Rankl binding switch receptors

Abstract

Disclosed herein are methods and compositions of RANKL-binding switch receptors and engineered immune cell comprising said switch receptors, wherein the switch receptor comprises a RANKL-binding ectodomain, transmembrane domain and a costimulatory endodomain.

Description

Attorney Docket Number 10110-470WO1 RANKL BINDING SWITCH RECEPTORS CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 671,759 filed on July 15, 2024, the disclosure of which is expressly incorporated by reference herein in their entireties. REFERENCE TO SEQUENCE LISTING The sequence listing submitted on July 15, 2025, as an .XML entitled “10110- 470WO1_ST26.xml” created on July 12, 2025, and having a file size of 9,166 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5). STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with Government support under CA241169 awarded by the National Institutes of Health. The U.S. Government has certain rights in this invention. BACKGROUND Bone is a common site of metastasis for multiple malignancies, including breast, prostate, and lung cancers. Among the molecular pathways involved in tumor-induced bone disease, the Receptor Activator of Nuclear Factor kappa-B Ligand (RANKL) signaling axis plays a central role. RANKL is a key regulator of bone remodeling and homeostasis through its interaction with the receptor RANK, which is expressed on osteoclast precursors and mature osteoclasts. Engagement of RANK by RANKL promotes osteoclast differentiation, activation, and survival, leading to increased bone resorption. In the context of cancer, RANKL is frequently expressed not only by cells of the bone microenvironment, such as osteoblasts and stromal cells, but also by tumor cells themselves. This ectopic expression of RANKL contributes to the establishment of a bone-destructive niche that facilitates tumor cell colonization, proliferation, and survival within the skeletal compartment. Osteolytic lesions resulting from excessive osteoclast activation release a variety of growth factors and cytokines embedded in the bone matrix, which, in turn, fuel further tumor growth and metastasis. This pathological feedback loop is commonly referred to as the “vicious cycle” of bone metastasis, representing a significant clinical challenge. Elevated levels of RANKL in patients with advanced cancers are indicative of a shift in bone homeostasis toward resorption and are associated with poor clinical outcomes. WhileAttorney Docket Number 10110-470WO1 RANKL-targeting agents have demonstrated clinical benefit in reducing skeletal-related events, there remains an unmet need for therapeutic strategies that not only inhibit bone degradation but also modulate the tumor promoting effects of the bone microenvironment. Furthermore, recent evidence suggests that RANKL signaling may influence immune responses in the tumor microenvironment, highlighting its potential role beyond bone biology. This has prompted interest in combinatorial approaches that integrate RANKL-targeted interventions with immune-based therapies, such as immune checkpoint inhibitors, to enhance anti-tumor immunity and improve therapeutic outcomes. Accordingly, there is a need in the art for novel therapeutics that can disrupt RANKL- mediated tumor-bone interactions while offering potential synergy with existing immunotherapies. Such approaches would ideally mitigate bone resorption, attenuate metastatic progression, and reprogram the immunosuppressive tumor niche, thereby addressing critical gaps in current treatment paradigms. SUMMARY Disclosed are methods and compositions related to RANKL binding switch receptors and its use as cancer and autoimmune therapy. In one aspect, disclosed herein are switch receptors comprising a) a Receptor Activator of Nuclear Factor-κB Ligand (RANKL)-binding ectodomain (such as, for example, a RANK-derived ectodomain or an anti-RANKL antibody of RANKL binding fragment thereof including, but not limited to Denosumab (or an scFv thereof), b) a transmembrane domain (such as, for example, the transmembrane domain of CD28, CD3ζ, NKG2D, or a combination thereof), and c) a costimulatory endodomain (such as, for example, the endodomain of CD28, CD27, CD2, OX40, 4-1BB, or a combination thereof). In some embodiments, the switch receptor is encoded by a gene carried by a viral vector. In some aspects, the viral vector further comprises a truncated CD34 (tCD34) marker gene. In some embodiments, the switch receptor comprises an amino acid sequence as set forth in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or a sequence having at least 95%, 98%, 99% or 99.8% identity thereto. In one aspect, disclosed herein are viral vectors comprising a polynucleotide sequence encoding a switch receptor, a chimeric antigen receptor (CAR) or a combination thereof. In some embodiments, the viral vector is an Adenovirus-associated Viral Vector (AAV). In some embodiments, the CAR gene in the viral vector further comprises a CAR with tumor-antigen binding domain, a CAR with pattern recognition receptor domain (PRR), a CAR with killer activated receptor (KAR) domain, a CAR with natural killer group 2D receptor (NKG2D) domain,Attorney Docket Number 10110-470WO1 a CAR with complement receptor domain, a CAR with Fc / scFv domain, a CAR with cytokine receptor domain or a split, universal, and programmable CAR (SUPRA CAR). Also disclosed herein are engineered immune cells (including but not limited to a CD4+ T cell, a CD8+ T cell, an alpha / beta T cell (αβ T cell), a gamma / delta T cell (γδ T cell), macrophages, natural killer (NK) cells and NKT cells) comprising at least one nucleic acid sequence encoding the CAR of any preceding aspect or the switch receptor of any preceding aspect, wherein the at least one nucleic acid sequence (SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5) encoding the CAR or the switch receptor is integrated in at least one viral vector of any preceding aspect. In some embodiments, the engineered cell co-expresses the viral vector comprising the nucleic acid sequences for CAR and the viral vector comprising the nucleic acid sequence encoding the switch receptor. In some embodiments, the CAR comprises the tumor antigen binding domains (for examples, including but not limited to a B-cell maturation antigen (BCMA), a CD19, a human epidermal growth factor 2 (HER2), or an epidermal growth factor receptor (EGFR)). In some aspects, the engineered immune cells can further comprise at least one additional immune receptor (such as, for example, including but not limited to a chimeric antigen receptor (CAR), a pattern recognition receptor (PRR), a T cell receptor (TCR), a killer activated receptors (KAR), a natural killer group 2D receptor (NKG2D), a complement receptor, an Fc receptor, a cytokine receptor and a programmed cell death protein 1 receptor (PD-1)). In some embodiments, the engineered cell co-expresses the viral vector comprising the nucleic acid sequences for CAR, the viral vector comprising the nucleic acid sequence encoding the switch receptor, and the viral vector comprising the nucleic acid sequence encoding the immune receptor. In some embodiments, the engineered cell transduced with a viral vector comprising the switch receptors also expresses a truncated CD34 molecule used as marker / enrichment element separated by a P2A cleavage site attached to the costimulatory endodomain in the viral vector (SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5). For example, disclosed herein are engineered immune cells comprising at least one nucleic acid sequence encoding the switch receptor of any preceding aspect and at least one other immune receptor of any preceding aspect. In some embodiments, the switch receptor, comprises a) a RANKL-binding ectodomain (such as, for example, a RANK-derived ectodomain or an anti-RANKL antibody of RANKL binding fragment thereof including, but not limited to Denosumab (or an scFv thereof), b) a transmembrane domain (such as, for example, the transmembrane domain of CD28, CD3ζ, NKG2D, or a combination thereof) (such as, for example, the transmembrane domain of CD28, CD3ζ, NKG2D, or a combination thereof); and c) a costimulatory endodomain (such as, for example, the endodomain of CD28, CD27, CD2, OX40, 4-1BB, or a combination thereof). In some aspects, the switch receptor is encoded by a geneAttorney Docket Number 10110-470WO1 carried by a viral vector. In some aspects, the viral vector further comprises a truncated CD34 (tCD34) marker gene. In one aspect disclosed herein are engineered immune cells of any preceding aspect, wherein the switch receptor is encoded by a gene carried by a viral vector. In some aspects, the switch receptor and the at least one other immune cell are carried by the same or different viral vectors. Also disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating and / or preventing a cancer and / or metastasis (such as for example, including but not limited to breast cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), prostate cancer, renal cell carcinoma, hepatocellular carcinoma, bone tumors, leukemia, osteosarcoma, multiple myeloma, or giant cell tumor) in a subject with a cancer comprising of administering to the subject a therapeutically effective dose of the switch receptor of any preceding aspect and / or an engineered immune cell of any preceding aspect, including, but not limited to engineered immune cells co-expressing a CAR, a switch receptor and at least one other immune receptor. For example, disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating and / or preventing a cancer and / or metastasis of any preceding aspect in a subject comprising of administering to the subject a therapeutically effective dose of the switch receptor comprising a) a RANKL-binding ectodomain (such as, for example, a RANK-derived ectodomain or an anti-RANKL antibody of RANKL binding fragment thereof including, but not limited to Denosumab (or an scFv thereof), b) a transmembrane domain (such as, for example, the transmembrane domain of CD28, CD3ζ, NKG2D, or a combination thereof); and c) a costimulatory endodomain (such as, for example, the endodomain of CD28, CD27, CD2, OX40, 4-1BB, or a combination thereof) and / or an engineered immune cell (including but not limited to a CD4+ T cell, a CD8+ T cell, an alpha / beta T cell (αβ T cell), a gamma / delta T cell (γδ T cell), macrophages, natural killer (NK) cells and NKT cells) comprising the switch receptors of any preceding aspect. In some aspects, the engineered immune cell further comprises at least one additional immune receptor (such as, for example, including but not limited to a chimeric antigen receptor (CAR) (including, but not limited to CARs with antigen binding domains that bind B-cell maturation antigen (BCMA), CD19, HER2, or EGFR), a pattern recognition receptor (PRR), a T cell receptor (TCR), a killer activated receptors (KAR), a natural killer group 2D receptor (NKG2D), a complement receptor, an Fc receptor, a cytokine receptor and a programmed cell death protein 1 receptor (PD-1)). In one aspect disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating and / or preventing a cancer and / or metastasis of any preceding aspect, wherein theAttorney Docket Number 10110-470WO1 switch receptor is encoded by a gene carried by a viral vector. In some aspects, the switch receptor and the at least one other immune cell are carried by the same or different viral vectors. In some aspects, the viral vector further comprises a truncated CD34 (tCD34) marker gene. In one aspect disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating and / or preventing an autoimmune disease (including but not limited to diabetes mellitus, chronic colitis, rheumatoid arthritis, multiple sclerosis (MS), or Alzheimer's disease) in a subject by administering a therapeutically effective dose of the switch receptor of any preceding aspect, the viral vector of any preceding aspect, and / or the engineered cell of any preceding aspect, further comprising the engineered immune cells co-expressing the CAR, the switch receptor and at least one other immune receptor. For example, disclosed herein is a method of treating, inhibiting, reducing, decreasing, ameliorating and / or preventing an autoimmune disease in a subject, comprising: administering to the subject a therapeutically effective dose of the switch receptor comprising a) a RANKL-binding ectodomain (such as, for example, a RANK-derived ectodomain, or an anti-RANKL antibody of RANKL binding fragment thereof including, but not limited to Denosumab (or an scFv thereof), b) a transmembrane domain (such as, for example, the transmembrane domain of CD28, CD3ζ, NKG2D, or a combination thereof); and c) a costimulatory endodomain (such as, for example, the endodomain of CD28, CD27, CD2, OX40, 4-1BB, or a combination thereof) and / or an engineered immune cell (including but not limited to a CD4+ T cell, a CD8+ T cell, an alpha / beta T cell (αβ T cell), a gamma / delta T cell (γδ T cell), macrophages, natural killer (NK) cells and NKT cells) comprising the switch receptors of any preceding aspect. In some aspects, the engineered immune cell further comprises at least one additional immune receptor (such as, for example, including but not limited to a chimeric antigen receptor (CAR)(including, but not limited to CARs with antigen binding domains that bind B-cell maturation antigen (BCMA), CD19, HER2, or EGFR), a pattern recognition receptor (PRR), a T cell receptor (TCR), a killer activated receptors (KAR), a natural killer group 2D receptor (NKG2D), a complement receptor, an Fc receptor, a cytokine receptor and a programmed cell death protein 1 receptor (PD-1)). In one aspect disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating and / or preventing an autoimmune disease of any preceding aspect, wherein the switch receptor is encoded by a gene carried by a viral vector. In some aspects, the switch receptor and the at least one other immune cell are carried by the same or different viral vectors. In some aspects, the viral vector further comprises a truncated CD34 (tCD34) marker gene.Attorney Docket Number 10110-470WO1 BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments and together with the description illustrate the disclosed compositions and methods. Some figures are generated using BioRender®. Figures 1A, 1B and 1C show a conceptual diagram of CAR-T cells expressing RANKL switch receptors. Figure 1A shows that T cells are engineered to co-express a chimeric antigen receptor (CAR) and a switch receptor composed of a RANKL-binding ectodomain, a transmembrane domain, and a co-stimulatory endodomain (for instance, CD27). As a result, switch receptors bind RANKL and transmit a positive signal for survival of the T cells. Figure 1B shows examples of switch receptor designs including the use of antibody (Denosumab)-derived ectodomains, or RANK-derived ectodomains, combined with CD2-, CD28-, CD27-, or 41BB- derived endodomain. Figure 1C shows switch receptors can be expressed from a viral vector used to co-transduce T cells at the same moment they are transduced with a CAR-encoding vector. P2A: cleavage site; tCD34: truncated CD34, as a marker gene; LTR: long terminal repeats; ψ: encapsidation signal; scFv: single chain fragment variable; ECD: extracellular domain. Figures 2A, 2B, 2C, 2D and 2E show RANKL binding by switch receptors and its association with T cell phenotype. Figure 2A shows a diagram of RANKL receptors including two Denosumab-based constructs, two RANK-based constructs, and the full RANK protein used as a control. Costimulatory domains derived from CD2, CD28, CD27, or 41BB. A truncated CD34 molecule is co-expressed as marker / enrichment element separated by a P2A cleavage site. Figure 2B shows CD34 expression analyzed by flow cytometry as a measure of T cell transduction. Histograms show data from a representative experiment. Bar chart to the right shows results from three independent donors. Figure 2C shows RANKL binding by CAR T cells co-transduced with RANKL switch receptors. Histograms show data from a representative experiment. Bar chart to the right shows results from three independent donors. T cells were incubated with recombinant human RANKL fused to an Fc domain, and then stained with a fluorescently labelled anti-Fc antibody. Figure 2D shows flow cytometry analysis to test the co-expression CD34 and CAR in γδ T cells. Figure 2E shows bar charts representing the distribution of different differentiation phenotypes in T cells expressing different RANKL switch receptors. Representative flow cytometry zebra to the right, for the comparison of CAR-T vs CAR-T + RANK-CD27 switch receptor. For all flow cytometry analyses, samples were gated on lymphoid, single, viable, CD3+, Vd2 TCR+ cells. Figures 3A, 3B, 3C, and 3D show switch receptor (RANK CD27)- armored CAR-T cells induce reduce tumor burden and persist longer than CAR-T cells. Figure 3A shows experimentalAttorney Docket Number 10110-470WO1 design to test in vivo activity of switch receptor-armored CAR-T cells. C42B intratibial xenografts were generated in NSG mice, which were treated with systemic injections of zoledronate (ZOL) and gamma / delta T cells, two weeks apart. IL-2 support was provided for 7 days post adoptive T cell transfer. Bioluminescence was monitored as a proxy of tumor burden. Figure 3B shows RANK CD27-armored gamma / delta T cells induced significant tumor reduction compared to untransduced (UT) gamma / delta T cells and untreated mice. Of note, RANK 41BB-armored CAR- T cells performed worse, with no significant difference compared to negative controls. *p<0.05, **p<0.01. Figure 3C depicts the same results as shown in Figure 3B but displayed in a linear scale. Figure 3D shows an analysis of T cell persistence in tumor-bearing tibiae. Gamma / delta CAR-T cells armored with RANK CD27 switch receptors were found in significantly greater numbers than gamma / delta CAR-cells or (UT) untransduced gamma / delta T cells. ****p<0.0001. DETAILED DESCRIPTION Before the present compounds, compositions, articles, devices, and / or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods or specific recombinant biotechnology methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. I. Definitions As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possibleAttorney Docket Number 10110-470WO1 ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “10” is disclosed the “less than or equal to 10”as well as “greater than or equal to 10” is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point 15 are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings: An “adeno-associated virus” or an “AAV” as used herein refers to a small virus belonging to the genus Dependoparvovirus which are replicative defective, non-enveloped viruses with linear single-stranded DNA. These viruses are commonly used for creating viral vectors for gene therapy, wherein said viruses can infect dividing and quiescent cells and persist in an extrachromosomal state without integrating into the host genome. AAVs can be engineered to express desired genes or gene products such as mRNA, shRNA, or miRNAs to overexpress or silence a target gene. The term “administer,” “administering”, or derivatives thereof refer to delivering a composition, substance, inhibitor, or medication to a subject or object by one or more the following routes: oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation or via an implanted reservoir. The term “parenteral” includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. The term "antibody" is used in the broadest sense, and specifically covers monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, and multispecific antibodies (e.g., bispecific antibodies). Antibodies (Abs) and immunoglobulins (Igs) are glycoproteins that have the same structural characteristics. While antibodies exhibit binding specificity to a specific target, immunoglobulins include both antibodies and other antibody-like molecules which lack target specificity. Native antibodies and immunoglobulins are usually heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each heavy chain has at one end a variable domainAttorney Docket Number 10110-470WO1 (VH) followed by a number of constant domains. Each light chain has a variable domain at one end (VL) and a constant domain at its other end. The term "antibody fragment" refers to a portion of a full-length antibody, generally the target binding or variable region. Examples of antibody fragments include Fab, Fab', F(ab')2 and Fv fragments. The phrase "functional fragment or analog" of an antibody is a compound having qualitative biological activity in common with a full-length antibody. For example, a functional fragment or analog of an anti-IgE antibody is one which can bind to an IgE immunoglobulin in such a manner so as to prevent or substantially reduce the ability of such molecule from having the ability to bind to the high affinity receptor, FcεRI. As used herein, "functional fragment" with respect to antibodies, refers to Fv, F(ab) and F(ab')2 fragments. An "Fv" fragment is the minimum antibody fragment which contains a complete target recognition and binding site. This region consists of a dimer of one heavy and one light chain variable domain in a tight, non-covalent association (VH-VL dimer). It is in this configuration that the three CDRs of each variable domain interact to define a target binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer target binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for a target) has the ability to recognize and bind target, although at a lower affinity than the entire binding site. "Single-chain Fv" or "sFv" antibody fragments comprise the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. Generally, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the sFv to form the desired structure for target binding. The term “amino acid,” includes but is not limited to amino acids contained in the group consisting of alanine (Ala or A), cysteine (Cys or C), aspartic acid (Asp or D), glutamic acid (Glu or E), phenylalanine (Phe or F), glycine (Gly or G), histidine (His or H), isoleucine (Ile or I), lysine (Lys or K), leucine (Leu or L), methionine (Met or M), asparagine (Asn or N), proline (Pro or P), glutamine (Gln or Q), arginine (Arg or R), serine (Ser or S), threonine (Thr or T), valine (Val or V), tryptophan (Trp or W), and tyrosine (Tyr or Y) residues. The term “amino acid residue” also may include amino acid residues contained in the group consisting of homocysteine, 2- Aminoadipic acid, N-Ethylasparagine, 3-Aminoadipic acid, Hydroxylysine, β-alanine, β-Amino- propionic acid, allo-Hydroxylysine acid, 2-Aminobutyric acid, 3-Hydroxyproline, 4- Aminobutyric acid, 4-Hydroxyproline, piperidinic acid, 6-Aminocaproic acid, Isodesmosine, 2- Aminoheptanoic acid, allo-Isoleucine, 2-Aminoisobutyric acid, N-Methylglycine, sarcosine, 3- Aminoisobutyric acid, N-Methylisoleucine, 2-Aminopimelic acid, 6-N-Methyllysine, 2,4- Diaminobutyric acid, N-Methylvaline, Desmosine, Norvaline, 2,2′-Diaminopimelic acid,Attorney Docket Number 10110-470WO1 Norleucine, 2,3-Diaminopropionic acid, Ornithine, and N-Ethylglycine. Typically, the amide linkages of the peptides are formed from an amino group of the backbone of one amino acid and a carboxyl group of the backbone of another amino acid. The terms “anticancer” and “anticarcinogen” refer to a substance, composition, or formula that counteracts the effects or inhibits the development of a cancerous cells and tissues. An “antigen” refers to a molecule, moiety, foreign particulate matter, or an allergen that can bind to a specific antibody or T cell receptor. The presence of antigens within a host can illicit an immune response against said molecule, moiety, foreign particulate matter, or allergen. As used herein, the term “agent” refers to a living organism or biological substance, such as a bacterium, virus, protozoan, parasite, fungus, chemical, or toxin, that can be designed to purposefully fulfill a biological function or action. "Biocompatible" generally refers to a material and any metabolites or degradation products thereof that are generally non-toxic to the recipient and do not cause significant adverse effects to the subject. As used herein, the term “buffer” refers to a solution consisting of a mixture of acid and its conjugate base, or vice versa. The solution is used as a means of keeping the pH at a nearly constant range to be used in a wide variety of chemical and biological applications. The term “cytotoxic” as used herein refers to the ability to kill a target cell. A cytotoxic T cell or NK cell may kill a target cell via target cell apoptosis using one or more different mechanisms including release of one or more cytotoxins or expression of a Fas ligand. In some embodiments, a cytotoxic T cell or NK cell kills a tumor cell via the release of one or more cytotoxins. “Cytotoxin” includes, but is not limited to, a perforin, a granzyme and a granulysin. Currently known granzymes are Granzyme A (GZMA), Granzyme B (GZMB), Granzyme H (GZMH), Granzyme K (GZMK), and Granzyme M (GZMM). The term “cancer” is used to address any neoplastic disease and is not limited to epithelial neoplasms (surface and glandular cancers; such a squamous cancers or adenomas)). It is used here to describe both solid tumors and hematologic malignancies, including epithelial (surface and glandular) cancers, soft tissue and bone sarcomas, angiomas, mesothelioma, melanoma, lymphomas, leukemias and myeloma. "Comprising" is intended to mean that the compositions, methods, etc. include the recited elements, but do not exclude others. "Consisting essentially of'' when used to define compositions and methods, shall mean including the recited elements, but excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation andAttorney Docket Number 10110-470WO1 purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. "Consisting of'' shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions provided and / or claimed in this disclosure. Embodiments defined by each of these transition terms are within the scope of this disclosure. A “control” is an alternative subject or sample used in an experiment for comparison purposes. A control can be "positive" or "negative." A “chimeric antigen receptor” is an artificial T cell receptor used for immunotherapy. CAR are protein receptors that have been engineered to give T cells an enhanced ability to target a specific protein. CAR receptors are chimeric because the antigen binding and T cell activating functions have been combined into a single receptor. The term “detect” or “detecting” refers to an output signal released for the purpose of sensing of physical phenomenon. An event or change in environment is sensed and signal output released in the form of light. A "decrease" can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity. A substance is also understood to decrease the genetic output of a gene when the genetic output of the gene product with the substance is less relative to the output of the gene product without the substance. Also, for example, a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed. A decrease can be any individual, median, or average decrease in a condition, symptom, activity, composition in a statistically significant amount. Thus, the decrease can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% decrease so long as the decrease is statistically significant. As used herein, “diagnose”, “diagnosed”, “diagnosing”, and any grammatical variations thereof as used herein, refers to the act of process of identifying the nature of an illness, disease, disorder, or condition in a subject by examination or monitoring of symptoms. An “epitope” or “antigenic determinant” refer to the part of an antigen, a molecular structure, or foreign particulate that can bind to a specific antibody or T-cell receptor. The presence of antigens or epitopes of antigens within a host can illicit an immune response. “Effective amount” of an agent refers to a sufficient amount of an agent to provide a desired effect. The amount of agent that is “effective” will vary from subject to subject, depending on many factors such as the age and general condition of the subject, the particular agent or agents, and the like. Thus, it is not always possible to specify a quantified “effective amount.” However, an appropriate “effective amount” in any subject case may be determined by one of ordinary skillAttorney Docket Number 10110-470WO1 in the art using routine experimentation. Also, as used herein, and unless specifically stated otherwise, an “effective amount” of an agent can also refer to an amount covering both therapeutically effective amounts and prophylactically effective amounts. An “effective amount” of an agent necessary to achieve a therapeutic effect may vary according to factors such as the age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. As used herein, “enhance”, “enhanced”, “enhancement”, “enhancing”, and any grammatical variations thereof as used herein, refers to an act of intensifying, increasing, or further improving the quality, value, or extent of a biological function, composition, compound, cell, or tissue. “Expression” as used herein refers to the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce a peptide / protein end product, and ultimately affect a phenotype, as the final effect. Variants comprising a fragment of a reference amino acid sequence or nucleotide sequence are contemplated herein. A “fragment” is a portion of an amino acid sequence or a nucleotide sequence which is identical in sequence to but shorter in length than the reference sequence. A fragment may comprise up to the entire length of the reference sequence, minus at least one nucleotide / amino acid residue. For example, a fragment may comprise from 5 to 1000 contiguous nucleotides or contiguous amino acid residues of a reference polynucleotide or reference polypeptide, respectively. In some embodiments, a fragment may comprise at least 5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 150, 250, or 500 contiguous nucleotides or contiguous amino acid residues of a reference polynucleotide or reference polypeptide, respectively. Fragments may be preferentially selected from certain regions of a molecule, for example the N-terminal region and / or the C-terminal region of a polypeptide or the 5′-terminal region and / or the 3′ terminal region of a polynucleotide. The term “at least a fragment” encompasses the full-length polynucleotide or full-length polypeptide. A "gene" refers to a polynucleotide containing at least one open reading frame that is capable of encoding a particular polypeptide or protein after being transcribed and translated. Any of the polynucleotide sequences described herein may be used to identify larger fragments or full- length coding sequences of the gene with which they are associated. Methods of isolating larger fragment sequences are known to those of skill in the art, some of which are described herein. A "gene product" refers to the amino acid (e.g., peptide or polypeptide) generated when a gene is transcribed and translated.Attorney Docket Number 10110-470WO1 “Homology” refers to sequence similarity or, interchangeably, sequence identity, between two or more polypeptide sequences or polynucleotide sequences. Homology, sequence similarity, and percentage sequence identity may be determined using methods in the art and described herein. Variants comprising insertions or additions relative to a reference sequence are contemplated herein. The words “insertion” and “addition” refer to changes in an amino acid or nucleotide sequence resulting in the addition of one or more amino acid residues or nucleotides. An insertion or addition may refer to 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, or 200 amino acid residues or nucleotides. The terms “immunotherapy” and “immunotherapeutic” refer to the treatment of disease by activating or suppressing the immune system. In cancer treatment, the most effective immunotherapies are cell-based immunotherapies that utilize lymphocytes, macrophages, dendritic cells, natural killer cells, cytotoxic T lymphocytes, etc. to defend the body against cancer by targeting abnormal antigens expressed on the surface of tumor cells. An "increase" can refer to any change that results in a greater amount of a symptom, disease, composition, condition or activity. An increase can be any individual, median, or average increase in a condition, symptom, activity, composition in a statistically significant amount. Thus, the increase can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% increase so long as the increase is statistically significant. "Inhibit," "inhibiting," and "inhibition" mean to decrease an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels. A “macrophage” is a type of white blood of the immune system that engulfs and digests pathogens inside a body, including cancer cells, microbes, cellular debris, and foreign substance, which do not have proteins that are specific to healthy body cells on their cell surfaces. A “nucleotide” is a compound consisting of a nucleoside, which consists of a nitrogenous base and a 5-carbon sugar, linked to a phosphate group forming the basic structural unit of nucleic acids, such as DNA or RNA. The four types of nucleotides are adenine (A), cytosine (C), guanine (G), and thymine (T), each of which are bound together by a phosphodiester bond to form a nucleic acid molecule.Attorney Docket Number 10110-470WO1 A “nucleic acid” is a chemical compound that serves as the primary information-carrying molecules in cells and makes up the cellular genetic material. Nucleic acids comprise nucleotides, which are the monomers made of a 5-carbon sugar (usually ribose or deoxyribose), a phosphate group, and a nitrogenous base. A nucleic acid can also be a deoxyribonucleic acid (DNA) or a ribonucleic acid (RNA). A chimeric nucleic acid comprises two or more of the same kind of nucleic acid fused together to form one compound comprising genetic material. As used herein, “operably fused” refers to two or more compositions or compounds being bound or linked together in such a way the optimizes the intended function. When bound or linked, these compositions or compounds can be linked covalently, electrostatic interaction, through hydrogen bonding, or any combinations thereof. An “osteoblast” refers to a specialized cell type with a single nucleus that synthesizes bone. “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. By “prevent” or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed. As used herein, the term “antibody or fragments thereof” encompasses chimeric antibodies and hybrid antibodies, with dual or multiple antigen or epitope specificities, and fragments, such as F(ab’)2, Fab’, Fab, Fv, sFv, scFv, and the like, including hybrid fragments. Thus, fragments of the antibodies that retain the ability to bind their specific antigens are provided. For example, fragments of antibodies which maintain RANKL binding activity are included within the meaning of the term “antibody or fragment thereof.” Such antibodies and fragments can be made by techniques known in the art and can be screened for specificity and activity according to the methods set forth in the Examples and in general methods for producing antibodies and screening antibodies for specificity and activity (See Harlow and Lane. Antibodies, A Laboratory Manual. Cold Spring Harbor Publications, New York, (1988)).Attorney Docket Number 10110-470WO1 A "pharmaceutically acceptable" component can refer to a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into a pharmaceutical formulation provided by the disclosure and administered to a subject as described herein without causing significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained. When used in reference to administration to a human, the term generally implies the component has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration. "Pharmaceutically acceptable carrier" (sometimes referred to as a “carrier”) means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and / or human pharmaceutical or therapeutic use. The terms "carrier" or "pharmaceutically acceptable carrier" can include, but are not limited to, phosphate buffered saline solution, water, emulsions (such as an oil / water or water / oil emulsion) and / or various types of wetting agents. As used herein, the term "carrier" encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations and as described further herein. “Pharmacologically active” (or simply “active”), as in a “pharmacologically active” derivative or analog, can refer to a derivative or analog (e.g., a salt, ester, amide, conjugate, metabolite, isomer, fragment, etc.) having the same type of pharmacological activity as the parent compound and approximately equivalent in degree. Reference also is made herein to peptides, polypeptides, proteins, and compositions comprising peptides, polypeptides, and proteins. As used herein, a polypeptide and / or protein is defined as a polymer of amino acids, typically of length≥100 amino acids (Garrett & Grisham, Biochemistry, 2nd edition, 1999, Brooks / Cole, 110). A peptide is defined as a short polymer of amino acids, of a length typically of 20 or less amino acids, and more typically of a length of 12 or less amino acids (Garrett & Grisham, Biochemistry, 2nd edition, 1999, Brooks / Cole, 110). The peptides, polypeptides, and proteins disclosed herein may be modified to include non- amino acid moieties. Modifications may include but are not limited to carboxylation (e.g., N- terminal carboxylation via addition of a di-carboxylic acid having 4-7 straight-chain or branched carbon atoms, such as glutaric acid, succinic acid, adipic acid, and 4,4-dimethylglutaric acid), amidation (e.g., C-terminal amidation via addition of an amide or substituted amide such as alkylamide or dialkylamide), PEGylation (e.g., N-terminal or C-terminal PEGylation via additional of polyethylene glycol), acylation (e.g., O-acylation (esters), N-acylation (amides), S-Attorney Docket Number 10110-470WO1 acylation (thioesters)), acetylation (e.g., the addition of an acetyl group, either at the N-terminus of the protein or at lysine residues), formylation lipoylation (e.g., attachment of a lipoate, a C8 functional group), myristoylation (e.g., attachment of myristate, a C14 saturated acid), palmitoylation (e.g., attachment of palmitate, a C16 saturated acid), alkylation (e.g., the addition of an alkyl group, such as an methyl at a lysine or arginine residue), isoprenylation or prenylation (e.g., the addition of an isoprenoid group such as farnesol or geranylgeraniol), amidation at C- terminus, glycosylation (e.g., the addition of a glycosyl group to either asparagine, hydroxylysine, serine, or threonine, resulting in a glycoprotein). Distinct from glycation, which is regarded as a nonenzymatic attachment of sugars, polysialylation (e.g., the addition of polysialic acid), glypiation (e.g., glycosylphosphatidylinositol (GPI) anchor formation, hydroxylation, iodination (e.g., of thyroid hormones), and phosphorylation (e.g., the addition of a phosphate group, usually to serine, tyrosine, threonine, or histidine). The phrases “percent identity” and “% identity,” as applied to polypeptide sequences, refer to the percentage of residue matches between at least two polypeptide sequences aligned using a standardized algorithm. Methods of polypeptide sequence alignment are well-known. Some alignment methods consider conservative amino acid substitutions. Such conservative substitutions, explained in more detail above, generally preserve the charge and hydrophobicity at the site of substitution, thus preserving the structure (and therefore function) of the polypeptide. Percent identity for amino acid sequences may be determined as understood in the art. (See, e.g., U.S. Pat. No. 7,396,664, which is incorporated herein by reference in its entirety). A suite of commonly used and freely available sequence comparison algorithms is provided by the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST) (Altschul, S. F. et al. (1990) J. Mol. Biol.215:403410), which is available from several sources, including the NCBI, Bethesda, Md., at its website. The BLAST software suite includes various sequence analysis programs including “blastp,” that is used to align a known amino acid sequence with other amino acids sequences from a variety of databases. Percent identity may be measured over the length of an entire defined polypeptide sequence or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polypeptide sequence, for instance, a fragment of at least 15, at least 20, at least 30, at least 40, at least 50, at least 70 or at least 150 contiguous residues. Such lengths are exemplary only, and it is understood that any fragment length may be used to describe a length over which percentage identity may be measured.Attorney Docket Number 10110-470WO1 It is understood that the average molecular weight of one amino acid is about 110 Daltons (Da). Therefore, 10 amino acids are about 1100 Da. It is further understood that 1000 Da is the same as 1 kiloDalton (kDa). A "promoter," as used herein, refers to a sequence in DNA that mediates the initiation of transcription by an RNA polymerase. Transcriptional promoters may comprise one or more of a number of different sequence elements as follows: sequence elements present at the site of transcription initiation; 2) sequence elements present upstream of the transcription initiation site and; 3) sequence elements down- stream of the transcription initiation site. The individual sequence elements function as sites on the DNA, where RNA polymerases and transcription factors facilitate positioning of RNA polymerases on the DNA bind. As used herein, the term "polymerase chain reaction" ("PCR") refers to a method for increasing the concentration of a segment of a target sequence in a mixture of genomic DNA without cloning or purification. This process for amplifying the target sequence typically consists of introducing a large excess of two oligonucleotide primers to the DNA mixture containing the desired target sequence, followed by a precise sequence of thermal cycling in the presence of a DNA polymerase. The two primers are complementary to their respective strands of the double stranded target sequence. To effect amplification, the mixture is denatured, and the primers then annealed to their complementary sequences within the target molecule. Following annealing, the primers are extended with a polymerase so as to form a new pair of complementary strands. The steps of denaturation, primer annealing, and polymerase extension can be repeated many times to obtain a high concentration of an amplified segment of the desired target sequence. Unless otherwise noted, PCR, as used herein, also includes variants of PCR such as allele-specific PCR, asymmetric PCR, hot-start PCR, ligation-mediated PCR, multi- plex-PCR, reverse transcription PCR, or any of the other PCR variants known to those skilled in the art. “Primers” are a subset of probes which are capable of supporting some type of enzymatic manipulation and which can hybridize with a target nucleic acid such that the enzymatic manipulation can occur. A primer can be made from any combination of nucleotides or nucleotide derivatives or analogs available in the art which do not interfere with the enzymatic manipulation. “Probes” are molecules capable of interacting with a target nucleic acid, typically in a sequence specific manner, for example through hybridization. The hybridization of nucleic acids is well understood in the art and discussed herein. Typically, a probe can be made from any combination of nucleotides or nucleotide derivatives or analogs available in the art.Attorney Docket Number 10110-470WO1 By “reduce” or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic (e.g., tumor growth). It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to. For example, “reduces tumor growth” means reducing the rate of growth of a tumor relative to a standard or a control. A “receptor is a cellular protein whose activation causes a cell to modify its present functions or actions. The term “subject” refers to any individual who is the target of administration or treatment. The subject can be a vertebrate, for example, a mammal. In one aspect, the subject can be human, non-human primate, bovine, equine, porcine, canine, or feline. The subject can also be a guinea pig, rat, hamster, rabbit, mouse, or mole. Thus, the subject can be a human or veterinary patient. The term “patient” refers to a subject under the treatment of a clinician, e.g., physician. "Transformation" of a cellular organism with DNA means introducing DNA into an organism so that at least a portion of the DNA is replicable, either as an extrachromosomal element or by chromosomal integration. "Transfection" of a cellular organism with DNA refers to the taking up of DNA, e.g., an expression vector, by the cell or organism whether or not any coding sequences are in fact expressed. The terms "transfected host cell" and "transformed" refer to a cell in which DNA was introduced. The cell is termed "host cell" and it may be either prokaryotic or eukaryotic. Typical prokaryotic host cells include various strains of E. coli. Typical eukaryotic host cells are mammalian, such as Chinese hamster ovary or cells of human origin. The introduced DNA sequence may be from the same species as the host cell of a different species from the host cell, or it may be a hybrid DNA sequence, containing some foreign and some homologous DNA. The term “therapeutically effective” refers to the amount of the composition used is of sufficient quantity to ameliorate one or more causes or symptoms of a disease or disorder. Such amelioration only requires a reduction or alteration, not necessarily elimination. The term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportiveAttorney Docket Number 10110-470WO1 treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. Targeted therapy is a type of cancer treatment that uses a drug, substance, composition or formula that precisely identifies and targets proteins that control how cancer cells grow, divide, and spread and then attacks / kills the cancer cell. A targeted therapy can be used by itself or in combination with other anti-cancer treatments, such as, for example chemotherapy, surgery, or radiation therapy. A “T cell” refers to a type of lymphocyte that is one of the most important white blood cells of the immune system. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface. The immune-mediated cell death function of T cells is carried by two major subtypes: CD8+“killer” T cells and CD4+“helper T cells. As used herein, a “therapeutic regimen” refers to a structured treatment plan or strategy designed to improve and maintain health. Generally, a therapeutic regimen will be designed, prescribed, and / or administered by a licensed medical practitioner. The therapeutic regimen generally specifies the treatment dosage, the treatment scheduling, and the duration of the treatment. In some embodiments, the therapeutic regimen comprises one or more therapeutic compositions. In some embodiments, the therapeutic regimen comprises one or more therapeutic agents. In some embodiments, the therapeutic regimen comprises any combination of therapeutic compositions and therapeutic agents, such as for example the combination of an inhibitor and an antibody. In some embodiments, a therapeutic regimen comprises modifying, continuing, and / or initiating at least one therapeutic agent and / or therapeutic composition. In some embodiments, a therapeutic regimen comprises treating and / or preventing a disease, disorder, and / or condition. “Therapeutic agent” refers to any composition that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, e.g., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, e.g., prevention of a disorder or other undesirable physiological condition (e.g., a non-immunogenic cancer). The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, salts, esters, amides, proagents, active metabolites, isomers, fragments, analogs, and the like. When the terms “therapeutic agent” is used, then, or when a particular agent is specifically identified, it is to be understood that the term includes the agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, proagents, conjugates, active metabolites, isomers, fragments, analogs, etc. “Therapeutically effective amount” or “therapeutically effective dose” of a composition (e.g. a composition comprising an agent) refers to an amount that is effective to achieve a desiredAttorney Docket Number 10110-470WO1 therapeutic result. In some embodiments, a desired therapeutic result is the control of type I diabetes. In some embodiments, a desired therapeutic result is the control of obesity. Therapeutically effective amounts of a given therapeutic agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the subject. The term can also refer to an amount of a therapeutic agent, or a rate of delivery of a therapeutic agent (e.g., amount over time), effective to facilitate a desired therapeutic effect, such as pain relief. The precise desired therapeutic effect will vary according to the condition to be treated, the tolerance of the subject, the agent and / or agent formulation to be administered (e.g., the potency of the therapeutic agent, the concentration of agent in the formulation, and the like), and a variety of other factors that are appreciated by those of ordinary skill in the art. In some instances, a desired biological or medical response is achieved following administration of multiple dosages of the composition to the subject over a period of days, weeks, or years. The term “variant” means a polypeptide derived from a parent polypeptide by one or more (several) alteration(s), i.e., a substitution, insertion, and / or deletion, at one or more (several) positions. A substitution means a replacement of an amino acid occupying a position with a different amino acid; a deletion means removal of an amino acid occupying a position; and an insertion means adding 1 or more, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1-3 amino acids immediately adjacent an amino acid occupying a position. In relation to substitutions, ‘immediately adjacent’ may be to the N-side (‘upstream’) or C-side (‘downstream’) of the amino acid occupying a position (‘the named amino acid’). Therefore, for an amino acid named / numbered ‘X,’ the insertion may be at position ‘X+1’ (‘downstream’) or at position ‘X−1’ (‘upstream’). The word “vector” refers to any vehicle that carries a polynucleotide into a cell for the expression of the polynucleotide in the cell. The vector may be, for example, a plasmid, a virus, a phage particle, or a nanoparticle. Once transformed into a suitable host, the vector may replicate and function independently of the host genome, or may in some instances, integrate into the genome itself. In some embodiments, the vector is a DNA construct containing a DNA sequence which is operably linked to a suitable control sequence capable of affecting the expression of the DNA in a suitable host cell. Such control sequences can include a promoter to effect transcription, an optional operator sequence to control such transcription, a sequence encoding suitable mRNA ribosome binding sites, and sequences which control the termination of transcription and translation. In other embodiments, the vector is a lipid nanoparticle. Lipid nanoparticles can be used to deliver mRNA to a host cell for expression of the mRNA in the host cell.Attorney Docket Number 10110-470WO1 Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. II. Sequences There are a variety of sequences related to the protein molecules disclosed herein, for example RANK-41BB-CD34, all of which are encoded by nucleic acids or are nucleic acids. The sequences for the human analogs of these genes, as well as other analog, and alleles of these genes, and splice variants and other types of variants, are available in a variety of protein and gene databases, including Genbank. Those of skill in the art understand how to resolve sequence discrepancies and differences and to adjust the compositions and methods relating to a particular sequence to other related sequences. Primers and / or probes can be designed for any given sequence given the information disclosed herein and known in the art. III. Switch Receptors Switch receptors also known as chimeric switch receptors are created to reverse the outcomes of their original signaling pathways in order to confer the ability to overcome the immunosuppressive tumor microenvironment on immune cells and to allow them to have greater in vivo persistence. An activating switch receptor exploits the inhibitory molecules expressed by cancer cells to further stimulate the tumor antigen-specific T lymphocytes while an inhibitory switch receptor inhibits the effects of tumor-reactive T lymphocytes on unintended targets. The examples of switch receptors include but are not limited to PD1CD28 switch-receptor, TIGIT-28 chimeric co-stimulatory switch receptor, and T3 / 28 switch receptor. In one aspect, disclosed herein are switch receptors comprising a) a Receptor Activator of Nuclear Factor-κB Ligand (RANKL)-binding ectodomain (such as, for example, a RANK-derived ectodomain or an anti-RANKL antibody of RANKL binding fragment thereof including, but not limited to Denosumab (or an scFv thereof), b) a transmembrane domain (such as, for example, the transmembrane domain of CD28, CD3ζ, NKG2D, or a combination thereof), and c) a costimulatory endodomain (such as, for example, the endodomain of CD28, CD27, CD2, OX40, 4-1BB, or a combination thereof). In some embodiments, the switch receptor is encoded by a gene carried by a viral vector. In some aspects, the viral vector further comprises a truncated CD34 (tCD34) marker gene. In some embodiments, the switch receptor comprises an amino acid sequence as set forth in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or a sequence having at least 95%, 98%, 99% or 99.8% identity thereto.Attorney Docket Number 10110-470WO1 IV. Engineered immune cells comprising a switch receptor Disclosed herein, are engineered immune cells comprising any of the switch receptors disclosed herein. For example, disclosed herein are engineered immune cells comprising a switch receptor, wherein the switch receptor comprises a) a RANKL-binding ectodomain (such as, for example, a RANK-derived ectodomain or an anti-RANKL antibody of RANKL binding fragment thereof including, but not limited to Denosumab (or an scFv thereof), b) a transmembrane domain (such as, for example, the transmembrane domain of CD28, CD3ζ, NKG2D, or a combination thereof); and c) a costimulatory endodomain (such as, for example, the endodomain of CD28, CD27, CD2, OX40, 4-1BB, or a combination thereof). The engineered immune cell can be selected from a group including but not limited to a CD4+ T cell, a CD8+ T cell, an alpha / beta T cell (αβ T cell), a gamma / delta T cell (γδ T cell), macrophages, and an NK cell. Accordingly, disclosed herein are engineered immune cells (including but not limited to a CD4+ T cell, a CD8+ T cell, an alpha / beta T cell (αβ T cell), a gamma / delta T cell (γδ T cell), macrophages, natural killer (NK) cells and NKT cells) comprising a switch receptor, wherein the switch receptor comprises a) a RANKL-binding ectodomain (such as, for example, a RANK-derived ectodomain or an anti-RANKL antibody of RANKL binding fragment thereof including, but not limited to Denosumab (or an scFv thereof), b) a transmembrane domain (such as, for example, the transmembrane domain of CD28, CD3ζ, NKG2D, or a combination thereof); and c) a costimulatory endodomain (such as, for example, the endodomain of CD28, CD27, CD2, OX40, 4-1BB, or a combination thereof). These immune cells can be engineered to express a switch receptor alone, or in combination with at least one other immune receptor such as for example, including but not limited to a chimeric antigen receptor (CAR), a pattern recognition receptor (PRR), a T cell receptor (TCR), a killer activated receptors (KAR), a natural killer group 2D receptor (NKG2D), a complement receptor, an Fc receptor, a cytokine receptor and a programmed cell death protein 1 receptor (PD-1). In some aspects, the CAR comprises a tumor antigen binding domain (for example, including but not limited to a B-cell maturation antigen (BCMA), a CD19, a human epidermal growth factor 2 (HER2), or an epidermal growth factor receptor (EGFR)). V. Delivery of the engineered immune cells comprising a switch receptor As disclosed herein the switch receptor and / or the at least one other immune receptor are encoded by genes carried by the same or different viral vectors, wherein the viral vector further comprises a truncated CD34 (tCD34) marker gene. There are a number of compositions and methods which can be used to deliver nucleic acids (encoding the switch receptor, as disclosed herein) to cells, either in vitro or in vivo. TheseAttorney Docket Number 10110-470WO1 methods and compositions can largely be broken down into two classes: viral based delivery systems and non-viral based delivery systems. For example, the nucleic acids can be delivered through a number of direct delivery systems such as, electroporation, lipofection, calcium phosphate precipitation, plasmids, viral vectors, viral nucleic acids, phage nucleic acids, phages, cosmids, or via transfer of genetic material in cells or carriers such as cationic liposomes. Appropriate means for transfection, including viral vectors, chemical transfectants, or physico- mechanical methods such as electroporation and direct diffusion of DNA, are described by, for example, Wolff, J. A., et al., Science, 247, 1465-1468, (1990); and Wolff, J. A. Nature, 352, 815- 818, (1991). Such methods are well known in the art and readily adaptable for use with the compositions and methods described herein. In certain cases, the methods will be modified to specifically function with large DNA molecules. Further, these methods can be used to target certain diseases and cell populations by using the targeting characteristics of the carrier. In one aspect, disclosed herein are viral vectors comprising a polynucleotide sequence encoding a switch receptor, a chimeric antigen receptor (CAR) or a combination thereof. In some embodiments, the viral vector is an Adenovirus-associated Viral Vector (AAV). In some embodiments, the CAR gene in the viral vector further comprises a CAR with tumor-antigen binding domain, a CAR with pattern recognition receptor domain (PRR), a CAR with killer activated receptor (KAR) domain, a CAR with natural killer group 2D receptor (NKG2D) domain, a CAR with complement receptor domain, a CAR with Fc / scFv domain, a CAR with cytokine receptor domain or a split, universal, and programmable CAR (SUPRA CAR). VI. Nucleic acid-based delivery systems Transfer vectors can be any nucleotide construction used to deliver genes into cells (e.g., a plasmid), or as part of a general strategy to deliver genes, e.g., as part of recombinant retrovirus or adenovirus (Ram et al. Cancer Res.53:83-88, (1993)). As used herein, plasmid or viral vectors are agents that transport the disclosed nucleic acids, encoding the switch receptor into the cell without degradation and include a promoter yielding expression of the gene in the cells into which it is delivered. In some embodiments the vectors are derived from either a virus or a retrovirus. Viral vectors are, for example, Adenovirus, Adeno-associated virus, Herpes virus, Vaccinia virus, Polio virus, AIDS virus, neuronal trophic virus, Sindbis and other RNA viruses, including these viruses with the HIV backbone. Also preferred are any viral families which share the properties of these viruses which make them suitable for use as vectors. Retroviruses include Murine Maloney Leukemia virus, MMLV, and retroviruses that express the desirable properties of MMLV as a vector. Retroviral vectors are able to carry a larger genetic payload, i.e., a transgene or marker gene, than other viral vectors, and forAttorney Docket Number 10110-470WO1 this reason are a commonly used vector. However, they are not as useful in non-proliferating cells. Adenovirus vectors are relatively stable and easy to work with, have high titers, and can be delivered in aerosol formulation, and can transfect non-dividing cells. Pox viral vectors are large and have several sites for inserting genes, they are thermostable and can be stored at room temperature. A preferred embodiment is a viral vector which has been engineered so as to suppress the immune response of the host organism, elicited by the viral antigens. Preferred vectors of this type will carry coding regions for Interleukin 8 or 10. Viral vectors can have higher transaction (ability to introduce genes) abilities than chemical or physical methods to introduce genes into cells. Typically, viral vectors contain, nonstructural early genes, structural late genes, an RNA polymerase III transcript, inverted terminal repeats necessary for replication and encapsulation, and promoters to control the transcription and replication of the viral genome. When engineered as vectors, viruses typically have one or more of the early genes removed and a gene or gene / promotor cassette is inserted into the viral genome in place of the removed viral DNA. Constructs of this type can carry up to about 8 kb of foreign genetic material. The necessary functions of the removed early genes are typically supplied by cell lines which have been engineered to express the gene products of the early genes in trans. For example, in one aspect, disclosed herein are viral vectors comprising a polynucleotide sequence encoding a switch receptor, a chimeric antigen receptor (CAR) or a combination thereof. In some embodiments, the viral vector is an Adenovirus-associated Viral Vector (AAV). In some embodiments, the CAR gene in the viral vector further comprises a CAR with tumor-antigen binding domain, a CAR with pattern recognition receptor domain (PRR), a CAR with killer activated receptor (KAR) domain, a CAR with natural killer group 2D receptor (NKG2D) domain, a CAR with complement receptor domain, a CAR with Fc / scFv domain, a CAR with cytokine receptor domain or a split, universal, and programmable CAR (SUPRA CAR). VII. Retroviral Vectors A retrovirus is an animal virus belonging to the virus family of Retroviridae, including any types, subfamilies, genus, or tropisms. Retroviral vectors, in general, are described by Verma, I.M., Retroviral vectors for gene transfer. A retrovirus is essentially a package which has packed into its nucleic acid cargo. The nucleic acid cargo carries with it a packaging signal, which ensures that the replicated daughter molecules will be efficiently packaged within the package coat. In addition to the package signal, there are a number of molecules which are needed in cis, for the replication, and packaging of the replicated virus. Typically, a retroviral genome contains the gag, pol, and env genes which are involved in the making of the protein coat. It is the gag, pol, and env genes which are typicallyAttorney Docket Number 10110-470WO1 replaced by the foreign DNA that is to be transferred to the target cell. Retrovirus vectors typically contain a packaging signal for incorporation into the package coat, a sequence which signals the start of the gag transcription unit, elements necessary for reverse transcription, including a primer binding site to bind the tRNA primer of reverse transcription, terminal repeat sequences that guide the switch of RNA strands during DNA synthesis, a purine rich sequence 5' to the 3' LTR that serve as the priming site for the synthesis of the second strand of DNA synthesis, and specific sequences near the ends of the LTRs that enable the insertion of the DNA state of the retrovirus to insert into the host genome. The removal of the gag, pol, and env genes allows for about 8 kb of foreign sequence to be inserted into the viral genome, become reverse transcribed, and upon replication be packaged into a new retroviral particle. This amount of nucleic acid is sufficient for the delivery of a one-to-many genes depending on the size of each transcript. It is preferable to include either positive or negative selectable markers along with other genes in the insert. Since the replication machinery and packaging proteins in most retroviral vectors have been removed (gag, pol, and env), the vectors are typically generated by placing them into a packaging cell line. A packaging cell line is a cell line which has been transfected or transformed with a retrovirus that contains the replication and packaging machinery but lacks any packaging signal. When the vector carrying the DNA of choice is transfected into these cell lines, the vector containing the gene of interest is replicated and packaged into new retroviral particles, by the machinery provided in cis by the helper cell. The genomes for the machinery are not packaged because they lack the necessary signals. VIII. Adenoviral Vectors The construction of replication-defective adenoviruses has been described (Berkner et al., J. Virology 61:1213-1220 (1987); Massie et al., Mol. Cell. Biol.6:2872-2883 (1986); Haj-Ahmad et al., J. Virology 57:267-274 (1986); Davidson et al., J. Virology 61:1226-1239 (1987); Zhang "Generation and identification of recombinant adenovirus by liposome-mediated transfection and PCR analysis" BioTechniques 15:868-872 (1993)). The benefit of the use of these viruses as vectors is that they are limited in the extent to which they can spread to other cell types, since they can replicate within an initial infected cell, but are unable to form new infectious viral particles. Recombinant adenoviruses have been shown to achieve high efficiency gene transfer after direct, in vivo delivery to airway epithelium, hepatocytes, vascular endothelium, CNS parenchyma and a number of other tissue sites (Morsy, J. Clin. Invest. 92:1580-1586 (1993); Kirshenbaum, J. Clin. Invest. 92:381-387 (1993); Roessler, J. Clin. Invest. 92:1085-1092 (1993); Moullier, Nature Genetics 4:154-159 (1993); La Salle, Science 259:988-990 (1993); Gomez-Foix, J. Biol. Chem. 267:25129-25134 (1992); Rich, Human Gene Therapy 4:461-476 (1993); Zabner, Nature GeneticsAttorney Docket Number 10110-470WO1 6:75-83 (1994); Guzman, Circulation Research 73:1201-1207 (1993); Bout, Human Gene Therapy 5:3-10 (1994); Zabner, Cell 75:207-216 (1993); Caillaud, Eur. J. Neuroscience 5:1287- 1291 (1993); and Ragot, J. Gen. Virology 74:501-507 (1993)). Recombinant adenoviruses achieve gene transduction by binding to specific cell surface receptors, after which the virus is internalized by receptor-mediated endocytosis, in the same manner as wild type or replication-defective adenovirus (Chardonnet and Dales, Virology 40:462-477 (1970); Brown and Burlingham, J. Virology 12:386-396 (1973); Svensson and Persson, J. Virology 55:442-449 (1985); Seth, et al., J. Virol. 51:650-655 (1984); Seth, et al., Mol. Cell. Biol. 4:1528-1533 (1984); Varga et al., J. Virology 65:6061-6070 (1991); Wickham et al., Cell 73:309-319 (1993)). A viral vector can be one based on an adenovirus which has had the E1 gene removed and these virions are generated in a cell line such as the human 293 cell line. In another preferred embodiment both the E1 and E3 genes are removed from the adenovirus genome. IX. Adeno-associated viral vectors Another type of viral vector is based on an adeno-associated virus (AAV). This defective parvovirus is a preferred vector because it can infect many cell types and is nonpathogenic to humans. AAV type vectors can transport about 4 to 5 kb and wild type AAV is known to stably insert into chromosome 19. Vectors which contain this site-specific integration property are preferred. An especially preferred embodiment of this type of vector is the P4.1 C vector produced by Avigen, San Francisco, CA, which can contain the herpes simplex virus thymidine kinase gene, HSV-tk, and / or a marker gene, such as the gene encoding the green fluorescent protein, GFP. In another type of AAV virus, the AAV contains a pair of inverted terminal repeats (ITRs) which flank at least one cassette containing a promoter which directs cell-specific expression operably linked to a heterologous gene. Heterologous in this context refers to any nucleotide sequence or gene which is not native to the AAV or B19 parvovirus. Typically, the AAV and B19 coding regions have been deleted, resulting in a safe, noncytotoxic vector. The AAV ITRs, or modifications thereof, confer infectivity and site-specific integration, but not cytotoxicity, and the promoter directs cell-specific expression. United states Patent No.6,261,834 is herein incorporated by reference for material related to the AAV vector. The disclosed vectors thus provide DNA molecules which are capable of integration into a mammalian chromosome without substantial toxicity. The inserted genes in viral and retroviral usually contain promoters, and / or enhancers to help control the expression of the desired gene product. A promoter is generally a sequence or sequences of DNA that function when in a relatively fixed location in regard to the transcriptionAttorney Docket Number 10110-470WO1 start site. A promoter contains core elements required for basic interaction of RNA polymerase and transcription factors and may contain upstream elements and response elements. X. Large payload viral vectors Molecular genetic experiments with large human herpesviruses have provided a means whereby large heterologous DNA fragments can be cloned, propagated and established in cells permissive for infection with herpesviruses (Sun et al., Nature genetics 8: 33-41, 1994; Cotter and Robertson,. Curr Opin Mol Ther 5: 633-644, 1999). These large DNA viruses (herpes simplex virus (HSV) and Epstein-Barr virus (EBV), have the potential to deliver fragments of human heterologous DNA > 150 kb to specific cells. EBV recombinants can maintain large pieces of DNA in the infected B-cells as episomal DNA. Individual clones carried human genomic inserts up to 330 kb appeared genetically stable The maintenance of these episomes requires a specific EBV nuclear protein, EBNA1, constitutively expressed during infection with EBV. Additionally, these vectors can be used for transfection, where large amounts of protein can be generated transiently in vitro. Herpesvirus amplicon systems are also being used to package pieces of DNA > 220 kb and to infect cells that can stably maintain DNA as episomes. Other useful systems include, for example, replicating and host-restricted non-replicating vaccinia virus vectors. XI. Expression systems The nucleic acids that are delivered to cells typically contain expression controlling systems. For example, the inserted genes in viral and retroviral systems usually contain promoters, and / or enhancers to help control the expression of the desired gene product. A promoter is generally a sequence or sequences of DNA that function when in a relatively fixed location in regard to the transcription start site. A promoter contains core elements required for basic interaction of RNA polymerase and transcription factors and may contain upstream elements and response elements. XII. Viral Promoters and Enhancers Preferred promoters controlling transcription from vectors in mammalian host cells may be obtained from various sources, for example, the genomes of viruses such as: polyoma, Simian Virus 40 (SV40), adenovirus, retroviruses, hepatitis-B virus and most preferably cytomegalovirus, or from heterologous mammalian promoters, e.g. beta actin promoter. The early and late promoters of the SV40 virus are conveniently obtained as an SV40 restriction fragment which also contains the SV40 viral origin of replication (Fiers et al., Nature, 273: 113 (1978)). The immediate early promoter of the human cytomegalovirus is conveniently obtained as a HindIII E restrictionAttorney Docket Number 10110-470WO1 fragment (Greenway, P.J. et al., Gene 18: 355-360 (1982)). Of course, promoters from the host cell or related species also are useful herein. Enhancer generally refers to a sequence of DNA that functions at no fixed distance from the transcription start site and can be either 5' (Laimins, L. et al., Proc. Natl. Acad. Sci. 78: 993 (1981)) or 3' (Lusky, M.L., et al., Mol. Cell Bio. 3: 1108 (1983)) to the transcription unit. Furthermore, enhancers can be within an intron (Banerji, J.L. et al., Cell 33: 729 (1983)) as well as within the coding sequence itself (Osborne, T.F., et al., Mol. Cell Bio. 4: 1293 (1984)). They are usually between 10 and 300 bp in length, and they function in cis. Enhancers f unction to increase transcription from nearby promoters. Enhancers also often contain response elements that mediate the regulation of transcription. Promoters can also contain response elements that mediate the regulation of transcription. Enhancers often determine the regulation of expression of a gene. While many enhancer sequences are now known from mammalian genes (globin, elastase, albumin, -fetoprotein and insulin), typically one will use an enhancer from a eukaryotic cell virus for general expression. Preferred examples are the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. The promotor and / or enhancer may be specifically activated either by light or specific chemical events which trigger their function. Systems can be regulated by reagents such as tetracycline and dexamethasone. There are also ways to enhance viral vector gene expression by exposure to irradiation, such as gamma irradiation, or alkylating chemotherapy drugs. In certain embodiments the promoter and / or enhancer region can act as a constitutive promoter and / or enhancer to maximize expression of the region of the transcription unit to be transcribed. In certain constructs the promoter and / or enhancer region be active in all eukaryotic cell types, even if it is only expressed in a particular type of cell at a particular time. A preferred promoter of this type is the CMV promoter (650 bases). Other preferred promoters are SV40 promoters, cytomegalovirus (full length promoter), and retroviral vector LTR. It has been shown that all specific regulatory elements can be cloned and used to construct expression vectors that are selectively expressed in specific cell types such as melanoma cells. The glial fibrillary acetic protein (GFAP) promoter has been used to selectively express genes in cells of glial origin. Expression vectors used in eukaryotic host cells (yeast, fungi, insect, plant, animal, human or nucleated cells) may also contain sequences necessary for the termination of transcription which may affect mRNA expression. These regions are transcribed as polyadenylated segments in the untranslated portion of the mRNA encoding tissue factor protein. The 3' untranslated regions alsoAttorney Docket Number 10110-470WO1 include transcription termination sites. It is preferred that the transcription unit also contains a polyadenylation region. One benefit of this region is that it increases the likelihood that the transcribed unit will be processed and transported like mRNA. The identification and use of polyadenylation signals in expression constructs is well established. It is preferred that homologous polyadenylation signals be used in the transgene constructs. In certain transcription units, the polyadenylation region is derived from the SV40 early polyadenylation signal and consists of about 400 bases. It is also preferred that the transcribed units contain other standard sequences alone or in combination with the above sequences improve expression from, or stability of, the construct. XIII. Markers The viral vectors can include nucleic acid sequence encoding a marker product. This marker product is used to determine if the gene has been delivered to the cell and once delivered is being expressed. Preferred marker genes are the E. Coli lacZ gene, which encodes ß-galactosidase, and green fluorescent protein or truncated CD34, as disclosed herein. In some embodiments the marker may be a selectable marker. Examples of suitable selectable markers for mammalian cells are dihydrofolate reductase (DHFR), thymidine kinase, neomycin, neomycin analog G418, hydromycin, and puromycin. When such selectable markers are successfully transferred into a mammalian host cell, the transformed mammalian host cell can survive if placed under selective pressure. There are two widely used distinct categories of selective regimes. The first category is based on a cell's metabolism and the use of a mutant cell line which lacks the ability to grow independent of a supplemented media. Two examples are: CHO DHFR- cells and mouse LTK- cells. These cells lack the ability to grow without the addition of such nutrients as thymidine or hypoxanthine. Because these cells lack certain genes necessary for a complete nucleotide synthesis pathway, they cannot survive unless the missing nucleotides are provided in a supplemented media. An alternative to supplementing the media is to introduce an intact DHFR or TK gene into cells lacking the respective genes, thus altering their growth requirements. Individual cells which were not transformed with the DHFR or TK gene will not be capable of survival in non-supplemented media. As used herein, in some embodiments, the switch receptor is encoded by a gene carried by a viral vector. In some aspects, the viral vector further comprises a truncated CD34 (tCD34) marker gene. In some embodiments, the switch receptor comprises an amino acid sequence as set forth in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or a sequence having at least 95%, 98%, 99% or 99.8% identity thereto.Attorney Docket Number 10110-470WO1 The second category is dominant selection which refers to a selection scheme used in any cell type and does not require the use of a mutant cell line. These schemes typically use a drug to arrest growth of a host cell. Those cells which have a novel gene would express a protein conveying drug resistance and would survive the selection. Examples of such dominant selection use the drugs neomycin, (Southern P. and Berg, P., J. Molec. Appl. Genet. 1: 327 (1982)), mycophenolic acid, (Mulligan, R.C. and Berg, P. Science 209: 1422 (1980)) or hygromycin, (Sugden, B. et al., Mol. Cell. Biol.5: 410-413 (1985)). The three examples employ bacterial genes under eukaryotic control to convey resistance to the appropriate drug G418 or neomycin (geneticin), xgpt (mycophenolic acid) or hygromycin, respectively. Others include the neomycin analog G418 and puramycin. XIV. Peptides A. Protein variants As discussed herein there are numerous variants of the switch receptor proteins that are known and herein contemplated. Protein variants and derivatives are well understood to those of skill in the art and in can involve amino acid sequence modifications. For example, amino acid sequence modifications typically fall into one or more of three classes: substitutional, insertional or deletional variants. Insertions include amino and / or carboxyl terminal fusions as well as intrasequence insertions of single or multiple amino acid residues. Insertions ordinarily will be smaller insertions than those of amino or carboxyl terminal fusions, for example, on the order of one to four residues. Immunogenic fusion protein derivatives, such as those described in the examples, are made by fusing a polypeptide sufficiently large to confer immunogenicity to the target sequence by cross-linking in vitro or by recombinant cell culture transformed with DNA encoding the fusion. Deletions are characterized by the removal of one or more amino acid residues from the protein sequence. Typically, no more than about from 2 to 6 residues are deleted at any one site within the protein molecule. These variants ordinarily are prepared by site specific mutagenesis of nucleotides in the DNA encoding the protein, thereby producing DNA encoding the variant, and thereafter expressing the DNA in recombinant cell culture. Techniques for making substitution mutations at predetermined sites in DNA having a known sequence are well known, for example M13 primer mutagenesis and PCR mutagenesis. Amino acid substitutions are typically of single residues but can occur at a number of different locations at once; insertions usually will be on the order of about from 1 to 10 amino acid residues; and deletions will range about from 1 to 30 residues. Deletions or insertions preferably are made in adjacent pairs, i.e. a deletion of 2 residues or insertion of 2 residues. Substitutions, deletions, insertions or any combination thereof may be combined to arrive at a final construct. The mutations must not placeAttorney Docket Number 10110-470WO1 the sequence out of reading frame and preferably will not create complementary regions that could produce secondary mRNA structure. Substitutional variants are those in which at least one residue has been removed and a different residue inserted in its place. Such substitutions generally are made in accordance with the following Tables 1 and 2 and are referred to as conservative substitutions. Substantial changes in function or immunological identity are made by selecting substitutions that are less conservative, i.e., selecting residues that differ more significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site or (c) the bulk of the side chain. The substitutions which in general are expected to produce the greatest changes in the protein properties will be those in which (a) a hydrophilic residue, e.g. seryl or threonyl, is substituted for (or by) a hydrophobic residue, e.g. leucyl, isoleucyl, phenylalanyl, valyl or alanyl; (b) a cysteine or proline is substituted for (or by) any other residue; (c) a residue having an electropositive side chain, e.g., lysyl, arginyl, or histidyl, is substituted for (or by) an electronegative residue, e.g., glutamyl or aspartyl; or (d) a residue having a bulky side chain, e.g., phenylalanine, is substituted for (or by) one not having a side chain, e.g., glycine, in this case, (e) by increasing the number of sites for sulfation and / or glycosylation. For example, the replacement of one amino acid residue with another that is biologically and / or chemically similar is known to those skilled in the art as a conservative substitution. For example, a conservative substitution would be replacing one hydrophobic residue for another, or one polar residue for another. The substitutions include combinations such as, for example, Gly, Ala; Val, Ile, Leu; Asp, Glu; Asn, Gln; Ser, Thr; Lys, Arg; and Phe, Tyr. Such conservatively substituted variations of each explicitly disclosed sequence are included within the mosaic polypeptides provided herein. Substitutional or deletional mutagenesis can be employed to insert sites for N- glycosylation (Asn-X-Thr / Ser) or O-glycosylation (Ser or Thr). Deletions of cysteine or other labile residues also may be desirable. Deletions or substitutions of potential proteolysis sites, e.g. Arg, is accomplished for example by deleting one of the basic residues or substituting one by glutaminyl or histidyl residues. Certain post-translational derivatizations are the result of the action of recombinant host cells on the expressed polypeptide. Glutaminyl and asparaginyl residues are frequently post- translationally deamidated to the corresponding glutamyl and asparyl residues. Alternatively, these residues are deamidated under mildly acidic conditions. Other post-translational modifications include hydroxylation of proline and lysine, phosphorylation of hydroxyl groups ofAttorney Docket Number 10110-470WO1 seryl or threonyl residues, methylation of the o-amino groups of lysine, arginine, and histidine side chains (T.E. Creighton, Proteins: Structure and Molecular Properties, W. H. Freeman & Co., San Francisco pp 79-86

[1983] ), acetylation of the N-terminal amine and, in some instances, amidation of the C-terminal carboxyl. It is understood that one way to define the variants and derivatives of the disclosed proteins herein is through defining the variants and derivatives in terms of homology / identity to specific known sequences. Specifically disclosed are variants of these and other proteins herein disclosed which have at least, 70% or 75% or 80% or 85% or 90% or 95% homology to the stated sequence. Those of skill in the art readily understand how to determine the homology of two proteins. For example, the homology can be calculated after aligning the two sequences so that the homology is at its highest level. Another way of calculating homology can be performed by published algorithms. Optimal alignment of sequences for comparison may be conducted by the local homology algorithm of Smith and Waterman Adv. Appl. Math. 2: 482 (1981), by the homology alignment algorithm of Needleman and Wunsch, J. MoL Biol. 48: 443 (1970), by the search for similarity method of Pearson and Lipman, Proc. Natl. Acad. Sci. U.S.A. 85: 2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by inspection. The same types of homology can be obtained for nucleic acids by for example the algorithms disclosed in Zuker, M. Science 244:48-52, 1989, Jaeger et al. Proc. Natl. Acad. Sci. USA 86:7706-7710, 1989, Jaeger et al. Methods Enzymol.183:281-306, 1989. It is understood that the description of conservative mutations and homology can be combined together in any combination, such as embodiments that have at least 70% homology to a particular sequence wherein the variants are conservative mutations. As this specification discusses various proteins and protein sequences it is understood that the nucleic acids that can encode those protein sequences are also disclosed. This would include all degenerate sequences related to a specific protein sequence, i.e. all nucleic acids having a sequence that encodes one particular protein sequence as well as all nucleic acids, including degenerate nucleic acids, encoding the disclosed variants and derivatives of the protein sequences. Thus, while each particular nucleic acid sequence may not be written out herein, it is understood that each and every sequence is in fact disclosed and described herein through the disclosed protein sequence.Attorney Docket Number 10110-470WO1 It is understood that there are numerous amino acid and peptide analogs which can be incorporated into the disclosed compositions. For example, there are numerous D amino acids or amino acids which have a different functional substituent than the amino acids known by the person skilled in the art. The opposite stereo isomers of naturally occurring peptides are disclosed, as well as the stereo isomers of peptide analogs. These amino acids can readily be incorporated into polypeptide chains by charging tRNA molecules with the amino acid of choice and engineering genetic constructs that utilize, for example, amber codons, to insert the analog amino acid into a peptide chain in a site-specific way. Molecules can be produced that resemble peptides, but which are not connected via a natural peptide linkage. For example, linkages for amino acids or amino acid analogs can include CH2NH--, --CH2S--, --CH2--CH2 --, --CH=CH-- (cis and trans), --COCH2 --, --CH(OH)CH2--, and --CHH2SO—(These and others can be found in Spatola, A. F. in Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins, B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983); Spatola, A. F., Vega Data (March 1983), Vol.1, Issue 3, Peptide Backbone Modifications (general review); Morley, Trends Pharm Sci (1980) pp.463-468; Hudson, D. et al., Int J Pept Prot Res 14:177-185 (1979) (--CH2NH--, CH2CH2--); Spatola et al. Life Sci 38:1243-1249 (1986) (-- CH H2--S); Hann J. Chem. Soc Perkin Trans. I 307-314 (1982) (--CH--CH--, cis and trans); Almquist et al. J. Med. Chem. 23:1392-1398 (1980) (--COCH2--); Jennings-White et al. Tetrahedron Lett 23:2533 (1982) (--COCH2--); Szelke et al. European Appln, EP 45665 CA (1982): 97:39405 (1982) (--CH(OH)CH2--); Holladay et al. Tetrahedron. Lett 24:4401-4404 (1983) (--C(OH)CH2--); and Hruby Life Sci 31:189-199 (1982) (--CH2--S--); each of which is incorporated herein by reference. A particularly preferred non-peptide linkage is --CH2NH--. It is understood that peptide analogs can have more than one atom between the bond atoms, such as b- alanine, g-aminobutyric acid, and the like. Amino acid analogs and analogs and peptide analogs often have enhanced or desirable properties, such as, more economical production, greater chemical stability, enhanced pharmacological properties (half-life, absorption, potency, efficacy, etc.), altered specificity (e.g., a broad-spectrum of biological activities), reduced antigenicity, and others. D-amino acids can be used to generate more stable peptides, because D amino acids are not recognized by peptidases and such. Systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (e.g., D-lysine in place of L-lysine) can be used to generate more stable peptides. Cysteine residues can be used to cyclize or attach two or more peptides together. This can be beneficial to constrain peptides into particular conformations.Attorney Docket Number 10110-470WO1 XV. Pharmaceutical carriers / Delivery of pharmaceutical products As described above, the compositions can also be administered in vivo in a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject, along with the nucleic acid or vector, without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The carrier would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art. The compositions may be administered orally, parenterally (e.g., intravenously), by intramuscular injection, by intraperitoneal injection, transdermally, extracorporeally, topically or the like, including topical intranasal administration or administration by inhalant. As used herein, "topical intranasal administration" means delivery of the compositions into the nose and nasal passages through one or both of the nares and can comprise delivery by a spraying mechanism or droplet mechanism, or through aerosolization of the nucleic acid or vector. Administration of the compositions by inhalant can be through the nose or mouth via delivery by a spraying or droplet mechanism. Delivery can also be delivered directly to any area of the respiratory system (e.g., lungs) via intubation. The exact amount of the compositions required will vary from subject to subject, depending on the species, age, weight and general condition of the subject, the severity of the allergic disorder being treated, the particular nucleic acid or vector used, its mode of administration and the like. Thus, it is not possible to specify an exact amount for every composition. However, an appropriate amount can be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein. Parenteral administration of the composition, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions. A more recently revised approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained. See, e.g., U.S. Patent No.3,610,795, which is incorporated by reference herein. The materials may be in solution, suspension (for example, incorporated into microparticles, liposomes, or cells). These may be targeted to a particular cell type via antibodies, receptors, or receptor ligands. The following references are examples of the use of this technology to target specific proteins to tumor tissue (Senter, et al., Bioconjugate Chem., 2:447-451, (1991); Bagshawe, K.D., Br. J. Cancer, 60:275-281, (1989); Bagshawe, et al., Br. J. Cancer, 58:700-703,Attorney Docket Number 10110-470WO1 (1988); Senter, et al., Bioconjugate Chem., 4:3-9, (1993); Battelli, et al., Cancer Immunol. Immunother., 35:421-425, (1992); Pietersz and McKenzie, Immunolog. Reviews, 129:57-80, (1992); and Roffler, et al., Biochem. Pharmacol, 42:2062-2065, (1991)). Vehicles such as "stealth" and other antibody conjugated liposomes (including lipid mediated drug targeting to colonic carcinoma), receptor mediated targeting of DNA through cell specific ligands, lymphocyte directed tumor targeting, and highly specific therapeutic retroviral targeting of murine glioma cells in vivo. The following references are examples of the use of this technology to target specific proteins to tumor tissue (Hughes et al., Cancer Research, 49:6214-6220, (1989); and Litzinger and Huang, Biochimica et Biophysica Acta, 1104:179-187, (1992)). In general, receptors are involved in pathways of endocytosis, either constitutive or ligand induced. These receptors cluster in clathrin-coated pits, enter the cell via clathrin-coated vesicles, pass through an acidified endosome in which the receptors are sorted, and then either recycle to the cell surface, become stored intracellularly, or are degraded in lysosomes. The internalization pathways serve a variety of functions, such as nutrient uptake, removal of activated proteins, clearance of macromolecules, opportunistic entry of viruses and toxins, dissociation and degradation of ligand, and receptor- level regulation. Many receptors follow more than one intracellular pathway, depending on the cell type, receptor concentration, type of ligand, ligand valency, and ligand concentration. Molecular and cellular mechanisms of receptor-mediated endocytosis have been reviewed (Brown and Greene, DNA and Cell Biology 10:6, 399-409 (1991)). XVI. Pharmaceutically Acceptable Carriers The compositions, including antibodies, can be used therapeutically in combination with a pharmaceutically acceptable carrier. Suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton, PA 1995. Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Examples of the pharmaceutically-acceptable carrier include, but are not limited to, saline, Ringer's solution and dextrose solution. The pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5. Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of composition being administered.Attorney Docket Number 10110-470WO1 Pharmaceutical carriers are known to those skilled in the art. These most typically would be standard carriers for administration of drugs to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. The compositions can be administered intramuscularly or subcutaneously. Other compounds will be administered according to standard procedures used by those skilled in the art. Pharmaceutical compositions may include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice. Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like. The pharmaceutical composition may be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Administration may be topically (including ophthalmically, vaginally, rectally, intranasally), orally, by inhalation, or parenterally, for example by intravenous drip, subcutaneous, intraperitoneal or intramuscular injection. The disclosed antibodies can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally. Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, inert gases and the like. Formulations for topical administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids or binders may be desirable.. Some of the compositions may potentially be administered as a pharmaceutically acceptable acid- or base- addition salt, formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolicAttorney Docket Number 10110-470WO1 acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mono-, di-, trialkyl and aryl amines and substituted ethanolamines. XVII. Therapeutic Uses Effective dosages and schedules for administering the compositions may be determined empirically, and making such determinations is within the skill in the art. The dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms of the disorder are effected. The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex and extent of the disease in the patient, route of administration, or whether other drugs are included in the regimen, and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any counterindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. For example, guidance in selecting appropriate doses for antibodies can be found in the literature on therapeutic uses of antibodies, e.g., Handbook of Monoclonal Antibodies, Ferrone et al., eds., Noges Publications, Park Ridge, N.J., (1985) ch.22 and pp.303-357; Smith et al., Antibodies in Human Diagnosis and Therapy, Haber et al., eds., Raven Press, New York (1977) pp.365-389. A typical daily dosage of the antibody used alone might range from about 1 µg / kg to up to 100 mg / kg of body weight or more per day, depending on the factors mentioned above. Following administration of a disclosed engineered immune cells, for treating, inhibiting, or preventing a cancer or an autoimmune disease, the efficacy of the therapeutic antibody can be assessed in various ways well known to the skilled practitioner. For instance, one of ordinary skill in the art will understand that an engineered immune cells, such as an antibody, disclosed herein is efficacious in treating or inhibiting a cancer or an autoimmune disease in a subject by observing that the engineered immune cells reduce cancer or prevent a further increase in cancer-associated symptoms. cancer-associated symptoms can be measured by methods that are known in the art, for example, using immunoassays, polymerase chain reaction assays to detect the presence of cancer cell nucleic acid or antibody assays to detect the presence of carcinogenic proteins in a sample (e.g., but not limited to, blood) from a subject or patient, or by measuring the level of circulating anti-cancer antibody levels in the patient. Efficacy of the administration of theAttorney Docket Number 10110-470WO1 disclosed engineered immune cells may also be determined by measuring the number of CD4+T cells in the cancer subject. The engineered immune cells that inhibit tumor cell growth disclosed herein may be administered prophylactically to patients or subjects who are at risk for cancer. Other molecules that interact with tumor cells to inhibit their growth which do not have a specific pharmaceutical function, but which may be used for tracking changes within cellular chromosomes or for the delivery of diagnostic tools for example can be delivered in ways similar to those described for the pharmaceutical products. The disclosed engineered immune cells and methods of treating cancer and other diseases, such as, for example, autoimmune diseases, can also be used for example as tools to isolate and test new drug candidates for a variety of cancer and autoimmunity related diseases. XVIII. Methods of using the switch receptors and / or engineered immune cells. A. Method of treating cancer The disclosed switch receptors and engineered immune cells can be used to treat any disease where uncontrolled cellular proliferation occurs such as cancers. A representative but non- limiting list of cancers that the disclosed switch receptors and / or engineered immune cells can be used to treat is the following: bone cancers including, osteosarcoma, osteochondromas, Ewing sarcomas, bone metastases; lymphomas such as B cell lymphoma and T cell lymphoma; mycosis fungoides; Hodgkin’s Disease; myeloid leukemia (including, but not limited to acute myeloid leukemia (AML) and / or chronic myeloid leukemia (CML)); bladder cancer; brain cancer; nervous system cancer; head and neck cancer; squamous cell carcinoma of head and neck; renal cancer; lung cancers such as small cell lung cancer, non-small cell lung carcinoma (NSCLC), lung squamous cell carcinoma (LUSC), and Lung Adenocarcinomas (LUAD); neuroblastoma / glioblastoma; ovarian cancer; pancreatic cancer; prostate cancer; skin cancer; hepatic cancer; melanoma; squamous cell carcinomas of the mouth, throat, larynx, and lung; cervical cancer; cervical carcinoma; breast cancer including, but not limited to triple negative breast cancer; genitourinary cancer; pulmonary cancer; esophageal carcinoma; head and neck carcinoma; large bowel cancer; hematopoietic cancers; testicular cancer; and colon and rectal cancers. Disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating and / or preventing a cancer and / or metastasis (such as for example, including but not limited to breast cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), prostate cancer, renal cell carcinoma, hepatocellular carcinoma, bone tumors, leukemia, osteosarcoma, multiple myeloma, or giant cell tumor) in a subject with a cancer comprising of administering to the subjectAttorney Docket Number 10110-470WO1 a therapeutically effective dose of the switch receptor of any preceding aspect and / or an engineered immune cell of any preceding aspect, including, but not limited to engineered immune cells co-expressing a CAR, a switch receptor and at least one other immune receptor. For example, disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating and / or preventing a cancer and / or metastasis of any preceding aspect in a subject comprising of administering to the subject a therapeutically effective dose of the switch receptor comprising a) a RANKL-binding ectodomain (such as, for example, a RANK-derived ectodomain or an anti- RANKL antibody of RANKL binding fragment thereof including, but not limited to Denosumab (or an scFv thereof), b) a transmembrane domain (such as, for example, the transmembrane domain of CD28, CD3ζ, NKG2D, or a combination thereof); and c) a costimulatory endodomain (such as, for example, the endodomain of CD28, CD27, CD2, OX40, 4-1BB, or a combination thereof) and / or an engineered immune cell (including but not limited to a CD4+ T cell, a CD8+ T cell, an alpha / beta T cell (αβ T cell), a gamma / delta T cell (γδ T cell), macrophages, natural killer (NK) cells and NKT cells) comprising the switch receptors of any preceding aspect. In some aspects, the engineered immune cell further comprises at least one additional immune receptor (such as, for example, including but not limited to a chimeric antigen receptor (CAR) (including, but not limited to CARs with antigen binding domains that bind B-cell maturation antigen (BCMA), CD19, HER2, or EGFR), a pattern recognition receptor (PRR), a T cell receptor (TCR), a killer activated receptors (KAR), a natural killer group 2D receptor (NKG2D), a complement receptor, an Fc receptor, a cytokine receptor and a programmed cell death protein 1 receptor (PD- 1)). In one aspect disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating and / or preventing a cancer and / or metastasis of any preceding aspect, wherein the switch receptor is encoded by a gene carried by a viral vector. In some aspects, the switch receptor and the at least one other immune cell are carried by the same or different viral vectors. In some aspects, the viral vector further comprises a truncated CD34 (tCD34) marker gene. In one aspect, the treatment of the cancer can include administration of the switch receptor and / or engineered immune cells, including, but not limited to, engineered immune cells co- expressing a switch receptor and at least one other immune receptor (such as, for example, including but not limited to a chimeric antigen receptor (CAR), a pattern recognition receptor (PRR), a T cell receptor (TCR), a killer activated receptors (KAR), a natural killer group 2D receptor (NKG2D), a complement receptor, an Fc receptor, a cytokine receptor and a programmed cell death protein 1 receptor (PD-1)). In some embodiments, the engineered cell co-expresses the viral vector comprising the nucleic acid sequences for CAR, the viral vector comprising theAttorney Docket Number 10110-470WO1 nucleic acid sequence encoding the switch receptor, and the viral vector comprising the nucleic acid sequence encoding the immune receptor. In some embodiments, the engineered cell transduced with a viral vector comprising the switch receptors also expresses a truncated CD34 molecule used as marker / enrichment element separated by a P2A cleavage site attached to the costimulatory endodomain in the viral vector (SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5). For example, disclosed herein are engineered immune cells comprising at least one nucleic acid sequence encoding the switch receptor of any preceding aspect and at least one other immune receptor of any preceding aspect. In some embodiments, the switch receptor, comprises a) a RANKL-binding ectodomain (such as, for example, a RANK-derived ectodomain or an anti- RANKL antibody of RANKL binding fragment thereof including, but not limited to Denosumab (or an scFv thereof), b) a transmembrane domain (such as, for example, the transmembrane domain of CD28, CD3ζ, NKG2D, or a combination thereof) (such as, for example, the transmembrane domain of CD28, CD3ζ, NKG2D, or a combination thereof); and c) a costimulatory endodomain (such as, for example, the endodomain of CD28, CD27, CD2, OX40, 4-1BB, or a combination thereof). In some aspects, the switch receptor is encoded by a gene carried by a viral vector. In some aspects, the viral vector further comprises a truncated CD34 (tCD34) marker gene. In one aspect disclosed herein are engineered immune cells of any preceding aspect, wherein the switch receptor is encoded by a gene carried by a viral vector. In some aspects, the switch receptor and the at least one other immune cell are carried by the same or different viral vectors. It is understood and herein contemplated that the disclosed treatment regimens can used alone or in combination with any anti-cancer therapy known in the art including, but not limited to Abemaciclib, Abiraterone Acetate, ABITREXATE® (Methotrexate), ABRAXANE® (Paclitaxel Albumin-stabilized Nanoparticle Formulation), ABVD, ABVE, ABVE-PC, AC, AC- T, ADCETRIS® (Brentuximab Vedotin), ADE, Ado-Trastuzumab Emtansine, ADRIAMYCIN® (Doxorubicin Hydrochloride), Afatinib Dimaleate, AFINITOR® (Everolimus), AKYNZEO® (Netupitant and Palonosetron Hydrochloride), ALDARA® (Imiquimod), Aldesleukin, ALECENSA® (Alectinib), Alectinib, Alemtuzumab, ALIMTA® (Pemetrexed Disodium), ALIQOPA® (Copanlisib Hydrochloride), ALKERAN™ for Injection (Melphalan Hydrochloride), ALKERAN™ Tablets (Melphalan), ALOXI® (Palonosetron Hydrochloride), ALUNBRIG® (Brigatinib), AMBOCHLORIN® (Chlorambucil), AMBOCLORIN® (Chlorambucil), Amifostine, Aminolevulinic Acid, Anastrozole, Aprepitant, AREDIA® (Pamidronate Disodium), ARIMIDEX® (Anastrozole), AROMASIN®Attorney Docket Number 10110-470WO1 (Exemestane),ARRANON® (Nelarabine), Arsenic Trioxide, ARZERRA® (Ofatumumab), Asparaginase Erwinia chrysanthemi, Atezolizumab, AVASTIN® (Bevacizumab), Avelumab, Axitinib, Azacitidine, BAVENCIO® (Avelumab), BEACOPP, BECENUM® (Carmustine), BELEODAQ® (Belinostat), Belinostat, Bendamustine Hydrochloride, BEP, BESPONSA® (Inotuzumab Ozogamicin) , Bevacizumab, Bexarotene, BEXXAR® (Tositumomab and Iodine I 131 Tositumomab), Bicalutamide, BICNU® (Carmustine), Bleomycin, Blinatumomab, BLINCYTO® (Blinatumomab), Bortezomib, BOSULIF® (Bosutinib), Bosutinib, Brentuximab Vedotin, Brigatinib, BuMel, Busulfan, BUSULFEX® (Busulfan), Cabazitaxel, CABOMETYX® (Cabozantinib-S-Malate), Cabozantinib-S-Malate, CAF, CAMPATH® (Alemtuzumab), CAMPTOSAR® (Irinotecan Hydrochloride), Capecitabine, CAPOX, CARAC® (Fluorouracil-- Topical), Carboplatin, CARBOPLATIN-TAXOL, Carfilzomib, CARMUBRIS® (Carmustine), Carmustine, Carmustine Implant, CASODEX® (Bicalutamide), CEM, Ceritinib, CERUBIDINE® (Daunorubicin Hydrochloride), CERVARIX® (Recombinant HPV Bivalent Vaccine), Cetuximab, CEV, Chlorambucil, CHLORAMBUCIL-PREDNISONE, CHOP, Cisplatin, Cladribine, CLAFEN® (Cyclophosphamide), Clofarabine, CLOFAREX® (Clofarabine), CLOLAR® (Clofarabine), CMF, Cobimetinib, COMETRIQ® (Cabozantinib-S- Malate), Copanlisib Hydrochloride, COPDAC, COPP, COPP-ABV, COSMEGEN® (Dactinomycin), COTELLIC® (Cobimetinib), Crizotinib, CVP, Cyclophosphamide, CYFOS® (Ifosfamide), CYRAMZA® (Ramucirumab), Cytarabine, Cytarabine Liposome, CYTOSAR-U® (Cytarabine), CYTOXAN® (Cyclophosphamide), Dabrafenib, Dacarbazine, DACOGEN® (Decitabine), Dactinomycin, Daratumumab, DARZALEX® (Daratumumab), Dasatinib, Daunorubicin Hydrochloride, Daunorubicin Hydrochloride and Cytarabine Liposome, Decitabine, Defibrotide Sodium, DEFITELIO® (Defibrotide Sodium), Degarelix, Denileukin Diftitox, Denosumab, DEPOCYT® (Cytarabine Liposome), Dexamethasone, Dexrazoxane Hydrochloride, Dinutuximab, Docetaxel, DOXIL® (Doxorubicin Hydrochloride Liposome), Doxorubicin Hydrochloride, Doxorubicin Hydrochloride Liposome, DOX-SL® (Doxorubicin Hydrochloride Liposome), DTIC-DOME® (Dacarbazine), Durvalumab, EFUDEX® (Fluorouracil--Topical), ELITEK® (Rasburicase), ELLENCE® (Epirubicin Hydrochloride), Elotuzumab, ELOXATIN® (Oxaliplatin), Eltrombopag Olamine, EMEND® (Aprepitant), EMPLICITI® (Elotuzumab), Enasidenib Mesylate, Enzalutamide, Epirubicin Hydrochloride , EPOCH, ERBITUX® (Cetuximab), Eribulin Mesylate, ERIVEDGE® (Vismodegib), Erlotinib Hydrochloride, ERWINAZE® (Asparaginase Erwinia chrysanthemi), ETHYOL® (Amifostine), Etopophos ETOPOPHOS® (Etoposide Phosphate), Etoposide, Etoposide Phosphate, EVACET® (Doxorubicin Hydrochloride Liposome), Everolimus, EVISTA® (Raloxifene Hydrochloride),Attorney Docket Number 10110-470WO1 EVOMELA® (Melphalan Hydrochloride), Exemestane, 5-FU® (Fluorouracil Injection), 5-FU® (Fluorouracil--Topical), FARESTON® (Toremifene), FARYDAK® (Panobinostat), FASLODEX® (Fulvestrant), FEC, FEMARA® (Letrozole), Filgrastim, FLUDARA® (Fludarabine Phosphate), Fludarabine Phosphate, FLUOROPLEX® (Fluorouracil--Topical), Fluorouracil Injection, Fluorouracil--Topical, Flutamide, FOLEX® (Methotrexate), FOLEX PFS® (Methotrexate), FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FOLOTYN® (Pralatrexate), FU-LV, Fulvestrant, GARDASIL® (Recombinant HPV Quadrivalent Vaccine), GARDASIL 9® (Recombinant HPV Nonavalent Vaccine), GAZYVA® (Obinutuzumab), Gefitinib, Gemcitabine Hydrochloride, GEMCITABINE-CISPLATIN, GEMCITABINE-OXALIPLATIN, Gemtuzumab Ozogamicin, GEMZAR® (Gemcitabine Hydrochloride), GILOTRIF® (Afatinib Dimaleate), GLEEVEC® (Imatinib Mesylate), GLIADEL® (Carmustine Implant), GLIADEL WAFER® (Carmustine Implant), Glucarpidase, Goserelin Acetate, HALAVEN® (Eribulin Mesylate), HEMANGEOL® (Propranolol Hydrochloride), HERCEPTIN® (Trastuzumab), HPV Bivalent Vaccine, Recombinant, HPV Nonavalent Vaccine, Recombinant, HPV Quadrivalent Vaccine, Recombinant, HYCAMTIN® (Topotecan Hydrochloride), HYDREA® (Hydroxyurea), Hydroxyurea, Hyper-CVAD, IBRANCE® (Palbociclib), Ibritumomab Tiuxetan, Ibrutinib, ICE, ICLUSIG® (Ponatinib Hydrochloride), IDAMYCIN® (Idarubicin Hydrochloride), Idarubicin Hydrochloride, Idelalisib, IDHIFA® (Enasidenib Mesylate), IFEX® (Ifosfamide), Ifosfamide, IFOSFAMIDUM® (Ifosfamide), IL-2 (Aldesleukin), Imatinib Mesylate, IMBRUVICA® (Ibrutinib), IMFINZI® (Durvalumab), Imiquimod, IMLYGIC® (Talimogene Laherparepvec), INLYTA® (Axitinib), Inotuzumab Ozogamicin, Interferon Alfa-2b, Recombinant, Interleukin-2 (Aldesleukin), INTRON A® (Recombinant Interferon Alfa-2b), Iodine I 131 Tositumomab and Tositumomab, Ipilimumab, IRESSA® (Gefitinib), Irinotecan Hydrochloride, Irinotecan Hydrochloride Liposome, ISTODAX® (Romidepsin), Ixabepilone, Ixazomib Citrate, IXEMPRA® (Ixabepilone), JAKAFI® (Ruxolitinib Phosphate), JEB, JEVTANA® (Cabazitaxel), KADCYLA® (Ado-Trastuzumab Emtansine), KEOXIFENE® (Raloxifene Hydrochloride), KEPIVANCE® (Palifermin), KEYTRUDA® (Pembrolizumab), KISQALI® (Ribociclib), KYMRIAH® (Tisagenlecleucel), KYPROLIS® (Carfilzomib), Lanreotide Acetate, Lapatinib Ditosylate, LARTRUVO® (Olaratumab), Lenalidomide, Lenvatinib Mesylate, LENVIMA® (Lenvatinib Mesylate), Letrozole, Leucovorin Calcium, LEUKERAN® (Chlorambucil), Leuprolide Acetate, LEUSTATIN® (Cladribine), LEVULAN® (Aminolevulinic Acid), LINFOLIZIN® (Chlorambucil), LIPODOX® (Doxorubicin Hydrochloride Liposome), Lomustine, LONSURF® (Trifluridine and Tipiracil Hydrochloride), LUPRON® (LeuprolideAttorney Docket Number 10110-470WO1 Acetate), LUPRON DEPOT® (Leuprolide Acetate), LUPRON DEPOT-PED® (Leuprolide Acetate), LYNPARZA® (Olaparib), MARQIBO® (Vincristine Sulfate Liposome), MATULANE® (Procarbazine Hydrochloride), Mechlorethamine Hydrochloride, Megestrol Acetate, MEKINIST® (Trametinib), Melphalan, Melphalan Hydrochloride, Mercaptopurine, Mesna, MESNEX® (Mesna), METHAZOLASTONE® (Temozolomide), Methotrexate, METHOTREXATE LPF® (Methotrexate), Methylnaltrexone Bromide, MEXATE® (Methotrexate), MEXATE-AQ® (Methotrexate), Midostaurin, Mitomycin C, Mitoxantrone Hydrochloride, MITOZYTREX® (Mitomycin C), MOPP, MOZOBIL® (Plerixafor), MUSTARGEN® (Mechlorethamine Hydrochloride) , MUTAMYCIN® (Mitomycin C), MYLERAN® (Busulfan), MYLOSAR® (Azacitidine), MYLOTARG® (Gemtuzumab Ozogamicin), NANOPARTICLE PACLITAXEL® (Paclitaxel Albumin-stabilized Nanoparticle Formulation), NAVELBINE® (Vinorelbine Tartrate), Necitumumab, Nelarabine, NEOSAR® (Cyclophosphamide), Neratinib Maleate, NERLYNX® (Neratinib Maleate), Netupitant and Palonosetron Hydrochloride, NEULASTA® (Pegfilgrastim), NEUPOGEN® (Filgrastim), NEXAVAR® (Sorafenib Tosylate), NILANDRON® (Nilutamide), Nilotinib, Nilutamide, NINLARO® (Ixazomib Citrate), Niraparib Tosylate Monohydrate, Nivolumab, NOLVADEX® (Tamoxifen Citrate), NPLATE® (Romiplostim), Obinutuzumab, ODOMZO® (Sonidegib), OEPA, Ofatumumab, OFF, Olaparib, Olaratumab, Omacetaxine Mepesuccinate, ONCASPAR® (Pegaspargase), Ondansetron Hydrochloride, ONIVYDE® (Irinotecan Hydrochloride Liposome), ONTAK® (Denileukin Diftitox), OPDIVO® (Nivolumab), OPPA, Osimertinib, Oxaliplatin, Paclitaxel, Paclitaxel Albumin-stabilized Nanoparticle Formulation, PAD, Palbociclib, Palifermin, Palonosetron Hydrochloride, Palonosetron Hydrochloride and Netupitant, Pamidronate Disodium, Panitumumab, Panobinostat, PARAPLAT® (Carboplatin), PARAPLATIN® (Carboplatin), Pazopanib Hydrochloride, PCV, PEB, Pegaspargase, Pegfilgrastim, Peginterferon Alfa-2b, PEG-INTRON® (Peginterferon Alfa-2b), Pembrolizumab, Pemetrexed Disodium, PERJETA® (Pertuzumab), Pertuzumab, PLATINOL® (Cisplatin), PLATINOL-AQ® (Cisplatin), Plerixafor, Pomalidomide, POMALYST® (Pomalidomide), Ponatinib Hydrochloride, PORTRAZZA® (Necitumumab), Pralatrexate, Prednisone, Procarbazine Hydrochloride, PROLEUKIN® (Aldesleukin), PROLIA® (Denosumab), PROMACTA® (Eltrombopag Olamine), Propranolol Hydrochloride, PROVENGE® (Sipuleucel- T), PURINETHOL® (Mercaptopurine), PURIXAN® (Mercaptopurine), Radium 223 Dichloride, Raloxifene Hydrochloride, Ramucirumab, Rasburicase, R-CHOP, R-CVP, Recombinant Human Papillomavirus (HPV) Bivalent Vaccine, Recombinant Human Papillomavirus (HPV) Nonavalent Vaccine, Recombinant Human Papillomavirus (HPV) Quadrivalent Vaccine, RecombinantAttorney Docket Number 10110-470WO1 Interferon Alfa-2b, Regorafenib, RELISTOR® (Methylnaltrexone Bromide), R-EPOCH, REVLIMID® (Lenalidomide), RHEUMATREX® (Methotrexate), Ribociclib, R-ICE, RITUXAN® (Rituximab), RITUXAN HYCELA® (Rituximab and Hyaluronidase Human), Rituximab, Rituximab and , Hyaluronidase Human, ,Rolapitant Hydrochloride, Romidepsin, Romiplostim, RUBIDOMYCIN® (Daunorubicin Hydrochloride), RUBRACA® (Rucaparib Camsylate), Rucaparib Camsylate, Ruxolitinib Phosphate, RYDAPT® (Midostaurin), Sclerosol Intrapleural Aerosol (Talc), Siltuximab, Sipuleucel-T, SOMATULINE DEPOT® (Lanreotide Acetate), Sonidegib, Sorafenib Tosylate, SPRYCEL® (Dasatinib), STANFORD V, Sterile Talc Powder (Talc), STERITALC® (Talc), STIVARGA® (Regorafenib), Sunitinib Malate, SUTENT® (Sunitinib Malate), SYLATRON® (Peginterferon Alfa-2b), SYLVANT® (Siltuximab), Synribo SYNRIBO® (Omacetaxine Mepesuccinate), TABLOID® (Thioguanine), TAC, TAFINLAR® (Dabrafenib), TAGRISSO® (Osimertinib), Talc, Talimogene Laherparepvec, Tamoxifen Citrate, TARABINE PFS® (Cytarabine), TARCEVA® (Erlotinib Hydrochloride), TARGRETIN® (Bexarotene), TASIGNA® (Nilotinib), TAXOL® (Paclitaxel), TAXOTERE® (Docetaxel), TECENTRIQ® (Atezolizumab), TEMODAR® (Temozolomide), Temozolomide, Temsirolimus, Thalidomide, THALOMID® (Thalidomide), Thioguanine, Thiotepa, Tisagenlecleucel, TOLAK® (Fluorouracil--Topical), Topotecan Hydrochloride, Toremifene, TORISEL® (Temsirolimus), Tositumomab and Iodine I 131 Tositumomab, TOTECT® (Dexrazoxane Hydrochloride), TPF, Trabectedin, Trametinib, Trastuzumab, TREANDA® (Bendamustine Hydrochloride), Trifluridine and Tipiracil Hydrochloride, TRISENOX® (Arsenic Trioxide), TYKERB® (Lapatinib Ditosylate) , UNITUXIN® (Dinutuximab), Uridine Triacetate, VAC, Vandetanib, VAMP, VARUBI® (Rolapitant Hydrochloride), VECTIBIX® (Panitumumab), VeIP, VELBAN® (Vinblastine Sulfate), VELCADE® (Bortezomib), VELSAR® (Vinblastine Sulfate), Vemurafenib, VENCLEXTA® (Venetoclax), Venetoclax, VERZENIO® (Abemaciclib), VIADUR® (Leuprolide Acetate), VIDAZA® (Azacitidine), Vinblastine Sulfate, VINCASAR PFS® (Vincristine Sulfate), Vincristine Sulfate, Vincristine Sulfate Liposome, Vinorelbine Tartrate, VIP, Vismodegib, VISTOGARD® (Uridine Triacetate), VORAXAZE® (Glucarpidase), Vorinostat, VOTRIENT® (Pazopanib Hydrochloride), VYXEOS® (Daunorubicin Hydrochloride and Cytarabine Liposome), WELLCOVORIN® (Leucovorin Calcium), XALKORI® (Crizotinib), XELODA® (Capecitabine), XELIRI, XELOX, XGEVA® (Denosumab), XOFIGO® (Radium 223 Dichloride), XTANDI® (Enzalutamide), YERVOY® (Ipilimumab), YONDELIS® (Trabectedin), ZALTRAP® (Ziv-Aflibercept), ZARXIO® (Filgrastim), ZEJULA® (Niraparib Tosylate Monohydrate), ZELBORAF® (Vemurafenib), ZEVALIN® (Ibritumomab Tiuxetan),Attorney Docket Number 10110-470WO1 ZINECARD® (Dexrazoxane Hydrochloride), Ziv-Aflibercept, ZOFRAN® (Ondansetron Hydrochloride), ZOLADEX® (Goserelin Acetate), Zoledronic Acid, ZOLINZA® (Vorinostat), ZOMETA® (Zoledronic Acid), ZYDELIG® (Idelalisib), ZYKADIA® (Ceritinib), and / or ZYTIGA® (Abiraterone Acetate). The treatment methods can include or further include checkpoint inhibitors including, but are not limited to antibodies that block PD-1 (such as, for example, Nivolumab (BMS-936558 or MDX1106), pembrolizumab, cemiplimab , CT-011, MK- 3475), PD-L1 (such as, for example, atezolizumab, avelumab, durvalumab, MDX-1105 (BMS- 936559), MPDL3280A, or MSB0010718C), PD-L2 (such as, for example, rHIgM12B7), CTLA- 4 (such as, for example, Ipilimumab (MDX-010), Tremelimumab (CP-675,206)), IDO, B7-H3 (such as, for example, MGA271, MGD009, omburtamab), B7-H4, B7-H3, T cell immunoreceptor with Ig and ITIM domains (TIGIT)(such as, for example BMS-986207, OMP-313M32, MK-7684, AB-154, ASP-8374, MTIG7192A, or PVSRIPO), CD96, B- and T-lymphocyte attenuator (BTLA), V-domain Ig suppressor of T cell activation (VISTA)(such as, for example, JNJ- 61610588, CA-170), TIM3 (such as, for example, TSR-022, MBG453, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, RO7121661), LAG-3 (such as, for example, BMS- 986016, LAG525, MK-4280, REGN3767, TSR-033, BI754111, Sym022, FS118, MGD013, and Immutep). XIX. Method of treating autoimmune diseases A. Role for RANKL-RANK signaling in autoimmune diseases A critical role for RANKL-RANK signaling has been established in thymic organ development, particularly in the development of epithelial lineage cells required for the negative selection of developing T cells. The thymus educates self-tolerant T cells by eliminating those expressing potentially self-reactive T cell receptors (TCRs) and by generating immunosuppressive T cells that are essential for preventing autoimmune disease. Epithelial cells localized in the thymic medulla, known as medullary thymic epithelial cells (mTECs), are of non-hematopoietic origin and are essential for negative selection. It has been shown that mTECs also contribute to the selection and survival of immunosuppressive Foxp3-positive regulatory T cells (Tregs). The significant reduction in mTEC populations in the absence of RANKL provision by thymocytes indicates that mTEC differentiation is driven by the very cells that undergo negative selection within mTECs. This differentiation process appears to be initiated during the neonatal period by innate RANKL-expressing gamma-delta lineage cells, prior to the emergence of alpha-beta T cells in the thymus. mTECs require signaling through members of the TNFRSF family, including LTβR, CD40, and RANK, to induce sufficient expression of critical factors such as autoimmune regulatorAttorney Docket Number 10110-470WO1 (Aire) and tissue-specific antigens (TSAs). It has remained unclear whether downstream activation by these receptors differs in quality or quantity. Cell-specific deletion of the non-canonical NF- κB inhibitor TRAF3 suggests that LTβR and CD40 similarly activate the non-canonical NF-κB pathway, whereas RANK provides additional essential signals during mTEC development. Genetic evidence further supports that the relevant RANK signals are transduced via TRAF6. Collectively, these findings demonstrate that RANK-mediated signaling is necessary for developmental processes that are vital to immune regulation and homeostasis. The receptor activator of nuclear factor kappa-B ligand (RANKL), its receptor RANK constitutes a central signaling axis that plays a critical role in both bone homeostasis and immune regulation. The ability of RANKL to regulate osteoclast differentiation and activation is well- established; however, it has also become evident that RANKL serves important immunological functions, including the promotion of dendritic cell (DC) survival and antigen-presenting capacity during immune responses. RANKL-RANK-OPG signaling is particularly relevant in a range of pathologies characterized by aberrant bone resorption and immune dysregulation, such as rheumatoid arthritis (RA), periodontal disease, osteoporosis, osteoarthritis, multiple myeloma, and metastatic bone tumors. Autoimmune diseases like rheumatoid arthritis shows elevated expression of RANKL within the inflamed synovium contributes to excessive osteoclast activity and bone erosion. Although T cells have been implicated as a potential source of RANKL, evidence suggests that synovial fibroblasts are the predominant contributors to the RANKL pool in this context. T helper 17 (Th17) cells further exacerbate disease by inducing RANKL expression in fibroblasts through cytokines such as IL-17, IL-1, TNF-α, and IL-6. Additionally, a subset of Th17 cells derived from phenotypically converted regulatory T cells (Tregs) has been identified as highly osteoclastogenic due to RANKL expression induced by IL-6. RANKL not only drives the differentiation of osteoclast precursors but also enhances the activity of mature osteoclasts, amplifying bone destruction without necessarily increasing osteoclast number. Beyond T cells, other immune populations, such as B cells, have been shown to contribute to osteoclastogenesis through RANKL expression, particularly in conditions like post-menopausal osteoporosis. While osteoblasts and stromal cells were traditionally considered the primary sources of RANKL during normal bone remodeling, recent studies suggest that osteocytes are the principal RANKL-producing cells in this context, further illustrating the complexity of its source and context dependent activity. RANKL also participates in the maintenance of immune tolerance. It is required for the differentiation and function of Tregs in several autoimmune settings, including models of type 1Attorney Docket Number 10110-470WO1 diabetes and colitis. In peripheral tissues, such as the skin, RANKL-expressing keratinocytes can modulate DC function to induce a regulatory phenotype in infiltrating T cells. Conversely, dysregulated RANKL signaling has been associated with disease states such as type 2 diabetes mellitus, where elevated serum RANKL correlates with hepatic insulin resistance via activation of the NF-κB pathway. Inhibition of hepatic RANKL signaling has shown promise in restoring glucose homeostasis. Furthermore, RANKL signaling within the thymus may represent a novel target for cancer immunotherapy. Blockade of RANKL in medullary thymic epithelial cells (mTECs) can disrupt negative selection and enhance T cell responses against tumor-associated antigens, suggesting a potential strategy to boost anti-tumor immunity. Collectively, these findings highlight RANKL as a key mediator of osteoimmune communication. Its diverse roles in promoting both immune activation and suppression depending on the cellular context and disease state underscore the importance of RANKL-RANK as a therapeutic target in a wide range of inflammatory, autoimmune, metabolic, and neoplastic disorders. The disclosed switch receptors and / or engineered immune cells, including, but not limited to engineered immune cells co-expressing a switch receptor and at least one other immune receptor can be used to treat any disease where the body's immune system attacks healthy cells. A representative but non-limiting list of autoimmune disease that the disclosed engineered immune cells comprising a switch receptor can be used to treat include, but are not limited to Examples of autoimmune diseases include, but are not limited to graft versus host disease, transplant rejection, Achalasia, Acute disseminated encephalomyelitis, Acute motor axonal neuropathy, Addison’s disease, Adiposis dolorosa , Adult Still's disease, Agammaglobulinemia, Alopecia areata, Alzheimer’s disease, Amyloidosis, Ankylosing spondylitis, Anti-GBM / Anti-TBM nephritis, Antiphospholipid syndrome, Aplastic anemia , Autoimmune angioedema, Autoimmune dysautonomia, Autoimmune encephalomyelitis, Autoimmune enteropathy, Autoimmune hemolytic anemia, Autoimmune hepatitis, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmune polyendocrine syndrome , Autoimmune retinopathy, Autoimmune urticaria, Axonal & neuronal neuropathy (AMAN), Baló disease, Behcet’s disease, Benign mucosal pemphigoid, Bickerstaff's encephalitis , Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS), Eosinophilic Granulomatosis (EGPA), Cicatricial pemphigoid, Cogan’s syndrome, ColdAttorney Docket Number 10110-470WO1 agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn’s disease, Dermatitis herpetiformis, Dermatomyositis, Devic’s disease (neuromyelitis optica), Diabetes mellitus type 1, Discoid lupus, Dressler’s syndrome, Endometriosis, Enthesitis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Felty syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture’s syndrome, Granulomatosis with Polyangiitis, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s encephalopathy, Hashimoto’s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), Hidradenitis Suppurativa (HS) (Acne Inversa), Hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), Inflamatory Bowel Disease (IBD), Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus nephritis, Lupus vasculitis, Lyme disease chronic, Meniere’s disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, Multifocal Motor Neuropathy (MMN) or MMNCB, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neonatal Lupus, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Ord's thyroiditis, Palindromic rheumatism (PR), PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud’s phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Rheumatoid vasculitis, Sarcoidosis, Schmidt syndrome, Schnitzler syndrome, Scleritis, Scleroderma, Sjögren’s syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Susac’s syndrome, Sydenham chorea, Sympathetic ophthalmia (SO), Systemic Lupus Erythematosus, Systemic scleroderma, Takayasu’s arteritis, Temporal arteritis / Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Urticaria, Urticarial vasculitis,Attorney Docket Number 10110-470WO1 Uveitis, Vasculitis, Vitiligo, Vogt-Koyanagi-Harada Disease, and Wegener’s granulomatosis (or Granulomatosis with Polyangiitis (GPA)). In one aspect disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating and / or preventing an autoimmune disease (including but not limited to diabetes mellitus, chronic colitis, rheumatoid arthritis, multiple sclerosis (MS), or Alzheimer's disease) in a subject by administering a therapeutically effective dose of the switch receptor of any preceding aspect, the viral vector of any preceding aspect, and / or the engineered cell of any preceding aspect, further comprising the engineered immune cells co-expressing the CAR, the switch receptor and at least one other immune receptor. For example, disclosed herein is a method of treating, inhibiting, reducing, decreasing, ameliorating and / or preventing an autoimmune disease in a subject, comprising: administering to the subject a therapeutically effective dose of the switch receptor comprising a) a RANKL-binding ectodomain (such as, for example, a RANK-derived ectodomain or an anti-RANKL antibody of RANKL binding fragment thereof including, but not limited to Denosumab (or an scFv thereof), b) a transmembrane domain (such as, for example, the transmembrane domain of CD28, CD3ζ, NKG2D, or a combination thereof); and c) a costimulatory endodomain (such as, for example, the endodomain of CD28, CD27, CD2, OX40, 4-1BB, or a combination thereof) and / or an engineered immune cell (including but not limited to a CD4+ T cell, a CD8+ T cell, an alpha / beta T cell (αβ T cell), a gamma / delta T cell (γδ T cell), macrophages, natural killer (NK) cells and NKT cells) comprising the switch receptors of any preceding aspect. In some aspects, the engineered immune cell further comprises at least one additional immune receptor (such as, for example, including but not limited to a chimeric antigen receptor (CAR)(including, but not limited to CARs with antigen binding domains that bind B-cell maturation antigen (BCMA), CD19, HER2, or EGFR), a pattern recognition receptor (PRR), a T cell receptor (TCR), a killer activated receptors (KAR), a natural killer group 2D receptor (NKG2D), a complement receptor, an Fc receptor, a cytokine receptor and a programmed cell death protein 1 receptor (PD-1)). In one aspect disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating and / or preventing an autoimmune disease of any preceding aspect, wherein the switch receptor is encoded by a gene carried by a viral vector. In some aspects, the switch receptor and the at least one other immune cell are carried by the same or different viral vectors. In some aspects, the viral vector further comprises a truncated CD34 (tCD34) marker gene. It is understood and herein contemplated that the disclosed treatment regimens can used alone or in combination with any immunosuppressive therapy known in the art including, but not limited to Steroids, such as, for example, prednisone, methylprednisolone, dexamethasone;Attorney Docket Number 10110-470WO1 colchicine, hydroxychloroquine, sulfasalazine, dapsone, methotrexate, mycophenolate mofetil, azathioprine, anti-IL-1 biologics (such as, for example, Anakinra (Kineret), Canakinumab (Ilaris), Rilonacept (Arcalyst)), anti-TNF biologics (such as, for example, Infliximab (Remicade), Adalimumab (Humira), Golimumab (Simponi), Etanercept (Enbrel), Certolizumab (Cimzia)), anti-IL-6 biologics (such as, for example, Tocilizumab, Sarilumab; Complement, Eculizumab), anti-CD20 biologics (such as, for example, Rituximab), B cell growth factor targeting biologics (such as, for example, Belimumab), adaptive immunity T cells (such as, for example, Cyclosporine), T cell co-stimulation and activation (such as, for example, Abatacept), Anti-IL-17 Biologics (such as, for example, Secukinumab, Ixekizumab, Brodalumab), anti-IL-23 Biologics (such as, for example, Guselkumab), Anti-IL-12 / 23 Biologics (such as, for example, Ustekinumab), Anti-IL-5 biologics (such as, for example, Mepolizumab, Reslizumab, Benralizumab), Anti-IL-4 / IL-13 Biologics (such as, for example, Dupilumab), biologics Targeting IgE (such as, for example, Omalizumab), lymphocyte, movement drug (such as, for example, Vedolizumab), JAK Inhibitors (such as, for example, Tofacitinib, Upadacitinib, Baricitinib). EXAMPLES The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated and are intended to be purely exemplary and are not intended to limit the disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. Example 1: Switch RANKL binding into a positive signal for CAR-T cells Described herein is a method to neutralize the negative effects of RANKL on bone health and on the immune system, and further to convert (switch) RANKL binding into a positive signal for CAR-T cells. As shown in Fig.1, CAR-T cells co-express a second receptor, which are called “switch”, consisting of a RANKL-binding ectodomain coupled with a co-stimulatory domain. Multiple combinations of RANKL-binding ectodomain have been generated (RANK-, antibody- derived) which can be coupled to different co-stimulatory intracellular moieties, including CD28, CD2, CD27, and 41BB, among others. Switch receptors can be encoded in the same viral vector as the CAR, or in a separate vector (alone or with a marker gene) for co-transduction, as shown in Fig.1C.Attorney Docket Number 10110-470WO1 CAR-T cells derived from primary human T lymphocytes, co-expressing different switch constructs, or the full RANK protein, as represented in Fig.2A. Transduction was confirmed with the vector based on staining of the marker gene, tCD34. While the intensity and percentage of transduction varied among constructs, all of them yielded positive transduction compared to the negative controls (CAR, and UT, Fig. 2B). However, RANKL binding was only detected consistently for the constructs with the design: RANK-CD27 and RANK-41BB (Fig. 2C). For these two constructs, the co-transduction was verified with two different vectors resulting in a relevant frequency of cells expressing simultaneously the CAR and the switch receptor cassette. As shown in Fig. 2D, the RANK-41BB and RANK-CD27 receptors were co-expressed with tCD34 (as a surrogate marker for the switch receptor) in 42% and 46% of the cells, respectively (Fig. 2D). Finally, it was observed that expression of the RANK-CD27 switch receptor resulted in increased abundance of CAR-T cells with naïve (CD27+CD45RA+) and central memory (CD27+CD45RA-) phenotypes (Fig. 2E), which has been associated with better performance in vivo. Example 2: In Vivo Evaluation of Prostate Stem Cell Antigen (PSCA) Targeted γδ CAR T Cells in a Prostate Cancer Bone Metastasis Model To investigate the therapeutic efficacy of PSCA-specific γδ CAR-T cells against metastatic prostate cancer in the bone microenvironment, an intratibial xenograft model was established in NSG (NOD-SCID IL2Rγnull) mice using luciferase-expressing C42B prostate cancer cells (C42B-Luc). On Day 0, each mouse received an intratibial injection of 5 × 10⁵ C42B-Luc cells, enabling tumor engraftment directly within the bone marrow compartment—a site relevant for bone metastasis in prostate cancer. Seven days later (Day 7), mice were randomized into five treatment groups and administered immune effector cells via intravenous (tail vein) injection: PSCA γδ CAR-T cells (5- 7x10⁶ cells), PSCA γδ CAR-T cells + IL-2, untransduced γδ T cells, and untransduced γδ T cells + IL-2 PBS (vehicle control). For the IL-2 treatment groups, exogenous recombinant IL-2 was administered systemically from Day 7 to Day 13, aiming to support T cell proliferation, persistence, and activity in vivo. Tumor progression was monitored longitudinally using bioluminescent imaging (BLI) to measure luciferase activity emitted by the engrafted C42B-Luc cells. BLI provides a quantitative readout of tumor burden over time, reported as total photon flux (photons / sec). Results Mice receiving PSCA γδ CAR T cells in combination with IL-2 demonstrated the most significant reduction in tumor burden over the course of the study. Tumor regression was evidentAttorney Docket Number 10110-470WO1 as early as Day 14 and continued to diverge from other treatment groups thereafter. These results suggest a synergistic effect between PSCA targeted CAR T cells and IL-2, likely due to enhanced in vivo expansion, survival, and cytotoxic function of the CAR T cells. Mice treated with PSCA γδ CAR T cells alone exhibited moderate tumor control, confirming that the CAR construct confers anti-tumor activity against PSCA expressing C42B- Luc cells in the bone niche. However, this effect was not as pronounced or durable as when combined with IL-2. In contrast, the untransduced γδ T cell groups, regardless of IL-2 administration, failed to suppress tumor growth significantly, with tumor progression resembling that of the PBS control group. This indicates that native γδ T cells without CAR engineering are insufficient to mediate tumor control in this model. Conclusion The data demonstrated in Fig.3A-3D suggests that PSCA γδ CAR-T cells can effectively target and suppress prostate cancer in the bone microenvironment, particularly when supported by IL-2 cytokine therapy. These findings highlight the importance of antigen specificity via CAR design and cytokine-mediated support in maximizing the therapeutic potential of γδ T cell-based adoptive immunotherapy. Mice treated with PSCA γδ CAR T cells exhibited a reduction in tumor progression compared to the vehicle-treated (PBS) control group. Notably, co-administration of IL-2 significantly enhanced the anti-tumor activity of CAR T cells, resulting in the most pronounced suppression of tumor growth. In contrast, mice treated with untransduced γδ T cells, with, or without IL-2, demonstrated minimal therapeutic benefit. These results indicate that PSCA γδ CAR T cells possess intrinsic anti-tumor activity in the bone metastasis model, and that IL-2 supplementation further potentiates their in vivo efficacy.Attorney Docket Number 10110-470WO1 SEQUENCES 1. SEQ ID NO: 1 - DenoH2L-2t2-CD34 (AA sequence) MEFGLSWLFLVAILKGVQCEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVR QAPGKGLEWVSGITGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAV YYCAKDPSATVLMSWFDPWGQGTLVTVSSASTKGSTSGSGKPGSGEGSTKGEIVITQS PGTLSLSPGERATLSCRASQSVRGRYLAWYQQKPGQAPRILLYGASSRATGLPDRF SGSGSGTDFTLTISRNKPEDFAVFYCQQYGSSPRTFGQGTKVEIKSKPKISWTCINT TLTCEVMNGTDPELNLYQDGKHLKLSQRVITHKWTTSLSAKFKCTAGNKVSKESS VEPVSCPEKGLDIYLIIGICGGGSLLMVFVALLVFYITKRKKQRSRRNDEELETRAHRV ATEERGRKPHQIPASTPQNPATSQHPPPPPGHRSQAPSHRPPPPGHRVQHQPQKRPPAPS GTQVHQQKGPPLPRPRVQPKPPHGAAENSLSPSSNEFGSGATNFSLLKQAGDVEENPG PMPRGWTALCLLSLLPSGFMSLDNNGTATPELPTQGTFSNVSTNVSYQETTTPSTLGSTS LHPVSQHGNEATTNITETTVKFTSTSVITSVYGNTNSSVQSQTSVISTVFTTPANVSTPET TLKPSLSPGNVSDLSTTSTSLATSPTKPYTSSSPILSDIKAEIKCSGIREVKLTQGICLEQNK TSSCAEFKKDRGEGLARVLCGEEQADADAGAQVCSLLLAQSEVRPQCLLLVLANRTEIS SKLQLMKKHQSDLKKLGILDFTEQDVASHQSYSQKTLIALVTSGALLAVLGITGYFLMN RRSWSPTGERLELEP Signal peptide-Italics Linker- Underline and Italics Extracellular domain- Bold Transmembrane domain -Italics and Bold Intracellular- Underline P2A-Bold and Underline tCD34- no change 2. SEQ ID NO: 2-DenoH2L-28t28-CD34 (AA sequence) MEFGLSWLFLVAILKGVQCEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVR QAPGKGLEWVSGITGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAV YYCAKDPSATVLMSWFDPWGQGTLVTVSSASTKGSTSGSGKPGSGEGSTKGEIVITQS PGTLSLSPGERATLSCRASQSVRGRYLAWYQQKPGQAPRILLYGASSRATGLPDRF SGSGSGTDFTLTISRNKPEDFAVFYCQQYGSSPRTFGQGTKVEIKIEVMYPPPYLDN EKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSAttorney Docket Number 10110-470WO1 RLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSEFGSGATNFSLLKQAGDVEEN PGPMPRGWTALCLLSLLPSGFMSLDNNGTATPELPTQGTFSNVSTNVSYQETTTPSTLG STSLHPVSQHGNEATTNITETTVKFTSTSVITSVYGNTNSSVQSQTSVISTVFTTPANVSTP ETTLKPSLSPGNVSDLSTTSTSLATSPTKPYTSSSPILSDIKAEIKCSGIREVKLTQGICLEQ NKTSSCAEFKKDRGEGLARVLCGEEQADADAGAQVCSLLLAQSEVRPQCLLLVLANRT EISSKLQLMKKHQSDLKKLGILDFTEQDVASHQSYSQKTLIALVTSGALLAVLGITGYFL MNRRSWSPTGERLELEP Signal peptide-Italics Linker- Underline and Italics Extracellular domain- Bold Transmembrane domain -Italics and Bold Intracellular- Underline P2A-Bold and Underline tCD34-no change 3. SEQ ID NO: 3- RANK-41BB-CD34 (AA sequence) MAPRARRRRPLFALLLLCALLARLQVALQIAPPCTSEKHYEHLGRCCNKCEPGKYMSSK CTTTSDSVCLPCGPDEYLDSWNEEDKCLLHKVCDTGKALVAVVAGNSTTPRRCAC TAGYHWSQDCECCRRNTECAPGLGAQHPLQLNKDTVCKPCLAGYFSDAFSSTDK CRPWTNCTFLGKRVEHHGTEKSDAVCSSSLPARKPPNEPHVYLPGLIILLLFASVAL VAAIIFGVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELEFGSGATNFS LLKQAGDVEENPGPMPRGWTALCLLSLLPSGFMSLDNNGTATPELPTQGTFSNVSTNV SYQETTTPSTLGSTSLHPVSQHGNEATTNITETTVKFTSTSVITSVYGNTNSSVQSQTSVIS TVFTTPANVSTPETTLKPSLSPGNVSDLSTTSTSLATSPTKPYTSSSPILSDIKAEIKCSGIRE VKLTQGICLEQNKTSSCAEFKKDRGEGLARVLCGEEQADADAGAQVCSLLLAQSEVRP QCLLLVLANRTEISSKLQLMKKHQSDLKKLGILDFTEQDVASHQSYSQKTLIALVTSGA LLAVLGITGYFLMNRRSWSPTGERLELEP Signal peptide-Italics Extracellular domain- Bold Transmembrane domain -Italics and Bold Intracellular- Underline P2A-Bold and Underline tCD34-no changeAttorney Docket Number 10110-470WO1 4. SEQ ID NO: 4- RANK-CD27-CD34 (AA sequence) MAPRARRRRPLFALLLLCALLARLQVALQIAPPCTSEKHYEHLGRCCNKCEPGKYMSSK CTTTSDSVCLPCGPDEYLDSWNEEDKCLLHKVCDTGKALVAVVAGNSTTPRRCAC TAGYHWSQDCECCRRNTECAPGLGAQHPLQLNKDTVCKPCLAGYFSDAFSSTDK CRPWTNCTFLGKRVEHHGTEKSDAVCSSSLPARKPPNEPHVYLPGLIILLLFASVAL VAAIIFGVQRRKYRSNKGESPVEPAEPCHYSCPREEEGSTIPIQEDYRKPEPACSPEFGSG ATNFSLLKQAGDVEENPGPMPRGWTALCLLSLLPSGFMSLDNNGTATPELPTQGTFSN VSTNVSYQETTTPSTLGSTSLHPVSQHGNEATTNITETTVKFTSTSVITSVYGNTNSSVQS QTSVISTVFTTPANVSTPETTLKPSLSPGNVSDLSTTSTSLATSPTKPYTSSSPILSDIKAEIK CSGIREVKLTQGICLEQNKTSSCAEFKKDRGEGLARVLCGEEQADADAGAQVCSLLLA QSEVRPQCLLLVLANRTEISSKLQLMKKHQSDLKKLGILDFTEQDVASHQSYSQKTLIAL VTSGALLAVLGITGYFLMNRRSWSPTGERLELEP Signal peptide-Italics Extracellular domain- Bold Transmembrane domain -Italics and Bold Intracellular- Underline P2A-Bold and Underline tCD34-no change 5. SEQ ID NO: 5-RANK-CD34 (AA sequence) MAPRARRRRPLFALLLLCALLARLQVALQIAPPCTSEKHYEHLGRCCNKCEPGKYMSSK CTTTSDSVCLPCGPDEYLDSWNEEDKCLLHKVCDTGKALVAVVAGNSTTPRRCAC TAGYHWSQDCECCRRNTECAPGLGAQHPLQLNKDTVCKPCLAGYFSDAFSSTDK CRPWTNCTFLGKRVEHHGTEKSDAVCSSSLPARKPPNEPHVYLPGLIILLLFASVAL VAAIIFGVCYRKKGKALTANLWHWINEACGRLSGDKESSGDSCVSTHTANFGQQGACE GVLLLTLEEKTFPEDMCYPDQGGVCQGTCVGGGPYAQGEDARMLSLVSKTEIEEDSFR QMPTEDEYMDRPSQPTDQLLFLTEPGSKSTPPFSEPLEVGENDSLSQCFTGTQSTVGSES CNCTEPLCRTDWTPMSSENYLQKEVDSGHCPHWAASPSPNWADVCTGCRNPPGEDCEP LVGSPKRGPLPQCAYGMGLPPEEEASRTEARDQPEDGADGRLPSSARAGAGSGSSPGGQ SPASGNVTGNSNSTFISSGQVMNFKGDIIVVYVSQTSQEGAAAAAEPMGRPVQEETLAR RDSFAGNGPRFPDPCGGPEGLREPEKASRPVQEQGGAKAEFGSGATNFSLLKQAGDVE ENPGPMPRGWTALCLLSLLPSGFMSLDNNGTATPELPTQGTFSNVSTNVSYQETTTPST LGSTSLHPVSQHGNEATTNITETTVKFTSTSVITSVYGNTNSSVQSQTSVISTVFTTPANVAttorney Docket Number 10110-470WO1 STPETTLKPSLSPGNVSDLSTTSTSLATSPTKPYTSSSPILSDIKAEIKCSGIREVKLTQGICL EQNKTSSCAEFKKDRGEGLARVLCGEEQADADAGAQVCSLLLAQSEVRPQCLLLVLAN RTEISSKLQLMKKHQSDLKKLGILDFTEQDVASHQSYSQKTLIALVTSGALLAVLGITGY FLMNRRSWSPTGERLELEP Signal peptide-Italics Extracellular domain- Bold Transmembrane domain -Italics and Bold Intracellular- Underline P2A-Bold and Underline tCD34-no change

Claims

Attorney Docket Number 10110-470WO1 CLAIMS What is claimed is:

1. A switch receptor, comprising: a Receptor Activator of Nuclear Factor-κB Ligand (RANKL)-binding ectodomain; a transmembrane domain; and a costimulatory endodomain.

2. The switch receptor of claim 1, wherein the RANKL-binding ectodomain is a RANK-derived ectodomain.

3. The switch receptor of claim 1 or 2, wherein the RANKL-binding ectodomain is a Denosumab-derived scFv ectodomain.

4. The switch receptor of claim 1, wherein the co-stimulatory endodomain is selected from CD28, CD27, CD2, OX40, 4-1BB, or a combination thereof.

5. The switch receptor of any one of claims 1-4, wherein the switch receptor comprises an amino acid sequence as set forth in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or a sequence having at least 95%, 98%, 99%, or 99.8% identity thereto.

6. A viral vector comprising a polynucleotide sequence encoding a switch receptor, a chimeric antigen receptor (CAR), or a combination thereof.

7. The viral vector of claim 6, wherein the switch receptor comprises a RANKL- binding ectodomain, a transmembrane domain, and / or a costimulatory endodomain.

8. The viral vector of claim 7, wherein the RANKL-binding ectodomain is selected from a RANK-derived ectodomain, or a Denosumab-derived scFv ectodomain.

9. The viral vector of claim 7 or 8, wherein the costimulatory endodomain is selected from CD28, CD27, CD2, OX40, 4-1BB, or a combination thereof.Attorney Docket Number 10110-470WO1 10. The viral vector of any one of claims 6-9, wherein the viral vector is an Adenovirus-associated Viral Vector (AAV).

11. The viral vector of any one of claims 6-10, wherein the CAR comprises a CAR with tumor-antigen binding domain, a CAR with pattern recognition receptor domain (PRR), a CAR with killer activated receptor (KAR) domain, a CAR with natural killer group 2D receptor (NKG2D) domain, a CAR with complement receptor domain, a CAR with Fc / scFv domain, a CAR with cytokine receptor domain, or a split, universal, and programmable CAR (SUPRA CAR).

12. The viral vector of any one of claims 6-11, further comprising a nucleic acid sequence encoding a truncated CD34 (tCD34) marker attached to the switch receptor.

13. An engineered cell comprising at least one nucleic acid sequence encoding a chimeric antigen receptor (CAR), or a switch receptor, wherein the at least one nucleic acid sequence encoding the CAR, or the switch receptor is integrated in at least one viral vector.

14. The engineered cell of claim 13, wherein the engineered cell is a CD4+ T cell, a CD8+ T cell, an alpha / beta T cell (αβ T cell), a gamma / delta T cell (γδ T cell), a macrophage, or an NK cell.

15. The engineered cell of claim 13 or 14, wherein the engineered cell co-expresses the at least one viral vector comprising the at least one nucleic acid sequence encoding the CAR, or the switch receptor.

16. The engineered cell of any one of claims 13-15, wherein the switch receptor further comprises a RANKL-binding ectodomain, a transmembrane domain, or a co-stimulatory endodomain.

17. The engineered cell of claim 16, wherein the RANKL-binding ectodomain of the switch receptor is selected from RANK-derived ectodomain, or a Denosumab- derived scFv ectodomain.Attorney Docket Number 10110-470WO1 18. The engineered cell of claim 16, wherein the costimulatory endodomain of the switch receptor is selected from CD28, CD27, CD2, OX40, 4-1BB, or a combination thereof.

19. The engineered cell of claim 16, wherein the transmembrane domain of the switch receptor comprises a CD28 transmembrane domain, a CD3ζ transmembrane domain, or an NKG2D transmembrane domain.

20. The engineered cell of any one of claims 13-15, wherein the CAR further comprises a tumor antigen binding domain.

21. The engineered cell of claim 20, wherein the tumor antigen binding domain of CAR recognizes at least one target on a tumor cell, wherein the target on tumor cell comprises a B-cell maturation antigen (BCMA), a CD19, a human epidermal growth factor 2 (HER2), or an epidermal growth factor receptor (EGFR).

22. The engineered cell of any one of claims 13-21, wherein the at least one nucleic acid sequence encoding the switch receptor translates into at least one amino acid sequence as set forth in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or a sequence having at least 95%, 98%, 99%, or 99.8% identity thereto.

23. The engineered cell of any one of claims 13-22, further comprising at least one nucleic acid sequence encoding an immune receptor, wherein the at least one nucleic acid sequence encoding the immune receptor is integrated into at least one viral vector.

24. The engineered cell of claim 23, wherein the immune receptor is selected from a group consisting of a chimeric antigen receptor (CAR), a pattern recognition receptor (PRR), a T cell receptor (TCR), a killer activated receptors (KAR), a natural killer group 2D receptor (NKG2D), a complement receptor, an Fc receptor, a cytokine receptor and a programmed cell death protein 1 receptor (PD- 1).

25. The engineered cell of any one of claims 13-24, wherein the engineered cell further co-expresses the at least one viral vector comprising the at least one nucleic acid sequence encoding the CAR, the switch receptor, or the immune receptor.Attorney Docket Number 10110-470WO1 26. The engineered cell of any one of claims 13-25, wherein the at least one viral vector further comprises a truncated CD34 (tCD34) marker gene.

27. A method of treating cancer in a subject, comprising: administering to the subject a therapeutically effective dose of the switch receptor of any one of claims 1-5, the viral vector of any one of claims 6-12, or the engineered cell of any one of claims 13-26.

28. A method of treating cancer in a subject, comprising: administering to the subject a therapeutically effective dose of an engineered cell, wherein the engineered cell comprises at least one nucleic acid sequence encoding a chimeric antigen receptor (CAR), or a switch receptor, wherein the at least one nucleic acid sequence encoding the CAR, or the switch receptor is integrated in at least one viral vector.

29. The method of claim 28, wherein the engineered cell is selected from the group of immune cells consisting of a CD4+ T cell, a CD8+ T cell, an alpha / beta T cell (αβ T cell), a gamma / delta T cell (γδ T cell),a macrophage, and an NK cell.

30. The method of claim 28 or 29, wherein the switch receptor further comprises a RANKL-binding ectodomain, a transmembrane domain, or a co-stimulatory endodomain.

31. The method of claim 30, wherein the RANKL-binding ectodomain of the switch receptor is selected from RANK-derived ectodomain, or a Denosumab-derived scFv ectodomain.

32. The method of claim 30, wherein the costimulatory endodomain of the switch receptor is selected from CD28, CD27, CD2, OX40, 4-1BB, or a combination thereof.

33. The method of claim 30, wherein the transmembrane domain of the switch receptor comprises a CD28 transmembrane domain, a CD3ζ transmembrane domain, or an NKG2D transmembrane domain.

34. The method of claim 28 or 29, wherein the CAR further comprises a tumor antigen binding domain.Attorney Docket Number 10110-470WO1 35. The method of claim 34, wherein the tumor antigen binding domain of CAR recognizes at least one target on a tumor cell, wherein the target on tumor cell comprises a B-cell maturation antigen (BCMA), a CD19, a human epidermal growth factor 2 (HER2), or an epidermal growth factor receptor (EGFR).

36. The method of any one of claims 28-35, wherein the at least one nucleic acid sequence encoding the switch receptor translates into at least one amino acid sequence as set forth in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or a sequence having at least 95%, 98%, 99%, or 99.8% identity thereto.

37. The method of any one of claims 28-36, further comprising at least one nucleic acid sequence encoding an immune receptor, wherein the at least one nucleic acid sequence encoding the immune receptor is integrated into at least one viral vector.

38. The method of claim 37, wherein the immune receptor is selected from a group consisting of a chimeric antigen receptor (CAR), a pattern recognition receptor (PRR), a T cell receptor (TCR), a killer activated receptors (KAR), a natural killer group 2D receptor (NKG2D), a complement receptor, an Fc receptor, a cytokine receptor and a programmed cell death protein 1 receptor (PD-1).

39. The method of any one of claims 28-38, wherein the at least one viral vector further comprises a truncated CD34 (tCD34) marker gene.

40. The method of any one of claims 28-39, wherein the engineered cell co-expresses the at least one viral vector comprising the at least one nucleic acid sequence encoding the CAR, the switch receptor, or the immune receptor.

41. The method of any one of claims 28-40, wherein the at least one nucleic acid sequence encoding the immune receptor, the switch receptor, or the CAR is transduced into the engineered cell by same viral vectors.

42. The method of any one of claims 28-40, wherein the at least one nucleic acid sequence encoding the immune receptor, the switch receptor, or the CAR is transduced into the engineered cell by different viral vectors.

43. The method of any one of claims 28-42, wherein the subject is a human.Attorney Docket Number 10110-470WO1 44. The method of any one of claims 28-43, wherein the cancer comprises breast cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), prostate cancer, renal cell carcinoma, hepatocellular carcinoma, bone tumors, leukemia, osteosarcoma, multiple myeloma, or giant cell tumor.

45. A method of treating an autoimmune disease in a subject, comprising: administering to the subject a therapeutically effective dose of the switch receptor of any one of claims 1-5, the viral vector of any one of claims 6-12, or the engineered cell of any one of claims 13-26.

46. A method of treating an autoimmune disease in a subject, comprising: administering to the subject a therapeutically effective dose of an engineered cell, wherein the engineered cell comprises at least one nucleic acid sequence encoding a chimeric antigen receptor (CAR), or a switch receptor, wherein the at least one nucleic acid sequence encoding the CAR, or the switch receptor is integrated in at least one viral vector.

47. The method of claim 46, wherein the engineered cell is selected from the group of immune cells consisting of a CD4+ T cell, a CD8+ T cell, an alpha / beta T cell (αβ T cell), a gamma / delta T cell (γδ T cell),a macrophage, and an NK cell.

48. The method of claim 46 or 47, wherein the switch receptor further comprises a RANKL-binding ectodomain, a transmembrane domain, or a co-stimulatory endodomain.

49. The method of claim 48, wherein the RANKL-binding ectodomain of the switch receptor is selected from RANK-derived ectodomain, or a Denosumab-derived scFv ectodomain.

50. The method of claim 48, wherein the costimulatory endodomain of the switch receptor is selected from CD28, CD27, CD2, OX40, 4-1BB, or a combination thereof.

51. The method of claim 48, wherein the transmembrane domain of the switch receptor comprises a CD28 transmembrane domain, a CD3ζ transmembrane domain, or an NKG2D transmembrane domain.Attorney Docket Number 10110-470WO1 52. The method of claim 46 or 47, wherein the CAR further comprises an antigen binding domain.

53. The method of claim 52, wherein the antigen binding domain of CAR recognizes at least one target on an immune cell, wherein the target on the immune cell comprises a B-cell maturation antigen (BCMA), a CD19, a human epidermal growth factor 2 (HER2), or an epidermal growth factor receptor (EGFR).

54. The method of any one of claims 46-53, wherein the at least one nucleic acid sequence encoding the switch receptor translates into at least one amino acid sequence as set forth in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or a sequence having at least 95%, 98%, 99%, or 99.8% identity thereto.

55. The method of any one of claims 46-54, further comprising at least one nucleic acid sequence encoding an immune receptor, wherein the at least one nucleic acid sequence encoding the immune receptor is integrated into at least one viral vector.

56. The method of claim 55, wherein the immune receptor is selected from a group consisting of a chimeric antigen receptor (CAR), a pattern recognition receptor (PRR), a T cell receptor (TCR), a killer activated receptors (KAR), a natural killer group 2D receptor (NKG2D), a complement receptor, an Fc receptor, a cytokine receptor and a programmed cell death protein 1 receptor (PD-1).

57. The method of any one of claims 46-56, wherein the at least one viral vector further comprises a truncated CD34 (tCD34) marker gene.

58. The method of any one of claims 46-57, wherein the engineered cell co-expresses the at least one viral vector comprising the at least one nucleic acid sequence encoding the CAR, the switch receptor, or the immune receptor.

59. The method of any one of claims 46-58, wherein the at least one nucleic acid sequence encoding the immune receptor, the switch receptor, or the CAR is transduced into the engineered cell by same viral vectors.

60. The method of any one of claims 46-58, wherein the at least one nucleic acid sequence encoding the immune receptor, the switch receptor, or the CAR is transduced into the engineered cell by different viral vectors.Attorney Docket Number 10110-470WO1 61. The method of any one of claims 46-60, wherein the subject is a human.

62. The method of any one of claims 46-61, wherein the autoimmune disease comprises diabetes mellitus, chronic colitis, rheumatoid arthritis, multiple sclerosis (MS), or Alzheimer’s disease.

Images