.SEQ ID NO: 51 KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVEFSRSADAPAYQQGQNQEYNEENEGR REEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATK DTYDALHMQALPPR( 41BB endo-CD3 )[000209] The intracellular domain of an ADR may be non-covalently linked to the extracellular domain of the ADR via a transmembrane domain. In some embodiments, the ADR comprises a transmembrane domain that may be of any kind so long as it allows the CD3ζ component of the ADR to be located intracellularly and the extracellular domain that targets 4-1BB or CD38 to be located extracellularly. In other instances, ADRs are soluble proteins that can bind to the respective ligand on activated T cells and promote cytotoxicity by crosslinking TCR (e.g., ADR-CD3 T-cell engager protein). In a case wherein the extracellular domain is from a surface protein having a transmembrane domain, (CD40, for example), the ADR may comprise the transmembrane domain from that corresponding endogenous molecule. In some embodiments in which the ADR molecule comprises one or more costimulatory domains, the transmembrane domain (TM) may be from the same endogenous molecule that has the costimulatory domain. Non limiting examples of TMs include those from CD3, CD8a, CD27, CD28, 4- IBB, 0X40, and CD4.[000210] In some embodiments, the ADR comprises a spacer between the extracellular protein and the transmembrane domain. In some embodiments, the spacer may comprise a sequence that is inert or contributes substantially little or nothing with respect to any function the ADR may have; whereas in other cases the spacer comprises a sequence that enhances a function of the ADR and / or allows it to be detectable and / or able to be targeted for inhibition. In specific embodiments, the spacer comprises an encoded protein sequence that facilitates detection of cells that express the ADR. For example, the spacer may encode an Fc region or fragments thereofthat would allow for surface detection of the cells expressing the ADR, such as by using anti-Fc antibodies. In particular embodiments, the spacer provides separation between the ligand binding extracellular domain and the membrane to avoid potential steric hindrances. As understood by one skilled in the art, the spacer can vary in sequence and / or in length, whether a function other than being a physical separation is intended or not. Exemplary spacers that may be included in the ADR are commonly known in the art, including, but not limited to, IgG4 spacers, CD28 spacers, CD8 spacers, or combinations of more than one spacer. The length of the spacers may also vary, from about 15 amino acids (a.a.) to about 300 a.a. or more. Non-limiting exemplary spacer peptides include those represented by an amino acid sequence of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identity to SEQ ID NO: 52 or 53. In some embodiments, the spacer peptide comprises an amino acid sequence of at least about 90% identity to SEQ ID NO: 52 or 53. In some embodiments, the spacer peptide comprises an amino acid sequence of at least about 95% identity to SEQ ID NO: 52 or 53. In some embodiments, the spacer peptide comprises the amino acid sequence of SEQ ID NO: 52. In some embodiments, the spacer peptide comprises the amino acid sequence of SEQ ID NO: 53.SEQ ID NO: 52 ESKYGPPCPPCPGGGSSGGGSGGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFL( 88 a. a. )SEQ ID NO: 53 PSXYGPPCPPCPGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPGKKDPK( 123 a. a. IgG4 hinge-lgGl CH3 )[000211] In one embodiment of the 4- IBB specific ADR, the 41BB-ADR is represented by an amino acid sequence of at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to any of SEQ ID NOs: 54-57. In some embodiments, the 41BB-ADR comprises an amino acid sequence of at least about 90% identity to any one of SEQ ID NOs: 54-57. In some embodiments, the the 41BB-ADR comprises an amino acid sequence of at least about 95% identity to any one of SEQ ID NOs: 54-57. In some embodiments, the the 41BB-ADR comprises the amino acid sequence of SEQ ID NO: 54. In some embodiments, the the 41BB-ADR comprises the amino acid sequence of SEQ ID NO: 55. In some embodiments, the the 41BB-ADR comprises the amino acid sequence of SEQ ID NO:56. In some embodiments, the the 41BB-ADR comprises the amino acid sequence of SEQ ID NO: 57.SEQ ID NO: 54 MFFGFSfVFFFVAFFXGVGCGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKEL VVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRL LHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLPSPRSEFSXYGFFCFFCFGQFFFFQ VYTLPPSRDEL TKNQVSL TCLVKGFYPSDTAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKL TVDKSRW QQGNVFSCSVMHEALHNA YTQKSL SF SFGXXF FKFWVLVWGGVLACY SLLVTVAF 11 FWVRSRVKFSRS ADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMK GERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSignal peptide-4 lBBL-spacer-CD28 (TM) -CD3z (the signal peptide, spacer and TM / transmembrane domain may vary)SEQ ID NO: 55 MFFGFSfVFFFVAFFXGVGCGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKEL VVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRL LHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLPSPRSEFSXYGFFCFFCFGQFFFFQ VYTLPPSRDEL TKNQVSL TCLVKGFYPSDTAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKL TVDKSRW QQGNVFSCSVMHEALHNA YTQKSL SF SFGXXF FKFWVLVWGGVLACY SLLVTVAF 11 FWVRS KRS RL L H S D YMNMT P RRPG PT RKH Y Q P Y AP P RD FAAY RSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKR RGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQA LPPRSignal peptide- 41BBL- spacer-CD28 (TM) -CD28 ( ICD) -CD3z (the signal peptide, spacer and TM / transmembrane domain may vary)SEQ ID NO: 56 MFFGFSfVFFFVAFFXG CGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKEL VVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRL LHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLPSPRSEFSXYGFFCFFCFGQFFFFQ VYTLPPSRDEL TKNQVSL TCLVKGFYPSDTAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKL TVDKSRW QQGNVFSCSVMHEALHNA YTQKSL SF SFGXXF FKFWVLVWGGVLACY SLLVTVAF 11 FWVRSRVKFSRS ADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLFNELQKDKMAEAFSEIGMK GERRRGKGHDGLFQGLSTATKDTFDALHMQALPPRSignal peptide-4 lBBL-spacer-CD28 (TM) -CD3zlxx (the signal peptide, spacer and TM / transmembrane domain may vary)SEQ ID NO: 57 MFFGFSfVFFFVAFFXGVGCGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKEL VVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRL LHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLPSPRSEFSXYGFFCFFCFGQFFFFQ VYTLPPSRDEL TKNQVSL TCLVKGFYPSDTAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKL TVDKSRW QQGNVFSCSVMHEALHNA YTQKSL SF SFGXXF FKFWVLVWGGVLACY SLLVTVAF 11 FWVRS KRS RL L H S D YMNMT P RRPG PT RKH Y Q P Y AP P RD FAAY RSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLFNELQKDKMAEAFSEIGMKGERRRGKGHDGLFQGLSTATKDTFDALHMQA LPPRSignal peptide-4 lBBL-spacer-CD28 (TM) -CD28 ( TCP) -CD3zlxx (the signal peptide, spacer and TM / transmembrane domain may vary)[000212] In one embodiment of the CD38 specific ADR, the CD38-ADR is represented by an amino acid sequence of at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to SEQ ID NO: 58. In some embodiments, the CD38-ADR comprises an amino acid sequence of at least about 90% sequence identity to SEQ ID NO: 58. In some embodiments, the CD38-ADR comprises an amino acid sequence of at least about 95% sequence identity to SEQ ID NO: 58. In some embodiments, the CD38-ADR comprises the amino acid sequence of SEQ ID NO: 58.SEQ ID NO: 58 MDFQVQJFSFFFJSASVJMSRDIQMTQSPSSLSASVGDRVTITCRASQGIRSWLAWYQQKPEKAPKSLIYAASSLQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNNYPLTFGGGTKVEIKGGGGSGGGGSGGGGSQVQLVQSGAEV KKPGSSVKVSCKPSGGTFRSYAISWVRQAPGQGLEWMGRIIVFLGKVNYAQRFQGRVTLTADKSTTTAYMELSSLRS EDTAVYYCTGEPGARDPDAFDIWGQGTMVTVSSTSTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFAC DIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADA PAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHD GLYQGLSTATKDTYDALHMQALPPRSignal peptide-antiCD38VH-2inker-antiCD38VL-CD8 (TM) -41BB (endo) -CD3z (endo) (the signal peptide, linker, and TM / transmembrane domain may vary)[000213] Accordingly, in some embodiments, the present application provides a solid tumor targeting backbone comprising a polynucleotide encoding an ADR specific to 4-1BB or CD38, among other components of the backbone, to equip an allogeneic effector cell with the ability to selectively deplete activated host immune cells while potentiating the effector cell through increased expansion in a tumor environment. Also provided in this application are immune cells, iPSCs, and iPSC-derived effector cells comprising a solid tumor targeting backbone comprising a polynucleotide encoding a 4-1BB specific ADR or a CD38 specific ADR, among other selected components, wherein the effector cells, including the genetically engineered T and NK cells, possess alloreactive resistance to the host immune system associated with the allogeneic use of the effector cells for treatment of tumors and infectious diseases in a patient.e. Exogenously introduced cytokine signaling complex[000214] By avoiding systemic high-dose administration of clinically relevant cytokines, the risk of dose-limiting toxicities due to such a practice is reduced while cytokine-mediated cellautonomy is being established. To achieve lymphocyte autonomy without the need to additionally administer soluble cytokines, a cytokine signaling complex comprising a partial or full length peptide of one or more of IL2, IL4, IL6, IL7, IL9, IL10, IL11, IL12, IL15, IL18, IL21, and / or their respective receptors may be introduced to the cell as part of the solid tumor targeting backbone to enable cytokine signaling with or without the expression of the cytokine itself, thereby maintaining or improving cell growth, proliferation, expansion, and / or effector function with reduced risk of cytokine toxicities. In some embodiments, the introduced cytokine and / or its respective native or modified receptor for cytokine signaling (signaling complex) are expressed on the cell surface. In some embodiments, the cytokine signaling is constitutively activated. In some embodiments, the activation of the cytokine signaling is inducible. In some embodiments, the activation of the cytokine signaling is transient and / or temporal. In some embodiments, the transient / temporal expression of a cell surface cytokine / cytokine receptor is through an expression construct carried by a retrovirus, Sendai virus, an adenovirus, an episome, mini-circle, or RNAs including mRNA.[000215] Various construct designs for introducing a protein complex for signaling of one, two, or more cytokines including, but not limited to, IL2, IL4, IL6, IL7, IL9, IL 10, IL 11, IL 12, IL15, IL18 and IL21, into the cell are provided herein. For example, in embodiments where the signaling complex is for IL15, the transmembrane (TM) domain can be native to the IL15 receptor or may be modified or replaced with the transmembrane domain of any other membrane bound proteins. In various embodiments, the cytokine signaling complex comprises an IL 15 receptor fusion (IL15RF) comprising a full or partial length of IL15 and a full or partial length of IL15 receptor (IL15R). In some embodiments, IL15 and IL15Ra are co-expressed by using a self-cleaving peptide, mimicking trans-presentation of IL15, without eliminating cis-presentation of IL15. In other embodiments, IL15Ra is fused to IL15 at the C-terminus through a linker, mimicking trans-presentation without eliminating cis-presentation of IL15 as well as ensuring that IL15 is membrane-bound. In other embodiments, IL15Ra with truncated intracellular domain is fused to IL 15 at the C-terminus through a linker, mimicking trans-presentation of IL15, maintaining IL15 membrane-bound, and additionally eliminating cis-presentation and / or any other potential signal transduction pathways mediated by a normal IL15R through its intracellular domain. In other embodiments, IL15Ra is fused to IL15 without an intracellular domain (IL15A), as described in International Pub. Nos. WO 2019 / 191495 and WO 2019 / 126748, the entire disclosure of each of which is incorporated herein by reference.[000216] In other various embodiments, the cytokine signaling complex comprises an IL7 receptor fusion (IL7RF) comprising a full or partial length of IL7 and a full or partial length of IL7 receptor. The transmembrane (TM) domain can be native to the IL7 receptor or may bemodified or replaced with a transmembrane domain of any other membrane bound proteins. In one embodiment, a native (or wildtype) or modified IL7R may be fused to IL7 at the C-terminus through a linker, enabling constitutive signaling and maintaining membrane-bound IL7. In some embodiments, such a construct comprises an amino acid sequence of at least 75%, 80%, 85%, 90%, 95% or 99% identity to SEQ ID NO: 59, with transmembrane domain, signal peptide and linker being flexible and varying in length and / or sequences. In some embodiments, the IL7 construct comprises an amino acid sequence of at least 90% identity to SEQ ID NO: 59, with transmembrane domain, signal peptide and linker being flexible and varying in length and / or sequences. In some embodiments, the IL7 construct comprises an amino acid sequence of at least 95% identity to SEQ ID NO: 59, with transmembrane domain, signal peptide and linker being flexible and varying in length and / or sequences. In some embodiments, the IL7 construct comprises the amino acid sequence of SEQ ID NO: 59.SEQ ID NO: 59MDWTWILFL VAAA TRVHSDCD I E GKDGKQYE SVLMVS I DQLLD SMKE I GSNCLNNE FNFFKRH I CDANKE GMFLFRAARKLRQFLKMNS TGD FDLHLLKVSE GT T I LLNC TGQVKGRKPAALGE AQPT KSLEENKSLKEOKKLNDLCFLKRLLOEIKTCWNKILMGTKEHSGGGSGGGGSGGGGSGGGGSGG^LQESGYAQNGDLEDAELDDYSFSCYSQLEVNGSQHSLTCAFEDPDVNITNLEFEICGALVEV KCLNFRKLQEIYFIETKKFLLIGKSNICVKVGEKSLTCKKIDLTTIVKPEAPFDLSWYREGAN DFWTFNTSHLQKKYVKVLMHDVAYRQEKDENKWTHVNLSSTKLTLLQRKLQPAAMYEIKVRSI PDH Y FKG FWSEWSPSYYFRTPEINNSS GEMDPILLTISILSFFSVALLVILACVLWKKR I KP I V WPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFPQQLEESE KQRLGGDVQSPNCPSEDWITPESFGRDSSLTCLAGNVSACDAPILSSSRSLDCRESGKNGPHV YQDLLLSLGTTNSTLPPPFSLQSGILTLNPVAQGQPILTSLGSNQEEAYVTMSSFYQNQ(Signal peptide-H l -linker-IL7R: transmembrane domain (TM), signal peptide and linker can vary in length and sequences)[000217] In another embodiment, a native or modified common receptor yC is fused to IL7 at the C-terminus through a linker for constitutive and membrane-bound cytokine signaling complex. In addition, engineered IL7R that forms a homodimer in the absence of IL7 is useful for producing constitutive signaling of the cytokine as well.[000218] In yet another embodiment, cytokine signaling is provided by exogenous and soluble IL2 or IL18. IL-2 is a cytokine that promotes proliferation and differentiation of T cells, while IL- 18 enhances T cell effector function. In the context of iPSC derived T cells, temporal and dose control of the exogenous cytokine can have important implications for the lymphoid lineage and T cell lineage commitment during the iPSC differentiation process. In some embodiments, the soluble cytokine expression is under the control of an endogenous TRAC -n-promoter. In some embodiments, the soluble cytokine expression is under the control of an endogenous Tim-3 promoter. In some embodiments, the cell comprises a polynucleotide encoding a soluble IL2 (sIL2), such as a polypeptide having the sequence of SEQ ID NO: 60. In some embodiments, the cell comprises a polynucleotide encoding a soluble IL 18 (sIL18), such as a polypeptide having the sequence of SEQ ID NO: 61.SEQ ID NO: 60 MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA TELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR WITFCQSI ISTLT(sIL2)SEQ ID NO: 61 MAAEPVEDNCINFVAMKFIDNTLYFIAEDDENLESDYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMT DSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQR SVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED(sIL18)[000219] One having ordinary skill in the art would appreciate that the signal peptide and the linker sequences above are illustrative and in no way limit their variations suitable for use as a signal peptide or linker. There are many suitable signal peptide or linker sequences known and available to those in the art. The ordinary skilled in the art understands that the signal peptide and / or linker sequences may be substituted for another sequence without altering the activity of the functional peptide led by the signal peptide or linked by the linker.[000220] As such, in various embodiments, the cytokines and / or receptors thereof, may be introduced to iPSCs using one or more of the construct designs described herein, and to their derivative cells upon iPSC differentiation. Also provided is a master cell bank comprising single cell sorted and expanded clonal engineered iPSCs having a solid tumor targeting backbone as disclosed herein, wherein the cell bank provides a platform for additional iPSC engineering and a renewable source for manufacturing off-the-shelf, engineered, homogeneous cell therapy products, which are well-defined and uniform in composition, and can be mass produced at a significant scale in a cost-effective manner.f TCE[000221] According to some embodiments, the T Cell Enhancer (TCE) as a T cell potentiator as disclosed herein is aimed at enhancing the antitumor activity and persistence of iPSC-derived CAR-T cells. TCE edits according to some embodiments have the ability to activate one or moreof cytokine signaling (e.g., soluble cytokines, or cytokine-receptor fusion constructs), costimulatory signals (e.g., over-expression of costimulatory receptors or other important signal transduction proteins), or gene expression profiles (e.g., over-expression of transcription factors). In the context of iPSC derived T cells according to some embodiments, the TCE edits are compatible with T cell differentiation process. As disclosed herein, TCF1 and CD27, among other candidates are suitable TCEs for potentiating iPSC derived T cells. In some embodiments, the TCF1 has a sequence of SEQ ID NO: 62. In some embodiments, the CD27 has a sequence of SEQ ID NO: 63.SEQ ID NO: 62 MPQLDSGGGGAGGGDDLGAPDELLAFQDEGEEQDDKSRDSAAGPERDLAELKSSLVNESEGAAGGAGIPG VPGAGAGARGEAEALGREHAAQRLFPDKLPEPLEDGLKAPECTSGMYKETVYSAFNLLMHYPPPSGAGQH PQPQPPLHKANQPPHGVPQLSLYEHFNSPHPTPAPADISQKQVHRPLQTPDLSGFYSLTSGSMGQLPHTV SWFTHPSLMLGSGVPGHPAAIPHPAIVPPSGKQELQPFDRNLKTQAESKAEKEAKKPTIKKPLNAFMLYM KEMRAKVIAECTLKESAAINQILGRRWHALSREEQAKYYELARKERQLHMQLYPGWSARDNYGKKKRRSR EKHQESTTGGKRNAFGTYPEKAAAPAPFLPMTVL(TCF1 )SEQ ID NO: 63 MARPHPWWLCVLGTLVGLSATPAPKSCPERHYWAQGKLCCQMCEPGTFLVKDCDQHRKAAQCDPCIPGVS FSPDHHTRPHCESCRHCNSGLLVRNCTITANAECACRNGWQCRDKECTECDPLPNPSLTARSSQALSPHP QPTHLPYVSEMLEARTAGHMQTLADFRQLPARTLSTHWPPQRSLCSSDFIRILVIFSGMFLVFTLAGALF LHQRRKYRSNKGESPVEPAEPCHYSCPREEEGSTIPIQEDYRKPEPACSP(CD27 )[000222] In some embodiments, the TCE is provide by a polynucleotide encoding the TCE. In some embodiments, the polynucleotide encoding a TCE as disclosed is operatively linked to an exogenous promoter. The promoters may be inducible, or constitutive, and may be temporal-, tissue- or cell type- specific. Suitable constitutive promoters for methods disclosed herein include, but are not limited to, cytomegalovirus (CMV), elongation factor la (EFla), phosphoglycerate kinase (PGK), hybrid CMV enhancer / chicken P-actin (CAG) and ubiquitin C (UBC) promoters. In one embodiment, the exogenous promoter is CAG.[000223]g. CD38 knockout[000224] The cell surface molecule CD38 is highly upregulated in multiple hematologic malignancies derived from both lymphoid and myeloid lineages, including multiple myeloma and a CD20 negative B-cell malignancy, which makes it an attractive target for antibody therapeutics to deplete cancer cells. Antibody mediated cancer cell depletion is usually attributable to a combination of direct cell apoptosis induction and activation of immune effectormechanisms such as ADCC (antibody-dependent cell-mediated cytotoxicity). In addition to ADCC, the immune effector mechanisms in concert with the therapeutic antibody may also include antibody-dependent cell-mediated phagocytosis (ADCP) and / or complement-dependent cytotoxicity (CDC).[000225] Other than being highly expressed on malignant cells, CD38 is also expressed on plasma cells, as well as on NK cells and activated T and B cells. During hematopoiesis, CD38 is expressed on CD34+stem cells and lineage-committed progenitors of lymphoid, erythroid, and myeloid, and during the final stages of maturation which continues through the plasma cell stage. As a type II transmembrane glycoprotein, CD38 carries out cell functions as both a receptor and a multifunctional enzyme involved in the production of nucleotide-metabolites. As an enzyme, CD38 catalyzes the synthesis and hydrolysis of the reaction from NAD+to ADP-ribose, thereby producing secondary messengers CADPR and NAADP which stimulate release of calcium from the endoplasmic reticulum and lysosomes, critical for the calcium dependent process of cell adhesion. As a receptor, CD38 recognizes CD31 and regulates cytokine release and cytotoxicity in activated NK cells. CD38 is also reported to associate with cell surface proteins in lipid rafts, to regulate cytoplasmic Ca2+flux, and to mediate signal transduction in lymphoid and myeloid cells.[000226] In malignancy treatment, systemic use of CD38 antigen binding receptor transduced T cells has been shown to lyse the CD38+fractions of CD34+hematopoietic progenitor cells, monocytes, NK cells, T cells and B cells, leading to incomplete treatment responses and reduced or eliminated efficacy because of the impaired recipient immune effector cell function. In addition, in multiple myeloma patients treated with daratumumab, a CD38-specific antibody, NK cell reduction in both bone marrow and peripheral blood was observed, although other immune cell types, such as T cells and B cells, were unaffected despite their CD38 expression (Casneuf et al., Blood Advances. 2017; l(23):2105-2114).[000227] Without being limited by theories, the present application includes a strategy to leverage the full potential of CD38 targeted cancer treatment by knocking out CD38 in the effector cell, thereby overcoming CD38-specific antibody and / or CD38 antigen binding domain-induced effector cell depletion or reduction through fratricide. In addition, since CD38 is upregulated on activated lymphocytes such as T or B cells, by suppressing activation of these recipient lymphocytes using a CD38-specific antibody, such as daratumumab, in the recipient of allogeneic effector cells, host allorej ection against these effector cells would be reduced and / or prevented, thereby increasing effector cell survival and persistency. As such, a CD38-specific antibody, a secreted CD38-specific engager or a CD38-CAR (chimeric antigen receptor) against activation of recipient T, Treg, NK, and / or B cells can be used as a replacement forlymphodepletion using chemotherapy such as Cy / Flu (cyclophosphamide / fludarabine) prior to adoptive cell transferring.[000228] In addition, when targeting CD38+T and pbNK cells using CD38' effector cells in the presence of anti-CD38 antibodies or CD38 inhibitors, the depletion of CD38+alloreactive cells increases the NAD+(nicotinamide adenine dinucleotide, a substrate of CD38) availability and decreases NAD+consumption related cell death, which, among other advantages, boosts effector cell responses in an immunosuppressive tumor microenvironment and supports cell rejuvenation in aging, degenerative or inflammatory diseases.[000229] According to some embodiments, CD38 knockout is compatible with other components and processes contemplated for establishing a solid tumor targeting backbone as disclosed in this application, thereby providing an immune cell, an iPSC and differentiated effector cell therefrom comprising a CD38 knockout with additional backbone edits. As disclosed herein, in various embodiments, the solid tumor targeting backbone comprised in the iPSC line or a derivative thereof, comprises an TCR promoter-driven ADR and / or a cytokine, and a constitutively expressed TCE, in addition to edits comprising a CAR, a TGFP-SRR, a C-X-C-motif chemokine receptor or a variant thereof, a CD 16 variant, and a CD38 knockout, among other edits as provided herein. In some embodiments, the provided CD38negiPSC line optionally comprises one or more additional engineered modalities described herein. As such, these CD38negderivative effector cells comprising a solid tumor targeting backbone are protected against fratricide and allorej ection when CD38 targeted therapeutic moi eties are employed with the effector cells, among other advantages including improved metabolic fitness, increased resistance to oxidative stress and inducing a protein expression program in the effector cell that enhances cell activation and effector function. In addition, anti-CD38 monoclonal antibody therapy significantly depletes a patient’s activated immune system without adversely affecting the patient’s hematopoietic stem cell compartment. ACD38negderivative cell has the ability to resist CD38 antibody mediated depletion, and may be effectively administered in combination with an anti-CD38 antibody or CD38-CAR without the use of toxic conditioning agents, thereby reducing and / or replacing chemotherapy-based lymphodepletion.[000230] In one embodiment as provided herein, the CD38 knockout in an iPSC line is a bi-allelic knockout. In another embodiment, knocking out CD38 at the same time as inserting one or more transgenes, including a C-X-C-motif chemokine receptor or a variant thereof, a TGFP-SRR, and / or a CD 16 variant as provided herein, at a selected position in CD38 can be achieved, for example, by a CD38-targeted knock-in / knockout (CD38-KI / KO) construct. In some embodiments of the construct, the construct comprises a pair of CD38 targeting homology arms for position-selective insertion within the CD38 locus. In some embodiments, the preselectedtargeting site is within an exon of CD38. The CD38-KI / KO constructs provided herein allow the transgene(s) to express either under the CD38 endogenous promoter or under an exogenous promoter comprised in the construct. When two or more transgenes are to be inserted at a selected location in the CD38 locus, a linker sequence, for example, a 2A linker or IRES, is placed between any two transgenes. The 2A linker encodes a self-cleaving peptide derived from FMDV, ERAV, PTV-I, and TaV (referred to as “F2A”, “E2A”, “P2A”, and “T2A”, respectively), allowing for separate proteins to be produced from a single translation. In some embodiments, insulators are included in the construct to reduce the risk of transgene and / or exogenous promoter silencing. The exogenous promoter comprised in a CD38-KI / KO construct may be CAG, or other constitutive, inducible, temporal-, tissue-, or cell type- specific promoters including, but not limited to CMV, EFla, PGK, and UBC.[000231] In various embodiments, said iPSC is capable of directed differentiation to produce functional derivative hematopoietic cells including, but not limited to, mesodermal cells with definitive hemogenic endothelium (HE) potential, definitive HE, CD34+hematopoietic cells, hematopoietic stem and progenitor cells, hematopoietic multipotent progenitors (MPP), T cell progenitors, NK cell progenitors, myeloid cells, neutrophil progenitors, T cells, NKT cells, NK cells, B cells, neutrophils, dendritic cells, and macrophages. In some embodiments, the CD38 negative effector cells are NK lineage cells derived from iPSCs. In some embodiments, the CD38 negative effector cells are T lineage cells derived from iPSCs. In some embodiments, the iPSC and derivative cells thereof comprise a solid tumor targeting backbone comprising CD38negand at least two of: a polynucleotide encoding a C-X-C motif chemokine receptor or a variant thereof, a polynucleotide encoding a TGFP-SRR, and a polynucleotide encoding a CD 16 variant, and optionally include one or more additional genomic edits as described herein.h. Stealth related edits[000232] Multiple HLA class I and class II proteins must be matched for histocompatibility in allogeneic recipients to avoid allogeneic rejection problems. Provided herein is an iPSC cell line and its derivative cells differentiated therefrom with eliminated or substantially reduced expression of HLA class I and / or HLA class II proteins. HLA class I deficiency can be achieved by functional deletion of any region of the HLA class I locus (chromosome 6p21), or deletion or disruption of HLA class-I associated genes including, but not limited to, beta-2 microglobulin (B2M) gene, TAPI gene, TAP2 gene and Tapasin. For example, the B2M gene encodes a common subunit essential for cell surface expression of all HLA class I heterodimers. B2M negative cells are HLA-I deficient. HLA class II deficiency can be achieved by functional deletion or disruption of HLA class II associated genes including, but not limited to, RFXANK,CIITA, RFX5 and RFXAP. CIITA is a transcriptional coactivator, functioning through activation of the transcription factor RFX5 required for class II protein expression. CIITA negative cells are HLA-II deficient. As such, this application provides an iPSC and derivative cells therefrom comprising HLA-I and / or HLA-II deficiency, for example by lacking B2M and / or CIITA expression, wherein the obtained derivative effector cells enable allogeneic cell therapies by eliminating the need for MHC (major histocompatibility complex) matching, and avoiding recognition and killing by host (allogeneic) T cells.[000233] Furthermore, a lack of HLA class I expression leads to lysis by host NK cells. Therefore, in addition to the above-discussed approach of CD38 conditioning to remove activated CD38-expressing host NK cells, to overcome this “missing self’ response, HLA-E, HLA-G or other non-classical HLA-I proteins may be optionally knocked in to avoid NK cell recognition and killing of the HLA-I deficient effector cells derived from an engineered iPSC. In one embodiment, the provided HLA-I deficient iPSC and its derivative cells further comprise HLA-G knock-in.[000234] Alternatively, in one embodiment, the provided HLA-I deficient iPSC and its derivative cells further comprise one or both of CD58 knockout and CD54 knockout. CD58 (or LFA-3) and CD54 (or ICAM-1) are adhesion proteins initiating signal-dependent cell interactions, and facilitating cell, including immune cell, migration. It was previously shown that CD58 and / or CD54 disruption effectively reduces the susceptibility of HLA-I deficient iPSC-derived effector cells to allogeneic NK cell killing. While it was shown that CD58 knockout has a higher efficiency in reducing allogeneic NK cell activation than CD54 knockout, double knockout of both CD58 and CD54 was shown to provide the most enhanced reduction of NK cell activation. In some observations, the CD58 and CD54 double knockout is even more effective than HLA-G overexpression for HLA-I deficient cells in overcoming “missing-self’ effect.[000235] As provided herein, in some embodiments, the iPSC and its derivative cells comprising a solid tumor targeting backbone comprising two or more of: a C-X-C-motif chemokine receptor or a variant thereof, a TGFP-SRR, and a CD 16 variant. In some embodiments, said iPSC and its derivative cells are CD58 negative. In some embodiments, said iPSC and its derivative cells are CD54 negative. In yet some other embodiments, said iPSC and its derivative cells are CD 54 negative and CD 58 negative.[000236] In some embodiments, the engineering for HLA-I and / or HLA-II deficiency may be bypassed, or kept intact, by expressing an inactivation CAR targeting an upregulated surface protein in activated recipient immune cells to avoid allorej ection. In some embodiments, the upregulated surface protein in the activated recipient immune cells includes, but is not limited to,CD38, CD25, CD69, CD44, 4-1BB, 0X40, or CD40L. When the cell expresses such an inactivation CAR, it is preferable that the cell does not express, or has knockout of, the same surface protein targeted by CAR. In some embodiments, the inactivation CAR comprises at least one of a CD38-CAR, a CD25-CAR, a CD69-CAR, a CD44-CAR, a 4-1BB-CAR, an 0X40-CAR, and a CD40L-CAR.[000237] Additionally provided in this application is a master cell bank comprising single cell sorted and expanded clonal engineered iPSCs having at least one phenotype as provided herein, including but not limited to, a solid tumor targeting backbone as described herein and HLA modification, wherein the cell bank provides a platform for additional iPSC engineering and a renewable source for manufacturing off-the-shelf, engineered, homogeneous cell therapy products, including but not limited to derivative NK and T cells, which are well-defined and uniform in composition, and can be mass produced at significant scale in a cost-effective manner.2. Genetically engineered iPSC line and derivative cells provided herein[000238] In light of the above, the present application provides an immune cell, an iPSC, an iPS cell line cell, or a population thereof, and a derivative functional cell obtained from differentiating the iPSC, wherein each cell comprises CAR and AvER, and optionally an TCR promoter-driven ADR, and / or a cytokine, TCE, a TGFP-SRR, a C-X-C-motif chemokine receptor or a variant thereof, a CD 16 variant, a CD38 knockout, a cytokine signaling complex, among other modifications which are all described in detail in, for example, PCT7US2024 / 040194 which is incorporated herein as a reference. Illustrative examples of such modalities are also described above. The cell expressing both CAR and AvER is an eukaryotic cell, an animal cell, a human cell, an induced pluripotent cell (iPSC), an iPSC-derived effector cell, an immune cell, or a feeder cell. In some embodiments, said cells are suitable for homing or migration of the effectors to tumor sites for CAR targeted tumor killing. In some embodiments, the functional derivative cells are hematopoietic cells including, but not limited to, mesodermal cells with definitive hemogenic endothelium (HE) potential, definitive HE, CD34+hematopoietic cells, hematopoietic stem and progenitor cells, hematopoietic multipotent progenitors (MPP), T cell progenitors, NK cell progenitors, myeloid cells, neutrophil progenitors, T lineage cells, NKT lineage cells, NK lineage cells, B lineage cells, neutrophils, dendritic cells, and macrophages. In some embodiments, the functional derivative hematopoietic cells comprise effector cells having one or more functional features that are not present in a counterpart primary T, NK, NKT, and / or B cell.3. Engagers[000239] In some embodiments, the genetically modified modalities further comprise one or more of safety switch proteins, targeting modalities, receptors, signaling molecules, transcription factors, pharmaceutically active proteins and peptides, drug target candidates; or proteins promoting engraftment, trafficking, homing, viability, self-renewal, persistence, immune response regulation and modulation, and / or survival of the iPSCs or derivative cells thereof. In some embodiments, the iPSC and its derivative effector cells may additionally comprise disruption of at least one of TAPI, TAP2, Tapasin, NLRC5, PD1, LAG3, TIM3, RFXANK, RFX5, RFXAP, and any gene in the chromosome 6p21 region; or introduction of at least one of HLA-E, 4-1BBL, CD3, CD4, CD8, CD47, CD113, CD131, CD137, CD80, PDL1, A2AR, antigen-specific TCR, an Fc receptor, an engager, and a surface triggering receptor for coupling with bi-, multi- specific or universal engagers.[000240] Engagers are fusion proteins consisting of two or more single-chain variable fragments (scFvs) of different antibodies, with at least one scFv that binds to an effector cell surface molecule or surface triggering receptor, and at least another to a target cell via a target cell specific surface molecule. Examples of engagers include, but are not limited to, bi-specific T cell engagers (BiTEs), bi-specific killer cell engagers (BiKEs), tri-specific killer cell engagers (TriKEs), multi-specific killer cell engagers, or universal engagers compatible with multiple immune cell types. Thus, engagers can be bi-specific or multi-specific. Such bi-specific or multi-specific engagers are capable of directing an effector cell (e.g., a T cell, a NK cell, an NKT cell, a B cell, a macrophage, and / or a neutrophil) to a tumor cell and activating the immune effector cell, and have shown great potential to maximize the benefits of CAR-T cell therapy.[000241] In some embodiments, the engager is used in combination with a population of the effector cells comprising a solid tumor targeting backbone as described herein by concurrent or consecutive administration, wherein the effector cells comprise a surface molecule, or surface triggering receptor, that is recognized by the engager. In some other embodiments, the engager is a bi-specific antibody expressed by a derivative effector cell through genetically engineering an iPSC comprising a solid tumor targeting backbone as described herein, and directed differentiation of the engineered iPSC. Exemplary effector cell surface molecules, or surface triggering receptors, that can be used for bi- or multi- specific engager recognition, or coupling, include, but are not limited to, CD3, CD28, CD5, CD16, NKG2D, CD64, CD32, CD89, NKG2C, and a chimeric Fc receptor as disclosed herein. As described herein, in some embodiments, the exogenous CD 16 expressed on the surface of the derivative effector cells for engager recognition is a hnCD16, comprising a CD 16 (containing Fl 76V and optionally S197P) or CD64 extracellular domain, and native or non-native transmembrane, stimulatory and / or signaling domains as described herein. In some embodiments, the exogenous CD 16 expressedon the surface of effector cells for engager recognition is a CD16-based chimeric Fc receptor (CFcR). In some embodiments, the CD16-based CFcR comprises a transmembrane domain of NKG2D, a stimulatory domain of 2B4, and a signaling domain of CD3ζ; wherein the extracellular domain of the exogenous CD 16 is derived from a full length or partial sequence of the extracellular domain of CD64 or CD 16; and wherein the extracellular domain of CD 16 comprises Fl 76V and optionally S197P[000242] In some embodiments, the target cell for an engager is a tumor cell. Exemplary tumor cell surface molecules for bi- or multi- specific engager recognition include, but are not limited to, B7H3, BCMA, CD10, CD19, CD20, CD22, CD24, CD30, CD33, CD34, CD38, CD44, CD79a, CD79b, CD 123, CD 138, CD 179b, CEA, CLEC12A, CS-1, DLL3, EGFR, EGFRvIII, EPCAM, FLT-3, FOLR1, FOLR3, GD2, gpA33, HER2, HM1.24, LGR5, MSLN, MCSP, MICA / B, PSMA, PAMA, P-cadherin, and ROR1. In one embodiment, the bi-specific engager is a bi-specific antibody specific to CD3 and CD19 (CD3-CD19). In another embodiment, the bi-specific antibody is CD16-CD30 or CD64-CD30. In another embodiment, the bi-specific antibody is CD16-BCMA or CD64-BCMA. In still another embodiment, the bi-specific antibody is CD3-CD33.[000243] In yet another embodiment, the bi-specific antibody further comprises a linker between the effector cell and tumor cell antigen binding domains. For example, a modified IL 15 may be used as a linker for effector NK cells to facilitate effector cell expansion (called TriKE, or Tri-specific Killer Engager, in some publications). In one embodiment, the TriKE is CD16-IL15-EPCAM or CD64-IL 15 -EPCAM. In another embodiment, the TriKE is CD16-IL15-CD33 or CD64-IL15-CD33. In yet another embodiment, the TriKE is NKG2C-IL15-CD33 (“2C1533”). In additition to IL15, cytokines suitable for inclusion in the TriKE include, but are not limited to, IL2, IL4, IL6, IL7, IL9, IL 10, IL 11, IL 12, IL 18, and IL21.[000244] In some embodiments, the surface triggering receptor for bi- or multi- specific engagers could be endogenous to the effector cells, sometimes depending on the cell types. In some other embodiments, one or more exogenous surface triggering receptors could be introduced to the effector cells using the methods and compositions provided herein,, then directing the differentiation of the iPSC to T, NK or any other effector cells comprising the same genotype and the surface triggering receptor as the source iPSC.4. Antibodies for immunotherapy[000245] In some embodiments, in addition to the genomically engineered effector cells comprising a solid tumor targeting backbone as provided herein, additional therapeutic agents comprising an antibody, or an antibody fragment that targets an antigen associated with acondition, a disease, or an indication may be used with these effector cells in a combinational therapy. In some embodiments, the antibody is used in combination with a population of the effector cells comprising a solid tumor targeting backbone as described herein by concurrent or consecutive administration to a subject. In other embodiments, such antibody or a fragment thereof may be expressed by the effector cells by genetically engineering an iPSC using an exogenous polynucleotide sequence encoding said antibody or fragment thereof, and directing differentiation of the engineered iPSC. In some embodiments, the effector cell expresses an exogenous CD 16 variant, wherein the cytotoxicity of the effector cell is enhanced by the antibody via ADCC.[000246] In some embodiments, the therapeutic antibody is a monoclonal antibody. In some embodiments, the therapeutic antibody is a humanized antibody, a humanized monoclonal antibody, or a chimeric antibody. In some embodiments, the therapeutic antibody, or antibody fragment, specifically binds to a viral antigen. In other embodiments, the antibody, or antibody fragment, specifically binds to a tumor antigen. In some embodiments, the tumor- or viral-specific antigen activates the administered iPSC-derived effector cells to enhance their killing ability. In some embodiments, the therapeutic antibodies suitable for combinational treatment as an additional therapeutic agent to the administered iPSC-derived effector cells include, but are not limited to, anti-CD20 antibodies (rituximab, veltuzumab, ofatumumab, ublituximab, ocaratuzumab, obinutuzumab), anti-HER2 antibodies (trastuzumab, pertuzumab), anti-CD52 antibodies (alemtuzumab), anti-EGFR antibodies (cetuximab), anti-GD2 antibodies (dinutuximab), anti-PDLl antibodies (avelumab), anti-CD38 antibodies (daratumumab, isatuximab, MOR202), anti-CD123 antibodies (7G3, CSL362), anti-SLAMF7 antibodies (elotuzumab), anti-MICA / B antibodies (7C6, 6F11, 1C2) and their humanized or Fc modified variants or fragments or their functional equivalents and biosimilars. In some embodiments, the antibodies suitable for combinational treatment as an additional therapeutic agent to the administered iPSC-derived effector cells further include bi-specific or multi-specific antibodies that target more than one antigen or epitope on a target cell or recruit effector cells (e.g., T cells, NK cells, or macrophage cells) toward target cells while targeting the target cells. Such bi-specific or multi-specific antibodies function as engagers capable of directing an effector cell (e.g., a T cell, a NK cell, an NKT cell, a B cell, a macrophage, and / or a neutrophil) to a tumor cell and activating the immune effector cell, and have shown great potential to maximize the benefits of antibody therapy.5. Checkpoint inhibitors[000247] Checkpoints are cell molecules, often cell surface molecules, capable of suppressing or downregulating immune responses when not inhibited. It is now clear that tumors co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumor antigens. Checkpoint inhibitors (Cis) are antagonists capable of reducing checkpoint gene expression or gene products, or deceasing activity of checkpoint molecules, thereby blocking inhibitory checkpoints, and restoring immune system function. The development of checkpoint inhibitors targeting PD1 / PDL1 or CTLA4 has transformed the oncology landscape, with these agents providing long term remissions in multiple indications. However, many tumor subtypes are resistant to checkpoint blockade therapy, and relapse remains a significant concern. Thus, one aspect of the present application provides a therapeutic approach to overcome CI resistance by including genomically-engineered functional iPSC-derived cells as provided herein in a combination therapy with CI.[000248] In some embodiments of the combination therapy, the checkpoint inhibitor is used in combination with a population of the effector cells comprising a solid tumor targeting backbone as described herein by concurrent or consecutive administration thereof to a subject. In some other embodiments, the checkpoint inhibitor is expressed by the effector cells by genetically engineering an iPSC using an exogenous polynucleotide sequence encoding said checkpoint inhibitor, or a fragment or variant thereof, and directing differentiation of the engineered iPSC. Some embodiments of the combination therapy with the effector cells comprising a solid tumor targeting backbone as described herein, comprise at least one checkpoint inhibitor to target at least one checkpoint molecule.[000249] In one embodiment, the iPSC-derived effector cell for checkpoint inhibitor combination therapy comprises knock-out of CD54, CD58, TIM3, TIGIT. In some embodiment, said derivative effector cell may additionally comprise deletion, disruption, or reduced expression of at least one of B2M, TAPI, TAP2, Tapasin, NLRC5, PD1, LAG3, TIM3, RFXANK, RFX5, RFXAP, RAG1, and any gene in the chromosome 6p21 region; or introduction of at least one of HLA-E, 4-1BBL, CD3, CD4, CD8, CD47, CD113, CD131, CD 137, CD80, PDL1, A? AR, CAR, Fc receptor, and surface triggering receptor for coupling with bi-, multi- specific or universal engagers.[000250] Suitable checkpoint inhibitors for combination therapy with the derivative NK or T cells as provided herein include, but are not limited to, antagonists of PD1 (Pdcdl, CD279), PDL-1 (CD274), TIM3 (Havcr2), TIGIT (WUCAM and Vstm3), LAG3 (CD223), CTLA4 (CD 152), 2B4 (CD244), 4-1BB (CD137), 4-1BBL (CD137L), A2AR, BATE, BTLA, CD39 (Entpdl), CD47, CD73 (NT5E), CD94, CD96, CD160, CD200, CD200R, CD274, CEACAM1, CSF-1R, Foxpl, GARP, HVEM, IDO, EDO, TDO, LAIR-1, MICA / B, NR4A2, MAFB, OCT-2 (Pou2f2), retinoicacid receptor alpha (Rara), TLR3, VISTA, NKG2A / HLA-E, and inhibitory KIR (for example, 2DL1, 2DL2, 2DL3, 3DL1, and 3DL2).[000251] In some embodiments, the antagonist inhibiting any of the above checkpoint molecules is an antibody. In some embodiments, the checkpoint inhibitory antibodies may be murine antibodies, human antibodies, humanized antibodies, a camel Ig, a single variable new antigen receptor (VNAR), a shark heavy-chain-only antibody (Ig NAR), chimeric antibodies, recombinant antibodies, or antibody fragments thereof. Non-limiting examples of antibody fragments include Fab, Fab', F(ab')2, F(ab')3, Fv, single chain antigen binding fragments (scFv), (scFv)2, disulfide stabilized Fv (dsFv), minibody, diabody, triabody, tetrabody, single-domain antigen binding fragments (sdAb, Nanobody), recombinant heavy-chain-only antibody (VHH), and other antibody fragments that maintain the binding specificity of the whole antibody, which may be more cost-effective to produce, more easily used, or more sensitive than the whole antibody. In some embodiments, the one, or two, or three, or more checkpoint inhibitors comprise at least one of atezolizumab (anti-PDLl mAb), avelumab (anti-PDLl mAb), durvalumab (anti-PDLl mAb), tremelimumab (anti-CTLA4 mAb), ipilimumab (anti-CTLA4 mAb), IPH4102 (anti-KIR antibody), IPH43 (anti-MICA antibody), IPH33 (anti-TLR3 antibody), lirimumab (anti-KIR antibody), monalizumab (anti-NKG2A antibody), nivolumab (anti-PDl mAb), pembrolizumab (anti-PDl mAb), and any derivatives, functional equivalents, or biosimilars thereof.[000252] In some embodiments, the antagonist inhibiting any of the above checkpoint molecules is microRNA-based, as many miRNAs are found as regulators that control the expression of immune checkpoints (Dragomir et al., Cancer Biol Med. 2018, 15(2): 103- 115). In some embodiments, the checkpoint antagonistic miRNAs include, but are not limited to, miR-28, miR-15 / 16, miR-138, miR-342, miR-20b, miR-21, miR-130b, miR-34a, miR-197, miR-200c, miR-200, miR-17-5p, miR-570, miR-424, miR-155, miR-574-3p, miR-513, and miR-29c.II. Methods for Targeted Genome Editing at Selected Locus in iPSCs[000253] Genome editing, or genomic editing, or genetic editing, as used interchangeably herein, is a type of genetic engineering in which DNA is inserted, deleted, and / or replaced in the genome of a targeted cell. Targeted genome editing (interchangeable with “targeted genomic editing” or “targeted genetic editing”) enables insertion, deletion, and / or substitution at preselected sites in the genome. When an endogenous sequence is deleted at the insertion site during targeted editing, an endogenous gene comprising the affected sequence may be knocked-out or knocked-down due to the sequence deletion. Therefore, targeted editing may also be used todisrupt endogenous gene expression with precision. Similarly used herein is the term “targeted integration,” referring to a process involving insertion of one or more exogenous sequences, with or without deletion of an endogenous sequence at the insertion site. In comparison, randomly integrated genes are subject to position effects and silencing, making their expression unreliable and unpredictable. For example, centromeres and sub-telomeric regions are particularly prone to transgene silencing. Reciprocally, newly integrated genes may affect the surrounding endogenous genes and chromatin, potentially altering cell behavior or favoring cellular transformation. Therefore, inserting exogenous DNA in a pre-selected locus such as a safe harbor locus, or genomic safe harbor (GSH) is important for safety, efficiency, copy number control, and for reliable gene response control.[000254] Targeted editing can be achieved either through a nuclease-independent approach, or through a nuclease-dependent approach. In the nuclease-independent targeted editing approach, homologous recombination is guided by homologous sequences flanking an exogenous polynucleotide to be inserted, through the enzymatic machinery of the host cell.[000255] Alternatively, targeted editing could be achieved with higher frequency through specific introduction of double strand breaks (DSBs) by specific rare-cutting endonucleases. Such nuclease-dependent targeted editing utilizes DNA repair mechanisms including non-homologous end joining (NHEJ), which occurs in response to DSBs. Without a donor vector containing exogenous genetic material, the NHEJ often leads to random insertions or deletions (in / dels) of a small number of endogenous nucleotides. In comparison, when a donor vector containing exogenous genetic material flanked by a pair of homology arms is present, the exogenous genetic material can be introduced into the genome during homology directed repair (HDR) by homologous recombination, resulting in a “targeted integration.” In some situations, the targeted integration site is intended to be within a coding region of a selected gene, and thus the targeted integration could disrupt the gene expression, resulting in simultaneous knock-in and knock-out (KI / KO) in one single editing step.[000256] Inserting one or more transgenes can be achieved at a selected position such as a genomic safe harbor (GSH) locus or at a gene locus of interest (GOI), and may also thereby knock out the gene at the locus of insertion. In some embodiments, the knocking out is desirable at the same time of knocking-in the transgene.[000257] Genomic safe harbor (GSH), which are intragenic or extragenic regions of the human genome that, theoretically, are able to accommodate predictable expression of newly integrated DNA without adverse effects on the host cell or organism. A useful safe harbor locus must permit sufficient transgene expression to yield desired levels of the vector-encoded protein or non-coding RNA. A safe harbor also must not predispose cells to malignant transformationnor alter cellular functions. For an genomic site to be a potential safe harbor locus, it ideally needs to meet criteria including, but not limited to: absence of disruption of regulatory elements or genes, as judged by sequence annotation; is an intergenic region in a gene dense area, or a location at the convergence between two genes transcribed in opposite directions; keep distance to minimize the possibility of long-range interactions between vector-encoded transcriptional activators and the promoters of adjacent genes, particularly cancer-related and microRNA genes; and has apparently ubiquitous transcriptional activity, as reflected by broad spatial and temporal expressed sequence tag (EST) expression patterns, indicating ubiquitous transcriptional activity. This latter feature is especially important in stem cells, where during differentiation, chromatin remodeling typically leads to silencing of some loci and potential activation of others. Within the region suitable for exogenous insertion, a locus chosen for insertion should be devoid of repetitive elements and conserved sequences and to which primers for amplification of homology arms could easily be designed.[000258] As disclosed herein, suitable sites for human genome editing, or specifically, targeted integration, include, but are not limited to, PH12, the adeno-associated virus site 1 (AAVS1), the chemokine (CC motif) receptor 5 (CCA5) gene locus and the human orthologue of the mouse ROSA26 locus. Further, the human orthologue of the mouse Hll locus may also be a suitable site for insertion using the composition and method of targeted integration disclosed herein. Furthermore, collagen and HTRP gene loci may also be used as safe harbor for targeted integration. However, validation of each selected site is typically needed, especially in stem cells for specific integration events, and optimization of insertion strategy including promoter election, exogenous gene sequence and arrangement, and construct design is often needed as well.[000259] For targeted simultaneous knock-in and knock-out (targeted in / del, or KI / KO), the editing site is often comprised in an endogenous gene whose expression and / or function is intended to be disrupted. In some embodiments, the endogenous gene comprising a targeted in / del is associated with a specific development stage, a targeting modality, receptors, signaling molecules, transcription factors, drug target candidates, immune response regulation and modulation, or proteins suppressing engraftment, trafficking, homing, viability, self-renewal, persistence, and / or survival of cells, including stem cells and / or progenitor cells, and the derived cells therefrom.[000260] As such, in one embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more exogenous polynucleotides to the cell, and introducing a construct comprising a pair of homologous arms specific to a desired integration site and one or more exogenous sequence, to enable site specific homologous recombination bythe cell host enzymatic machinery, wherein the desired integration site comprises AAVS1, CCR5, ROSA26, collagen, HTRP, Hll, PH12, GAPDH, TCR or RUNX1, or other loci meeting the criteria of a genome safe harbor. Additional integration sites include an endogenous gene locus intended for disruption, such as reduction or knockout, which comprises B2M, TAPI, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR a or 0 constant region (TRAC or TRBC), NKG2A, NKG2D, CD38, CD25, CD69, CD71, CD44, CD54, CD56, CD58, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, or TIGIT. In some embodiments, the method of targeted integration in a cell comprises introducing multiple constructs to two or more distinctive desired integration sites comprising TRAC, CD38, CD54, CD56, CD58, TIM3, TIGIT, Hll, PH12 or combinations thereof. In some embodiments of the cell comprising three integration sites, the sites are TRAC, CD38, and one of CD54, CD56, CD58, TIM3, TIGIT, Hll, or PH12. In some embodiments, the three integration sites are TRAC, CD38, and CD58, with all three endogenous genes knocked out upon transgene insertion. In some embodiments, the three integration sites are TRAC, CD38, and TIM3, with all three endogenous genes knocked out upon transgene insertion. In some embodiments, the three integration sites are TRAC, CD38, and TIGIT, with all three endogenous genes knocked out upon transgene insertion. In some embodiments, the three integration sites are TRAC, CD38, and PH12, with endogenous genes at TRAC and CD38 knocked out upon transgene insertion. In some embodiments, the three integration sites are TRAC, CD38, and Hll, with endogenous genes at TRAC and CD38 knocked out upon transgene insertion.[000261] With respective site-specific targeting homology arms for position-selective insertion, it allows the transgene(s) to express either under an endogenous promoter at the site or under an exogenous promoter comprised in the construct. When two or more transgenes are to be inserted at a selected location, a linker sequence, for example, a 2A linker or IRES, may be placed between any two transgenes. The 2A linker encodes a self-cleaving peptide derived from, e.g., FMDV, ERAV, PTV-I, or TaV (referred to as “F2A”, “E2A”, “P2A”, and “T2A”, respectively), allowing for separate proteins to be produced from a single translation. In some embodiments, insulators are included in the construct to reduce the risk of transgene and / or exogenous promoter silencing. In various embodiments, the exogenous promoter may be CAG, or other constitutive, inducible, temporal-, tissue-, or cell type- specific promoters including, but not limited to CMV, EFla, PGK, and UBC.[000262] In some embodiments, one or more exogenous polynucleotides integrated by the method described herein are driven by operatively-linked exogenous promoters comprised in the construct for targeted integration. The promoters may be inducible, or constructive, and may be temporal-, tissue- or cell type- specific. Illustrative constitutive promoters include, but are notlimited to, cytomegalovirus (CMV), elongation factor la (EFla), phosphoglycerate kinase (PGK), hybrid CMV enhancer / chicken P-actin (CAG) and ubiquitin C (UBC) promoters. In some embodiments, the exogenous promoter is CAG.[000263] The exogenous polynucleotides integrated by the method described herein may be driven by endogenous promoters in the host genome, at the integration site. In one embodiment, the method described herein is used for targeted integration of one or more exogenous polynucleotides at TRAC or TRBC locus in the genome of a cell. In one embodiment, at least one integrated polynucleotide is driven by the endogenous TRAC or TRBC promoter. In one embodiment, at least one integrated polynucleotide is driven by the endogenous Tim-3 promoter. In one embodiment, at least one integrated polynucleotide is driven by the endogenous TIGIT promoter. In one embodiment, at least one integrated polynucleotide is driven by the endogenous ASB2 promoter.[000264] In some embodiments, the one or more exogenous polynucleotides comprised in the construct for the methods of targeted integration are driven by one promoter. In some embodiments, the construct comprises one or more linker sequences between two adjacent polynucleotides driven by the same promoter to provide greater physical separation between the moieties and maximize the accessibility to enzymatic machinery. The linker peptide of the linker sequences may consist of amino acids selected to make the physical separation between the moieties (exogenous polynucleotides, and / or the protein or peptide encoded therefrom) more flexible or more rigid depending on the relevant function. The linker sequence may be cleavable by a protease or cleavable chemically to yield separate moieties. Examples of enzymatic cleavage sites in the linker include sites for cleavage by a proteolytic enzyme, such as enterokinase, Factor Xa, trypsin, collagenase, and thrombin. In some embodiments, the protease is one which is produced naturally by the host or it is exogenously introduced. Alternatively, the cleavage site in the linker may be a site capable of being cleaved upon exposure to a selected chemical, e.g., cyanogen bromide, hydroxylamine, or low pH. The optional linker sequence may serve a purpose other than the provision of a cleavage site. The linker sequence should allow effective positioning of the moiety with respect to another adjacent moiety for the moieties to function properly. The linker may also be a simple amino acid sequence of a sufficient length to prevent any steric hindrance between the moieties. In addition, the linker sequence may provide for post-translational modification including, but not limited to, e.g., phosphorylation sites, biotinylation sites, sulfation sites, y-carboxylation sites, and the like. In some embodiments, the linker sequence is flexible so as not to hold the biologically active peptide in a single undesired conformation. The linker may be predominantly comprised of amino acids with small side chains, such as glycine, alanine, and serine, to provide for flexibility. In some embodimentsabout 80 to 90 percent or greater of the linker sequence comprises glycine, alanine, or serine residues, particularly glycine and serine residues. In several embodiments, a G4S linker peptide separates the end-processing and endonuclease domains of the fusion protein. In other embodiments, a 2A linker sequence allows for two separate proteins to be produced from a single translation. Suitable linker sequences can be readily identified empirically. Additionally, suitable size and sequences of linker sequences also can be determined by conventional computer modeling techniques. In one embodiment, the linker sequence encodes a self-cleaving peptide. In one embodiment, the self-cleaving peptide is 2A. In some other embodiments, the linker sequence provides an Internal Ribosome Entry Sequence (IRES). In some embodiments, any two consecutive linker sequences are different.[000265] Further, as provided herein, the above method for targeted integration in a preselected locus is used to insert any polynucleotide of interest, for example, polynucleotides encoding safety switch proteins, targeting modality, receptors, signaling molecules, transcription factors, pharmaceutically active proteins and peptides, drug target candidates, and proteins promoting engraftment, trafficking, homing, viability, self-renewal, persistence, and / or survival of stem cells and / or progenitor cells. In some other embodiments, the construct comprising one or more exogenous polynucleotides further comprises one or more marker genes. In one embodiment, the exogenous polynucleotide in a construct of the invention is a suicide gene encoding a safety switch protein.[000266] The method of introducing into cells a construct comprising exogenous polynucleotides for targeted integration can be achieved using a method of gene transfer to cells known per se. In one embodiment, the construct comprises backbones of viral vectors such as adenovirus vectors, adeno-associated virus vectors, retrovirus vectors, lentivirus vectors, or Sendai virus vectors. In some embodiments, the plasmid vectors are used for delivering and / or expressing the exogenous polynucleotides to target cells (e.g., pAl- 11, pXTl, pRc / CMV, pRc / RSV, pcDNAI / Neo) and the like. In some other embodiments, the episomal vector is used to deliver the exogenous polynucleotide to target cells. In some embodiments, recombinant adeno-associated viruses (rAAV) can be used for genetic engineering to introduce insertions, deletions or substitutions through homologous recombination. Unlike lentiviruses, rAAVs do not integrate into the host genome. In addition, episomal rAAV vectors mediate homology-directed gene targeting at much higher rates compared to transfection of conventional targeting plasmids. In some embodiments, an AAV6 or AAV2 vector is used to introduce insertions, deletions or substitutions in a target site in the genome of iPSCs.[000267] Available endonucleases capable of introducing specific and targeted DSBs include, but are not limited to, zinc-finger nucleases (ZFN), transcription activator-like effectornucleases (TALEN), RNA-guided CRISPR (Clustered Regular Interspaced Short Palindromic Repeats) systems. Additionally, the DICE (dual integrase cassette exchange) system utilizing phiC31 and Bxbl integrases is also a promising tool for targeted integration.[000268] ZFNs are targeted nucleases comprising a nuclease fused to a zinc finger DNA binding domain. By a “zinc finger DNA binding domain” or “ZFBD” it is meant a polypeptide domain that binds DNA in a sequence-specific manner through one or more zinc fingers. A zinc finger is a domain of about 30 amino acids within the zinc finger binding domain whose structure is stabilized through coordination of a zinc ion. Examples of zinc fingers include, but are not limited to, C2H2zinc fingers, C3H zinc fingers, and C4zinc fingers. A “designed” zinc finger domain is a domain not occurring in nature whose design / composition results principally from rational criteria, e.g., application of substitution rules and computerized algorithms for processing information in a database storing information of existing ZFP designs and binding data. See, for example, U. S. Pat. Nos. 6,140,081; 6,453,242; and 6,534,261; see also WO 98 / 53058; WO 98 / 53059; WO 98 / 53060; WO 02 / 016536 and WO 03 / 016496. A “selected” zinc finger domain is a domain not found in nature whose production results primarily from an empirical process such as phage display, interaction trap or hybrid selection. ZFNs are described in greater detail in U. S. Pat. No. 7,888,121 and U. S. Pat. No. 7,972,854, the complete disclosures of which are incorporated herein by reference. The most recognized example of a ZFN in the art is a fusion of the FokI nuclease with a zinc finger DNA binding domain.[000269] A TALEN is a targeted nuclease comprising a nuclease fused to a TAL effector DNA binding domain. By “transcription activator-like effector DNA binding domain”, “TAL effector DNA binding domain”, or “TALE DNA binding domain”, it is meant the polypeptide domain of TAL effector proteins that is responsible for binding of the TAL effector protein to DNA. TAL effector proteins are secreted by plant pathogens of the genus Xanthomonas during infection. These proteins enter the nucleus of the plant cell, bind effector-specific DNA sequences via their DNA binding domain, and activate gene transcription at these sequences via their transactivation domains. TAL effector DNA binding domain specificity depends on an effector-variable number of imperfect 34 amino acid repeats, which comprise polymorphisms at select repeat positions called repeat variable-diresidues (RVD). TALENs are described in greater detail in US Pub. No. 2011 / 0145940, which is herein incorporated by reference. The most recognized example of a TALEN in the art is a fusion polypeptide of the FokI nuclease to a TAL effector DNA binding domain.[000270] Another example of a targeted nuclease that finds use in the subject methods is a targeted Spoil nuclease, a polypeptide comprising a Spoil polypeptide having nuclease activityfused to a DNA binding domain, e.g., a zinc finger DNA binding domain, a TAL effector DNA binding domain, etc. that has specificity for a DNA sequence of interest.[000271] Additional examples of targeted nucleases suitable for embodiments of the present invention include, but not limited to Bxbl, phiC31, R4, PhiBTl, and Wp / SPBc / TP901-l, whether used individually or in combination.[000272] Other non-limiting examples of targeted nucleases include naturally occurring and recombinant nucleases; CRISPR related nucleases from families including cas, cpf, cse, csy, csn, csd, cst, csh, csa, csm, and cmr; restriction endonucleases; meganucleases; homing endonucleases, and the like.[000273] Using Cas9 as an example, CRISPR / Cas9 requires two major components: (1) a Cas9 endonuclease and (2) the crRNA-tracrRNA complex. When co-expressed, the two components form a complex that is recruited to a target DNA sequence comprising PAM and a seeding region near PAM. The crRNA and tracrRNA can be combined to form a chimeric guide RNA (gRNA) to guide Cas9 to target selected sequences. These two components can then be delivered to mammalian cells via transfection or transduction.[000274] DICE-mediated insertion uses a pair of recombinases, for example, phiC31 and Bxbl, to provide unidirectional integration of an exogenous DNA that is tightly restricted to each enzymes’ own small attB and attP recognition sites. Because these target att sites that are not naturally present in mammalian genomes, they must be first introduced into the genome, at the desired integration site. See, for example, U. S. Pub. No. 2015 / 0140665, the disclosure of which is incorporated herein by reference.[000275] One aspect of the present invention provides a construct comprising one or more exogenous polynucleotides for targeted genome integration. In one embodiment, the construct further comprises a pair of homologous arms specific to a desired integration site, and the method of targeted integration comprises introducing the construct to cells to enable site specific homologous recombination by the cell host enzymatic machinery. In another embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more exogenous polynucleotides to the cell and introducing a ZFN expression cassette comprising a DNA-binding domain specific to a desired integration site to the cell to enable a ZFN-mediated insertion. In yet another embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more exogenous polynucleotides to the cell and introducing a TALEN expression cassette comprising a DNA-binding domain specific to a desired integration site to the cell to enable a TALEN-mediated insertion. In another embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more exogenous polynucleotides to the cell, introducing a Cas9 expressioncassette, and a gRNA comprising a guide sequence specific to a desired integration site to the cell to enable a Cas9-mediated insertion. In still another embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more att sites of a pair of DICE recombinases to a desired integration site in the cell, introducing a construct comprising one or more exogenous polynucleotides to the cell, and introducing an expression cassette for DICE recombinases, to enable DICE-mediated targeted integration.[000276] In another embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more exogenous polynucleotides to the cell, and introducing a ZFN expression cassette comprising a DNA-binding domain specific to a desired integration site to the cell to enable a ZFN-mediated insertion, wherein the desired integration site comprises AAVS1, CCR5, ROSA26, collagen, HTRP, Hll, PH12, GAPDH, RUNX1, B2M, TAPI, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR a or 0 constant region, NKG2A, NKG2D, CD25, CD38, CD44, CD54, CD56, CD58, CD69, CD71, 0X40, 4-1BB, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, or TIGIT. In yet another embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more exogenous polynucleotides to the cell, and introducing a TALEN expression cassette comprising a DNA-binding domain specific to a desired integration site to the cell to enable a TALEN-mediated insertion, wherein the desired integration site comprises AAVS1, CCR5, ROSA26, collagen, HTRP, Hll, PH12, GAPDH, RUNX1, B2M, TAPI, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR a or 0 constant region, NKG2A, NKG2D, CD25, CD38, CD44, CD54, CD56, CD58, CD69, CD71, 0X40, 4-1BB, CIS, CBL-B, S0CS2, PD1, CTLA4, LAG3, TIM3, or TIGIT. In another embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more exogenous polynucleotides to the cell, introducing a Cas9 expression cassette, and a gRNA comprising a guide sequence specific to a desired integration site to the cell to enable a Cas9-mediated insertion, wherein the desired integration site comprises AAVS1, CCR5, ROSA26, collagen, HTRP, Hll, PH12, GAPDH, RUNX1, B2M, TAPI, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR a or 0 constant region, NKG2A, NKG2D, CD25, CD38, CD44, CD54, CD56, CD58, CD69, CD71, 0X40, 4-1BB, CIS, CBL-B, S0CS2, PD1, CTLA4, LAG3, TIM3, or TIGIT. In still another embodiment, the method of targeted integration in a cell comprises introducing a construct comprising one or more att sites of a pair of DICE recombinases to a desired integration site in the cell, introducing a construct comprising one or more exogenous polynucleotides to the cell, and introducing an expression cassette for DICE recombinases, to enable DICE-mediated targeted integration, wherein the desired integration site comprises AAVS1, CCR5, ROSA26, collagen, HTRP, Hll, PH12, GAPDH, RUNX1, B2M, TAPI, TAP2, tapasin, NLRC5, CIITA,RFXANK, RFX5, RFXAP, TCR a or 0 constant region, NKG2A, NKG2D, CD25, CD38, CD44, CD54, CD56, CD58, CD69, CD71, 0X40, 4-1BB, CIS, CBL-B, S0CS2, PD1, CTLA4, LAG3, TIM3, or TIGIT.III. Method of Obtaining and Maintaining Genome-engineered iPSCs [000277] In various embodiments, the present invention also provides a method of obtaining and maintaining genome-engineered iPSCs comprising one or more targeted edits (e.g., multiplex engineering) at one or more desired sites, wherein the one or more targeted edits remain intact and functional in expanded genome-engineered iPSCs or the iPSC-derived non-pluripotent cells at the respective selected editing sites. The targeted editing introduces into the genome of the iPSC, and derivative cells thereof, insertions, deletions, and / or substitutions (targeted integration and / or in / dels at selected sites). In comparison to direct engineering of patient-sourced, peripheral blood originated primary effector cells, the many benefits of obtaining genomically-engineered derivative cells through editing and differentiating iPSC as provided herein include, but are not limited to: unlimited source for engineered effector cells; no need for repeated manipulation of the effector cells, especially when multiple engineered modalities are involved; the obtained effector cells are rejuvenated for having elongated telomere and experiencing less exhaustion; the effector cell population is homogeneous in terms of editing site, copy number, and void of allelic variation, random mutations and expression variegation, largely due to the enabled clonal selection in engineered iPSCs as provided herein.[000278] In some embodiments, the genome-engineered iPSCs comprising one or more targeted edits at one or more selected sites are maintained, passaged and expanded as single cells for an extended period in cell maintenance culture medium (FMM), wherein the iPSCs retain the targeted editing and functional modification at the selected site(s). The iPSCs cultured in FMM have been shown to continue to maintain their undifferentiated, and ground or naive, profile; provide genomic stability without the need for culture cleaning or selection; and readily to give rise to all three somatic lineages, in vitro differentiation via embryoid bodies or monolayer (without formation of embryoid bodies); and by in vivo differentiation via teratoma formation. See, for example, International Pub. No. WO2015 / 134652, the disclosure of which is incorporated herein by reference.[000279] In some embodiments, the genome-engineered iPSCs comprising one or more targeted integrations and / or in / dels are maintained, passaged and expanded in a medium (FMM) comprising a MEK inhibitor, a GSK3 inhibitor, and a ROCK inhibitor, and free of, or essentially free of, TGF0 receptor / ALK5 inhibitors, wherein the iPSCs retain the intact and functional targeted edits at the selected sites.[000280] Another aspect of the invention provides a method of generating genome-engineered iPSCs through targeted editing of iPSCs; or through first generating genome-engineered non-pluripotent cells by targeted editing, and then reprogramming the selected / isolated genome-engineered non-pluripotent cells to obtain iPSCs comprising the same targeted editing as the non-pluripotent cells. A further aspect of the invention provides genomeengineering non-pluripotent cells which are concurrently undergoing reprogramming by introducing targeted integration and / or targeted in / dels to the cells, wherein the contacted non-pluripotent cells are under sufficient conditions for reprogramming, and wherein the conditions for reprogramming comprise contacting non-pluripotent cells with one or more reprogramming factors and small molecules. In various embodiments of the method for concurrent genomeengineering and reprogramming, the targeted integrations and / or targeted in / dels may be introduced to the non-pluripotent cells prior to, or essentially concomitantly with, initiating reprogramming by contacting the non-pluripotent cells with one or more reprogramming factors and optionally one or more small molecules.[000281] In some embodiments, to concurrently genome-engineer and reprogram non-pluripotent cells, the targeted integrations and / or in / dels may also be introduced to the non-pluripotent cells after the multi-day process of reprogramming is initiated by contacting the non-pluripotent cells with one or more reprogramming factors and small molecules, and wherein the vectors carrying the constructs are introduced before the reprogramming cells present stable expression of one or more endogenous pluripotent genes including but not limited to, SSEA4, Tral81 and CD30.[000282] In some embodiments, the reprogramming is initiated by contacting the non-pluripotent cells with at least one reprogramming factor, and optionally a combination of a TGFP receptor / ALK inhibitor, a MEK inhibitor, a GSK3 inhibitor and a ROCK inhibitor. In some embodiments, the genome-engineered iPSCs produced through any methods above are further maintained and expanded using a mixture comprising a combination of a MEK inhibitor, a GSK3 inhibitor and a ROCK inhibitor.[000283] In some embodiments of the method of generating genome-engineered iPSCs, the method comprises: genomically engineering an iPSC by introducing one or more targeted integrations and / or in / dels into iPSCs to obtain genome-engineered iPSCs having a genotype provided herein. Alternatively, the method of generating genome-engineered iPSCs comprises: (a) introducing one or more targeted edits into non-pluripotent cells to obtain genome-engineered non-pluripotent cells comprising targeted integrations and / or in / dels at selected sites, and (b) contacting the genome-engineered non-pluripotent cells with one or more reprogramming factors, and optionally a small molecule composition comprising a TGFP receptor / ALKinhibitor, a MEK inhibitor, a GSK3 inhibitor and / or a ROCK inhibitor, to obtain genome-engineered iPSCs comprising targeted integrations and / or in / dels at selected sites. Alternatively, the method of generating genome-engineered iPSCs comprises: (a) contacting non-pluripotent cells with one or more reprogramming factors, and optionally a small molecule composition comprising a TGFP receptor / ALK inhibitor, a MEK inhibitor, a GSK3 inhibitor and / or a ROCK inhibitor to initiate the reprogramming of the non-pluripotent cells; (b) introducing one or more targeted integrations and / or in / dels into the reprogramming non-pluripotent cells for genomeengineering; and (c) obtaining clonal genome-engineered iPSCs comprising the targeted integrations and / or in / dels at selected sites. Any of the above methods may further comprise single cell sorting of the genome-engineered iPSCs to obtain a clonal iPSC, and / or screening for off-target editing and abnormal karyotypes in the genome-engineered iPSCs. Through clonal expansion of the genome-engineered iPSCs, a master cell bank is generated to comprise single cell sorted and expanded clonal engineered iPSCs having at least one phenotype as provided herein. The master cell bank is subsequently cryopreserved, providing a platform for additional iPSC engineering and a renewable source for manufacturing off-the-shelf, engineered, homogeneous cell therapy products, which are well-defined and uniform in composition, and can be mass produced at significant scale in a cost-effective manner.[000284] The reprogramming factors are selected from the group consisting of OCT4, SOX2, NANOG, KLF4, LIN28, C-MYC, ECAT1, UTF1, ESRRB, SV40LT, HESRG, CDH1, TDGF1, DPPA4, DNMT3B, ZIC3, L1TD1, and any combinations thereof as disclosed in International Pub. Nos. WO2015 / 134652 and WO 2017 / 066634, the disclosures of which are incorporated herein by reference. The one or more reprogramming factors may be in the form of polypeptides. The reprogramming factors may also be in the form of polynucleotides encoding the reprogramming factors, and thus may be introduced to the non-pluripotent cells by vectors such as, a retrovirus, a Sendai virus, an adenovirus, an episome, a plasmid, and a mini-circle. In some embodiments, the one or more polynucleotides encoding at least one reprogramming factor are introduced by a lentiviral vector. In some embodiments, the one or more polynucleotides are introduced by an episomal vector. In various other embodiments, the one or more polynucleotides are introduced by a Sendai viral vector. In some embodiments, the one or more polynucleotides introduced by a combination of plasmids. See, for example, International Pub. No. W02019 / 075057A1, the disclosure of which is incorporated herein by reference.[000285] In some embodiments, the non-pluripotent cells are transfected with multiple constructs comprising different exogenous polynucleotides and / or different promoters by multiple vectors for targeted integration at the same or different selected sites. These exogenous polynucleotides may comprise a suicide gene, or a gene encoding targeting modalities, receptors,signaling molecules, transcription factors, pharmaceutically active proteins and peptides, drug target candidates, or a gene encoding a protein promoting engraftment, trafficking, homing, viability, self-renewal, persistence, and / or survival of the iPSCs or derivative cells thereof. In some embodiments, the exogenous polynucleotides encode RNA, including but not limited to siRNA, shRNA, miRNA and antisense nucleic acids. These exogenous polynucleotides may be driven by one or more promoters selected from the group consisting of constitutive promoters, inducible promoters, temporal-specific promoters, and tissue or cell type specific promoters. Accordingly, the polynucleotides are expressible when under conditions that activate the promoter, for example, in the presence of an inducing agent or in a particular differentiated cell type. In some embodiments, the polynucleotides are expressed in iPSCs and / or in cells differentiated from the iPSCs. In one embodiment, one or more suicide gene is driven by a constitutive promoter, for example Caspase-9 driven by CAG. These constructs comprising different exogenous polynucleotides and / or different promoters can be transfected to non-pluripotent cells either simultaneously or consecutively. The non-pluripotent cells subjected to targeted integration of multiple constructs can simultaneously contact the one or more reprogramming factors to initiate the reprogramming concurrently with the genomic engineering, thereby obtaining genome-engineered iPSCs comprising multiple targeted integrations in the same pool of cells. As such, this robust method enables a concurrent reprogramming and engineering strategy to derive a clonal genomically-engineered iPSC with multiple modalities integrated into one or more selected target sites.IV. A method of Obtaining Genetically-Engineered Effector Cells by Differentiating Genome-engineered iPSC[000286] In some embodiments, the genome-engineered iPSCs comprising one or more genetic modifications as provided herein are used to derive hematopoietic cell lineages or any other specific cell types in vitro, wherein the derived non-pluripotent cells retain the functional genetic modifications including targeted editing at the selected site(s). In some embodiments, the genome-engineered iPSCs used to derive hematopoietic cell lineages or any other specific cell types in vitro are master cell bank cells that are cryopreserved and thawed right before their usage. In one embodiment, the genome-engineered iPSC-derived cells include, but are not limited to, mesodermal cells with definitive hemogenic endothelium (HE) potential, definitive HE, CD34+hematopoietic cells, hematopoietic stem and progenitor cells, hematopoietic multipotent progenitors (MPP), T cell progenitors, NK cell progenitors, myeloid cells, neutrophil progenitors, T cells, NKT cells, NK cells, B cells, neutrophils, dendritic cells, and macrophages,wherein the cells derived from the genome-engineered iPSCs retain the functional genetic modifications including targeted editing at the desired site(s).[000287] Applicable differentiation methods and compositions for obtaining iPSC-derived hematopoietic cell lineages include those depicted in, for example, International Pub. No.WO2017 / 078807, the disclosure of which is incorporated herein by reference. As provided, the methods and compositions for generating hematopoietic cell lineages are through definitive hemogenic endothelium (HE) derived from pluripotent stem cells, including iPSCs under serum-free, feeder-free, and / or stromal-free conditions and in a scalable and monolayer culturing platform without the need of EB formation. Cells that may be differentiated according to the provided methods range from pluripotent stem cells, to progenitor cells that are committed to particular terminally differentiated cells and transdifferentiated cells, and to cells of various lineages directly transitioned to hematopoietic fate without going through a pluripotent intermediate. Similarly, the cells that are produced by differentiating stem cells range from multipotent stem or progenitor cells, to terminally differentiated cells, and to all intervening hematopoietic cell lineages.[000288] The methods for differentiating and expanding cells of the hematopoietic lineage from pluripotent stem cells in monolayer culturing comprise contacting the pluripotent stem cells with a BMP pathway activator, and optionally, bFGF. As provided, the pluripotent stem cell-derived mesodermal cells are obtained and expanded without forming embryoid bodies from pluripotent stem cells. The mesodermal cells are then subjected to contact with a BMP pathway activator, bFGF, and a WNT pathway activator to obtain expanded mesodermal cells having definitive hemogenic endothelium (HE) potential without forming embryoid bodies from the pluripotent stem cells. By subsequent contact with bFGF, and optionally, a ROCK inhibitor, and / or a WNT pathway activator, the mesodermal cells having definitive HE potential are differentiated to definitive HE cells, which are also expanded during differentiation.[000289] The methods provided herein for obtaining cells of the hematopoietic lineage are superior to EB-mediated pluripotent stem cell differentiation, because EB formation leads to modest to minimal cell expansion, does not allow monolayer culturing which is important for many applications requiring homogeneous expansion and homogeneous differentiation of the cells in a population, and is laborious and of low efficiency.[000290] The provided monolayer differentiation platform facilitates differentiation towards definitive hemogenic endothelium resulting in the derivation of hematopoietic stem cells and differentiated progeny such as T, B, NKT and NK cells. The monolayer differentiation strategy combines enhanced differentiation efficiency with large-scale expansion, and enables the delivery of a therapeutically relevant number of pluripotent stem cell-derived hematopoietic cellsfor various therapeutic applications. Further, monolayer culturing using the methods provided herein leads to functional hematopoietic lineage cells that enable a full range of in vitro differentiation, ex vivo modulation, and in vivo long term hematopoietic self-renewal, reconstitution and engraftment. As provided, the iPSC-derived hematopoietic lineage cells include, but are not limited to, definitive hemogenic endothelium, hematopoietic multipotent progenitor cells, hematopoietic stem and progenitor cells, T cell progenitors, NK cell progenitors, T cells, NK cells, NKT cells, B cells, macrophages, and neutrophils.[000291] Thus, in various embodiments, the method for directing differentiation of pluripotent stem cells into cells of a definitive hematopoietic lineage, comprises: (i) contacting pluripotent stem cells with a composition comprising a BMP activator, and optionally bFGF, to initiate differentiation and expansion of mesodermal cells from the pluripotent stem cells; (ii) contacting the mesodermal cells with a composition comprising a BMP activator, bFGF, and a GSK3 inhibitor, wherein the composition is optionally free of TGFP receptor / ALK inhibitor, to initiate differentiation and expansion of mesodermal cells having definitive HE potential from the mesodermal cells; (iii) contacting the mesodermal cells having definitive HE potential with a composition comprising a ROCK inhibitor; one or more growth factors and cytokines selected from the group consisting of bFGF, VEGF, SCF, IGF, EPO, IL6, and IL11; and optionally, a Wnt pathway activator, wherein the composition is optionally free of TGFP receptor / ALK inhibitor, to initiate differentiation and expansion of definitive hemogenic endothelium from pluripotent stem cell-derived mesodermal cells having definitive hemogenic endothelium potential.[000292] In some embodiments, the method further comprises contacting pluripotent stem cells with a composition comprising a MEK inhibitor, a GSK3 inhibitor, and a ROCK inhibitor, wherein the composition is free of TGFP receptor / ALK inhibitors, to seed and expand the pluripotent stem cells. In some embodiments, the pluripotent stem cells are iPSCs, or naive iPSCs, or iPSCs comprising one or more genetic imprints; and the one or more genetic imprints comprised in the iPSCs are retained in the hematopoietic cells differentiated therefrom. In some embodiments of the method for directing differentiation of pluripotent stem cells into cells of a hematopoietic lineage, the differentiation of the pluripotent stem cells into cells of hematopoietic lineage is void of generation of embryoid bodies and is in a monolayer culturing form.[000293] In some embodiments of the above method, the obtained pluripotent stem cell-derived definitive hemogenic endothelium cells are CD34+. In some embodiments, the obtained definitive hemogenic endothelium cells are CD34+CD43‘. In some embodiments, the definitive hemogenic endothelium cells are CD34+CD43 CXCR4 CD73‘. In some embodiments, the definitive hemogenic endothelium cells are CD34+CXCR4 CD73‘. In some embodiments, thedefinitive hemogenic endothelium cells are CD34+CD43 CD93‘. In some embodiments, the definitive hemogenic endothelium cells are CD34+CD93‘.[000294] In some embodiments of the above method, the method further comprises (i) contacting pluripotent stem cell-derived definitive hemogenic endothelium with a composition comprising a ROCK inhibitor; one or more growth factors and cytokines selected from the group consisting of VEGF, bFGF, SCF, Flt3L, TPO, and IL7; and optionally a BMP activator; to initiate the differentiation of the definitive hemogenic endothelium to pre-T cell progenitors; and optionally, (ii) contacting the pre-T cell progenitors with a composition comprising one or more growth factors and cytokines selected from the group consisting of SCF, Flt3L, and IL7, but free of one or more of VEGF, bFGF, TPO, BMP activators and ROCK inhibitors, to initiate the differentiation of the pre-T cell progenitors to T cell progenitors or T cells. In some embodiments of the method, the pluripotent stem cell-derived T cell progenitors are CD34+CD45+CD7+. In some embodiments of the method, the pluripotent stem cell-derived T cell progenitors are CD45+CD7+.[000295] In yet some embodiments of the above method for directing differentiation of pluripotent stem cells into cells of a hematopoietic lineage, the method further comprises: (i) contacting pluripotent stem cell-derived definitive hemogenic endothelium with a composition comprising a ROCK inhibitor; one or more growth factors and cytokines selected from the group consisting of VEGF, bFGF, SCF, Flt3L, TPO, IL3, IL7, and IL15; and optionally, a BMP activator, to initiate differentiation of the definitive hemogenic endothelium to pre-NK cell progenitor; and optionally, (ii) contacting pluripotent stem cells-derived pre-NK cell progenitors with a composition comprising one or more growth factors and cytokines selected from the group consisting of SCF, Flt3L, IL3, IL7, and IL15, wherein the medium is free of one or more of VEGF, bFGF, TPO, BMP activators and ROCK inhibitors, to initiate differentiation of the pre-NK cell progenitors to NK cell progenitors or NK cells. In some embodiments, the pluripotent stem cell-derived NK progenitors are CD3 CD45+CD56+CD7+. In some embodiments, the pluripotent stem cell-derived NK cells are CD3 CD45+CD56+, and optionally further defined by being NKp46+, CD57+and CD16+.[000296] In some embodiments, the genome-engineered iPSC-derived cells obtained from the above methods comprise one or more inducible suicide genes integrated at one or more desired integration sites comprising AAVS1, CCR5, ROSA26, collagen, HTRP, Hll, PH12, GAPDH, RUNX1, B2M, TAPI, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR a or p constant region, NKG2A, NKG2D, CD25, CD38, CD44, CD54, CD56, CD58, CD69, CD71, 0X40, 4-1BB, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, and TIGIT, or other loci meeting the criteria of a genome safe harbor. In some other embodiments, the genome-engineered iPSC-derived cells comprise polynucleotides encoding safety switch proteins, targeting modality, receptors, signaling molecules, transcription factors, pharmaceutically active proteins and peptides, drug target candidates, or proteins promoting trafficking, homing, viability, self-renewal, persistence, and / or survival of stem cells and / or progenitor cells. In some embodiments, the genome-engineered iPSC-derived cells comprising one or more suicide genes further comprise one or more in / dels comprised in one or more endogenous genes associated with immune response regulation and mediation, including, but not limited to, checkpoint genes, endogenous T cell receptor genes, and MHC class I suppressor genes. In one embodiment, the genome-engineered iPSC-derived cells comprising one or more suicide genes further comprise an in / del in B2M gene, wherein the B2M is knocked-out.[000297] Additionally, applicable dedifferentiation methods and compositions for obtaining genomic-engineered hematopoietic cells of a first fate to genomic-engineered hematopoietic cells of a second fate include those depicted in, for example, International Pub. No. WO2011 / 159726, the disclosure of which is incorporated herein by reference. The method and composition provided therein allows partially reprogramming a starting non-pluripotent cell to a non-pluripotent intermediate cell by limiting the expression of endogenous Nanog gene during reprogramming; and subjecting the non-pluripotent intermediate cell to conditions for differentiating the intermediate cell into a desired cell type.V. Therapeutic Use of Derivative Immune Cells with Functional Modalities Differentiated from Genetically Engineered iPSCs[000298] The present invention provides, in some embodiments, a composition comprising an isolated population or subpopulation of functionally enhanced derivative immune cells that have been differentiated from genomically engineered iPSCs using the methods and compositions as disclosed. In some embodiments, the iPSCs of the composition comprise one or more targeted genetic edits as disclosed herein, which are retainable in the iPSC-derived effector cells, wherein the genetically engineered iPSCs and derivative cells thereof are suitable for cellbased adoptive therapies. In one embodiment, the isolated population or subpopulation of genetically engineered effector cells of the composition comprises iPSC-derived CD34+cells. In one embodiment, the isolated population or subpopulation of genetically engineered effector cells of the composition comprises iPSC-derived HSC cells. In one embodiment, the isolated population or subpopulation of genetically engineered effector cells of the composition comprises iPSC-derived proT or T cells. In one embodiment, the isolated population or subpopulation of genetically engineered effector cells of the composition comprises iPSC-derived proNK or NK cells. In one embodiment, the isolated population or subpopulation ofgenetically engineered effector cells of the composition comprises iPSC-derived immune regulatory cells or myeloid derived suppressor cells (MDSCs).[000299] In some embodiments of the composition, the iPSC-derived genetically engineered effector cells are further modulated ex vivo for improved therapeutic potential. In one embodiment of the composition, an isolated population or subpopulation of genetically engineered effector cells that have been derived from iPSCs comprises an increased number or ratio of naive T cells, stem cell memory T cells, and / or central memory T cells. In one embodiment of the composition, the isolated population or subpopulation of genetically engineered effector cells that have been derived from iPSCs comprises an increased number or ratio of type I NKT cells. In another embodiment of the composition, the isolated population or subpopulation of genetically engineered effector cells that have been derived from iPSCs comprises an increased number or ratio of adaptive NK cells. In some embodiments of the composition, the isolated population or subpopulation of genetically engineered CD34+cells, HSC cells, T cells, NK cells, or myeloid derived suppressor cells derived from iPSCs are allogeneic. In some other embodiments of the composition, the isolated population or subpopulation of genetically engineered CD34+cells, HSC cells, T cells, NK cells, or MDSCs derived from iPSC are autologous.[000300] In some embodiments of the composition, the iPSC for differentiation comprises genetic imprints selected to convey desirable therapeutic attributes in derived effector cells, provided that cell development biology during differentiation is not disrupted, and provided that the genetic imprints are retained and functional in the differentiated hematopoietic cells derived from said iPSC.[000301] In some embodiments of the composition, the genetic imprints of the pluripotent stem cells comprise (i) one or more genetically modified modalities obtained through genomic insertion, deletion or substitution in the genome of the pluripotent cells during or after reprogramming a non-pluripotent cell to iPSC; or (ii) one or more retainable therapeutic attributes of a source specific immune cell that is donor-, disease-, or treatment responsespecific, and wherein the pluripotent cells are reprogrammed from the source specific immune cell, wherein the iPSC retain the source therapeutic attributes, which are also comprised in the iPSC-derived hematopoietic lineage cells.[000302] In some embodiments of the composition, the genetically modified modalities comprise one or more of: safety switch proteins, targeting modalities, receptors, signaling molecules, transcription factors, pharmaceutically active proteins and peptides, drug target candidates; or proteins promoting engraftment, trafficking, homing, viability, self-renewal, persistence, immune response regulation and modulation, and / or survival of the iPSCs orderivative cells thereof. In some embodiments of the composition, the genetically modified iPSC and the derivative cells thereof comprise additional genetically modified modalities comprising (1) deletion or disruption of B2M, TAPI, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCRa or TCRp constant region (TRAC or TRBC), NKG2A, NKG2D, CD38, CD25, CD69, CD71, CD44, CD54, CD56, CD58, 0X40, 4-1BB, CIS, CBL-B, S0CS2, PD1, CTLA4, LAG3, TIM3, or TIGIT; and / or (2) introduction of HLA-E, HLA-G, 4-1BBL, CD3, CD4, CD8, CD47, CD113, CD131, CD137, CD80, PDL1, A2AR, CAR, TCR, Fc receptor, or surface triggering receptors for coupling with bi- or multi- specific or universal engagers.[000303] In still some other embodiments of the composition, the iPSC-derived hematopoietic lineage cells comprise the therapeutic attributes of the source specific immune cell relating to one or more of: (i) increased cytotoxicity; (ii) improved persistency and / or survival; (iii) enhanced ability in migrating, and / or activating or recruiting bystander immune cells, to tumor sites; (iv) improved tumor infiltration; (v) enhanced ability to reduce tumor immunosuppression; (vi) improved ability in rescuing tumor antigen escape; (vii) controlled apoptosis; (viii) enhanced or acquired ADCC; and (ix) ability to avoid fratricide, in comparison to its counterpart primary cell obtained from peripheral blood, umbilical cord blood, or any other donor tissues without the same genetic edit(s). In some embodiments of the composition, the iPSC-derived hematopoietic lineage cells additionally comprise the therapeutic attributes of promoting homing or trafficking and retention of the effector cells at a tumor site.[000304] In some embodiments of the composition, the engineered expression of the cytokine(s) and the CAR(s) is NK cell specific. In some other embodiments of the composition, the engineered expression of the cytokine(s) and the CAR(s) is T cell specific. In some embodiments of the composition, the iPSC-derived hematopoietic effector cells are antigen specific. In some embodiments of the composition, the antigen specific derivative effector cells target a liquid tumor. In some embodiments of the composition, the antigen specific derivative effector cells target a solid tumor. In some embodiments of the composition, the antigen specific iPSC-derived hematopoietic effector cells are capable of rescuing tumor antigen escape.Additionally, the present application makes possible a combined therapeutic approach by providing rationally designed effector cells capable of synergize with a tumor sensitizing procedure that upregulates tumor cell expression of a matching chemokine to augment effector cell tumor site homing, trafficking and retention, which contributes to increased effector cell cytotoxicity and persistency.[000305] As provided herein, exposing a tumor cell to a sensitizing agent (e.g., radiation) elevates secretion and / or surface expression of stress ligands including, but limited to, the chemokine IL8, by the tumor cells. Tumor preconditioning by sensitization, as described hereintherefore provides an additional strategy to further enhance the therapeutic efficacy of the effector cells overexpressing a C-X-C motif chemokine receptor or a variant thereof. Without being limited by theory, tumor sensitization may be utilized to overcome tumor resistance by modulating potential tumorigenic mechanisms (including, but not limited to cell cycle progression, inflammation, proliferation, apoptosis, invasion, perfusion, metastasis, and angiogenesis) to make the tumor cells more susceptible to activities of another selective drugs, such as the allogeneic effector cells with desired engineered therapeutic attributes as described herein, thereby enhancing the efficacy of the therapeutic effector cells targeting the tumor.[000306] Without being bound by theory, exemplary sensitizing agents useful in compositions and methods disclosed herein include, but are not limited to, radiation therapy, radiopharmaceuticals, or chemotherapeutic agents. Thus, the above-discussed compositions may further comprise a sensitizing agent, as described above. In various embodiments, the sensitizing agent increases secretion and / or surface expression of a chemokine, including CXCL8, by a tumor cell upon contact therewith.[000307] Embodiments of radiation therapy include, but are not limited to, external beam radiation therapy, wherein high-energy beams (e.g., x-rays, gamma rays, photons, protons, neutrons, ions, and any other forms of energy applicable to such treatments) are produced by a machine and aimed at the tumor; brachytherapy, wherein seeds, ribbons, or capsules that contain or are otherwise linked to a radiation source / particle are placed in or near a tumor or cancer cell. Embodiments of radioactive drugs (e.g., radiopharmaceuticals or radionuclides, including radiopeptides) comprise a radioactive compound linked to a targeting molecule (e.g., an antibody conjugate).[000308] In various embodiments, the amount of radiation agent being exposed to, or contacted with, a cancer or tumor cell ranges from about 0.0001 Gy to about 80Gy. Thus, in some embodiments, the amount of sensitizing agent provided to a subject and / or included in the compositions provided herein is at least about 0.0001 Gy, at least about 0.0005 Gy, at least about 0.001 Gy, at least about 0.0015 Gy, at least about 0.01 Gy, at least about 0.015 Gy, at least about 0.1 Gy, at least about 0.15 Gy, at least about 1.0 Gy, at least about 1.5 Gy, at least about 10.0 Gy, at least about 15 Gy, at least about 20.0 Gy, at least about 25.0 Gy, at least about 30.0 Gy, at least about 35.0 Gy, at least about 40.0 Gy, at least about 45.0 Gy, at least about 50.0 Gy, at least about 55.0 Gy, at least about 60.0 Gy, at least about 65.0 Gy, at least about 70.0 Gy, at least about 75.0 Gy, at least about 80.0 Gy or any range in-between. In some embodiments, the amount of sensitizing agent is about 25.0 Gy.[000309] Examples of radioactive compounds useful as radiopharmaceuticals include, but are not limited to calcium-47, carbon-11, carbon-14, chromium-51, cobalt-57, cobalt-58, erbium-169, fluorine-18, gallium-67, gallium-68, hydrogen-3, indium-111, iodine-123, iodine-125, iodine-131, iorn-59, krypton-81m, lutetium-177, nitrogen-13, oxygen-15, phosphorus-32, radium-223, rubidium-82, samarium-153, selenium-75, sodium-22, sodium-24, strontium-89, technetium-99m, thallium-201, xenon- 133, and yttrium-90.[000310] Exemplary chemotherapeutic agents that can be potentially used for tumor cell sensitization include, but are not limited to, alkylating agents (cyclophosphamide, mechlorethamine, mephalin, chlorambucil, heamethylmelamine, thiotepa, busulfan, carmustine, lomustine, semustine), animetabolites (methotrexate, fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, thioguanine, pentostatin), vinca alkaloids (vincristine, vinblastine, vindesine), epipodophyllotoxins (etoposide, etoposide orthoquinone, and teniposide), antibiotics (daunorubicin, doxorubicin, mitoxantrone, bisanthrene, actinomycin D, plicamycin, puromycin, and gramicidine D), colchicine, cytochalasin B, emetine, maytansine, and amsacrine. Additional agents include aminglu...

Claims

CLAIMSWhat is claimed is:

1. A cell or a population thereof, wherein(i) the cell is (a) an immune cell; (b) an induced pluripotent cell (iPSC); or (c) a derivative effector cell obtained from differentiating the iPSC; and(ii) the cell comprises:(a) a polynucleotide encoding a chimeric antigen receptor (CAR), wherein the CAR comprises a first target binding region, a first transmembrane domain, and an endodomain; and(b) a polynucleotide encoding an avidity-enhancing receptor (AvER), wherein the AvER comprises a second target binding region, a second transmembrane domain, but not an endodomain.

2. The cell or population thereof of claim 1, wherein the first target binding region and the second target binding region recognize a same or different antigen; or wherein the first target binding region and the second target binding region target the same or different epitope of a same antigen.

3. The cell or population thereof of claim 1, wherein the cell comprises a construct comprising at least one of:(i) a polynucleotide encoding an allo-immune defense receptor (ADR); and(ii) a polynucleotide encoding IL2, IL 18, or a IL7RF;wherein the construct is inserted into a T cell receptor (TCR) locus, thereby knocking out the TCR; and wherein the construct is expressed under control of an endogenous TCR promoter.

4. The cell or population thereof of claim 3, further comprising a construct at a first integration site (site 1), wherein:(i) the site 1 construct comprises two or more of:(a) a polynucleotide encoding a TGFp signaling redirector receptor (TGFP- SRR) comprising a partial or full peptide of the extracellular domain (ECD) of transforming growth factor beta receptor (TGFpR);(b) a polynucleotide encoding a C-X-C motif chemokine receptor or a variant thereof; and(c) a polynucleotide encoding an exogenous CD 16 or a variant thereof; and (ii) the site 1 construct comprises an exogenous promoter that regulates expression of the polynucleotides in the site 1 construct.

5. The cell or population thereof of claim 4, further comprising a construct at a second integration site (site 2), wherein the site 2 construct comprises one or more of:(a) a polynucleotide encoding a chimeric antigen receptor;(b) a polynucleotide encoding a T cell enhancer (TCE); and(c) a polynucleotide encoding a cytokine;(iii) the site 2 differs from the site 1; and(iv) the site 2 construct comprises an exogenous promoter that regulates expression of the polynucleotides in the site 2 construct.

6. The cell or population thereof of claim 4, wherein the site 1 comprises one of AAVS1, CCR5, ROSA26, collagen, HTRP, Hl 1, PH12, GAPDH, TCR constant region, RUNX1, B2M, TAPI, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR a or 0 constant region (TRAC or TRBC), NKG2A, NKG2D, CD38, CD25, CD69, CD71, CD44, CD54, CD56, CD58, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, or TIGIT.

7. The cell or population thereof of claim 6, wherein (i) the site 1 comprises one of CD38, CD54, CD56, CD58, TIM3, TIGIT, Hl 1 or PH12; and (ii) integration of the site 1 construct at any of CD38, CD54, CD56, CD58, TIM3, or TIGIT knocks out an endogenous gene at the site 1.

8. The cell or population thereof of claim 5, wherein the site 2 comprises one of AAVS1, CCR5, ROSA26, collagen, HTRP, Hl 1, PH12, GAPDH, TCR constant region, RUNX1, B2M, TAPI, TAP2, tapasin, NLRC5, CIITA, RFXANK, RFX5, RFXAP, TCR a or 0 constant region (TRAC or TRBC), NKG2A, NKG2D, CD38, CD25, CD69, CD71, CD44, CD54, CD56, CD58, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, or TIGIT.

9. The cell or population thereof of claim 8, wherein (i) the site 2 comprises one of CD38, CD54, CD56, CD58, TIM3, TIGIT, Hl 1 or PH12; and (ii) integration of the site 2 construct at any of CD38, CD54, CD56, CD58, TIM3, or TIGIT knocks out an endogenous gene at the site 2.

10. The cell or population thereof of claim 3, wherein the TCR locus is a constant region of TCR alpha (TRAC) or TCR beta (TRBC), wherein the gene at the TCR locus is TCRa or TCRP, and wherein the endogenous TCR promoter is a TRAC promoter or a TRBC promoter.

11. The cell or population thereof of claim 3, wherein the ADR is specific to 41BB.

12. The cell or population thereof of claim 4, wherein(i) the TGFP-SRR further comprises a partial or full peptide of the intracellular domain (ICD) of a cytokine receptor comprising an IL2R, IL12R, IL18R, IL21R, or any combination thereof;(ii) the C-X-C motif chemokine receptor comprises CXCR2 or CXCR3; or(iii) the exogenous CD 16 or variant thereof comprises at least one of:(a) a high affinity non-cleavable CD 16 (hnCD16);(b) Fl 76V and S197P in ectodomain domain of CD 16;(c) a full or partial ectodomain originated from CD64;(d) a non-native (or non-CD16) transmembrane domain;(e) a non-native (or non-CD16) intracellular domain;(f) a non-native (or non-CD16) signaling domain;(g) a non-native stimulatory domain; and(h) transmembrane, signaling, and stimulatory domains that are not originated from CD 16, and are originated from a same or different polypeptide.

13. The cell or population thereof of claim 1, wherein the first target binding region and the second target binding region are specific to the same antigen, and wherein:(i) the antigen comprises ADGRE2, B7H3, carbonic anhydrase IX (CAIX), CCR1, CCR4, carcinoembryonic antigen (CEA), CD3, CD5, CD7, CD8, CD10, CD20, CD22, CD30, CD33, CD34, CD38, CD41, CD44, CD44V6, CD49f, CD56, CD70, CD74, CD79b, CD99, CD123, CD133, CD138, CDS, CLEC12A, an antigen of a cytomegalovirus (CMV) infected cell, epithelial glycoprotein-2 (EGP-2), epithelial glycoprotein-40 (EGP-40), epithelial cell adhesion molecule (EpCAM), EGFRvIII, receptor tyrosine-protein kinases erb- B2,3,4, EGFIR, EGFR-VIII, ERBB folate-binding protein (FBP), fetal acetylcholine receptor (AChR), folate receptor-a, Ganglioside G2 (GD2), Ganglioside G3 (GD3), GPRC5D, human Epidermal Growth Factor Receptor 2 (HER2), human telomerase reverse transcriptase (hTERT), ICAM-1, Integrin B7, Interleukin- 13 receptor subunit alpha-2 (IL-13Ra2), K-light chain, kinase insert domain receptor(KDR), KLK2, Lewis A (CA19.9), Lewis Y (LeY), LI cell adhesion molecule (Ll-CAM), LILRB2, melanoma antigen family A 1 (MAGE-A1), MICA / B, Mucin 1 (Muc-1), Mucin 16 (Muc-16), Mesothelin (MSLN), NKCSI, NKG2D ligands, c-Met, cancer-testis antigen NY-ESO-1, oncofetal antigen (h5T4), PRAME, prostate stem cell antigen (PSCA), PRAME prostatespecific membrane antigen (PSMA), tumor-associated glycoprotein 72 (TAG-72), TIM-3, TRBCI, TRBC2, vascular endothelial growth factor R2 (VEGF-R2), Wilms tumor protein (WT-1), and a pathogen antigen; or(ii) the antigen comprises B7H3, BCMA, CD19, CD20, CD22, CD38, CD52, CD79b, CD 123, EGFR, EGP2 / EpCAM, GD2, GPRC5D, HER2, KLK2, MICA / B, MSLN, VEGF-R2, PSMA and PDLL14. The cell or population thereof of claim 13, wherein the first target binding region comprises an amino acid sequence that has at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identity to any of SEQ ID NOs: 6, 7, 14-25, and 32-34.

15. The cell or population thereof of claim 5, wherein the TCE is TCF1 or CD27.

16. The cell or population thereof of claim 5, wherein the site 1 is CD38, TIM3, TIGIT, or PH12; and wherein the site 2 is one of CD58, TIM3, TIGIT, or PH12.

17. The cell or population thereof of claim 1, wherein (i) the iPSC is a clonal iPSC, a single cell dissociated iPSC, an iPSC cell line cell, or an iPSC master cell bank (MCB) cell; or (ii) the derivative cell comprises a derivative CD34+cell, a derivative hematopoietic stem and progenitor cell, a derivative hematopoietic multipotent progenitor cell, a derivative T cell progenitor, a derivative NK cell progenitor, a derivative T lineage cell, a derivative NKT lineage cell, a derivative NK lineage cell, or a derivative B lineage cell; or (iii) the derivative cell comprises a derivative effector cell having one or more functional features that are not present in a counterpart primary T, NK, NKT, and / or B cell.

18. A composition comprising the cell or population thereof of any one of the claims 1-17.

19. The composition of claim 18, further comprising one or more therapeutic agents.

20. The composition of claim 19, wherein the one or more therapeutic agents comprise a peptide, a cytokine, a checkpoint inhibitor, a mitogen, a growth factor, a small RNA, a dsRNA (double stranded RNA), mononuclear blood cells, feeder cells, feeder cell components or replacement factors thereof, a vector comprising one or more polynucleic acids of interest, an antibody, an engager, a chemotherapeutic agent or a radioactive moiety, or an immunomodulatory drug (IMiD).

21. The composition of claim 20, wherein the antibody comprises:(a) an anti-CD20 antibody, an anti-HER2 antibody, an anti-CD52 antibody, an anti-EGFR antibody, an anti-CD123 antibody, an anti-GD2 antibody, an anti-PDLl antibody, or an anti-CD38 antibody; or(b) one or more of rituximab, veltuzumab, ofatumumab, ublituximab, ocaratuzumab, obinutuzumab, trastuzumab, pertuzumab, alemtuzumab, cetuximab, dinutuximab, avelumab, daclizumab, basiliximab, M-A251, 2A3, BC69, 24204, 22722, 24212, MAB23591, FN50, 298614, AF2359, CY1G4, DF1513, bivatuzumab, RG7356, G44-26, 7G3, CSL362, elotuzumab, daratumumab, isatuximab, MOR202, and their humanized or Fc modified variants or fragments and their functional equivalents and biosimilars thereof.

22. The composition of claim 20, wherein the engager comprises:(i) a bispecific T cell engager (BiTE);(ii) a bispecific killer cell engager (BiKE); or(iii) a tri-specific killer cell engager (TriKE); orwherein the engager comprises:(a) a first binding domain recognizing an extracellular portion of CD3, CD28, CD5, CD16, CD64, CD32, CD33, CD89, NKG2C, NKG2D, or any functional variants thereof of the cell or a by-stander immune effector cell; and(b) a second binding domain specific to an antigen comprising any one of: B7H3, CD10, CD19, CD20, CD22, CD24, CD30, CD33, CD34, CD38, CD44, CD52, CD79a, CD79b, CD 123, CD 138, CD 179b, CEA, CLEC12A, CS-1, DLL3, EGFR, EGFRvIII, EpCAM, FLT-3, FOLR1, FOLR3, GD2, gpA33, HER2, HM1.24, LGR5, MSLN, MCSP, MICA / B, Mucl, Mucl6, PDL1, PSMA, PAMA, P-cadherin, ROR1, or VEGF-R2.

23. A master cell bank (MCB) comprising the iPSC of any one of the claims 1-17.

24. Therapeutic use of the composition of any one of the claims 18-22 by introducing the composition to a subject in need of an adoptive cell therapy, wherein the subject has an autoimmune disorder, a hematological malignancy, a solid tumor, cancer, or a virus infection.

25. A method of treating a subject in need of an adoptive cell therapy, wherein the method comprises infusing the subject with effector cells, wherein the effector cells comprise the derivative cell or population thereof according to any one of claims 1-17.

26. The method of claim 25, wherein the effector cells comprise a CAR specific to an antigen expressed on a cancer cell, wherein the antigen comprises at least one of B7H3, BCMA, CD19, CD20, CD22, CD38, CD52, CD79b, CD 123, EGFR, EGP2 / EpCAM, GD2, GPRC5D, HER2, KLK2, MICA / B, MSLN, VEGF-R2, PSMA and PDL1.

27. The method of claim 25, further comprising administering one or more therapeutic agents to the subject, wherein the one or more therapeutic agents comprise:(i) a cytokine, an antibody, an engager, a checkpoint inhibitor, a chemotherapeutic agent or a radioactive moiety, or an immunomodulatory drug (IMiD);(ii) an anti-CD38 antibody comprising daratumumab, isatuximab, or MOR202;(iii) an engager comprising a BiTE (bi-specific T cell engager) or a TriKE (tri-specific Killer cell engager);(iv) a checkpoint inhibitor comprising atezolizumab, avelumab, durvalumab, ipilimumab, IPH4102, IPH43, IPH33, lirimumab, monalizumab, nivolumab, or pembrolizumab; and / or(v) a chemotherapeutic agent comprising cyclophosphamide and fludarabine (Cy / Flu).

28. The method of claim 25, wherein the effector cells comprise a CD38 knockout, a TCR knockout, and an ADR; wherein the method comprises administering to the subject an anti-CD38 antibody; and wherein the method does not require, or requires minimal, lymphodepletion comprising administering Cy / Flu to the subject.

29. The method of claim 25, wherein the effector cells are allogeneic, and wherein infusing the subject with effector cells is in an out-patient setting.

30. The method of claim 25, wherein the derivative cells are T lineage cells.-ISO-

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