CHIMERIC DLL3 RECEPTORS AND METHODS FOR THEIR USE

Abstract

The present invention relates to a chimeric antigen receptor, characterized in that it comprises an antigen-binding molecule that binds specifically to DLL3, at least one costimulatory domain, and an activator domain that is a CD3 zeta signaling domain, wherein the antigen-binding molecule comprises: a) a heavy chain variable region comprising complementarity-determining regions (CDRs) 1, 2, and 3 with amino acid sequences SEQ ID NO: 42, SEQ ID NO: 43, and SEQ ID NO: 44 respectively, and a light chain variable region comprising CDRs 1, 2, and 3 with amino acid sequences SEQ ID NO: 47, SEQ ID NO: 48, and SEQ ID NO: 49 respectively; b) a VH region comprising SEQ ID NO: 41 and a VL region comprising SEQ ID NO: 46;oc) a heavy chain variable region comprising CDRs 1, 2, and 3 with amino acid sequences SEQ ID NO: 52, SEQ ID NO: 53, and SEQ ID NO: 54, respectively, and a light chain variable region comprising CDRs 1, 2, and 3 with amino acid sequences SEQ ID NO: 57, SEQ ID NO: 58, and SEQ ID NO: 59, respectively; od) a VH region comprising SEQ ID NO: 51 and a VL region comprising SEQ ID NO: 56; oe) a heavy chain variable region comprising CDRs 1, 2 and 3 with amino acid sequences SEQ ID NO: 62, SEQ ID NO: 63, and SEQ ID NO: 64, respectively, and a light chain variable region comprising CDRs 1, 2, and 3 with amino acid sequences SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, respectively; of) a VH region comprising SEQ ID NO: 61 and a VL region comprising SEQ ID NO: 66;wherein the VH region and the VL region are joined by at least one connector to at least one costimulatory domain, wherein the at least one costimulatory domain is a CD28 costimulatory domain comprising SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 4 in combination with SEQ ID NO: 6, or SEQ ID NO: 8, or a 4-1BB costimulatory domain comprising SEQ ID NO: 16 or SEQ ID NO: 16 in combination with SEQ ID NO: 8.;

Description

CHIMERIC DLL3 RECEPTORS AND METHODS FOR THEIR USE RELATED APPLICATIONS Priority is requested over U.S. Provisional Patent Application No. e62 / 655.725, filed on April 10, 2018, the full content of which is incorporated herein by reference. LIST OF SEQUENCES This application contains a Sequence List that has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. This ASCII copy, created on April 10, 2019, is named A-2249-WO-PCT_SL.txt and has a size of 86,327 bytes. BACKGROUND OF THE INVENTION Small cell lung cancer (SCLC) accounts for approximately 15% of all diagnosed lung cancer cases, but it is an aggressive form of lung carcinoma (Enstone et al., (2017) Pharmacoecon Opendoi: 10.1007 / s41669-017-0045-0; Bunn et al., (2016) J Thorac Oncol 11: 453-74; Siegel et al., (2016) CA Cancer J Clin, 66: 7-30). Delta-like ligand 3 (DLL3) is a member of the Delta / Serrate / Lag 2 family of Notch receptor ligands and is thought to play a role in Notch signaling. DLL3 is an inhibitory ligand of the Notch signaling pathway that is generally expressed exclusively on intracellular membranes (Geffers et al., (2007) J Cell Biol, 178: 465-76). Representative orthologs of the DLL3 protein include, but are not limited to, human (Accession Nos. NP 058637 and NP 982353), chimpanzee (Accession No. XP_003316395), mouse (Accession No. NP 031892), and rat (Accession No. NP 446118) orthologs.In humans, the DKK3 gene consists of 8 exons spanning approximately 9.5 kBp located on chromosome 19q13. Alternative splicing in the last exon results in two processed transcripts, one of 2389 bases (Accession No. NM 016941) and one of 2052 bases (Accession No. NM 203486). The first transcript encodes a protein of 618 amino acids (Accession No. NP 058637; SEQ ID No.: 29), while the second encodes a protein of 587 amino acids (Accession No. NP 982353; SEQ ID No.: 30). In certain types of cancer, such as SCLC, DLL3 has been found to be expressed on the cell surface, making it a highly selective cell surface protein for tumors (Saunders et al., (2015) Sel Trans Med:, 7: 302ra136.). Modified immune cells have been shown to possess the desired qualities for therapeutic treatments, particularly in oncology. There are two fundamental types of modified immune cells: those containing chimeric antigen receptors (called “CAR” or “CAR-T”) and T cell receptors (“TCR”). These modified cells have been engineered to confer antigen specificity while retaining or enhancing their ability to recognize and kill a target cell. Chimeric antigen receptors may comprise, for example, (i) an antigen-specific component (“antigen-binding molecule”), (ii) one or more costimulatory domains, and (iii) one or more activating domains. Each domain may be heterogeneous, meaning it may be composed of sequences derived from different protein chains.Immune cells expressing a chimeric antigen receptor (such as T cells) can be used in various therapies, including cancer therapies. It will be shown that the costimulatory polypeptides defined herein can be used to enhance the activation of CAR-expressing cells against target antigens, thereby increasing the potency of adoptive immunotherapy. T cells can be modified to be specific to one or more desired targets. For example, T cells can be transduced with DNA or other genetic material that encodes an antigen-binding molecule, such as one or more single variable chain fragments (“scFv’j”) of an antibody, along with one or more signaling molecules, and / or one or more activating domains, such as CD3 zeta. In addition to the ability of CAR T cells to recognize and destroy the targeted cells, a successful T cell therapy could benefit from the ability of CAR T cells to persist and maintain the capacity to proliferate in response to an antigen. Therefore, there remains a need to identify new and improved therapies for the treatment of diseases and disorders related to DLL3. SUMMARY OF THE INVENTION The invention relates to modified immune cells (such as CAR or TCR), antigen-binding molecules (including, but not limited to, antibodies, scFv, heavy and / or light chains and CDRs of these antigen-binding molecules) with DLL3 specificity. The chimeric antigen receptors of the invention typically comprise: (i) a DLL3-specific antigen-binding molecule, (ii) one or more costimulatory domains, and (iii) one or more activating domains. It can be seen that each domain may be heterogeneous, and therefore may be composed of sequences derived from different protein chains. In some embodiments, the invention relates to a chimeric antigen receptor comprising an antigen-binding molecule that binds specifically to DLL3, wherein the antigen-binding molecule comprises at least one of: (a) a variable heavy chain CDR1 comprising an amino acid sequence that differs from the sequence of SEQ ID N2: 42 or SEQ ID N2: 52 or SEQ ID N2: 62 by no more than 3, 2, 1 or 0 amino acid residues; (b) a variable heavy chain CDR2 comprising an amino acid sequence that differs from the sequence of SEQ ID N2: 43 or SEQ ID N2: 53 or SEQ ID N2: 63 by no more than 3, 2, 1 or 0 amino acid residues; (c) a variable heavy chain CDR3 comprising an amino acid sequence differing from the sequence of SEQ ID N2:44 or SEQ ID N2:54 or SEQ ID N2:64 by no more than 3, 2, 1 or 0 amino acid residues;(d) a variable light chain CDR1 comprising an amino acid sequence that differs from the sequence of SEQ ID N2: 47 or SEQ ID N2: 57 or SEQ ID N2: 67 by no more than 3, 2, 1 or 0 amino acid residues; (e) a variable light chain CDR2 comprising an amino acid sequence that differs from the sequence of SEQ ID N2: 48 or SEQ ID N2: 58 or SEQ ID N2: 68 by no more than 3, 2, 1 or 0 amino acid residues; (f) a variable light chain CDR3 comprising an amino acid sequence that differs from the sequence of SEQ ID N2: 49 or SEQ ID N2: 59 or SEQ ID N2: 69 by no more than 3, 2, 1 or 0 amino acid residues. In other embodiments, the chimeric antigen receptor also comprises at least one costimulatory domain. In other embodiments, the chimeric antigen receptor further comprises at least one activating domain. In certain embodiments, the costimulatory domain is a signaling region of CD28, CD28T, CD8, OX-40, 4-1BB / CD137, CD2, CD7, CD27, CD30, CD40, Programmed Death-1 (PD-1), an inducible T-cell costimulatory factor (ICOS), a lymphocyte function-associated antigen-1 (LFA-1, CD11a / CD18), CD3 gamma, CD3 delta, CD3 epsilon, CD247, CD276 (B7-H3), LIGHT, (TNFSF14), NKG2C, Ig alpha (CD79a), DAP-10, an Fe gamma receptor, an MHC class 1 molecule, TNF receptor proteins, an immunoglobulin protein, a cytokine receptor, integrins, lymphocyte signal-activating molecules (SLAM proteins), NK cell activating receptors, BTLA, a Toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL-2R beta, IL-2R gamma, IL-7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, GDI Id, ITGAE, CD103, ITGAL, GDI la, LFA-1,ITGAM, GDI Ib, ITGAX, GDI le, ITGBI, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Touch), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, CD19a, a ligand that binds specifically to CD83 or any combination thereof., In some embodiments, the costimulatory domain is derived from 4-1BB. In other embodiments, the costimulatory domain is derived from CD28 or CD28T. In other embodiments, the costimulatory domain is derived from CD8. In other embodiments, the costimulatory domain is derived from OX40. See also Hombach et al., Oncoimmunology, July 1, 2012; 1(4): 458-466. In still other embodiments, the costimulatory domain comprises ICOS, as described in Guedan et al., August 14, 2014. Blood: 124 (7) and Shen et al., Journal of Hematology & Oncology (2013) 6: 33. In still other embodiments, the costimulatory domain comprises CD27, as described in Song et al., Oncoimmunology, July 1, 2012; 1(4):547-549. In certain embodiments, the CD28 costimulatory domain comprises SEQ ID No. 2, SEQ ID No. 4, SEQ ID No. 6, or SEQ ID No. 8. In additional embodiments, the CD8 costimulatory domain comprises SEQ ID No. 14. In additional embodiments, the 4-1BB costimulatory domain comprises SEQ ID No. 16. In other embodiments, the activator domain comprises CD3, CD3 zeta, or CD3 zeta whose sequence is illustrated in SEQ ID No. 10. In other embodiments, the invention relates to a chimeric antigen receptor wherein the costimulatory domain comprises SEQ ID No. 2 and the activating domain comprises SEQ ID No. 10. The invention further relates to polynucleotides encoding chimeric antigen receptors and to vectors comprising these polynucleotides. The vector may be, for example, a retroviral vector, a DNA vector, a plasmid, an RNA vector, an adenoviral vector, an adenovirus-associated vector, a lentiviral vector, or any combination thereof. The invention also relates to the immune cells comprising the vectors. In some embodiments, the lentiviral vector is a pGAR vector. Examples of immune cells include, but are not limited to, T cells, tumor-infiltrating lymphocytes (TILs), NK cells, TCR-expressing cells, dendritic cells, or T NK cells. T cells may be autologous, allogeneic, or heterologous. In other embodiments, the invention relates to pharmaceutical compositions comprising the immune cells described herein. In certain embodiments, the invention relates to antigen-binding molecules (and chimeric antigen receptors comprising these molecules) comprising at least one of the following: (a) a VH region differing from the amino acid sequence of the VH region of 1H2.1 by no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 amino acid residues and a VL region differing from the amino acid sequence of the VL region of 1H2.1 by no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 amino acid residues; (b) a VH region differing from the amino acid sequence of the VH region of 8D2 by no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 amino acid residues and a VL region differing from the amino acid sequence of the VL region of 8D2 by no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 amino acid residues and a VL region differing from the amino acid sequence of the VL region of 8D2 by no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 amino acid residues 4, 3, 2, 1 or 0 amino acid residues; (c) a VH region differing from the amino acid sequence of the VH region of 6B2 by no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 100 amino acid residues and a VL region differing from the amino acid sequence of the VL region of 6B2 by no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 amino acid residues; and where said one or more VH and VL regions are linked by at least one connector. In other embodiments, the invention relates to antigen-binding molecules (and chimeric antigen receptors comprising these molecules), wherein the connector comprises at least one of the scFv G4S connector and the scFv Whitlow connector. In other embodiments, the invention relates to vectors encoding the polypeptides of the invention and to immune cells comprising these polypeptides. The preferred immune cells include T cells, tumor-infiltrating lymphocytes (TILs), NK cells, TCR-expressing cells, dendritic cells, or T NK cells. The T cells may be autologous, allogeneic, or heterologous. In other embodiments, the invention relates to isolated polynucleotides encoding a chimeric antigen receptor (CAR) or a T-cell receptor (TCR) comprising an antigen-binding molecule that specifically binds to DLL3, wherein the antigen-binding molecule comprises a variable heavy chain (Vh) CDR3 comprising an amino acid sequence of SEQ ID No. 44, SEQ ID No. 54, or SEQ ID No. 64. The polynucleotides may also comprise an activator domain. In preferred embodiments, the activator domain is CD3, more preferably CD3 zeta, more preferably the amino acid sequence illustrated in SEQ ID No. 9. In other embodiments, the invention includes a costimulatory domain, such as CD28, CD28T, OX40, CD8, 4-1BB / CD137, CD2, CD3 (alpha, beta, delta, epsilon, gamma, zeta), CD4, CD5, CD7, CD9, CD16, CD22, CD27, CD30, CD33, CD37, CD40, CD45, CD64, CD80, CD86, CD134, CD137, CD154, PD-1, ICOS, a lymphocyte function-associated antigen-1 (LFA-1 (GDI1a / CD18)), CD247, CD276 (B7-H3), LIGHT (a member of the tumor necrosis factor superfamily 14; TNFSF14), NKG2C, Ig alpha (CD79a), DAP-10, an Fe receptor gamma, an MHC class I molecule, TNF, TNFr, an integrin, a lymphocyte signaling activating molecule, BTLA, a Toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL-2R beta, IL-2R gamma, IL-7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDI-ld, ITGAE, CD103, ITGAL, CDI-la, LFA-1, ITGAM, CDI-lb, ITGAX, CDI-lc, ITGBI,CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 ccjm η / ηζηζ / Ε / γίΛΐ (Tactile), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, CD19a, a CD83 ligand or fragments or combinations thereof. The preferred costimulatory domains will be indicated later in this document. In other embodiments, the invention relates to isolated polynucleotides encoding a chimeric antigen receptor (CAR) or a T-cell receptor (TCR), wherein said CAR or TCR comprises an antigen-binding molecule that binds specifically to DLL3, and wherein the antigen-binding molecule comprises a variable light chain (Vl) CDR3 comprising an amino acid sequence selected from SEQ ID No. 47, SEQ ID No. 57, and SEQ ID No. 67. The polynucleotide may further comprise an activator domain. The polynucleotide may also comprise a costimulatory domain. In other embodiments, the invention relates to isolated polynucleotides encoding a chimeric antigen receptor (CAR) or a T cell receptor (TCR) comprising an antigen-binding molecule that binds specifically to DLL3, wherein the heavy chain of the antigen-binding molecule comprises CDR1 (SEQ ID No.: 42), CDR2 (SEQ ID No.: 43) and CDR3 (SEQ ID No.: 44) and the light chain of the antigen-binding molecule comprises CDR1 (SEQ ID No.: 47), CDR2 (SEQ ID No.: 48) and CDR3 (SEQ ID No.: 49). In other embodiments, the invention relates to isolated polynucleotides encoding a chimeric antigen receptor (CAR) or a T cell receptor (TCR) comprising an antigen-binding molecule that binds specifically to DLL3, wherein the heavy chain of the antigen-binding molecule comprises CDR1 (SEQ ID No.: 52), CDR2 (SEQ ID No.: 53) and CDR3 (SEQ ID No.: 54) and the light chain of the antigen-binding molecule comprises CDR1 (SEQ ID No.: 57), CDR2 (SEQ ID No.: 58) and CDR3 (SEQ ID No.: 59). In other embodiments, the invention relates to isolated polynucleotides encoding a chimeric antigen receptor (CAR) or a T cell receptor (TCR) comprising an antigen-binding molecule that binds specifically to DLL3, wherein the heavy chain of the antigen-binding molecule comprises CDR1 (SEQ ID No.: 62), CDR2 (SEQ ID No.: 63) and CDR3 (SEQ ID No.: 64) and the light chain of the antigen-binding molecule comprises CDR1 (SEQ ID No.: 67), CDR2 (SEQ ID No.: 68) and CDR3 (SEQ ID No.: 69). The invention further relates to antigen-binding molecules for DLL3 comprising at least one sequence of the variable heavy chain CDR3 or the variable light chain CDR3, as described herein. The invention further relates to antigen-binding molecules for DLL3 comprising at least one sequence of the variable heavy chain CDR1, CDR2, and CDR3, as described herein. The invention further relates to antigen-binding molecules for DLL3 comprising at least one sequence of the variable light chain CDR1, CDR2, and CDR3, as described herein. The invention further relates to antigen-binding molecules for DLL3 comprising both variable heavy chain CDR1, CDR2, and CDR3 sequences and variable light chain CDR1, CDR2, and CDR3 sequences, as described herein. Other variable heavy and light chain domains and polynucleotide and amino acid sequences of CDR suitable for use in DLL3-binding molecules according to the present invention can be found in U.S. Provisional Patent Application No. 62 / 199,944, filed July 31, 2015. The invention further relates to methods of treating a disease or disorder in a subject in need, comprising administering to the subject the antigen-binding molecules, CARs, TCRs, polynucleotides, vectors, cells, or compositions according to the invention. Diseases suitable for treatment include, but are not limited to, adrenal, liver, kidney, bladder, breast, gastric, ovarian, cervical, uterine, esophageal, colorectal, prostate (e.g., prostate adenocarcinoma), pancreatic, lung (both small cell and non-small cell), thyroid, carcinomas, sarcomas, glioblastomas, head and neck tumors, large cell neuroendocrine carcinoma (LCNEC), medullary thyroid cancer, glioblastoma, neuroendocrine prostate cancer (NEPO), high-grade gastroenteropancreatic (GEP) cancer, and malignant melanoma. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the CAR expression of DLL3 in T cells from a healthy donor. Figure 2 shows the cytolytic activity of CAR transduced T cells from a healthy donor. Figure 3 shows the production of cytokines by CAR T cells from a healthy donor. Figure 4 shows a flow cytometry analysis of T cell proliferation in response to target cells expressing DLL3. Figure 5 shows the in vivo antitumor activity of CAR DLL3 T cells in a xenogeneic mouse model of SCLC. Figure 6 shows a survival analysis of the mouse xenogeneic SCLC model after treatment with CAR DLL3 T cells. Figure 7 shows the pGAR vector map. ccyni n / nznz / E / YiAi DETAILED DESCRIPTION OF THE INVENTION It will be observed that chimeric antigen receptors (CARs or CAR-Ts) and T-cell receptors (TCRs) are genetically modified receptors. These modified receptors can be easily inserted and expressed on immune cells, including T cells, using techniques known to the art. With a CAR, a single receptor can be programmed to recognize a specific antigen and, when bound to that antigen, activate the immune cell to attack and destroy the cell containing that antigen. When these antigens are present on tumor cells, an immune cell expressing the CAR can seek out and kill the tumor cell. CARs can be modified to bind to an antigen (such as a cell surface antigen) by incorporating an antigen-binding molecule that interacts with the desired antigen. Preferably, the antigen-binding molecule is an antibody fragment of the antigen, and more preferably one or more single-chain antibody fragments (“scFv”). An scFv is a single-chain antibody fragment having the variable regions of the heavy and light chains of an antibody linked together. See U.S. Patent Nos. 7,741,465 and 6,319,494, as well as Eshhar et al., Cancer Immunol Immunotherapy (1997) 45: 131–136. An scFv retains the ability of the parental antibody to interact specifically with a target antigen. scFvs are preferred for use in chimeric antigen receptors because they can be modified to be expressed as part of a single chain along with the other CAR components. Id.See also Krause et al., J. Exp. Med., Volume 188, No. 4, 1998 (619-626); Finney et al., Journal of Immunology, 1998, 161: 2791-2797. It can be seen that the antigen-binding molecule is typically contained in the extracellular portion of the CAR so that it can recognize and bind to the antigen of interest. Bispecific and multispecific CARs, which have specificity for more than one target of interest, are included within the scope of the invention. Costimulatory domains: Chimeric antigen receptors can incorporate costimulatory (signaling) domains to increase their potency. See U.S. Patent Nos. 7,741,465 and 6,319,494, as well as Krause et al., and Finney et al., (supra), Song et al., Blood 119: 696-706 (2012); Kalos et al., Sel Transí. Med. 3: 95 (2011); Porter et al., N. Engl. J. Med. 365: 725-33 (2011) and Gross et al., Annu. Rev. Pharmacol. Toxicol. 56: 5983 (2016). For example, CD28 is a costimulatory protein naturally found on T cells. The complete native amino acid sequence of CD28 is described in NCBI, reference sequence: NP 006130.1. The complete native nucleic acid sequence of CD28 is described in NCBI, reference sequence: NM 006139.1. Some CD28 domains have been used in chimeric antigen receptors. According to the invention, a new extracellular domain ccyni η / ηζηζ / E / γίΛΐ has now been found CD28, called “CD28T”, unexpectedly provides some benefits when used in a CAR construction. The nucleotide sequence of the CD28T molecule, which includes the extracellular CD28T domain and the transmembrane and intracellular CD28 domains, is illustrated in SEQ ID No. 1: CTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCT GTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTG GAGTCCTCGCTTGTTACTCTCTGCTCGTCACCTGGCTTTTATAATCTTCTGGGTTAGATC CAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCC CACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGC The corresponding amino acid sequence is illustrated in SEQ ID No. 2: LDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRS K RSRLLHSDYM NMTPRRPGPT RKHYQPYAPP RDFAAYRS The nucleotide sequence of the extracellular portion of CD28T is illustrated in SEQ ID No. 3: CTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCT GTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCA The corresponding amino acid sequence of the extracellular CD28T domain is shown in SEQ ID N°: 4: LDNEKSNGTI IHVKGKHLCP SPLFPGPSKP The nucleotide sequence of the CD28 transmembrane domain is shown in SEQ ID No: 5): TTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCA CCGTGGCTTTTATAATCTTCTGGGTT The amino acid sequence of the CD28 transmembrane domain is shown in SEQ ID No: 6: FWVLVVVGGV LACYSLLVTV AFIIFWV The nucleotide sequence of the CD28 intracellular signaling domain is illustrated in SEQ ID No: 7: AGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCC GCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGATTTCGCTGCCT ATCGGAGC The amino acid sequence of the CD28 intracellular signaling domain is illustrated in SEQ ID No: 8: RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS Other suitable CD28 sequences that are useful in the invention include the CD28 nucleotide sequence illustrated in SEQ ID No.: 11: ATTGAGGTGATGTATCCACCGCCTTACCTGGATAACGAAAAGAGTAACGGTACCA TCATTCACGTGAAAGGTAAACACCTGTGTCCTTCTCCCTCTTCCCCGGGCCATCAAAGC CC ccjm n / nznz / E / YiAi The corresponding amino acid sequence is illustrated in SEQ ID No.: 12: IEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP Other suitable extracellular or transmembrane sequences may be derived from CD8. The nucleotide sequence of a suitable CD8 extracellular and transmembrane domain is illustrated in SEQ ID No. 13. GCTGCAGCATTGAGCAACTCAATAATGTATTTTAGTCACTTTGTACCAGTGTTCTTG CCGGCTAAGCCTACTACCACACCCGCTCCACGGCCACCTACCCCAGCTCCTACCATCGC TTCACAGCCTCTGTCCCTGCGCCCAGAGGCTTGCCGACCGGCCGCAGGGGGCGCTGTT CATACCAGAGGACTGGATTTCGCCTGCGATATCTATATCTGGGCACCCCTGGCCGGAACC TGCGGCGTACTCCTGCTGTCCCTGGTCATCACGCTCTATTGTAATCACAGGAAC The corresponding amino acid sequence is illustrated in SEQ ID No.: 14: AAALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVH TRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRN Other suitable intracellular signaling sequences may be derived from 41-BB. The nucleotide sequence of a suitable 41-BB intracellular signaling domain is shown in SEQ ID N2: 15: CGCTTTTCCGTCGTTAAGCGGGGGAGAAAAAAGCTGCTGTACATTTTCAAACAGC CGTTTATGAGGCCGGTCCAAACGACTCAGGAAGAGGACGGCTGCTCCTGCCGCTTTCCT GAGGAGGAGGAGGGCGGGTGCGAACTG The corresponding amino acid sequence is illustrated in SEQ ID No.: 16: RFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL The suitable costimulatory domains that are within the scope of the invention may be derived from, among other sources, CD28, CD28T, OX40, 4-1BB / CD137, CD2, CD3 (alpha, beta, delta, epsilon, gamma, zeta), CD4, CD5, CD7, CD9, CD16, CD22, CD27, CD30, CD33, CD37, CD40, CD45, CD64, CD80, CD86, CD134, CD137, CD154, PD-1, ICOS, a lymphocyte function-associated antigen-1 (LFA-1 (CDI la / CD18), CD247, CD276 (B7H3), LIGHT (a member of the tumor necrosis factor superfamily 14;TNFSF14), NKG2C, Ig alpha (CD79a), DAP-10, a gamma Fe receptor, an MHC class I molecule, TNF, TNFr, an integrin, a signal-activating lymphocyte molecule, BTLA, a Toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL-2R beta, IL-2R gamma, IL-7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDI-ld, ITGAE, CD103, ITGAL, CDI-la, LFA-1, ITGAM, CDI-lb, ITGAX, CDI-lc, ITGBI, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Táctil), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG / Cbp, ccyni η / ηζηζ / Ε / γίΛΐ; CD19a, un ligand CD83 o fragmentos o combinaciones de los mismos. Dominios activadores: CD3 is an element of T cell receptors on native T cells and has been shown to be an important intracellular activating element in CARs. In a preferred embodiment, the CD3 is CD3 zeta, the nucleotide sequence of which is illustrated in SEQ ID No: 9: AGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACC AACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCA GAGGACGGGACCCTGAGATGGGTGGCAAACCAAGGAAAAAACCCCCAGGAGGGTCT CTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGG AGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGA AGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTAGG The corresponding amino acid sequence of the intracellular CD3 zeta is shown in SEQ ID No: 10: RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQ EGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR DOMAIN ORIENTATION From a structural point of view, it can be seen that these domains correspond to locations related to the immune cell. Therefore, these domains can form part of (i) the extracellular (EC) “hinge” or domain (EC), (ii) the transmembrane (TM) domain, and / or (ii) the intracellular (cytoplasmic) (IC) domain. The intracellular component frequently includes, in part, a member of the CD3 family, preferably CD3 zeta, which has the ability to activate the T cell upon binding of the antigen-binding molecule to its target. In one embodiment, the hinge domain is typically composed of at least one costimulatory domain, as defined herein. It can also be seen that the hinge region may also contain some or all members of the immunoglobulin family such as IgG1, lgG2, lgG3, lgG4, IgA, IgD, IgE, IgM or a fragment thereof. Examples of CAR constructions according to the invention are shown in Table 1. Table 1 Construct name scFv Costimulatory domains Activator domain 1H2.1 CD28T 1H2.1 CD28T CD3 zeta 1H2.1 4-1BB 1H2.1 4-1 BB CD3 zeta 8D2 CD28T 8D2 CD28T CD3 zeta 8D2 4-1BB 8D2 4-1 BB CD3 zeta 6B2 CD28T 6B2 CD28T CD3 zeta 6B2 4-1 BB 6B2 4-1 BB CD3 zeta CELL-RELATED DOMAINS It will be observed that, with respect to the cell carrying the receptor, the modified T cells of the invention comprise an antigen-binding molecule (such as a scFv), an extracellular domain (which may comprise a “hinge” domain), a transmembrane domain, and an intracellular domain. The intracellular domain comprises at least partly an activating domain, preferably composed of a member of the CD3 family such as CD3 zeta, CD3 epsilon, CD3 gamma, or portions thereof. It will also be observed that the antigen-binding molecule (e.g., one or more scFvs) is modified so that it is located in the extracellular portion of the molecule / construct, enabling it to recognize and bind to its targets. Extracellular domain: The extracellular domain is advantageous for signaling and for achieving an efficient lymphocyte response to an antigen. The extracellular domains of particular utility in this invention may be derived from (i.e., comprise) CD28, CD28T, OX-40, 4-1BB / CD137, CD2, CD7, CD27, CD30, CD40, Programmed Cell Death-1 (PD-1), an inducible T-cell costimulatory agent (ICOS), a lymphocyte function-associated antigen-1 (LFA-1, CD11a / CD18), CD3 gamma, CD3 delta, CD3 epsilon, CD247, CD276 (B7-H3), LIGHT, (TNFSF14), NKG2C, Ig alpha (CD79a), DAP-10, an Fe gamma receptor, an MHC class 1 molecule, TNF receptor proteins, an immunoglobulin protein, a cytokine receptor, integrins, lymphocyte signal activator molecules (SLAM proteins), NK cell activator receptors, BTLA, a Toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha,CD8beta, IL-2R beta, IL-2R gamma, IL-7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDI Id, ITGAE, CD103, ITGAL, GDI la, LFA-1, ITGAM, GDI Ib, ITGAX, GDI le, ITGBI, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Táctil), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, CD19a, a ligand that is specifically linked to CD83 or any other combination. The extracelular domain can derive from a natural or synthetic sea source. As described herein, extracellular domains often comprise a hinge portion. This is a portion of the extracellular domain, often referred to as a “spacer” region. A variety of hinges can be employed according to the invention, including the costimulatory molecules described above, as well as immunoglobulin (Ig) sequences or other suitable molecules to achieve the desired spatial distance from the target cells. In some embodiments, the entire extracellular region comprises a hinge region. In some embodiments, the hinge region comprises CD28T or the EC domain of CD28. Transmembrane Domain: The CAR can be designed to comprise a transmembrane domain fused to the extracellular domain of the CAR. Similarly, it can be fused to the intracellular domain of the CAR. In one embodiment, the transmembrane domain that is naturally associated with one of the domains in a CAR is used. In some cases, the transmembrane domain can be selected or modified by amino acid substitution to prevent such domains from binding to the transmembrane domains of the same or different surface membrane proteins, thereby minimizing interactions with other members of the receptor complex. The transmembrane domain can be derived from either a natural or synthetic source. When the source is natural, the domain can be derived from any membrane-bound or transmembrane protein. Transmembrane regions of particular use in this invention can be derived from (i.e., comprise) CD28, CD28T, OX-40, 4-1BB / CD137, CD2,CD7, CD27, CD30, CD40, Death Program-1 (PD-1), a T cell-inducible costimulant (ICOS), an antigen associated with the function of lymphocytes-1 (LFA-1, CDI-la / CD18), CD3 gamma, CD3 delta, CD3 épsilon, CD247, CD276 (B7-H3), LIGHT, (TNFSF14), NKG2C, Ig alpha (CD79a), DAP-10, a Fe gamma receptor, an MHC class 1 molecule, TNF receptor proteins, an immunoglobulin protein, a cytokine receptor, integrins, signal-activating lymphocyte molecules (SLAM proteins), receptores NK cell activators, BTLA, Toll-ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL-2R beta, IL-2R gamma, IL-7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, GDI Id, ITGAE, CD103, ITGAL, GDI la, LFA-1, ITGAM, GDI Ib, ITGAX, GDI le, ITGBI, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84,CD96 (Tactile), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, CD19a, a ligand that binds specifically to CD83, or any combination thereof. Optionally, short connectors can form links between any or some of the extracellular, transmembrane, and intracellular domains of the CAR. In one embodiment, the transmembrane domain in the CAR of the invention is a CD8 transmembrane domain. In one embodiment, the transmembrane domain of ccjm n / nznz / E / YiAi CD8 comprises the transmembrane portion of the nucleic acid sequence of SEQ ID No: 13. In another embodiment, the transmembrane domain of CD8 comprises the nucleic acid sequence encoding the transmembrane amino acid sequence contained in SEQ ID No: 14. In certain embodiments, the transmembrane domain in the CAR of the invention is the CD28 transmembrane domain. In one embodiment, the CD28 transmembrane domain comprises the nucleic acid sequence of SEQ ID No. 5. In one embodiment, the CD28 transmembrane domain comprises the nucleic acid sequence encoding the amino acid sequence of SEQ ID No. 6. In another embodiment, the CD28 transmembrane domain comprises the amino acid sequence of SEQ ID No. 6. Intracellular (cytoplasmic) domain: The intracellular (cytoplasmic) domain of the modified T cells of the invention can provide activation of at least one of the normal effector functions of the immune cell. The effector function of a T cell can be, for example, cytolytic activity or an auxiliary activity, including the secretion of cytokines. It will be observed that the appropriate intracellular molecules include (i.e., comprise), but are not exhaustive, CD28, CD28T, OX-40, 4-1BB / CD137, CD2, CD7, CD27, CD30, CD40, Programmed Cell Death-1 (PD-1), an inducible T-cell costimulatory molecule (ICOS), a lymphocyte function-associated antigen-1 (LFA-1, CD11a / CD18), CD3 gamma, CD3 delta, CD3 epsilon, CD247, CD276 (B7-H3), LIGHT, (TNFSF14), NKG2C, Ig alpha (CD79a), DAP-10, an Fe gamma receptor, an MHC class 1 molecule, TNF receptor proteins, an immunoglobulin protein, a cytokine receptor, integrins, lymphocyte signal-activating molecules (SLAM proteins), and cell-activating receptors NK, BTLA, a Toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL-2R beta, IL-2R gamma, IL-7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, GDI Id, ITGAE, CD103,ITGAL, GDI la, LFA-1, ITGAM, GDI Ib, ITGAX, GDI le, ITGBI, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Touch), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, CD19a, a ligand that is specifically binds CD83 or any combination of the same. In a preferred embodiment, the cytoplasmic domain of the CAR can be designed to comprise the CD3 zeta signaling domain alone or in combination with any other desired cytoplasmic domain useful in the context of the CAR of the invention. For example, the cytoplasmic domain of the CAR may comprise a portion of the CD3 zeta chain and a costimulatory signaling region. The cytoplasmic signaling sequences in the cytoplasmic signaling portion of the CAR of the invention can be joined together in a random or specific order. In a preferred embodiment, the cytoplasmic domain is designed to comprise the CD3 zeta signaling domain and the CD28 signaling domain. In another embodiment, the cytoplasmic domain is designed to comprise the CD3 zeta signaling domain and the 4-1BB signaling domain, wherein the cytoplasmic CD28 comprises the nucleic acid sequence shown in SEQ ID N2: 15 and the amino acid sequence shown in SEQ ID N2: 16. In another embodiment, the cytoplasmic domain in the CAR of the invention is designed to comprise a portion of CD28 and CD3 zeta, wherein the cytoplasmic CD28 comprises the nucleic acid sequence illustrated in SEQ ID N°: 7 and the amino acid sequence illustrated in SEQ ID N°: 8. The nucleic acid sequence of CD3 zeta is illustrated in SEQ ID N°: 9 and the amino acid sequence is illustrated in SEQ ID N°: 8. It can be seen that a preferred orientation of the CARs according to the invention comprises an antigen-binding domain (such as scFv) in tandem with a costimulatory domain and an activating domain. The costimulatory domain may comprise one or more of an extracellular portion, a transmembrane portion, and an intracellular portion. It can also be seen that multiple costimulatory domains can be used in tandem. In some embodiments, nucleic acids are provided comprising a promoter operatively linked to a first polynucleotide encoding an antigen-binding molecule, at least one costimulatory molecule, and an activator domain. In some embodiments, the nucleic acid construct is contained within a viral vector. In some embodiments, the viral vector is selected from the group consisting of retroviral vectors, murine leukemia virus vectors, SFG vectors, adenoviral vectors, lentiviral vectors, adeno-associated virus (AAV) vectors, herpesvirus vectors, and vacciniavirus vectors. In some embodiments, the nucleic acid is contained within a plasmid. The invention further relates to isolated polynucleotides encoding chimeric antigen receptors and to vectors comprising the polynucleotides. Any vector known in the art may be suitable for the present invention. In some embodiments, the vector is a viral vector. In some embodiments, the vector is a retroviral vector (such as pMSVGI), a DNA vector, a murine leukemia virus vector, an SFG vector, a plasmid, an RNA vector, an adenoviral vector, a baculoviral vector, an Epstein-Barr virus vector, a papovaviral vector, a Vaccinia virus vector, a Herpes simplex virus vector, an adenovirus-associated vector (AAV), a lentiviral vector (such as pGAR), or any combination thereof. The pGAR vector map is shown in Figure 7. The pGAR sequence is: CTGACGCGCCCTGTAGCGGCGCATTAAGCGCGGCGGGTGTGGTGGTTACGCGC AGCGTGACCGCTACACTTGCCAGCGCCCTAGCGCCCGCTCCTTTCGCTTTCTTCCCTTCC TTTCTCGCCACGTTCGCCGGCTTTCCCCGTCAAGCTCTAAATCGGGGGCTCCCTTTAGGG TTCCGATTTAGTGCTTTACGGCACCTCGACCCCAAAAAACTTGATTAGGGTGATGGTTCAC GTAGTGGGCCATCGCCCTGATAGACGGTTTTTCGCCCTTTGACGTTGGAGTCCACGTTCT TTAATAGTGGACTCTTGTTCCAAACTGGAACAACACTCAACCCTATCTCGGTCTATTCTTTT GATTTATAAGGGATTTTGCCGATTTCGGCCTATTGGTTAAAAAATGAGCTGATTTAACAAAA ATTTAACGCGAATTTTAACAAAATATTAACGCTTACAATTTGCCATTCGCCATTCAGGCTGC GCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAA GGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACG TTGTAAAACGACGGCCAGTGAATTGTAATACGACTCACTATAGGGCGACCCGGGGATGGC GCGCCAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACA TAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTC AATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTG GAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGC CCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGCTGAT GCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAG TCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAATCAACGGGACTTTCCA AAATGTCGTAACAACTCGCCCCATTGACGCAAATGGGCGGTAGGCGTTACGGTGGGA GGTCTATATAAGCAGAGCTGGTTTAGTGAACCGGGGTCTCTCTGGTTAGACCAGATCGA GCCTGGGAGCTCTCTGGCTAACTAGGGAACCCACTGCTTAAGCCTCAATAAAGCTTGCCT TGAGTGCTTCAAGTAGTGTGTGCCCGTCTGTTGTGTGACTCTGGTAACTAGAGATCCCTC AGACCCTTTTTAGTCAGTGTGGAAAATCTCTAGCAGTGGCGCCCGAAACAGGGACTTGAAAG CGAAAGGGAAACCAGAGGAGCTCTCTCGACGCAGGACTCGGCTTGCTGAAGCGGCGCAC GGCAAGAGGCGAGGGGCGGCGACTGGTGATGCCAAAAATTTTGACTAGCGGAGGC TAGAAGGAGAGAGATGGGTGCGAGAGCGTCAGTATTAAGCGGGGGAGAATTAGATCGCG ATGGGAAAAAATTCGGTTAAGGCCAGGGGGAAAAGAAAAATATAAATTAAAAACATATAGTA TGGGCAAGCAGGAGCTAGAACGATTCGCAGTTAATCCTGGCCTGTTAGAAACATCAGAA GGCTGTAGACAAATACTGGGACAGCTACAACCATCCCTTCAGACAGGATCAGAAAGACTT AGATCATTATATAATACAGTAGCAACCCTCTATTGTGTGTGCATCAAAGGATAGATAAAAG ACACCAAGGAAGCTTTAGACAAGAGAGAAGAGCAAAAAGTAAGCACCACCGCACAGCAAGCCGCCGCTGATCTTCAGACCTGGAGGAGGAGATATGAGGGACAATTGGAGAAG rom η / ηζηζ / Ε / γίΛΐ TGAATTATAATAAATATAAAGTAGTAAAAATTGAACCATTAGGAGTAGCACCACCAAGGCA AAGAGAAGTGGGTGCAGAGAAAAAAGAGCAGTGGGAATATAGGAGCTTTGTTCCTTGG GTTCTTGGGAGCAGCAGGAAGCACTATGGGCGCAGCGGTCAATGACGCTGACGGATACAGG CCAGACAATTATTGTCTGGTATAGTGCAGCAGCAGAACAATTTGCTGAGGGCTATTGAGG CGCAACAGCATCTGTTGCAACTCACAGTCTGGGGCATCAAGCAGCTCCAGGCAAGAATCC TGGCTGTGGGAAAGATACCTAAAAGGATCAACAGCTCTGGGATTTGGGTTGCTCTGGAA AACTCATTGCACCACTGCTGTGGCCTTGGAATGCTAGTTGGAGTAATAAATCTCTGGAACA GATTTGGAATCACACACCTGGATGGATGGGACAGAAATTAACAATTACACAACAAGCTT AATACACTCTCTAATTGAAGAATCGCAAACCAGCAAGAAAAGAATGAACAAATTG GAATTTAGATAAATGGGCAAGTTTGTGGATTGAACATAACAAATTGGCTTGGTATAACATAACAAATTGGCTTGGTATA TAAAATTATTCATAATGATAGTAGGAGGCTTGGTAGGTTTAAGAATAGTTTTGCTGTACTT TCTATAGTGAATAGAGTTAGGCAGGGATATTCACCATTATCGTTTCAGACCCACCTCCCAA CCCCGAGGGGACCCGACAGGCCCGAAGGAATAGAAGAAGAAGGTGGAGAGAGAGACAG AGACAGATCCATTCGATTAGTGAACGGATCTCGACGGTATCGGTTTAACTTTTAAAGAAAA GGGGGGGGTTACAGTGCAGGGAAAGAATAGTAGACATATAGCAACAGACAT AAAAAAAAAATTCAAAAAACAAATTACAAAAATTCAAAATTTTATCGCGATCGCGGAATGAAAGACCCCACCTGTAGGTTTGGCAAGCTAGCTTAAGTAACGCCATTTTGCAAGGCATGG AAAATACATAACTGAGAATAGAGAAGTTCAGATCAAGGTTAGGAACAGAGAGACAGCAGA ATATGGGCCAAACAGGATATCTGTGGTAAGCAGTTCCTGCCCCGGCTCAGGGCCAAGAA CAGATGGTCCCCAGATGCGGTCCCGCCCTCAGCAGTTTCTAGAGAACCATCAGATGTTTC CAGGGTGCCCCAAGGACCTGAAAATGACCCTGTGCCTTATTTGAACTAACCAATCAGTTC GCTTCTCGCTTCTGTTCGCGCGCTTCTGCTCCCCGAGCTCAATAAAAGAGCCCACAACCC CTCACTCGGCGCGCCAGTCCTTCGAAGTAGATCTTTGTCGATCCTACCATCCACTCGACA CACCCGCCAGCGGCCGCTGCCAAGCTTCCGAGCTCTCGAATTAATTCACGGTACCCACC ATGGCCTAGGGAGACTAGTCGAATCGATATCAACCTCTGGATTACAAAATTTGTGAAAGAT TGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAATGCCT TTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTT GCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGT GTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGG GACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCG CTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGC TGACGTCCTTTTCATGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCG GCTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGG GCCGCCTCCCCGCCTGGTTAATTAAAGTACCTTTAAGACCAATGACTTACAAGGCAGCTG TAGATCTTAGCCACTTTTTAAAAGAAAAGGGGGGACTGGAAGGGCGAATTCACTCCCAAC GAAGACAAGATCTGCTTTTTGCTTGTACTGGGTCTCTCTGGTTAGACCAGATCTGAGCCTG ccyni η / ηζηζ / Ε / γίΛΐ GGAGCTCTCTGGCTAACTAGGGAACCCACTGCTTAAGCCTCAATAAAGCTTGCCTTGAGT GCTTCAAGTAGTGTGTGCCCGTCTGTTGTGTGACTCTGGTAACTAGAGATCCCTCAGACC CTTTTAGTCAGTGTGGAAAATCTCTAGCAGGCATGCCAGACATGATAAGATACATTGATGA GTTTGGACAAACCACAACTAGAATGCAGTGAAAAAAATGCTTTATTTGTGAAATTTGTGAT GCTATTGCTTTATTTGTAACCATTATAAGCTGCAATAAACAAGTTAACAACAACAATTGCAT TCATTTTATGTTTCAGGTTCAGGGGGAGGTGTGGGAGGTTTTTTGGCGCGCCATCGTCGA GGTTCCCTTTAGTGAGGGTTAATTGCGAGCTTGGCGTAATCATGGTCATAGCTGTTTCCTG TGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAA AGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGC TTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGA GAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCG GTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCAC AGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGA ACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCAT CACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAG GCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAG GTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCG TTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGAC ACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTA GGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTA TTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGAT CCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGC GCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGT GGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTA GATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTC TGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCA TCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCT GGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGC AATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCT CCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTT GCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAA AAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTT ATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGC TTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCG AGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAA ccyni η / ηζηζ / Ε / γίΛΐ GTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTG AGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCA CCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGG GCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCA GGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGG GTTCCGCGCACATTTCCCCGAAAAGTGCCAC (SEQ ID N2: 70) Additional suitable vector examples include, for example, pBABE-pure, pBABE-neo largeTcDNA, pBABE-hygro-hTERT, pMKO.1 GFP, MSCV-IRES-GFP, pMSCV PIG (Pure IRES GFP empty plasmid), pMSCV-loxp-dsRed-loxp-eGFP-Pure-WPRE, MSCV IRES Luciferase, pMIG, MDH1-PGK-GFP_2,0, TtRMPVIR, pMSCV-IRES-mCherry FP, pRetroX GFP T2A Cre, pRXTN, pLncEXP, and pLXIN-Luc. In some embodiments, the modified immune cell is a T cell, a tumor-infiltrating lymphocyte (TIL), an NK cell, a TCR-expressing cell, a dendritic cell, or a T NK cell. In some embodiments, the cell is obtained or prepared from peripheral blood. In some embodiments, the cell is obtained or prepared from peripheral blood mononuclear cells (PBMCs). In some embodiments, the cell is obtained or prepared from bone marrow. In some embodiments, the cell is obtained or prepared from umbilical cord blood. In some embodiments, the cell is a human cell.In some embodiments, the cell is transfected or transduced by the nucleic acid vector using a method selected from the group consisting of electroporation, sonoporation, biolistics (e.g., gene gun), lipid transfection, polymer transfection, nanoparticles, or polyplexes. In some embodiments, the chimeric antigen receptors are expressed on modified immune cells comprising the nucleic acids of this application. These chimeric antigen receptors of this application may comprise, in some embodiments, (i) an antigen-binding molecule (such as an scFv), (ii) a transmembrane region, and (iii) a T-cell activation molecule or region. ANTIGEN-BINDING MOLECULES Antigen-binding molecules are within the scope of the invention. An “antigen-binding molecule,” as used herein, refers to any protein that binds to a specific target antigen. In this application, the specified target antigen is the DLL3 protein or a fragment thereof. Antigen-binding molecules include, but are not limited to, antibodies and binding components thereof, such as immunologically functional fragments. Peptibodies (i.e., Fe fusion molecules comprising peptide-binding domains) are another example of suitable antigen-binding molecules. In some embodiments, the antigen-binding molecule binds to an antigen on a tumor cell. In some embodiments, the antigen-binding molecule binds to an antigen on a cell involved in a hyperproliferative disease or to a viral or bacterial antigen. In certain embodiments, the antigen-binding molecule binds to DLL3. In other embodiments, the antigen-binding molecule is an antibody or a fragment thereof, including one or more of the complementarity-determining regions (CDRs) thereof. In other embodiments, the antigen-binding molecule is a single-chain variable fragment (scFv). The term “immunologically functional fragment” (or “fragment”) of an antigen-binding molecule refers to a type of antigen-binding molecule comprising a portion (regardless of how that portion is obtained or synthesized) of an antibody that lacks at least some of the amino acids present in a full-length chain but can still specifically bind to an antigen. These fragments exhibit biological activity if they specifically bind to the target antigen and can compete with other antigen-binding molecules, including intact antibodies, for specific binding to a given epitope. In some embodiments, the fragments are neutralizing fragments. In some embodiments, the fragments can block or reduce the activity of DLL3.In one aspect, this fragment will retain at least one CDR present in the complete light or heavy chain, and in some embodiments, it will comprise a single heavy chain and / or a light chain, or a portion thereof. These fragments can be produced by recombinant DNA procedures or by enzymatic or chemical cleavage of antigen-binding molecules, including intact antibodies. Immunologically functional immunoglobulin fragments include, but are not limited to, scFv fragments, Fab fragments (Fab1, F(abjz), and the like), one or more CDRs, a diabody (a heavy-chain variable domain on the same polypeptide as a light-chain variable domain, linked by a short peptide bridge that is too short to allow pairing between the two domains on the same chain), antibody domains, and single-chain antibodies. These fragments may be derived from any mammalian source, including, but not limited to, human, mouse, rat, camelid, or rabbit. As a practitioner in the field will appreciate, an antigen-binding molecule may include non-protein components. The variants of the antigen-binding molecules are also within the scope of the invention, for example, variable light and / or variable heavy chains, each of which has at least 70-80%, 80-85%, 85-90%, 90-95%, 95-97%, 97-99%, or more than 99% identity with the amino acid sequences described herein. In some cases, such molecules include at least one heavy chain and one light chain, while in other cases the variant forms contain two identical light chains and two identical heavy chains (or subparts thereof). The skilled worker may determine the appropriate variants of the antigen-binding molecules described herein using well-known techniques.In some embodiments, the art specialist will also be able to identify suitable areas of the molecule that can be changed without destroying the activity by searching for regions that are not considered important for the activity. In certain embodiments, the polypeptide structure of the antigen-binding molecules is based on antibodies, including, but not limited to, monoclonal antibodies, bispecific antibodies, minibodies, antibody domains, synthetic antibodies (sometimes referred to as “antibody mimetics” herein), chimeric antibodies, humanized antibodies, human antibodies, antibody fusions (sometimes referred to as “antibody conjugates” herein), and fragments thereof, respectively. In some embodiments, the antigen-binding molecule comprises or consists of avimers. In some embodiments, a DLL3 antigen-binding molecule is delivered alone. In other embodiments, the DLL3 antigen-binding molecule is delivered as part of a CAR, TCR, or other immune cell. In such immune cells, the DLL3 antigen-binding molecule may be under the control of the same promoter region or a separate promoter. In certain embodiments, the genes encoding protein agents and / or a DLL3 antigen-binding molecule may be contained in separate vectors. The invention also provides pharmaceutical compositions comprising a DLL3 antigen-binding molecule together with a pharmaceutically acceptable diluent, vehicle, solubilizer, emulsifier, preservative, and / or adjuvant. In certain embodiments, the pharmaceutical compositions include more than one different DLL3 antigen-binding molecule. In certain embodiments, the pharmaceutical compositions include more than one DLL3 antigen-binding molecule, wherein the DLL3 antigen-binding molecules bind to more than one epitope. In some embodiments, the various antigen-binding molecules do not compete with each other for binding to DLL3. In other embodiments, the pharmaceutical composition may be selected for parenteral administration, inhalation, or administration via the digestive tract, such as orally. The preparation of such compositions suitable for pharmaceutical use is within the capabilities of a person skilled in the art. In certain embodiments, buffer solutions are used to maintain the composition at physiological pH or a slightly lower pH, typically within a pH range of approximately 5 to approximately 8. In certain embodiments, where parenteral administration is contemplated, a therapeutic composition may be in the form of a pyrogen-free aqueous solution suitable for parenteral use comprising a desired antigen-binding molecule for DLL3, with or without additional therapeutic agents, in a pharmaceutically acceptable vehicle.In certain embodiments, a vehicle for parenteral injection is sterile distilled water in which an antigen-binding molecule against DLL3 is formulated, with or without at least one additional therapeutic agent, as a suitably preserved sterile isotonic solution. In certain embodiments, the preparation may involve formulating the desired molecule with polymeric compounds (such as polylactic acid or polyglycolic acid), beads, or liposomes, which can provide controlled or sustained release of the product, which can be administered by depot injection. In certain embodiments, implantable drug delivery devices can be used to introduce the desired molecule. In some embodiments, the antigen-binding molecule is used as a diagnostic or validation tool. The antigen-binding molecule can be used to assess the amount of DLL3 present in a sample and / or in a subject. In some embodiments, the diagnostic antigen-binding molecule is non-neutralizing. In some embodiments, the antigen-binding molecules disclosed herein are used or provided in an assay kit and / or method for the detection of DLL3 in mammalian tissues or cells to detect / diagnose a disease or disorder associated with changes in DLL3 levels. The kit may comprise an antigen-binding molecule that binds to DLL3, along with means for indicating the binding of the antigen-binding molecule to DLL3, if present, and optionally the levels of the DLL3 protein. Antigen-binding molecules will be further understood in view of the following definitions and descriptions. An “Fe” region comprises two heavy chain fragments comprising the antibody domains CH1 and CH2. The two heavy chain fragments are held together by two or more disulfide bonds, and by hydrophobic interactions between the CH3 domains. A “Fab fragment” comprises a light chain and the CH1 and variable regions of a heavy chain. A Fab heavy chain molecule cannot form a disulfide bond with another heavy chain molecule. A “Fab' fragment” comprises a light chain and a portion of a heavy chain containing the VH domain and the Ch1 domain, and also the region between the Ch1 and Ch2 domains, so that a disulfide bond can form between the two heavy chains of two Fab' fragments to form an F(ab')2 molecule. An “F(ab')2 fragment” comprises two light chains and two heavy chains containing a portion of the constant region between the CH1 and CH2 domains, so that a disulfide bond forms between the two heavy chains. Therefore, an F(ab')2 is composed of two Fab' fragments held together by a disulfide bond between the two heavy chains. The “Fv region” comprises the variable regions of the heavy and light chains, but lacks the constant regions. A “variable single-chain fragment” (“scFv,” also called a “single-chain antibody”) refers to Fv molecules in which the variable regions of the heavy and light chains have been joined by a flexible connector to form a single polypeptide chain, which constitutes an antigen-binding region. See PCT Application WO88 / 01649 and U.S. Patent Nos. 4,946,778 and 5,260,203, disclosures of which are incorporated herein by reference. A “bivalent antigen-binding molecule” comprises two antigen-binding sites. In some cases, the two binding sites have the same antigenic specificities. Bivalent antigen-binding molecules can be bispecific. A “multispecific antigen-binding molecule” is a molecule directed against more than one antigen or epitope. A “bispecific,” “double-specific,” or “bifunctional” antigen-binding molecule is an antigen-binding molecule or a hybrid antibody, respectively, that has two different antigen-binding sites. The two binding sites of a bispecific antigen-binding molecule will bind to two different epitopes, which may reside on the same protein targets or on different targets. An antigen-binding molecule is said to "bind specifically" to its target antigen when its dissociation constant (Kd) is approximately 1 x 10⁻⁷ M. The antigen-binding molecule binds specifically to the antigen with "high affinity" when its Kd is 1.5 x 10⁻⁹ M, and with "very high affinity" when its Kd is 1.5 x 10⁻¹⁰ M. In one embodiment, the antigen-binding molecule has a Kd < 10⁻⁹ M. In another embodiment, the dissociation constant is < 1 x 10⁻⁵ M. In other embodiments, antigen-binding molecules will bind to human DLL3 with a Kd between approximately 10⁻⁷ M and 10⁻¹³ M, and in yet another embodiment, antigen-binding molecules will bind with a Kd of 10⁻⁵ x 10⁻¹⁰ M. An antigen-binding molecule is said to be "selective" when it binds to one target with greater affinity than to a second target. The term “antibody” refers to an intact immunoglobulin of any isotype or a fragment thereof that can compete with the intact antibody for specific binding to the target antigen, and includes, for example, chimeric, humanized, fully human, and bispecific antibodies. An “antibody” is a type of antigen-binding molecule as defined herein. In general, an intact antibody will comprise at least two complete heavy chains and two complete light chains, but in some cases, it may include fewer chains, such as natural antibodies in camelids, which may comprise only heavy chains. Antibodies may be derived from a single source or may be chimeric, that is, different portions of the antibody may be derived from two different antibodies, as will be described in more detail later.Antigen-binding molecules, antibodies, or binding fragments can be produced in hybridomas, by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Unless otherwise stated, the term “antibody” includes, in addition to antibodies comprising two full-length heavy chains and two full-length light chains, derivatives, variants, fragments, and mutations thereof, examples of which are described later.Furthermore, unless explicitly excluded, antibodies include monoclonal antibodies, bispecific antibodies, minibodies, antibody domains, synthetic antibodies (sometimes referred to herein as “antibody mimetics”), chimeric antibodies, humanized antibodies, human antibodies, antibody fusions (sometimes referred to herein as “antibody conjugates”), and fragments thereof, respectively. Variable regions typically exhibit the same general structure of relatively conserved frame regions (FRs) linked by the three hypervariable regions (i.e., “CDRs”). The CDRs of the two strands in each pair are typically aligned by the frame regions, which can enable binding to a specific epitope. From the amino terminus to the carboxyl terminus, the variable regions of the light and heavy chains typically comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. By convention, the CDRs in the heavy chain are typically referred to as CDR1, CDR2, and CDR3 HC. The CDRs in the light chain are typically referred to as CDR1, CDR2, and CDR3 LC. The assignment of amino acids to each domain is typically in accordance with the definitions of Kabat {Seqs of Proteins of Immunological Interest (NIH, Bethesda, MD (1987 and 1991)) or of Chothia (J. Mol. Bio!., 196: 901-917 (1987); Chothia et al., Nature, 342: 878-883 (1989)).Several analytical methods can be used to identify or approximate CDR regions, including not only Kabat or Chothia, but also the AbM definition. The term “light chain” includes a complete light chain and fragments thereof that have sufficient variable region sequence to confer binding specificity. A complete light chain includes a variable region domain, Vl, and a constant region domain, Cl. The variable region domain of the light chain is located at the amino terminus of the polypeptide. Light chains include kappa and lambda chains. The term “heavy chain” includes a complete heavy chain and fragments thereof that have sufficient variable region sequence to confer binding specificity. A complete heavy chain includes one variable region domain, VH, and three constant region domains, CH1, CH2, and CH3. The VH domain is located at the amino terminus of the polypeptide, and the CH domains are located at the carboxyl terminus, with CH3 being the closest to the carboxyl terminus. Heavy chains can be of any isotype, including IgG (including subtypes IgG1, IgG2, IgG3, and IgG4) and IgA (including subtypes IgA1 and IgA2), IgM, and IgE. The term “variable region” or “variable domain” refers to a portion of the light and / or heavy chains of an antibody, typically including approximately 120 to 130 amino-terminal amino acids of the heavy chain and approximately 100 to 110 amino-terminal amino acids of the light chain. The variable region of an antibody typically determines the specificity of a particular antibody for its target. Variability is not evenly distributed across all antibody variable domains; it is concentrated in subdomains of each of the heavy and light chain variable regions. These subdomains are called “hypervariable regions” or “complementarity-determining regions” (CDRs). The more conserved (i.e., non-hypervariable) portions of the variable domains are known as “framework” regions (FRMs or FRs) and provide a scaffold for the six CDRs in three-dimensional space to form an antigen-binding surface. The natural heavy and light chain variable domains each comprise four FRMs (FR1, FR2, FR3, and FR4), which mostly adopt a β-sheet configuration, linked by three hypervariable regions, which form loops that connect, and in some cases are part of, the β-sheet structure.The hypervariable regions of each chain are held very close to each other by the FRM and, together with the hypervariable regions of the other chain, contribute to the formation of the antigen-binding site (see Kabat et al., loe. cit.). The terms “CDRs” and their plural form “CDRs” refer to the complementarity-determining region, of which three constitute the binding character of a variable region of the light chain (CDR-L1, CDR-L2, and CDR-L3) and three constitute the binding character of a variable region of the heavy chain (CDR-H1, CDR-H2, and CDR-H3). CDRs contain most of the residues responsible for the specific interactions of the antibody with the antigen and thus contribute to the functional activity of an antibody molecule: they are the main determinants of antigen specificity. The exact boundaries and lengths that define CDRs are subject to different classification and numbering systems. Therefore, CDRs can be referred to using the Kabat, Chothia, contact, or any other boundary definition, including the numbering system described herein. Despite the different boundaries, each of these systems exhibits some degree of overlap in what constitute the so-called “hypervariable regions” within variable sequences. CDR definitions according to these systems may thus differ in terms of boundary length and area relative to the adjacent frame region. See, for example, Kabat (an approach based on interspecies variability), Chothia (an approach based on crystallographic studies of antigen-antibody complexes), and / or MacCallum (Kabat et al., ibid., Chothia et al., J. Mol.Biol, 1987, 196: 901-917; and MacCallum et al., J. Mol. Biol, 1996, 262: 732). Yet another standard for characterizing the antigen-binding site is the AbM definition used by the Oxford Molecular AbM antibody modeling software. See, for example, 'Protein Sequence and Structure Analysis of Antibody Variable Domains', in: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R., SpringerVerlag, Heidelberg). To the extent that two residue identification techniques define overlapping, but not identical, regions, they can be combined to define a hybrid CDR. However, numbering according to the Kabat system is preferred. Typically, CDRs form a loop structure that can be classified as a canonical structure. The term “canonical structure” refers to the main chain conformation adopted by antigen-binding loops (CDRs). From comparative structural studies, five of the six antigen-binding loops have been found to have only a limited repertoire of available conformations. Each canonical structure can be characterized by the twist angles of the polypeptide backbone. Loops between corresponding antibodies can then have very similar three-dimensional structures, despite the high variability of amino acid sequences in most loops (Chothia and Lesk, J. Mol. Biol., 1987, 196: 901; Chothia et al., Nature, 1989, 342: 877; Martin and Thornton, J. Mol. Biol., 1996, 263: 800). Furthermore, there is a relationship between the structure adopted by the loop and the amino acid sequences that surround it.The composition of a particular canonical class is determined by the loop length and the amino acid residues residing in key positions within the loop, as well as within the conserved frame (i.e., outside the loop). Therefore, assignment to a particular canonical class can be made based on the presence of these key amino acid residues. The term “canonical structure” may also include considerations regarding the linear sequence of the antibody, for example, according to Kabat (Kabat et al., loe. cit.). The Kabat numbering scheme (system) is a widely adopted standard for numbering the amino acid residues of a variable domain of an antibody in a consistent manner and is the preferred scheme applied in the present invention, as also mentioned elsewhere herein. Additional structural considerations may also be used to determine the canonical structure of an antibody. For example, differences not fully reflected by the Kabat numbering may be described by the Chothia et al. numbering system and / or revealed by other techniques, such as crystallography and two- or three-dimensional computer modeling.Therefore, a given antibody sequence can be assigned to a canonical class, allowing, among other things, the identification of appropriate sequences (for example, based on the desire to include a variety of canonical structures in a library). The Kabat numbering of antibody amino acid sequences and the structural considerations described by Chothia et al., cited above, and their implications for interpreting canonical aspects of antibody structure, are described in the literature. The subunit structures and three-dimensional configurations of the different immunoglobulin classes are well known. For a review of antibody structure, see Antibodies: A Laboratory Manual, Coid Spring Harbor Laboratory, eds. Harlow et al., 1988. The CDR3 of the light chain, and particularly the CDR3 of the heavy chain, may be the most important determinants of antigen binding within the variable regions of the light and heavy chains. In some antibody constructs, the CDR3 of the heavy chain appears to be the main contact area between the antigen and the antibody. In vitro selection schemes, in which only the CDR3 is varied, can be used to alter the binding properties of an antibody or to determine which residues contribute to antigen binding. Therefore, the CDR3 is typically the greatest source of molecular diversity within the antibody binding site. For example, H3 can be as short as two amino acid residues or as long as 26 amino acids. The term “neutralization” refers to an antigen-binding molecule, scFv or antibody, respectively, that binds to a ligand and prevents or reduces the biological effect of that ligand. This can be accomplished, for example, by directly blocking a binding site on the ligand or by binding to the ligand and indirectly altering the ligand's ability to bind (such as through structural or energetic alterations in the ligand). In some embodiments, the term can also refer to an antigen-binding molecule that prevents the protein to which it is bound from performing a biological function. The term “target” or “antigen” refers to a molecule or a portion of a molecule capable of binding to an antigen-binding molecule. In certain embodiments, a target may have one or more epitopes. The term “compete,” when used in the context of antigen-binding molecules competing for the same epitope, refers to competition between antigen-binding molecules as determined by an assay in which the antigen-binding molecule (e.g., an antibody or an immunologically functional fragment thereof) being evaluated prevents or inhibits (e.g., reduces) the specific binding of a reference antigen-binding molecule to an antigen. Numerous types of competitive binding assays can be used to determine whether one antigen-binding molecule competes with another, e.g., a direct or indirect solid-phase radioimmunoassay (RIA), a direct or indirect solid-phase enzyme immunoassay (EIA), a sandwich competition assay (Stahli et al., 1983, Methods in Enzymology 9: 242-253). a direct solid-phase EIA with biotin-avidin (Kirkland et al., 1986, J. Immunol.137: 3614-3619), a direct labeled solid-phase assay, a direct labeled solid-phase sandwich assay (Harlow and Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press); a direct solid-phase RIA using a 1-125 label (Morel et al., 1988, Molec. Immunol. 25: 7-15); a direct solid-phase EIA with biotin-avidin (Cheung, et al., 1990, Virology 176: 546-552); and a direct labeled RIA (Moldenhauer et al., 1990, Scand. J. Immunol. 32: 77-82). The term “epitope” includes any determinant capable of binding to an antigen-binding molecule, such as an scFv, an antibody, or an immune cell of the invention. An epitope is a region of an antigen that binds to an antigen-binding molecule directed to that antigen, and when the antigen is a protein, it includes specific amino acids that are in direct contact with the antigen-binding molecule. As used herein, the terms “mark” or “marking” refer to the incorporation of a detectable mark, for example, the incorporation of a radiolabeled amino acid or the attachment to a polypeptide of biotin units that can be detected with labeled avidin (e.g., streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or colorimetric methods). In certain embodiments, the mark or marker may also be therapeutic. Various methods for marking polypeptides and glycoproteins are known in the art. According to the invention, the present invention may incorporate on-off control switching techniques or other types of control switching techniques. These techniques may employ the use of dimerization domains and optional activators of such domain dimerization. These techniques include, for example, those described by Wu et al., Science 2014 350 (6258) using FKBP / Rapalog dimerization systems in some cells, the contents of which are incorporated herein by reference. Additional dimerization technology is described, for example, in Fegan et al., Chem. Rev. 2010, 110, 3315-3336, as well as in U.S. Patent Nos. 5,830,462; 5,834,266; 5,869,337; and 6,165,787, whose contents are also fully incorporated herein by reference.Additional dimerization pairs may include cyclosporine-A / cyclophilin receptor, estrogen / estrogen receptor (optionally using tamoxifen), glucocorticoid / glucocorticoid receptor, tetracycline / tetracycline receptor, and vitamin D / vitamin D receptor. Other examples of dimerization technology can be found, for example, in WO 2014 / 127261, WO 2015 / 090229, US 2014 / 0286987, US 2015 / 0266973, US 2016 / 0046700, US Patent No. 8,486,693, US 2014 / 0171649, and US 2012 / 0130076, the contents of which are also incorporated herein in full by reference. TREATMENT METHODS Native T cells can be (i) removed from a patient, (ii) genetically modified to express a chimeric antigen receptor (CAR) that binds to at least one tumor antigen, (iii) expanded ex vivo to form a larger population of modified T cells, and (iv) reintroduced into the patient using adoptive immunotherapy. See, for example, U.S. Patent Nos. 7,741,465 and 6,319,494, Eshhar et al. (Cancer Immunol., supra), Krause et al. (supra), and Finney et al. (supra). After reintroduction into the patient, the modified T cells can mediate an immune response against cells expressing the tumor antigen. See, for example, Krause et al., J. Exp. Med., Vol. 188, No. 4, 1998 (619–626). This immune response includes the secretion of IL-2 and other cytokines by T cells, clonal expansion of T cells that recognize the tumor antigen, and T cell-mediated specific killing of target-positive cells.See Hombach et al., Journal of Immun., 167: 6123-6131 (2001). Therefore, in some respects the invention comprises a method for treating or preventing a condition associated with undesirable and / or elevated levels of DLL3 in a patient, comprising administering to a patient in need an effective amount of at least one isolated antigen-binding molecule, CAR or TCR disclosed herein. Methods are provided for treating diseases or disorders, including cancer. In some embodiments, the invention relates to creating a T-cell-mediated immune response in a subject, comprising administering to said subject an effective quantity of the modified immune cells of the present application. In some embodiments, the T-cell-mediated immune response is directed against one or more target cells. In some embodiments, the modified immune cell comprises a chimeric antigen receptor (CAR) or a T-cell receptor (TCR). In some embodiments, the target cell is a tumor cell. In some aspects, the invention comprises a method for treating or preventing a malignant condition, wherein said method comprises administering to a subject in need an effective quantity of at least one isolated antigen-binding molecule described herein.In some respects, the invention comprises a method for treating or preventing a malignant form, wherein said method comprises administering to a subject in need an effective amount of at least one immune cell, wherein said immune cell comprises at least one chimeric antigen receptor, a T cell receptor and / or an isolated antigen-binding molecule as described herein. In some aspects, the invention comprises a pharmaceutical composition comprising at least one antigen-binding molecule described herein and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises an additional active agent. The antigen-binding molecules, CARs, TCRs, immune cells, and the like of the invention can be used to treat myeloid diseases including, but not limited to, adrenal, liver, kidney, bladder, breast, gastric, ovarian, cervical, uterine, esophageal, colorectal, prostate (e.g., prostate adenocarcinoma), pancreatic, lung (both small cell and non-small cell), thyroid, carcinomas, sarcomas, glioblastomas, head and neck tumors, large cell neuroendocrine carcinoma (LCNEC), medullary thyroid cancer, glioblastoma, neuroendocrine prostate cancer (NEO), high-grade gastroenteropancreatic (GEP) cancer, and malignant melanoma. It will be observed that the target doses for CAR+ / CAR-T7 TCR+ cells can vary within a range of 1 x 10⁶ to 2 x 10¹⁰ cells / kg, preferably 2 x 10¹⁰ cells / kg more preferably. It will be observed that doses above and below this range may be appropriate for certain subjects, and a healthcare professional may determine the appropriate dose levels as needed. Additionally, multiple cell doses can be provided according to the invention. Methods are also provided for reducing the size of a tumor in a subject, comprising administering a modified cell of the present invention to the subject, wherein the cell comprises a chimeric antigen receptor, a T-cell receptor, or a chimeric antigen receptor based on a T-cell receptor comprising an antigen-binding molecule that binds to an antigen on the tumor. In some embodiments, the subject has a solid tumor or a malignant blood cancer, such as lymphoma or leukemia. In some embodiments, the modified cell is delivered to a tumor bed. In some embodiments, the cancer is present in the subject's bone marrow. In some embodiments, the modified cells are autologous T cells. In some embodiments, the modified cells are allogeneic T cells. In some embodiments, the modified cells are heterologous T cells. In some embodiments, the modified cells of this application are transfected or transduced in vivo. In other embodiments, the modified cells are transfected or transduced ex vivo. The methods may also include administering one or more chemotherapeutic agents. In certain embodiments, the chemotherapeutic agent is a lymphocyte-reducing chemotherapeutic (preconditioner). Beneficial preconditioning treatment regimens, along with correlative beneficial biomarkers, are described in U.S. Provisional Patent Applications Nos. 62 / 262,143 and 62 / 167,750, which are incorporated herein in full by reference. For example, methods are described for conditioning a patient requiring T-cell therapy, comprising administering to the patient specific beneficial doses of cyclophosphamide (between 200 mg / m² / day and 2000 mg / m² / day) and specific doses of fludarabine (between 20 mg / m² / day and 900 mg / m² / day).A preferred dosing regimen comprises treating a patient by administering approximately 500 mg / m2 / day of cyclophosphamide and approximately 60 mg / m2 / day of fludarabine daily for three days prior to administering a therapeutically effective amount of modified T cells to the patient. In other embodiments, the antigen-binding molecule, the transduced (or otherwise modified) cells (such as with CAR or TCR), and the chemotherapeutic agent are each administered in an amount effective to treat the disease or condition in the subject. In certain embodiments, the compositions comprising the CAR-expressing effector immune cells disclosed herein may be administered in conjunction with any number of chemotherapeutic agents. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN™); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamylamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine. nitrogen mustards such as chlorambucllo, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, fenesterin, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomycins, actinomycin, autramycin, azaserin, bleomycins, cactinomycin, caliqueamycin, carabicin, carminomycin, carzinophylline, cromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, chelamicin, rhodorubicin, streptonigrine, streptozocin, tubercidine, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxyfluridine, enocitabine, floxuridine, 5-FU;androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as frolinic acid; aceglatone; aldofosfamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisanthrene; edatratane; defofamine; demecolcine; diaziquone; elfomitin; eliptinium acetate; ethoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenammet; pyrarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; sizophyran; spirogermanium; tenuazonic acid; triaziquone; 2',2-tnchlorotriethylamine; urethane; vindesine; dacarbazine; manomustine; mitobronitol; mitolactol; pipobromano; gacitosin; arabinoside (“Ara-C'j; cyclophosphamide; thiotepa; taxanes, for example, paclitaxel (TAXOL™, Bristol-Myers Squibb) and docetaxel (TAXOTERE®, RhonePoulenc Rorer);Chlorambucil, gemcitabine, 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoic acid derivatives such as Targretin™ (bexarotene), Panretin™ (alitretinoin); ONTAK™ (denileukin diftitox); spermamycins; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. This definition also includes anti-hormonal agents, which act in the regulation or inhibition of the action of the hormone in tumors, such as antiestrogens which include, for example, tamoxifen, raloxifene, 4(5)-imidazole aromatase inhibitors, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone and toremifene (Fareston);and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the aforementioned agents. Combinations of chemotherapeutic agents are also administered when appropriate, including, but not limited to, CHOP, i.e., cyclophosphamide (Cytoxan®), doxorubicin (hydroxydoxorubicin), vincristine (Oncovin®), and prednisone. In some embodiments, the chemotherapeutic agent is administered at the same time as, or within one week of, administration of the modified cell or nucleic acid. In other embodiments, the chemotherapeutic agent is administered between 1 and 4 weeks, or between 1 week and 1 month, between 1 week and 2 months, between 1 week and 3 months, between 1 week and 6 months, between 1 week and 9 months, or between 1 week and 12 months after administration of the modified cell or nucleic acid. In other embodiments, the chemotherapeutic agent is administered at least 1 month before administering the cell or nucleic acid. In some embodiments, the methods also include administering two or more chemotherapeutic agents. A variety of additional therapeutic agents may be used in conjunction with the compositions described herein. For example, potentially useful additional therapeutic agents include PD-1 inhibitors such as nivolumab (Opdivo®), pembrolizumab (Keytruda®), pidilizumab, and atezolizumab. Additional suitable therapeutic agents that are useful in combination with the invention include, but are not limited to, ibrutinib (Imbruvica®), ofatumumab (Arzerra®), rituximab (Rituxan®), bevacizumab (Avastin®), trastuzumab (Herceptin®), trastuzumab emtansine (KADCYLA®), imatinib (Gleevec®), cetuximab (Erbitux®), panitumumab (Vectibix®), catumaxomab, ibritumomab, ofatumumab, tositumomab, brentuximab, alemtuzumab, gemtuzumab, erlotinib, gefitinib, vandetanib, afatinib, lapatinib, neratinib, axitinib, masitinib, pazopanib, sunitinib, sorafenib, toceranib, lestaurtinib, axitinib, cediranib, lenvatinib, nintedanib, pazopanib, regorafenib, semaxanib, sorafenib, sunitinib, tivozanib, toceranib, vandetanib, entrectinib, cabozantinib, imatinib, dasatinib, nilotinib, ponatinib, radotinib, bosutinib, lestaurtinib, ruxolitinib, pacritinib, cobimetinib, selumetinib, trametinib, binimetinib, alectinib, ceritinib, crizotinib, aflibercept, adipotida, denileuquina diftitox,mTOR inhibitors such as everolimus and temsirolimus, Hedgehog pathway inhibitors such as sonidegib and vismodegib, CDK inhibitors such as a CDK inhibitor (palbociclib). In further embodiments, the composition comprising immune cells containing CARs may be administered with an anti-inflammatory agent. Anti-inflammatory agents or drugs include, but are not limited to, steroids and glucocorticoids (including betamethasone, budesonide, dexamethasone, hydrocortisone acetate, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone), and nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, ibuprofen, naproxen, methotrexate, sulfasalazine, leflunomide, anti-TNF medications, cyclophosphamide, and mycophenolate. Examples of NSAIDs include ibuprofen, naproxen, naproxen sodium, COX-2 inhibitors, and sialilates. Examples of analgesics include acetaminophen, oxycodone, and proproxyphene hydrochloride. Examples of glucocorticoids include cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, or prednisone.Examples of biological response modifiers include molecules targeting cell surface markers (e.g., CD4, CD5, etc.), cytokine inhibitors such as TNF antagonists (e.g., etanercept (ENBREL®), adalimumab (HUMIRA®), and infliximab (REMICADE®)), chemokine inhibitors, and adhesion molecule inhibitors. Biological response modifiers include monoclonal antibodies as well as recombinant forms of the molecules. Examples of DMARDs include azathioprine, cyclophosphamide, cyclosporine, methotrexate, penicillamine, leflunomide, sulfasalazine, hydroxychloroquine, gold (oral (auranofin) and intramuscular), and minocycline. In certain embodiments, the compositions described herein are administered together with a cytokine. The term “cytokine,” as used herein, refers to proteins released by a cell population that act on another cell as intercellular mediators. Examples of cytokines include lymphokines, monokines, and traditional polypeptide hormones. Cytokines include growth hormones, such as human growth hormone, human N-methionyl growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones, such as follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and luteinizing hormone (LH); liver growth factor (HGF); fibroblast growth factor (FGF); prolactin; placental lactogen; and Müllerian-inhibiting substance.mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors (NGFs), such as NGF-alpha; platelet growth factor; transforming growth factors (TGFs), such as TGF-alpha and TGF-beta; insulin-like growth factors I and II; erythropoietin (EPO); osteoinductive factors; interferons, such as alpha, beta, and gamma interferons; colony-stimulating factors (CSFs), such as macrophage CSF (M-CSF), granulocyte-macrophage CSF (GM-CSF), and granulocyte-macrophage CSF (G-CSF); interleukins (IL), such as IL-1, IL-1-alpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12; IL-15; a tumor necrosis factor, such as TNF-alpha or TNF-beta;and other polypeptide factors, including LIF and the Kit ligand (KL). As used herein, the term cytokine includes proteins from natural sources or recombinant cell cultures, and biologically active equivalents of native cytokine sequences. In some aspects, the invention comprises an antigen-binding molecule that binds to DLL3 with a Kd of less than 100 pM. In some embodiments, the antigen-binding molecule binds with a Kd of less than 10 pM. In other embodiments, the antigen-binding molecule binds with a Kd of less than 5 pM. METHODS OF PREPARATION A variety of known techniques can be used in the preparation of the polynucleotides, polypeptides, vectors, antigen-binding molecules, immune cells, compositions and the like according to the invention. Prior to the in vitro manipulation or genetic modification of the immune cells described herein, cells may be obtained from a subject. In some embodiments, the immune cells comprise T cells. T cells may be obtained from numerous sources, including peripheral blood mononuclear cells (PBMCs), bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from an infection site, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments, T cells may be obtained from a unit of blood collected from the subject using any of numerous techniques known to the practitioner, such as FICOLL™ separation. Preferably, the cells may be obtained from an individual's circulating blood by apheresis.The product of apheresis typically contains lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and platelets. In certain embodiments, the cells collected by apheresis can be washed to remove the plasma fraction and placed in a buffer solution or medium appropriate for subsequent processing. The cells can be washed with PBS. As can be seen, a washing step can be employed, such as using a semi-automated flow centrifuge—for example, the Cobe™ 2991 Cell Processor, the Baxter CytoMate™, or similar systems. After washing, the cells can be resuspended in a variety of biocompatible buffer solutions, or other saline solution with or without buffer. In certain embodiments, unwanted components can be removed from the apheresis sample. In certain embodiments, T cells are isolated from PBMCs by lysing red blood cells and exhausting monocytes, for example, using centrifugation through a PERCOLL™ gradient. A specific T cell subpopulation, such as CD28+, CD4+, CD8+, CD45RA+, and CD45RO+ T cells, can be further isolated using positive or negative selection techniques known to the art. For example, enrichment of a T cell population by negative selection can be achieved with a combination of antibodies targeting surface markers unique to negatively selected cells. One useful method here is cell separation and / or selection by negative magnetic immunoadherence or flow cytometry, which employs a cocktail of monoclonal antibodies targeting cell surface markers present on negatively selected cells.For example, for CD4+ cell enrichment by negative selection, the monoclonal antibody cocktail typically includes antibodies against CD14, CD20, CD11b, CD16, HLA-DR, and CD8. Flow cytometry and cell separation can also be used to isolate cell populations of interest that are useful in the present invention. PBMCs can be used directly for genetic modification of immune cells (such as CAR or TCR cells) using the methods described herein. In certain embodiments, after isolating the PBMCs, T lymphocytes can be further isolated, and cytotoxic and helper T lymphocytes can be separated into previously unexposed, memory, and effector T cell subpopulations, either before or after genetic modification and / or expansion. ccyni n / nznz / E / YiAi In some embodiments, CD8+ cells are also separated into previously unexposed, central memory, and effector cells by identifying the cell surface antigens associated with each of these CD8+ cell types. In some embodiments, the expression of phenotypic markers of central memory T cells includes CD45RO, CD62L, CCR7, CD28, CD3, and CD127, and they are negative for granzyme B. In some embodiments, central memory T cells are CD45RO+, CD62L+, and CD8+. In some embodiments, effector T cells are negative for CD62L, CCR7, CD28, and CD127, and positive for granzyme B and perforin. In certain embodiments, CD4+ T cells are also separated into subpopulations.For example, CD4+ helper T cells can be separated into previously unexposed, central memory, and effector cells by identifying cell populations that present antigens on the cell surface. Immune cells, such as T cells, can be genetically modified after isolation using known methods, or immune cells can be activated and expanded (or differentiated in the case of progenitor cells) in vitro before being genetically modified. In another embodiment, immune cells, such as T cells, are genetically modified with the chimeric antigen receptors described herein (e.g., they are transduced with a viral vector comprising one or more nucleotide sequences encoding a CAR) and then activated and / or expanded in vitro. Methods for activating and expanding T cells are known in the art and are described, for example, in U.S. Patent No. 6,905,874; U.S. Patent No. 6,867,041; and U.S. Patent No. 6,797,514. and in PCT WO2012 / 079000, the contents of which are incorporated herein in full by way of reference.In general, these methods involve placing PBMCs or isolated T cells in contact with a stimulating and a costimulatory agent, such as anti-CD3 and anti-CD28 antibodies, usually bound to a bead or other surface, in a culture medium containing appropriate cytokines, such as IL-2. The anti-CD3 and anti-CD28 antibodies bound to the same bead serve as a surrogate antigen-presenting cell (APC). One example is the Dynabeads® system, a CD3 / CD28 activator / stimulator system for the physiological activation of human T cells. In other embodiments, T cells can be activated and stimulated to proliferate with nutrient cells and appropriate antibodies and cytokines using methods such as those described in U.S. Patent No. 6,040,177; U.S. Patent No. 5,827,642; and WO2012129514, the contents of which are incorporated herein in full by reference. Some methods for preparing the constructs and modified immune cells of the invention are described in PCT Application PCT / US15 / 14520, the contents of which are incorporated herein by reference. Other methods for preparing the constructs and cells can be found in US Provisional Patent Application No. 62 / 244036, the contents of which are incorporated herein by reference. It will be noted that PBMCs can also include other cytotoxic lymphocytes, such as NK cells or NK-T cells. An expression vector comprising the coding sequence of a chimeric receptor disclosed herein can be introduced into a population of donor human T cells, NK cells, or NK-T cells. Successfully transduced T cells comprising the expression vector can be separated using flow cytometry to isolate CD3-positive T cells and then propagated to increase the number of these CAR-expressing T cells. This can be further enhanced by cell activation using anti-CD3 and IL-2 antibodies or other methods known in the art and described elsewhere herein. Standard procedures are employed for the cryopreservation of CAR-expressing T cells for storage and / or preparation prior to use in a human subject.In one embodiment, the transduction, culture and / or expansion of T cells in vitro are carried out in the absence of products derived from a non-human animal, such as fetal calf serum and fetal bovine serum. For polynucleotide cloning, the vector can be introduced into a host cell (an isolated host cell) to allow replication of the vector itself and thus amplify the copies of the polynucleotide it contains. Cloning vectors can contain sequence components that generally include, but are not limited to, an origin of replication, promoter sequences, transcription initiation sequences, enhancer sequences, and selectable markers. These elements can be selected, as needed, by a specialist in the field. For example, the origin of replication can be selected to promote autonomous replication of the vector in the host cell. In certain embodiments, this disclosure provides isolated host cells containing the vector provided herein. The vector-containing host cells may be useful in the expression or cloning of the polynucleotide contained in the vector. Suitable host cells may include, but are not limited to, prokaryotic cells, fungal cells, yeast cells, or higher eukaryotic cells, such as mammalian cells. Prokaryotic cells suitable for this purpose include, in a non-limiting sense, eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as Escheríchia, for example, E. coli, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, for example, Salmonella typhimurium, Serratia, for example, Serratia marcescans and Shigella, as well as Bacilli such as B. subtilis and B. licheniformis, Pseudomonas such as P. aeruginosa and with ι η / ηζηζ / Ε / νίΛΐ Streptomyces. The vector can be introduced into the host cell using any of the suitable methods known in the art, including, but not limited to, DEAE-dextran-mediated delivery, the calcium phosphate precipitation method, cationic lipid-mediated delivery, liposome-mediated transfection, electroporation, microprojectile bombardment, receptor-mediated gene delivery, and delivery via polylysine, histone, chitosan, and peptides. Standard methods for transfecting and transforming cells for the expression of a vector of interest are well known in the art. In a further embodiment, a mixture of different expression vectors can be used in the genetic modification of a donor population of effector immune cells, wherein each vector encodes a different CAR as disclosed herein.The resulting transduced effector immune cells form a mixed population of modified cells, with a ratio of the modified cells expressing more than one different CAR. In one embodiment, the invention provides a method for storing genetically modified cells expressing CARs or TCRs targeting the DLL3 protein. This comprises cryopreserving the immune cells in such a way that the cells remain viable after thawing. A fraction of the CAR-expressing immune cells can be cryopreserved using methods known in the art to provide a permanent source of such cells for the future treatment of patients with a malignant form of the disease. When required, the cryopreserved transformed immune cells can be thawed, grown, and expanded to obtain more of these cells. As used herein, the term “cryopreserve” refers to the preservation of cells by cooling to sub-zero temperatures, such as (typically) 77 Kelvin or -196°C (the boiling point of liquid nitrogen). Cryoprotective agents are often used at sub-zero temperatures to preserve cells against damage due to freezing at low temperatures or warming to room temperature. Cryopreservative agents and optimal cooling rates can offer protection against cell injury. Cryoprotective agents that may be used according to the invention include, but are not limited to: dimethyl sulfoxide (DMSO) (Lovelock & Bishop, Nature (1959); 183: 1394-1395; Ashwood-Smith, Nature (1961); 190: 1204-1205), glycerol, polyvinylpyrrolidone (Rinfret, Ann. NY Acad. Sci. (1960); 85: 576) and polyethylene glycol (Sloviter & Ravdin, Nature (1962); 196: 48).The preferred cooling rate is 1-3eC / minute. The term “substantially pure” is used to indicate that a given component is present at a high level. Preferably, the component is the predominant component present in a composition. Preferably, it is present at a level of more than 30%, more than 50%, more than 75%, more than 90%, or even more than 95%, where such level is determined on a dry weight / dry weight basis with respect to the total composition under consideration. At very high levels (e.g., levels of more than 90%, more than 95%, or more than 99%), the component may be considered to be in a “pure form.” The biologically active substances of the present invention (including polypeptides, nucleic acid molecules, antigen-binding molecules, and portions) may be provided in a form that is substantially free from one or more contaminants with which the substance would otherwise be associated.When a composition is substantially free of a given contaminant, that contaminant will be found at a low level (e.g., at a level of less than 10%, less than 5%, or less than 1% on a dry weight / dry weight basis as indicated above). In some embodiments, cells are first prepared by harvesting them from their culture medium and then washing and concentrating them in a suitable medium and container system for administration (a “pharmaceutically acceptable” vehicle) in an amount effective for treatment. Suitable infusion media may comprise any formulation of an isotonic medium, typically normal saline, Normosol™ R (Abbott), or Plasma-Lyte™ A (Baxter), but 5% dextrose in water or Ringer’s lactate may also be used. The infusion medium may be supplemented with human serum albumin. The desired treatment quantities of cells present in the composition are generally at least 2 cells (e.g., at least 1 subset of CD8+ core memory T cells and at least 1 subset of CD4+ helper T cells) or more, typically more than 10² cells and up to 10⁶, up to and including 10⁸ or 10⁹ cells, and may be more than 10¹⁰ cells. The number of cells will depend on the intended use of the composition and the type of cells included. The desired cell density is typically greater than 10⁶ cells / ml and generally greater than 10⁷ cells / ml, usually 10⁸ cells / ml or higher. The clinically relevant number of immune cells can be distributed in multiple infusions that cumulatively are equal to or exceed 105, 106, 107, 108, 109, 1010, 1011 or 1012 cells.In some aspects of the present invention, particularly since all infused cells will be redirected to a specific target antigen (DLL3), a smaller number of cells can be administered, in the range of 10⁶ / kilogram (10⁶-10¹¹ per patient). CAR T-cell therapies can be administered multiple times at dosages within these ranges. The cells can be autologous, allogeneic, or heterologous to the patient receiving the therapy. The CAR-expressing cell populations of the present invention can be administered either alone or as a pharmaceutical composition in combination with diluents and / or other components such as IL-2 or other cytokines or cell populations. The pharmaceutical compositions of the present invention may comprise a CAR- or TCR-expressing cell population, such as T cells, as described herein, in combination with one or more pharmaceutically or physiologically acceptable vehicles, diluents, or excipients. Such compositions may comprise buffer solutions such as a neutral saline buffer, a phosphate saline buffer, and the like; carbohydrates such as glucose, mannose, sucrose, or dextrans, mannitol; proteins; polypeptides or amino acids such as glycine; antioxidants; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and preservatives.The compositions of the present invention are preferably formulated for intravenous administration. Pharmaceutical compositions (solutions, suspensions, or the like) may include one or more of the following: sterile diluents such as water for injection, saline solution (preferably physiological saline), Ringer's solution, isotonic sodium chloride, modified oils such as synthetic mono- or diglycerides, which may serve as a solvent or as a suspension medium, polyethylene glycols, glycerin, propylene glycol, or other solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffer solutions such as acetates, citrates, or phosphate; and tonicity-adjusting agents such as dextrose or sodium chloride. The parenteral preparation may be contained in ampoules, disposable syringes, or multidose vials, made of either plastic or glass.An injectable pharmaceutical composition is preferably sterile. It will be seen that it is possible to minimize adverse events by transducing immune cells (containing one or more CARs or TCRs) with a suicide gene. It may also be desirable to incorporate an inducible “activator” or “accelerator” switch into the immune cells. Suitable techniques include the use of an inducible caspase (U.S. Patent Application No. 2011 / 0286980) or thymidine kinase, before, after, or at the same time as transducing the cells with the CAR construct of the present invention. Other methods for introducing suicide genes and / or “activated” switches include TALEN, zinc fingers, RNAi, RNAsi, hsRNA, antisense technology, and other techniques known in the art. It is understood that the descriptions herein are provided for illustrative and explanatory purposes only and are not intended to be a restrictive interpretation of the claimed invention. In this application, the singular includes the plural unless specifically defined otherwise. The section headings used herein are for organizational purposes only and should not be considered as limiting the subject matter described. All documents, or portions thereof, cited in the application, including, but not limited to, patents, patent applications, articles, books, and treatises, are expressly and fully incorporated herein by reference. As used in accordance with this description, the following terms, unless otherwise indicated, shall have the meanings set forth below: In this application, the use of “or” means “and / or” unless otherwise stated. Furthermore, the use of the term “including,” as well as other forms such as “includes” and “included,” is not limiting. Additionally, terms such as “element” or “component” encompass elements and components that constitute a unit, and elements and components that comprise more than one subunit, unless specifically stated otherwise. The term “DLL3 activity” includes any biological effect of DLL3. In certain embodiments, DLL3 activity includes the ability of DLL3 to interact with or bind to a substrate or receptor. The term “polynucleotide,” “nucleotide,” or “nucleic acid” encompasses polymers of single- or double-stranded nucleotides. The nucleotides comprising the polynucleotide may be ribonucleotides or deoxyribonucleotides, or a modified form of any type of nucleotide. These modifications include base modifications, such as bromouridine and inosine derivatives; ribose modifications, such as 2',3'-dideoxyribose; and modifications of the bonds between nucleotides, such as phosphorothioate, phosphorodithioate, phosphorosenate, phosphorodisenate, phosphoranilothioate, phosphoranylate, and phosphoramidate. The term “oligonucleotide” refers to a polynucleotide comprising 200 nucleotides or fewer. Oligonucleotides can be single-stranded or double-stranded, for example, for use in constructing a mutating gene. Oligonucleotides can be frame-sense or antisense. An oligonucleotide may include a label, such as a radiolabel, fluorescent label, hapten, or antigenic label, for screening assays. Oligonucleotides can be used, for example, as POR primers, cloning primers, or hybridization probes. The term “control sequence” refers to a polynucleotide sequence that can affect the expression and processing of the coding sequences to which it is bound. The nature of these control sequences can depend on the host organism. In particular embodiments, control sequences for prokaryotes may include a promoter, a ribosome binding site, and a transcription termination sequence. For example, control sequences for eukaryotes may include promoters comprising one or more recognition sites for transcription factors, transcription enhancer sequences, and transcription termination sequences. “Control sequences” may also include guide sequences (signal peptides) and / or fusion member sequences. As used herein, the term “operationally linked” means that the components covered by the term are in a relationship that enables them to perform their inherent functions under appropriate conditions. The term “vector” refers to any molecule or entity (e.g., nucleic acid, plasmid, bacteriophage, or virus) used to transfer protein-coding information into a host cell. The term “expression vector” or “expression construct” refers to a vector that is suitable for transforming a host cell and contains nucleic acid sequences that direct and / or control (in conjunction with the host cell) the expression of one or more operatively joined heterologous coding regions. An expression construct may include, but is not limited to, sequences that affect or control the expression, translation, and, if introns are present, the cleavage of RNA from an operatively joined coding region. The term “host cell” refers to a cell that has been transformed, or can be transformed, with a nucleic acid sequence, thereby expressing a gene of interest. The term includes the progeny of the parent cell, whether or not such progeny has a morphology or genetic composition identical to that of the original parent cell, as long as the gene of interest is present. The term “transformation” refers to a change in the genetic characteristics of cells, and a cell is transformed when it has been modified to contain new DNA or RNA. For example, a cell is transformed when it has been genetically modified from its native state by the introduction of new genetic material through transfection, transduction, or other procedures. After transfection or transduction, the transforming DNA may recombine with the cell's DNA, physically integrating into a chromosome; it may remain transiently as an episomal element without replicating; or it may replicate independently as a plasmid. A cell is considered “stably transformed” when the transforming DNA replicates upon cell division. The term “transfection” refers to the uptake of foreign or exogenous DNA by a cell. Numerous transformation procedures are known in the art, and these are described herein. See, for example, Graham et al., 1973, Virology 52: 456; Sambrook et al., 2001, Molecular Cloning: A Laboratory Manual, supra; Davis et al., 1986, Basic Methods in Molecular Biology, Elsevier; Chu et al., 1981, Gene 13: 197. The term “transduction” refers to the process by which foreign DNA is introduced into a cell by means of a viral vector. See Jones et al., (1998), Genetics: principles and analysis, Boston: Jones & Bartlett Publ. ccyni η / ηζηζ / Ε / γίΛΐ The terms “polypeptide” or “protein” refer to a macromolecule that has the amino acid sequence of a protein, including deletions, additions, and / or substitutions of one or more amino acids from the native sequence. The terms “polypeptide” and “protein” specifically encompass DLL3 antigen-binding molecules, antibodies, or sequences that have deletions, additions, and / or substitutions of one or more amino acids from the antigen-binding protein. The term “polypeptide fragment” refers to a polypeptide that has an amino-terminal deletion, a carboxy-terminal deletion, and / or an internal deletion, compared to the full-length native protein. These fragments may also contain modified amino acids compared to the native protein. Useful polypeptide fragments include immunologically functional fragments of antigen-binding molecules.The fragments that are useful include, but are not limited to, one or more CDR regions, variable domains of a heavy and / or light chain, a portion of other portions of an antibody chain, and the like. The term “isolated” means that (i) it is free from at least some other proteins with which it would normally be found, (ii) it is essentially free from other proteins of the same source, e.g., of the same species, (iii) it is separated from at least approximately 50 percent of polynucleotides, lipids, carbohydrates, or other materials with which it is associated in nature, (iv) it is operatively associated (by a covalent or non-covalent interaction) with a polypeptide with which it is not associated in nature, or (v) it does not occur in nature. A “variant” of a polypeptide (e.g., an antigen-binding molecule or an antibody) comprises an amino acid sequence in which one or more amino acid residues have been inserted, deleted, and / or replaced, compared to another polypeptide sequence. Variants include fusion proteins. The term “identity” refers to a relationship between the sequences of two or more polypeptide molecules, or two or more nucleic acid molecules, determined by aligning and comparing the sequences. The “percentage of identity” refers to the percentage of identical residues among the amino acids or nucleotides in the compared molecules, and is calculated based on the size of the smallest molecule being compared. For these calculations, any mismatches in the alignments are preferably addressed using a specific model or computer program (i.e., an “algorithm”). To calculate the percent identity, the sequences to be compared are aligned in a way that provides the greatest match between the sequences. An example of a computer program for determining the percent identity is the set of programs ccyni n / nznz / E / YiAi GCG, which includes GAP (Devereux et al., 1984, Nuci. Acid Res., 12: 387; Genetics Computer Group, University of Wisconsin, Madison, Wis.). The GAP computer algorithm is used to align two polypeptides or polynucleotides whose percentage sequence identity is to be determined. The sequences are aligned to obtain an optimal match of their respective amino acids or nucleotides (the “extent of match” determined by the algorithm). In certain implementations, the algorithm also employs a conventional comparison matrix (see Dayhoff et al., 1978, Atlas of Protein Sequence and Structure 5: 345-352 regarding the PAM 250 comparison matrix; Henikoff et al., 1992, Proc. Nati. Acad. Sel. USA 89: 10915-10919 regarding the BLOSUM 62 comparison matrix). As used herein, the twenty conventional (e.g., natural) amino acids and their abbreviations are used according to conventional usage. See Immunology - A Synthesis (2nd Edition, Golub and Gren, Eds., Sinauer Assoc., Sunderland, Mass. (1991)), incorporated herein for all purposes by reference. Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids, non-natural amino acids such as alpha-disubstituted amino acids, N-alkyl amino acids, lactic acid, and other non-conventional amino acids may also be suitable building blocks for the polypeptides of the present invention. Examples of non-conventional amino acids include: 4-hydroxyproline, gamma-carboxyglutamate, epsilon-N,N,N-trimethylserine, e-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, sigma-N-methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline).In the polypeptide notation used herein, the leftward direction is the amino-terminal direction and the rightward direction is the carboxy-terminal direction, in accordance with convention and standard usage. Conservative amino acid substitutions can encompass non-natural amino acid residues, which are typically incorporated through chemical peptide synthesis rather than synthesis in biological systems. These include peptidomimetics and other reversed or inverted forms of amino acid groups. Natural residues can be divided into classes based on common side-chain properties: a) hydrophobic: Norleucine, Met, Ala, Val, Leu, lie; b) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; c) Acids: Asp, Glu; d) Basics: His, Lys, Arg; e) Residues that affect chain orientation: Gly, Pro; and f) aromatics: Trp, Tyr, Phe. For example, non-conservative substitutions may involve the exchange of a member of one of the above classes for a member of another class. Such substituted residues can be introduced, for example, into regions of the antibody that are homologous to non-human antibodies or into non-homologous regions of the molecule. By modifying the antigen-binding molecule, the costimulatory or activating domains of the modified T cell, according to certain embodiments, can be considered the hydropathic index of the amino acids. Each amino acid has been assigned a hydropathic index based on its hydrophobicity and charge characteristics. These are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine / cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); Usinine (-3.9) and arginine (-4.5). See Kyte et al., J. Mol. Biol., 157: 105-131 (1982). It is also known that it is possible to substitute certain amino acids with other amino acids that have a similar hydropathic index or rating and still retain similar biological activity.It is also known in the art that the substitution of identical amino acids can be effectively achieved on the basis of hydrophilicity, particularly when the biologically functional protein or peptide thus created is intended for use in immunological formulations, as in the present case. Examples of amino acid substitutions are shown in Table 2. Table 2 Original residues Examples of substitutions Preferred substitutions ccyni n / nznz / E / YiAi Wing Val; Leu; lie Val Arg Lys; Gln; Asn Lys Asn Gln Gln Asp Glu Glu Cys Ser; Ala Ser Gln Asn Asn Glu Asp Asp Gly pro, ala Ala His Asn; Gln; Lys; Arg Arg lie Leu, Val, Met, Ala, Phe, norleucine Leu Leu norleucine; lie; Vale; Met; To the; Phe He Lys Arg, 1,4-diamino-butyric Arg acid, Gln, Asn Met Leu; Phe; lie Leu Phe Val; Leu; lie; Ala Leu Tyr Pro Ala Gly Ser Thr, Ala, Cys Thr Thr Ser Ser Trp Tyr; Phe Tyr Tyr Trp; Phe; Thr; Ser Phe Val lie, Met, Leu, Phe, Leu Ala, Norleucina ccyni n / nznz / E / YiAi The term “derivative” refers to a molecule that includes a chemical modification other than an insertion, deletion, or substitution of amino acids (or nucleic acids). In certain embodiments, derivatives comprise covalent modifications, including, but not limited to, chemical linkage with polymers, lipids, or other organic or inorganic units. In certain embodiments, an antigen-binding molecule that has undergone a chemical modification may have a longer circulating half-life than an antigen-binding molecule that has not undergone a chemical modification. In some embodiments, a derivative of an antigen-binding molecule has been covalently modified to include one or more water-soluble bonded polymers, including, but not limited to, polyethylene glycol, polyoxyethylene glycol, or polypropylene glycol. Peptide analogues are commonly used in the pharmaceutical industry as non-peptide drugs with properties analogous to those of the template peptide. These types of non-peptide compounds are called “peptide mimetics” or “peptidomimetics.” Fauchere, J., Adv. Drug Res., 15: 29 (1986); Veber and Freidinger, TINS, page 392 (1985); and Evans et al., J. Med. Chem., 30: 1229 (1987), are incorporated herein for reference purposes. The term “therapeutically effective amount” refers to the quantity of a specific DLL3 antigen-binding molecule required to produce a therapeutic response in a mammal. A specialist in the field can readily determine such therapeutically effective amounts. The terms “patient” and “subject” are used interchangeably, and include human subjects and non-human animals, and also those with formally diagnosed disorders, those without formally diagnosed disorders, those receiving medical care, those at risk of developing disorders, etc. The terms “treat” and “treatment” include therapeutic treatments, prophylactic treatments, and applications that reduce the risk of an individual developing a disorder or other risk factor. Treatment does not require the complete cure of a disorder and encompasses methods that reduce symptoms or underlying risk factors. The term “prevent” does not require the complete elimination of the possibility of an event. Instead, it indicates that the likelihood of the event occurring has been reduced in the presence of the compound or method. Standard techniques for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection) can be used. Enzymatic reactions and purification procedures can be carried out according to suppliers' specifications, in ways known in the art, or as described herein. The techniques and procedures mentioned in general can be carried out according to conventional methods well known in the art and as described in various general and more specific references cited and described throughout this document. See, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual (2nd ed., Coid Spring Harbor Laboratory Press, Coid Spring Harbor, NY (1989)), the contents of which are incorporated herein by reference for any purpose. The following sequences will serve as additional examples of the invention. Extracellular, transmembrane, intracellular DNA of CD28T CTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCT GTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTG GAGTCCTCGCTTGTTACTCTCTGCGTCACCGTGGCTTTAATCTCTCTGGGTTAGATC CAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCC CACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGC (SEQ ID NO:1) Intracellular, transmembrane, extracellular AA of CD28T: LDNEKSNGTI IHVKGKHLCP SPLFPGPSKP FWVLVVVGGV LACYSLLVTV AFIIFWVRSK RSRLLHSDYM NMTPRRPGPT RKHYQPYAPP RDFAAYRS (SEQ ID Na: 2) DNA: extracellular de CD28T CTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCT GTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCA (SEQ ID Ns: 3) AA of CD28T: extracellular LDNEKSNGTI IHVKGKHLCP SPLFPGPSKP (SEQ ID Ns: 4) CD28 transmembrane domain DNA ccyni n / nznz / E / YiAi TTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCA CCGTGGCTTTTATAATCTTCTGGGTT (SEQ ID Na: 51). AA of the transmembrane domain of CD28 FWVLVVVGGV LACYSLLVTV AFIIFWV (SEQ ID No: 6) DNA of the intracellular domain of CD28 AGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCC GCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCT ATCGGAGC (SEQ ID Na: 7) AA of the intracellular domain of CD28 RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS (SEQ ID Na: 8) Zeta CD3 DNA AGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACC AACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGGTATGACGTTTTGGACAAGCGCA GAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCT CTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGG AGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGA AGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTAGG (SEQ ID Na: 9) AA of CD3 zeta RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQ EGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID Na: 10) DNA from CD28 ATTGAGGTGATGTATCCACCGCCTTACCTGGATAACGAAAAGAGTAACGGTACCA TCATTCACGTGAAAGGTAAACACCTGTGTCCTTCCCCCCTTCCCCGGGCCATCAAAGC CC (SEQ ID Ns: 11) AA of CD28 IEVMYPPPYL DNEKSNGTII HVKGKHLCPS PLFPGPSKP (SEQ ID Ns: 12) DNA from the extracellular and transmembrane domain of CD8 GCTGCAGCATTGAGCAACTCAATAATGTATTTTAGTCACTTTGTACCAGTGTTCTTG CCGGCTAAGCCTACTACCACCCGCTCCACGGCCACCTACCCCAGCTCCTACCATCGC TTCACAGCCTCTGTCCCTGCGCCCAGAGGCTTGCCGACCGGCAGGGGGCGCTGTTGTT CATACCAGAGGACTGGATTTCGCCTGCGATATCTATATCTGGGCACCCCTGGCCGGAACC TGCGGCGTACTCCTGCTGTCCCTGGTCATCACGCTCTATTGTAATCACAGGAAC (SEQ ID Ns: 13) AA of the extracellular and transmembrane domain of CD8 AAALSNSIMYFSHFVPPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVH TRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRN (SEQ ID Ns: 14) ccyni η / ηζηζ / Ε / γίΛΐ DNA from the intracellular domain of 4-1BB CGCTTTTCCGTCGTTAAGCGGGGGAAAAAAGCTGCTGTACATTTTCAAACAGGC CGTTTATGAGGCCGGTCCAAACGACTCAGGAAGAGGACGGCTGCTCCTGCCGCTTTCCT ccyni n / nznz / E / YiAi GAGGAGGAGGAGGGCGGGTGCGAACTG (SEQ ID Ns: 15) AA of the intracellular domain of 4-1 BB RFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (SEQ ID Ns: 161 DNA of the HCdel clone 1H2.1 CAGGTGCAACTGCAGGAAAGCGGGCCCGGTCTGGTGAAGCCCTCAGAAACGCTC TCCCTCACCTGTACAGTCTCTGGCGATTCAATCTCTTCATATTACTGGACGTGGATCAGGC AGCCTCCCGGCAAGGGACTGGAGTGGATCGGATATATCTACTATAGTGGCACCACTAACT ATAATCCTTCCCTGAAAAGCCGGGTGACAATCTCTGTTGACACCTCCAAGAGCCAGTTCA GCCTGAAACTCTCCAGTGTGACAGCCGCCGATACAGCCGTGTATTACTGTGCCTCTATCG CTGTGCGCGGGTTCTTTTTTGATTATTGGGGCCAGGGGACACTGGTGACCGTTAGCAGC (SEQ ID Ns: 40) AA of the HC of clone 1 H2.1: CDRs are underlined QVQLQESGPGLVKPSETLSLTCTVSGDSISSYWTWIRQPPGKGLEWIGYIYYSGTTN YNPSLKSRVTISVDTSKSQFSLKLSSVTAADTAVYYCASIAVRGFFFDYWGQGTLVTVSS (SEQ ID Na:41) AA of the CDR1 of the HC of clone 1H2.1: AA of the CDR2 of the HC of clone 1H2.1: AA of the CDR3 of the HC of clone 1H2.1: LC DNA of clone 1H2.1 SYYWT (SEQ ID Na: 42) YIYYSGTTNYNPSLKS (SEQ ID Na: 43) IAVRGFFFDY (SEQ ID Na: 44) GAAATTGTACTGACCCAGTCCCCCGGCACGCTCTCTCTCCCCAGGGGAAAGG GCAACCCTTAGCTGCCGGGCGAGCCAGAGCGTGAGTTCCTCCTACCTCGCGTGGTATCA GCAGAAGCCCTGGACAGGCTCCCAGACTGCTGATTTACGGGGCTTCTACGAGAGCCACCG GCATACCTGATAGGTTCTCTGGCTCCGGGTCTGGGACCGACTTACTTCTTACAATCAGCA GACTTGAGCCTGAAGACTTCGCTGTGTATTATTGTCAACAATACGGAACGTCCCCCCTTAC CTTTGGTGGCGGGACAAAGTGGAAATTAAGAGG (SEQ ID N2: 45) AA of the LC of clone 1 H2.1 (CDRs are underlined) EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASTRATG IPDRFSGSGSGTDFTLTISRLEPEDFAVYCQQYGTSPLTFGGGTKVEIKR (SEQ ID Ns: 46) AA of the CDR1 of the LC of clone 1 H2.1: AA of the CDR2 of the LC of clone 1 H2.1: AA of the CDR3 of the LC of clone 1 H2.1: RASQSVSSYLA (SEQ ID N2: 47) GASTRATE (SEQ ID N2: 48) QQYGTSPLT (SEQ ID N2: 49) HC DNA from clone 8D2 CAGGTCCAGCTGGTGCAGTCTGGGGCAGAGGTGAAACGGCCGGGTGCAAGCGT GAAGGTGTCCTGCAAAGCCTCTGGCTATACCTTTACTGGGTACTATATGCACTGGGGTTCG GCAGGCGCCAGGACAGGGTCTTGAGTGGATGGGTTGGATTGATCCAAACTCTGGCGATA CAAATTACGCACAGAAATTCCAGGCCGCGTGACGATGACTCGACCATCTATCTT CCGCCTATATGGAAGTGAATAGACTCCGGTCTGACGACACTGCTGTCTATTACTGTGCAA GGGATCCCAACCGGCGGAGTTGGTATTACGGAATGGATGTCTGGGCCCAGGGTACTACC GTCACGGTGTCTTCT (SEQ ID N2: 50) AA of the HC of clone 8D2 (CDRs are underlined) QVQLVQSGAEVKRPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWIDPN SG DTNYAQKFQG RVTMTR DTSISTAYM E VN RLRS D DTAVYYCAR D PN R RS WYYG MDV WAQ GTTVTVSS (SEQ ID N2: 51) AA de la CDR1 de la HC del clone 8D2: GYYMH [SEQ ID N2: 52] AA of CDR2 of HC of clone 8D2: WIDPNSGDTNYAQKFQG (SEQ ID N2: 53) AA of CDR2 of HC of clone 8D2: DPNRSWYYGMDV (SEQ ID N2: 54) ADN de la LC del clon 8D2 CAGGTCCAGCTGGTGCAGTCTGGGGCAGAGGTGAAACGGCCGGGTGCAAGCGT GAAGGTGTCCTGCAAAGCCTCTGGCTATACCTTTACTGGGTACTATATGCACTGGGTTCG GCAGGCGCCAGGACAGGGTCTTGAGTGGGGGGTTGGATT CAAATTACGCACAGAAATTCCAGGGCCGCGTGACGATGACTCGAGACACTTCCATATCCA CCGCCTATATGGAAGTGAATAGACTCCGGTCTGACGACACTGCTGTCTATTACTGTGCAA GGGATCCCAACCGGCGGAGTTGGTATTACGGAATGGATGTCTGGGCCCAGGGTTACCTACCAA GTCACGGTGTCTTCTGGCGGCGGGGGCTCAGGAGGAGGAGGCAGCGGTGGAGGAGGC AGCGATATTCAGATGACAAAGCCCTTCTAGTCTCTCCGCAAGCGTTGGCGACCGCGTG ACCATTACGTGTCAGGCTTCAAGATATTCGAAACTACCTGAACTAGGAGGAGGCAGGC CCGGCAAAGCACCTAAGCTGCTGATTTATGACGCTAGCAACCTTGAGACTGGCGTCCCCT CCAGATTTTCCGGCAGCGGCTCAGGCACCGACTTTACTTTTACCATCCACACTCCAGC CAGAAGATATTGCAACGTATTACTGCCAACATTAGATAACCTGCCTTTGACCTTGGAGGAGGAGGAGGAGGAGTAGGAQTAGGAQTAGCAGC: 55) AA of the LC of clone 8D2 (CDRs are underlined) DIQMTQSPSS LSAS VG DR VTITCQASQDIRNYLN WYQQKPGKAPKLLIYDASNLETG V PSRFSGSGSGTDFTFTISTLQPEDIATYYCQHYDNLPLTFGGGTKVEIRR (SEQ ID N2: 56) AA of the CDR1 of the LC of clone 8D2: QASQDIRNYLN (SEQ ID N2: 57) AA of the CDR2 of the LC of clone 8D2: DASNLET (SEQ ID N2: 58) AA of the CDR3 of the HC of clone 8D2: QHYDNLPLTF (SEQ ID N2: 59) DNA from the HC of clone 6B2 CAAGTGCAGTTGGTGCAGTCTGGAGCTGAAGTGAAGAAACCAGGCGCTAGCGTC AAAGTGAGCTGTAAGGCCTCAGGTTACACGTTTACTGGGTACTATATGCATTGGGTCAGG CAAGCCCCCTGGCCAGGGCCTCGAGTGGATGGGCTGGATTTAATCCTAACGACCGGGGNI η / ηζηζ / Ε / γίΛΐ AAGCTATGCCCAACGCTTCCTGGGCAGAGTAACAATGACACGGGATACAAGTATTAACAC CGTCCATATGGAACTCTCTCGGCTCGGCTCAGATGATACCGGTTTATTACTGTGCTAG GGAGGACGACTCCTCTTGGTATGGCAGCTTCGATTATTGGGGGCAGGGAGGAGGAGGATTCATTATTGGGGGCAGGGAGGASEGGATTCATTACTGTGCTAG GGAGGACGACTCCTCTTGGTATGGCAGCTTCGATTATTGGGGGCAGGGAGGAGGASEGGATTCATTACTGGGGGGAGGAGGASEGGGASE: 60) AA of the HC of clone 4E9 (CDRs are underlined) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNS GDTSYAQRFLG R VTMTRDTSI NT VH Μ E LS R LGS D DTA V YYCAR EDDSSWYGSFDYWGQGTL VTVSS (SEQ61 ID NTV2) AA of the CDR1 of the HC of clone 6B2: GYYMH [SEQ ID N2: 62] AA of CDR2 of HC of clone 6B2: WINPSGDTSYAQRFLG (SEQ ID N2: 63) AA of CDR3 of HC clone 6B2: EDDSSWYGSFDY (SEQ ID N2: 64) ADN of LC of clone 6B2 GATATACAGATGACTCAGAGTCCCTCAAGCTTGAGTGCCAGTGTAGGCGACCGGG TGACGATAACCTGTAGGGCTTCACAGGGAATCAGAAATTATCTGGGTTGGTACCAGCAGA AGCCAGGAAAGGCACCTAAAAGACTTATTTACGCCGCATCCTCCTTGCAGTCCCGGTGC CATCAAAATTTTCTGGGAGCGGCTCTGGAACCGAGTTCACCCTCACGATCTCCAGCCTCC AGCCCGAGGACTTTGCCACTACTATTGCCCTGCAGCACGATAGTGATCTGCGAACTTTTG GGCAAGGCACTAAAGTGGAAATTAAGAGA (SEQ ID N2: 65) AA del clone 6B2 LC (also CDR available) DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLGWYQQKPGKAPKRLIYAASSLQSGV PSKFSGSGSGTEFTLTISSLQPEDFATYYCLQHDSDLRTFGQGTKVEIKR (SEQ ID N2: 66) AA of CDR1 of LC of clone 6B2: RASQGIRNYLG (SEQ ID N2: 67) AA of CDR2 of LC of clone 6B2: AASSLQS (SEQ ID N2: 68) AA of CDR3 of LC of clone 6B2: LQHDSDLRTF (SEQ ID N2: 69) Construct DNA 1 H2.1 4-1BB (signal sequence is in bold) ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCC GCACGCCCGCAGGTGCAACTGCAGGAAAGCGGGCCCGGTCTGGTGAAGCCCTCAGAAA CGCTCTCCCTCACCTGTACAGTCTCTGGCGATTCAATCTCTTCATATTACTGGACGTGGGAT CAGGCAGCCTCCCGGCAAGGGACTGGAGTGGATCGGATATATCTACTATAGTGGCACCA CTAACTATAATCCTTCCCTGAAAAGCCGGGTGACAATCTCTGTTGACACCTCCAAGAGCCA GTTCAGCCTGAAACTCTCCAGTGACAGCCCCGATACAGCCGTGTTACTGTGCCTCTT TATCGCTGTGCGCGGGTTCTTTTGATTATTGGGGCCAGGGGACACTGGTGACCGTTAG CAGCGGGGAGGAGGGTCCGGTGGCGGCGGCAGCGGCGGGGTTCAGAAATTGT ACTGACCCA GCCGGGCGAGCCAGAGCGTGAGTTCCTCCTACCTCGCGTGGTATCAGCAGAAGCCTGGA CAGGCTCCCAGACTGCTGATTTACGGGGCTTCTACGAGAGCCACCGGCATACCTGATAG GTTCTCTGGCTCCGGGTCTGGGACCGACTTACTTACAATCAATCAGCAGACTTGAGCCTGA ccyni η / ηζηζ / Ε / γίΛΐ AGACTTCGCTGTGTATTATTGTCAACAATACGGAACGTCCCCCCTTTACCTTGGTGGGCGG GACAAAAGTGGAAATTAAGGGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAT CATTCACGTGAAGGGCAAGCACCTGTCCGTCACCCTT ATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGT GGCTTTTATAATCTTCTGGGTTCGCTTTTCCGTCGTTAAGCGGGGGAAAAAAGCTGCT CTCCTGCCGCTTTCCTGAGGAGGAGGAGGCGGGTGCGAACTGAGGGTGAAGTTTTCCCA GATCTGCAGATGCACCAGCGTATCAGCAGGCCAGAACCAACTGTATAACGAGCTCAACC TGGGACGCAGGGAAGA GGTGGCAAACCAAGACGAAAAAACCCCCAGGGGGTCTCTATAATGAGCTGCAGAAGGA TAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAG GGCACGACGGTTTGTACCAGGGACTCACTGCTACGAAGGATACTTATTGACCATCACCCAGCCAGGCCTAGCTACGAAGGTACTTACTGACCATCACTCACCTAGCCTAGCCTA Ns: 17) AA of construct 1 H2.1 4-1BB (signal sequence is in bold; CDRs are underlined) MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGDSISSYWTWI RQPPGKGLEWIGYIYSGTTNYNPSLKSRVTISVDTSKSQFSLKLSSVTAADTAVYYCASIAVR GFFFDYWGQGTLVSSGGGGSGGGGGGGSEIVLTQSPGTLSLSPGERATLSCRASQSV SSSYLAWYQQKPGQAPRLLIYGASTRATGIPDRFSGSGSGGTDFTLTISRLEPEDFAVYYCQQY GTSPLTFGGGTKVEIKRAAALDNEKSNGTHHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLAC YSLLVTVAFIIFWVRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGGVLAC KFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNEL QKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID Na: 18) H2.1 -CD28T construct 1 DNA (signal sequence is in bold) ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCC GCACGCCCGCAGGTGCAACTGCAGGAAAGCGGGCCCGGTCTGGTGAAGCCCTCAGAAA CGCTCTCCCTCACCTGTACAGTCTCTGGCGATTCAATCTCTTCATATTACTGGACGTGGAT CAGGCAGCCTCCCGGCAAGGGACTGGAGTGGATCGGATATATCTACTATAGTGGCACCA CTAACTATAATCCTTCCCTGAAAAGCCGGGTGACAATCTCTGTTGACACCTCCAAGAGCCA GTTCAGCCTGAAACTCTCCAGTGTGACAGCCGCCGATACAGCCGTGTATTACTGTGCCTC TATCGCTGTGCGCGGGTTCTTTTTTGATTATTGGGGCCAGGGGACACTGGTGACCGTTAG CAGCGGGGGAGGAGGGTCCGGTGGCGGCGGCAGCGGAGGCGGGGGTTCAGAAATTGT ACTGACCCAGTCCCCCGGCACGCTCTCTCTCTCCCCAGGGGAAAGGGCAACCCTTAGCT GCCGGGCGAGCCAGAGCGTGAGTTCCTCCTACCTCGCGTGGTATCAGCAGAAGCCTGGA CAGGCTCCCAGACTGCTGATTTACGGGGCTTCTACGAGAGCCACCGGCATACCTGATAG GTTCTCTGGCTCCGGGTCTGGGACCGACTTTACTCTTACAATCAGCAGACTTGAGCCTGA AGACTTCGCTGTGTATTATTGTCAACAATACGGAACGTCCCCCCTTACCTTTGGTGGCGG ccjm n / nznz / E / YiAi GACAAAAGTGGAAATTAAGAGGGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAT CATTCACGTGAAGGGCAAGCACCTCTGTCCGTTCACCCTTGTTCCCTGGTCCATCCAAGCC ATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTCTGTCCCTT GGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATG AATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCT AGAGATTTCGCTGCCTATCGGAGCCGAGTGAATTTTCTAGATCAGCTGATGCTCCCGCC TATCAGCAGGGACAGAATCAACTTTACAATGAGCTGAACCTGGGTCGCAGAGAAGAGTAC GACGTTTTGGACAAACGCCGGGGCCGAGATCCTGAGATGGGGGGGAAGCCGAAGGA AGAATCCTCAAGAAGGCCTGTACAACGAGCTTCAAAAAGACAAAATGGCTGAGCTGCTG CTGAGATCGGCATGAAGGGCGAGCGGAGACGAGGCAAGGGTCACGATGGCTTGTATCA GGGCCTGAGTACAGCCACAAAGGACACCTATGACGCCCTCCACATGCAGGCACTGCCCC CACGCTAG (SEQ ID N2: 19) AA of the 1H2.1 CD28T construct (signal sequence is in bold; CDRs are underlined) MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGDSISSYYWTWI RQPPGKGLEWIGYIYYSGTTNYNPSLKSRVTISVDTSKSQFSLKLSSVTAADTAVYYCASIAVR GFFFDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVLTQSPGTLSLSPGERATLSCRASQSV SSSYLAWYQQKPGQAPRLLIYGASTRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQY GTSPLTFGGGTKVEIKRAAALDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLAC YSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSA DAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMA EAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID N2: 20) ADN de la construcción 8D2 4-1 BB (la secuencia señal está en negrita) ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCC GCACGCCCGCAGGTCCAGCTGGTGCAGTCTGGGGCAGAGGTGAAACGGCCGGGTGCAA GCGTGAAGGTGTCCTGCAAAGCCTCTGGCTATACCTTTACTGGGTACTATATGCACTGGG TTCGGCAGGCGCCAGGACAGGGTCTTGAGTGGATGGGTTGGATTGATCCAAACTCTGGC GATACAAATTACGCACAGAAATTCCAGGGCCGCGTGACGATGACTCGAGACACTTCCATA TCCACCGCCTATATGGAAGTGAATAGACTCCGGTCTGACGACACTGCTGTCTATTACTGT GCAAGGGATCCCAACCGGCGGAGTTGGTATTACGGAATGGATGTCTGGGCCCAGGGTAC TACCGTCACGGTGTCTTCTGGCGGCGGGGGCTCAGGAGGAGGAGGCAGCGGTGGAGGA GGCAGCGATATTCAGATGACACAAAGCCCTTCTAGTCTCTCCGCAAGCGTTGGCGACCGC GTGACCATTACGTGTCAGGCTTCACAAGATATTCGAAACTACCTGAACTGGTATCAGCAGA AGCCCGGCAAAGCACCTAAGCTGCTGATTTATGACGCTAGCAACCTTGAGACTGGCGTCC CCTCCAGATTTTCCGGCAGCGGCTCAGGCACCGACTTTACTTTTACCATCTCCACACTCC AGCCAGAAGATATTGCAACGTATTACTGCCAACATTATGATAACCTGCCTTTGACCTTCGG AGGTGGCACCAAGGTAGAGATCAGAAGAGCCGCTGCCCTTGATAATGAAAAGTCAAACG ccyni η / ηζηζ / Ε / γίΛΐ GAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCAT CAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCG TCACCGTGGCTTTTATAATCTCTGGGTTCGCTTTTCCG GCTGCTGTACATTTTCAAACAGCCGTTTATGAGGCCGGTCCAAACGACTCAGGAAGAAGA CGGCTGCTCCTGCCGCTTTCCTGAGGAGGAGGAGGCGGGTGCGAACTGAGGGTGAAG TTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAG CTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCC TGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGGGTCTCTATAATGAGCTGC AGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGAGGAGGGGG GGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGA CGCTCTCCACATGCAAGCCCTGCCACCTAGGTAA (SEQ ID N2: 21) AA of the construction 8D2 4-1BB (the signal sequence is in bold) MALPVTALLLPLALLLHAARPQVQLVQSGAEVKRPGASVKVSCKASGYTFTGYYMH WVRQAPGQGLEWMGWIDPNSGDTNYAQKFQGRVTMTRDTSYSTAYMEVNRLRSDDTAVYY CARDPNRRSWYYGMDVWAQGTTVTVSSGGGGSGGGSGGGGSDIQMTQSPSSLSASVGD RVTITCQASQDIRNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISTLQPE DIATYYCQHYDNLPLTFGGGTKVEIRRAAALDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVL VVVGGVLACYSLLVTVAFIIFWVRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEE EEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKN PQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID N2: 22) DNA of the 8D2-CD28T construct (signal sequence is in bold) ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCC GCACGCCCGCAGGTCCAGCTGGTGCAGTCTGGGGCAGAGGTGAAACGGCCGGGTGCAA GCGTGAAGGTGTCCTGCAAAGCCTCTGGCTATACCTTTACTGGGTACTATATGCACTGGG TTCGGCAGGCGCCAGGACAGGGTCTTGAGTGGATGGGTTGGATTGATCCAAACTCTGGC GATACAAATTACGCACAGAAATTCCAGGGCCGCGTGACGATGACTCGAGACACTTCCATA TCCACCGCCTATATGGAAGTGAATAGACTCCGGTCTGACGACACTGCTGTCTATTACTGT GCAAGGGATCCCAACCGGCGGAGTTGGTATTACGGAATGGATGTCTGGGCCCAGGGTAC TACCGTCACGGTGTCTTCTGGCGGCGGGGGCTCAGGAGGAGGAGGCAGCGGTGGAGGA GGCAGCGATATTCAGATGACACAAAGCCCTTCTAGTCTCTCCGCAAGCGTTGGCGACCGC GTGACCATTACGTGTCAGGCTTCACAAGATATTCGAAACTACCTGAACTGGTATCAGCAGA AGCCCGGCAAAGCACCTAAGCTGCTGATTTATGACGCTAGCAACCTTGAGACTGGCGTCC CCTCCAGATTTTCCGGCAGCGGCTCAGGCACCGACTTTACTTTTACCATCTCCACACTCC AGCCAGAAGATATTGCAACGTATTACTGCCAACATTATGATAACCTGCCTTTGACCTTCGG AGGTGGCACCAAGGTAGAGATCAGAAGAGCCGCTGCCCTTGATAATGAAAAGTCAAACG GAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCAT ccyni n / nznz / E / YiAi CCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCG TCACCGTGGCTTTTATAATCTCTGGGTTAGATCCAAAGAAGCCCTGCTCCATAGCGA TTACATGAATATGACTCCACGCCGCCCTGGCCCCAAGGAAAACACTACCTACCTACCTTCG ACCACCTAGAGATTTCGCTGCCTATCGGAGCCGAGTGAAATTTTCTAGATCAGCTGATGC TCCCGCCTATCAGCAGGGACAGAATCAACTTTACAATGAACCTGGGTCGCAGAGA AGAGTACGACGTTTTGGACAAAACGCCGGGCCGAGATCCTGAGATGGGGGGGAAGCCG AGAAGGAAGAATCCTCAAGAAGGCCTGTACAACGAGCTTCAAAAAGACAAAATGGCTGAG GCGTACTCTGAGATCGGCATGAAGGGCGAGCGGAGACGAGGCAAGGGTCACGATGGCT TGTATCAGGGCCTGAGTACAGCCACAAAGGACCTATGACGCCCTCCATGCCAGCCAGCAAGGACCTATGACGCCCTCCATGCCAGCCAGGCAAGGCAAGGCAAGGCTATGACGCCCTCCATGCCAGGCAGCAAGGCAAGGCAAGGCTATGACGCCCTCCATGAGTACCAGCCAGGCAAGGCAAGGCTATGACGCCCCATGGCT23: AA of the 8D2-CD28T construct (the signal sequence is in bold) MALPVTALLLPLALLLHAARPQVQLVQSGAEVKRPGASVKVSCKASGYTFTGYYMH WVRQAPGQGLEWMGWIDPNSGDTNYAQKFQGRVTMTRDTSISTAYMEVNRLRSDDTAVYY CARDPNRRSWYYGMDVWAQGTTVTVSSGGGGGSGGGGSGGGGSDIQMTQSPSSSLSASVGD RVTITCQASQDIRNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISTLQPE DIATYYCQHYDNLPLTFGGGTKVEIRRAAALDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVL VVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPPTRKHYQPYAPPRDFAAY RSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGL YNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID N2: 24) ADN of the construction 6B2-CD28T (the following devices are used) ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCC GCACGCCCGCAAGTGCAGTTGGTGCAGTCTGGAGCTGAAGTGAAGAAACCAGGCGCTAG CGTCAAAGTGAGCTGTAAGGCCTCAGGTTACACGTTTACTGGGTACTATATGCATTGGGT CAGGCAAGCCCCTGGCCAGGGCCTCGAGTGGATGGGCTGGATTAATCCTAACAGCGGG GACACAAGCTATGCCCAACGCTTCCTGGGCAGAGTAACAATGACACGGGATACAAGTATT AACACCGTCCATATGGAACTCTCTCGGCTCGGCTCAGATGATACCGCGGTTTATTACTGT GCTAGGGAGGACGACTCCTCTTGGTATGGCAGCTTCGATTATTGGGGGCAGGGAACCCT GGTGACAGTCTCATCTGGTGGAGGGGGCTCCGGGGGTGGGGGCAGCGGAGGGGGAGG TTCTGATATACAGATGACTCAGAGTCCCTCAAGCTTGAGTGCCAGTGTAGGCGACCGGGT GACGATAACCTGTAGGGCTTCACAGGGAATCAGAAATTATCTGGGTTGGTACCAGCAGAA GCCAGGAAAGGCACCTAAAAGACTTATTTACGCCGCATCCTCCTTGCAGTCCGGCGTGCC ATCAAAATTTTCTGGGAGCGGCTCTGGAACCGAGTTCACCCTCACGATCTCCAGCCTCCA GCCCGAGGACTTTGCCACCTACTATTGCCTGCAGCACGATAGTGATCTGCGAACTTTTGG GCAAGGCACTAAAGTGGAAATTAAGAGAGCCGCTGCCCTTGATAATGAAAAGTCAAACGG AACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATC CAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGT ccyni η / ηζηζ / Ε / γίΛΐ CACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGAT TACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCA CCACCTAGAGATTTCGCTGCCTATCGGAGCCGAGTGAAATTTTCTAGATCAGCTGATGCTGCT CCCGCCTATCAGCAGGGACAGAATCAACTTTACAATGAGCTGAACCTGGGTCGCAGAGAA GAGTACGACGTTTTGGACAAACGCCGGGGCCGATCCTGAGATGGGGGGGAAGCCGA GAAGGAAGAATCCTCAAGAAGGCTACAACGAGCTTCAAAAAGACAGACTGAGAGGAGGA CGTACTCTGAGATCGGCATGAAGGGCGAGCGGAGACGAGGCAAGGGTCACGATGGCTT GTATCAGGGCCTGAGTACAGCCACAAAGGACACCTATGACGCCCTCCACATGCAGGCAC TGCCCCCACGCTAG (SEQ ID Ns: 25) AA of the 6B2-CD28T construct (the signal sequence is in bold) MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMH WVRQAPGQGLEWMGWINPNSGDTSYAQRFLGRVTMTRDTSINTVHMELSRLGSDDTAVYY CAREDDSSWYGSFDYWGQGTLVTVSSGGGGSGGGGGGGSDIQMTQSPSSLSASVGDR VTITCRASQGIRNYLGWYQQKPGKAPKRLIYAASSLQSGVPSKFSGSGSGTEFTLTISSLQPE DFATYYCLQHDSDLRTFGQGTKVEIKRAAALDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWV LVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAY RSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGL YNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID Na: 26) DNA of the 6B2 4-1BB construct (the signal sequence is in bold) ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCC GCACGCCCGCAAGTGCAGTTGGTGCAGTCTGGAGCTGAAGTGAAGAAACCAGGCGCTAG CGTCAAAGTGAGCTGTAAGGCCTCAGGTTACACGTTTACTGGGTACTATATGCATTGGGT CAGGCAAGCCCCTGGCCAGGGCCTCGAGTGGATGGGCTGGATTAATCCTAACAGCGGG GACACAAGCTATGCCCAACGCTTCCTGGGCAGAGTAACAATGACACGGGATACAAGTATT AACACCGTCCATATGGAACTCTCTCGGCTCGGCTCAGATGATACCGCGGTTTATTACTGT GCTAGGGAGGACGACTCCTCTTGGTATGGCAGCTTCGATTATTGGGGGCAGGGAACCCT GGTGACAGTCTCATCTGGTGGAGGGGGCTCCGGGGGTGGGGGCAGCGGAGGGGGAGG TTCTGATATACAGATGACTCAGAGTCCCTCAAGCTTGAGTGCCAGTGTAGGCGACCGGGT GACGATAACCTGTAGGGCTTCACAGGGAATCAGAAATTATCTGGGTTGGTACCAGCAGAA GCCAGGAAAGGCACCTAAAAGACTTATTTACGCCGCATCCTCCTTGCAGTCCGGCGTGCC ATCAAAATTTTCTGGGAGCGGCTCTGGAACCGAGTTCACCCTCACGATCTCCAGCCTCCA GCCCGAGGACTTTGCCACCTACTATTGCCTGCAGCACGATAGTGATCTGCGAACTTTTGG GCAAGGCACTAAAGTGGAAATTAAGAGAGCCGCTGCCCTTGATAATGAAAAGTCAAACGG AACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATC CAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTCTGGGTTCGCTTTTCCGTCGTTAAGCGGGGGAAAAAAA ccyni n / nznz / E / YiAi GCTGCTGTACATTTTCAAACAGCCGTTTATGAGGCCGGTCCAAACGACTCAGGAAGAAGA CGGCTGCTCCTGCCGCTTTCCTGAGGAGGAGGAGGCGGGTGCGAACTGAGGGTGAAG TTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAG CTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCC TGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGGGTCTCTATAATGAGCTGC AGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGAGGAGGGGG GGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGA CGCTCTCCACATGCAAGCCCTGCCACCTAGGTAA (SEQ ID N2: 27) AA of the construction 6B2 4-1 BB AA (the signal sequence is in bold) MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMH WVRQAPGQGLEWMGWINPNSGDTSYAQRFLGRVTMTRDTSINTVHMELSRLGSDDTAVYY CAREDDSSWYGSFDYWGQGTLVTVSSGGGGSGGGGGGGSDIQMTQSPSSLSASVGDR VTITCRASQGIRNYLGWYQQKPGKAPKRLIYAASSLQSGVPSKFSGSGSGTEFTLTISSLQPE DFATYYCLQHDSDLRTFGQGTKVEIKRAAALDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWV LVVVGGVLACYSLLVTVAFIIFWVRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEE EEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKN PQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID N2: 28) AAde the ¡subform 1 NM 016941 of human DLL3 (618 amino acids) MVSPRMSGLLSQTVILALIFLPQTRPAGVFELQIHSFGPGPGPGAPRSPCSARLPCRL FFRVCLKPGLSEEAAESPCALGAALSARGPVYTEQPGAPAPDLPLPDGLLQVPFRDAWPGTF SFIIETWREELGDQIGGPAWSLLARVAGRRRLAAGGPWARDIQRAGAWELRFSYRARCEPPA VGTACTRLCRPRSAPSRCGPGLRPCAPLEDECEAPLVCRAGCSPEHGFCEQPGECRCLEG WTGPLCTVPVSTSSCLSPRGPSSATTGCLVPGPGPCDGNPCANGGSCSETPRSFECTCPRG FYGLRCEVSGVTCADGPCFNGGLCVGGADPDSAYICHCPPGFQGSNCEKRVDRCSLQPCR NGGLCLDLGHALRCRCRAGFAGPRCEHDLDDCAGRACANGGTCVEGGGAHRCSCALGFGG RDCRERADPCAARPCAHGGRCYAHFSGLVCACAPGYMGARCEFPVHPDGASALPAAPPGL RPGDPQRYLLPPALGLLVAAGVAGAALLLVHVRRRGHSQDAGSRLLAGTPEPSVHALPDALN NLRTQEGSGDGPSSSVDWNRPEDVDPQGIYVISAPSIYAREVATPLFPPLHTGRAGQRQHLL FPYPSSILSVK (SEQ ID N2: 29) AA of the human DLL3 isoform 2 NM 203486 (587 amino acids) MVSPRMSGLLSQTVILALIFLPQTRPAGVFELQIHSFGPGPGPGAPRSPCSARLPCRL FFRVCLKPGLSEEAAESPCALGAALSARGPVYTEQPGAPAPDLPLPDGLLQVPFRDAWPGTF SFIIETWREELGDQIGGPAWSLLARVAGRRRLAAGGPWARDIQRAGAWELRFSYRARCEPPA VGTACTRLCRPRSAPSRCGPGLRPCAPLEDECEAPLVCRAGCSPEHGFCEQPGECRCLEG WTGPLCTVPVSTSSCLSPRGPSSATTGCLVPGPGPCDGNPCANGGSCSETPRSFECTCPRG FYGLRCEVSGVTCADGPCFNGGLCVGGADPDSAYICHCPPGFQGSNCEKRVDRCSLQPCR rom η / ηζηζ / Ε / γίΛΐ NGGLCLDLGHALRCRCRAGFAGPRCEHDLDDCAGRACANGGTCVEGGGAHRCSCALGFGG RDCRERADPCAARPCAHGGRCYAHFSGLVCACAPGYMGARCEFPVHPDGASALPAAPPGL RPGDPQRYLLPPALGLLVAAGVAGAALLLVHVRRRGHSQDAGSRLLAGTPEPSVHALPDALN NLRTQEGSGDGPSSSVDWNRPEDVDPQGIYVISAPSIYAREA (SEQ ID N2: 30) ADN del péptido señal de CAR ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCG CACGCCCG (SEQ ID N2: 31) Péptido señal de CAR: MALPVTALLLPLALLLHAARP (SEQ ID N2: 32) ADN del conector G4S de scFv GGCGGTGGAGGCTCCGGAGGGGGGGGCTCTGGCGGAGGGGGCTCC (SEQ ID N2: 33) Connector G4s of the scFv: GGGGSGGGGSGGGGS (SEQ ID N2: 34) Whitlow connector DNA of scFv GGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGG G (SEQ ID N2: 35) Whitlow connector of the scFv: GSTSGSGKPGSGEGSTKG (SEQ ID N2: 36) 4-1BB nucleic acid sequence (intracellular domain) AAGCGGGGGAGAAAAAAGCTGCTGTACATTTTCAAACAGCCGTTTATGAGGCCG TCCAAACGACTCAGGAAGAAGACGGCTGCTCCTGCCGCTTTCCTGAGGAGGAGGAGGC GGGTGCGAACTG (SEQ ID Na: 37) AA of 4-1 BB (intracellular domain) KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (SEQ ID N“: 38) AA of 0X40 RRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI (SEQ ID N2: 39) REFERENCE MODE INCORPORATION All publications, patents, and patent applications mentioned in this description are incorporated herein by reference to the same extent that each individual publication, patent, or patent application is specifically and individually incorporated by reference. However, the citation of a reference herein should not be construed as an acknowledgment that such reference constitutes prior art to the present invention. To the extent that any of the definitions or terms provided in the references incorporated by reference differ from the terms and description provided herein, the terms and definitions herein shall prevail. EQUIVALENTS The preceding written description is considered sufficient for a person skilled in the art to practice the invention. The preceding description and examples detail certain preferred embodiments of the invention and describe the best manner contemplated by the inventors. However, it should be noted that no matter how detailed the preceding text may appear, the invention can be practiced in many ways, and the invention should be considered with reference to the appended claims and any equivalents thereof. The following examples, including the experiments performed and the results obtained, are provided for illustrative purposes only and should not be considered as limitations of the present invention. EXAMPLE 1 A third-generation lentiviral transfer vector containing the different CAR constructs was used along with the ViraPower lentiviral packaging mix (Life Technologies) to generate the lentiviral supernatants. Briefly, a transfection mixture was generated by mixing 15 pg of DNA and 22.5 µL of polyethyleneimine (Polysciences, 1 mg / ml) in 600 µL of OptiMEM medium. The mixture was incubated for 5 minutes at room temperature. Simultaneously, 293 T cells (ATCC) were trypsinized, counted, and a total of 10 x 10⁻⁶ cells were plated into a T75 flask along with the transfection mixture. Three days post-transfection, the supernatants were collected, filtered through a 0.45 µm filter, and stored at -80 °C until use. PBMCs were isolated from Leukopaks from healthy donors (Hemacare) using density centrifugation with Ficoll-Paque according to the supplier's instructions.PBMCs were stimulated using OKT3 (50 ng / ml, Miltenyi Biotec) in R10 + IL-2 medium (300 IU / ml, Proleukin®, Prometheus® Therapeutics and Diagnostics). Forty-eight hours after stimulation, cells were transduced using lentivirus at an MOI of 10. Cells were maintained at 0.5–2.0 x 10⁶ cells / ml prior to use in activity assays. To examine CAR expression, T cells were stained with either DLL3-Fc (Amgen, Inc.) or biotinylated Protein L (Thermo Scientific) in staining buffer (BD Pharmingen) for 30 minutes at 4°C. The cells were then washed and stained with anti-Fc-PE (Miltenyi Biotec) or PE streptavidin (BD Pharmingen) in staining buffer for 30 minutes at 4 °C. The cells were then washed and resuspended in propidium iodine staining buffer (BD Pharmingen) before data acquisition. CAR DLL3 expression in healthy donor T cells is shown in Figure 1.The numbers in each box indicate the percentage of the population that tested positive. EXAMPLE 2 To examine cytolytic activity in lentivirus-transduced CAR DLL3 T cells, effector cells were cultured with target cells at a 1:1 E:T ratio in R10 medium. At 16 and 40 hours post-culture, the supernatants were analyzed by Luminex (EMD Millipore), and target cell viability was assessed by flow cytometry analysis of propidium iodide (Pl) uptake by CD3ccjm n / nznz / E / YiAi-negative cells. The average cytolytic activity of lentivirus-transduced CAR T cells from healthy donors is shown in Figure 2 (EoL1 cells are control cells; H82 and EoL1DLL3 cells express DLL3 on their surface), and cytokine production by CAR T cells from a healthy donor is shown in Figure 3. EXAMPLES To assess CAR T cell proliferation in response to DLL3-expressing target cells, T cells were labeled with CFSE before co-culture with target cells at a 1:1 E:T ratio in R10 medium. Five days later, T cell proliferation was assessed by flow cytometry analysis of the CFSE dilution (Figure 4). DLL3 CAR T cell proliferation is shown in Figure 5. EXAMPLE 4 To examine antitumor activity in vivo, utility CAR DLL3 T cells were generated in a xenogeneic model of human SCLC. Luciferase-labeled SHP-77 cells (2 x 10⁶ / animal) were injected intravenously into 5- to 6-week-old female NSG mice. After 6 days, 6 x 10⁶ T cells (-50% CAR+) were injected intravenously in 200 μL of PBS, and the tumor burden of the animals was measured weekly using bioluminescence imaging. As shown in Figure 6, CAR DLL3 T cell injection significantly reduced tumor burden at all time points examined (nt = non-transfected control; CAR1 = 1 H2.1 Ό28T-ΰΟ28-ΰϋ3ζ; CAR2 = 1 H2.1C28T-4-1 ΒΒ-ΰϋ3ζ; CAR3 = 1 H2.1 Ό8K-Οϋ28-ΟΟ3ζ; CAR4 = 1H2.1-Ο8K-4-1ΒΒ-ΰϋ3ζ).As shown in Figure 6, this was also confirmed by a survival analysis, where injection of CAR T cells expressing 1H2-CD28T or 1 H2-4-1BB conferred a significant survival advantage over animals that received sham transduction cells. ccyni n / nznz / E / YiAi NOVELTY OF THE INVENTION Having described the present invention as above, it is considered novel and, therefore, the contents contained in the following are claimed as property:

Claims

CLAIMS 1. A chimeric antigen receptor comprising an antigen-binding molecule that binds specifically to DLL3, wherein the antigen-binding molecule comprises: a) a variable heavy chain CDR1 comprising an amino acid sequence that does not differ by more than 3, 2, 1 or 0 amino acid residues from the sequence of SEQ ID No. 42 or SEQ ID No. 52; or SEQ ID No. 62; b) a variable heavy chain CDR2 comprising an amino acid sequence that does not differ by more than 3, 2, 1 or 0 amino acid residues from the sequence of SEQ ID No. 43 or SEQ ID No. 53; or SEQ ID No. 63; oc) a variable heavy chain CDR3 comprising an amino acid sequence that does not differ by more than 3, 2, 1 or 0 amino acid residues from the sequence of SEQ ID No.: 44 or SEQ ID No.: 54; or SEQ ID No.: 64;(od) a variable light chain CDR1 comprising an amino acid sequence that does not differ by more than 3, 2, 1 or 0 amino acid residues from the sequence of SEQ ID No.: 47 or SEQ ID No.: 57; or SEQ ID No.: 67; (e) a variable light chain CDR2 comprising an amino acid sequence that does not differ by more than 3, 2, 1 or 0 amino acid residues from the sequence of SEQ ID No.: 48 or SEQ ID No.: 58; or SEQ ID No.: 68; (of) a variable light chain CDR3 comprising an amino acid sequence that does not differ by more than 3, 2, 1 or 0 amino acid residues from the sequence of SEQ ID No.: 49 or SEQ ID No.: 59; or SEQ ID No.: 69; og) a variable heavy chain CDR1 comprising an amino acid sequence from a variable heavy chain CDR1 sequence of clone 1 H2.1, clone 8D2 or clone 6B2;(oh) a variable heavy chain CDR2 comprising an amino acid sequence from a variable heavy chain CDR2 sequence of clone 1 H2.1, clone 8D2 or clone 6B2; (oi) a variable heavy chain CDR3 comprising an amino acid sequence from a variable heavy chain CDR3 sequence of clone 1 H2.1, clone 8D2 or clone 6B2; (oj) a variable light chain CDR1 comprising an amino acid sequence from a variable light chain CDR1 sequence of clone 1 H2.1, clone 8D2 or clone 6B2; (ok) a variable light chain CDR2 comprising an amino acid sequence from a variable light chain CDR2 sequence of clone 1 H2.1, clone 8D2 or clone 6B2; or I) a variable light chain CDR3 comprising an amino acid sequence from a variable light chain CDR3 sequence of clone 1 H2.1, clone 8D2 or clone 6B2;om) a variable heavy chain sequence that differs by no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 residues from the variable heavy chain sequence of clone 1 H2.1, clone 8D2 or clone 6B2; on) a variable light chain sequence that differs by no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 residues from the variable light chain sequence of clone 1 H2.1, clone 8D2 or clone 6B2.; 2. The chimeric antigen receptor according to claim 1, further comprising at least one costimulatory domain.

3. The chimeric antigen receptor according to claim 1, further comprising at least one activator domain.

4. The chimeric antigen receptor according to claim 2, wherein the costimulatory domain is a signaling region of CD28, CD8, OX-40, 41BB / CD137, CD2, CD7, CD27, CD30, CD40, Programmed Death-1 (PD-1), an inducible T-cell costimulatory factor (ICOS), a lymphocyte function-associated antigen-1 (LFA-1 (GDI α / CD18)), CD3 γ, CD3 δ, CD3 ε, CD247, CD276 (B7-H3), LIGHT, (TNFSF14), NKG2C, Ig α (CD79a), DAP-10, an Fe γ receptor, an MHC class I molecule, TNF receptor proteins, an immunoglobulin protein, a cytokine receptor, integrins, lymphocyte signal activator molecules (SLAM proteins), activating receptors of NK cells, BTLA, a Toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL-2R beta, IL-2R gamma, IL-7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, GDI Id,ITGAE, CD103, ITGAL, GDI la, LFA-1, ITGAM, GDI Ib, ITGAX, GDI le, ITGBI, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Touch), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, CD19a, a ligand that specifically links to CD83 or any combination thereof.

5. The chimeric antigen receptor according to claim 4, wherein the costimulatory domain comprises CD28. ccyni n / nznz / E / YiAi 6. The chimeric antigen receptor according to claim 5, wherein the CD28 costimulatory domain comprises a sequence that does not differ by more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 amino acid residues from the sequence of SEQ ID No. 2, SEQ ID No. 4, SEQ ID No. 6 or SEQ ID No.

8.

7. The chimeric antigen receptor according to claim 4, wherein the costimulatory domain comprises CD8.

8. The chimeric antigen receptor according to claim 7, wherein the CD8 costimulatory domain comprises a sequence that does not differ by more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 amino acid residues from the sequence of SEQ ID No:

14.

9. The chimeric antigen receptor according to claim 4, wherein the costimulatory domain comprises 4-1BB.

10. The chimeric antigen receptor according to claim 9, wherein the CD8 costimulatory domain comprises a sequence that does not differ by more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 amino acid residues from the sequence of SEQ ID No:

16.

11. The chimeric antigen receptor according to claim 3, wherein the activator domain comprises CD3.

12. The chimeric antigen receptor according to claim 7, wherein CD3 comprises CD3 zeta.

13. The chimeric antigen receptor according to claim 8, wherein the CD3 zeta comprises a sequence that does not differ by more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 amino acid residues from the sequence of SEQ ID No.

10.

14. The chimeric antigen receptor according to claim 1, wherein the costimulatory domain comprises a sequence that does not differ by more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 amino acid residues from the sequence of SEQ ID No. 2 and the activator domain comprises a sequence that does not differ by more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 amino acid residues from the sequence of SEQ ID No.

10.

15. A polynucleotide encoding the chimeric antigen receptor of claim 1.

16. A vector comprising the polynucleotide of claim 15.

17. The vector according to claim 16, which is a retroviral vector, a DNA vector, a plasmid, an RNA vector, an adenoviral vector, an adenovirus-associated vector, a lentiviral vector, or any combination thereof.

18. An immune cell comprising the vector of claim 16.

19. The immune cell according to claim 18, wherein the immune cell is a T cell, a tumor-infiltrating lymphocyte (TIL), an NK cell, a TCR-expressing cell, a dendritic cell, or a T NK cell.

20. The immune cell according to claim 19, wherein the cell is an autologous T cell.

21. The immune cell according to claim 19, wherein the cell is an allogeneic T cell.

22. The immune cell of claim 18, wherein the vector is introduced into a cell that is isolated from a patient's body or that was grown from a sample taken from the patient's body.

23. The immune cell of claim 18, wherein the vector is introduced into a cell that is isolated from the body of a donor or that was grown from a sample taken from the patient's body.

24. A pharmaceutical composition comprising an immune cell of claim 18.

25. A chimeric antigen receptor comprising: (a) a clone 1 H2.1 VH region and a clone 1 H2.1 VL region; (b) a clone 8D2 VH region and a clone 8D2 VL region; or (c) a clone 6B2 VH region and a clone 6B2 VL region; wherein the VH and VL regions are joined by at least one connector.

26. The chimeric antigen receptor according to claim 25, wherein the connector comprises the scFv G4S connector or the scFv Whitlow connector.

27. The chimeric antigen receptor according to claim 25, further comprising a costimulatory domain.

28. The chimeric antigen receptor according to claim 25, further comprising an activator domain.

29. The chimeric antigen receptor according to claim 27, wherein the costimulatory domain is a signaling region of CD28, OX-40, 41BB / CD137, CD2, CD7, CD27, CD30, CD40, Programmed Death-1 (PD-1), an inducible T-cell costimulatory factor (ICOS), a lymphocyte function-associated antigen-1 (LFA-1 (GDI α1 / CD18)), CD3 γ, CD3 δ, CD3 ε, CD247, CD276 (B7-H3), LIGHT, (TNFSF14), NKG2C, Ig α (CD79a), DAP-10, an Fe γ receptor, an MHC class I molecule, TNF receptor proteins, an immunoglobulin protein, a cytokine receptor, integrins, lymphocyte signal-activating molecules (SLAM proteins), cell-activating receptors NK, BTLA, a Toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL-2R beta, IL-2R gamma, IL-7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDI Id, ITGAE,CD103, ITGAL, CDI la, LFA-1, ITGAM, CDI Ib, ITGAX, CDI le, ITGBI, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Touch), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, ccjm η / ηζηζ / Ε / γίΛΐ SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, CD19a, a ligand that binds specifically to CD83, or any combination thereof.

30. An immune cell comprising the chimeric antigen receptor of claim 25.

31. The immune cell according to claim 30, wherein the immune cell is a T cell, a tumor-infiltrating lymphocyte (TIL), an NK cell, a TCR-expressing cell, a dendritic cell, or a T NK cell.

32. The T cell of claim 31 is an autologous T cell.

33. The T cell of claim 32 is an allogeneic T cell.

34. A pharmaceutical composition comprising the cell of claim 30.

35. An isolated polynucleotide comprising a sequence encoding the chimeric antigen receptor of claim 25.

36. A vector comprising the polynucleotide according to claim 35.

37. An immune cell comprising the vector of claim 36.

38. The immune cell according to claim 37, wherein the immune cell is a T cell, a tumor-infiltrating lymphocyte (TIL), an NK cell, a TCR-expressing cell, a dendritic cell, or a T NK cell.

39. The T cell of claim 38 is an autologous T cell.

40. The T cell of claim 38 is an allogeneic T cell.

41. An isolated polypeptide comprising the amino acid sequence of the 1H2.1 CD28T construct, the 1H2.1 4-1 BB construct, the 8D2 CD28T construct, the 8D2 4-1 BB construct, the 6B2 CD28T construct, or the 6B2 4-1 BB construct.

42. A vector encoding the polypeptide of claim 41.

43. An immune cell comprising the polypeptide of claim 41.

44. The immune cell according to claim 43 wherein the immune cell is a T cell, a tumor-infiltrating lymphocyte (TIL), an NK cell, a cell expressing TCR, a dendritic cell, or a T NK cell.

45. The T cell of claim 44 is an autologous T cell.

46. ​​The T cell of claim 44 is an allogeneic T cell.

47. An isolated polynucleotide encoding a chimeric antigen receptor (CAR) or a T cell receptor (TCR) comprising an antigen-binding molecule that binds specifically to DLL3, wherein the antigen-binding molecule comprises a variable heavy chain CDR3 comprising the amino acid sequence of a variable heavy chain CDR3 of clone 1H2.1, clone 8D2, or clone 6B2.

48. The polynucleotide according to claim 47, further comprising an activator domain.

49. The polynucleotide according to claim 48, wherein the activator domain is CD3.

50. The polynucleotide according to claim 49, wherein CD3 is CD3 zeta.

51. The polynucleotide according to claim 50, wherein the CD3 zeta comprises the amino acid sequence illustrated in SEQ ID No.

9.

52. The polynucleotide according to claim 47, further comprising a costimulatory domain.

53. The polynucleotide according to claim 52, wherein the costimulatory domain is a signaling region of CD28, OX-40, 4-1BB / CD137, CD2, CD7, CD27, CD30, CD40, Programmed Death-1 (PD-1), an inducible T-cell costimulatory factor (ICOS), a lymphocyte function-associated antigen-1 (LFA-1 (GDI1a / CD18)), CD3 gamma, CD3 delta, CD3 epsilon, CD247, CD276 (B7-H3), LIGHT, (TNFSF14), NKG2C, Ig alpha (CD79a), DAP-10, an Fe gamma receptor, an MHC class I molecule, TNF receptor proteins, an immunoglobulin protein, a cytokine receptor, integrins, lymphocyte signal-activating molecules (SLAM proteins), NK cell activating receptors, BTLA, a Toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL-2R beta, IL-2R gamma, IL-7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, GDI Id, ITGAE, CD103, ITGAL,GDI la, LFA-1, ITGAM, GDI Ib, ITGAX, GDI le, ITGBI, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Touch), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, CD19a, a binding ligand specifically aCD83 or any combination of the same., 54. The polynucleotide according to claim 53, wherein the costimulatory domain of CD28 encodes the amino acid sequence illustrated in SEQ ID No.

2.

55. A vector comprising the polynucleotide of claim 47.

56. An immune cell comprising the vector of claim 55.

57. The immune cell of claim 56, wherein the immune cell is a T cell, a tumor-infiltrating lymphocyte (TIL), an NK cell, a TCR-expressing cell, a dendritic cell, or a T NK cell.

58. The T cell of claim 57 is an autologous T cell.

59. The T cell of claim 57 is an allogeneic T cell.

60. An isolated polynucleotide encoding a chimeric antigen receptor (CAR) or a T cell receptor (TCR), wherein said CAR or TCR comprises an antigen-binding molecule that binds specifically to DLL3, wherein the antigen-binding molecule comprises: a. a variable heavy chain sequence that differs by no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 residues from the variable heavy chain sequence of clone 1H2.1, clone 8D2 or clone 6B2; and / or b. a variable light chain sequence that differs by no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 residues from the variable light chain sequence of clone 1 H2.1, clone 8D2 or clone 6B2.

61. The polynucleotide according to claim 60, further comprising an activator domain.

62. The polynucleotide according to claim 61, wherein the activator domain is CD3.

63. The polynucleotide according to claim 62, wherein CD3 is CD3 zeta.

64. The polynucleotide according to claim 63, wherein the CD3 zeta comprises the amino acid sequence illustrated in SEQ ID No.

9.

65. The polynucleotide according to claim 60, further comprising a costimulatory domain.

66. The polynucleotide according to claim 65, wherein the costimulatory domain is a signaling region of CD28, OX-40, 4-1BB / CD137, CD2, CD7, CD27, CD30, CD40, Programmed Death-1 (PD-1), an inducible T-cell costimulatory factor (ICOS), a lymphocyte function-associated antigen-1 (LFA-1 (GDI1a / CD18)), CD3 gamma, CD3 delta, CD3 epsilon, CD247, CD276 (B7-H3), LIGHT, (TNFSF14), NKG2C, Ig alpha (CD79a), DAP-10, an Fe gamma receptor, an MHC class I molecule, TNF receptor proteins, an immunoglobulin protein, a cytokine receptor, integrins, lymphocyte signal-activating molecules (SLAM proteins), NK cell activating receptors, BTLA, a Toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL-2R beta, IL-2R gamma, IL-7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDI Id, ITGAE, CD103, ITGAL,CDI la, LFA-1, ITGAM, CDI Ib, ITGAX, CDI le, ITGBI, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Touch), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, CD19a, a binding ligand specifically aCD83 or any combination thereof. rom η / ηζηζ / Ε / γίΛΐ, 67. The polynucleotide according to claim 66, wherein the CD28 costimulatory domain comprises the nucleotide sequence illustrated in SEQ ID No.:

3.

68. The polynucleotide according to claim 67, wherein the CD28 costimulatory domain comprises the nucleotide sequence illustrated in SEQ ID No.

1.

69. An isolated polynucleotide encoding a chimeric antigen receptor (CAR) or a T cell receptor (TCR) comprising an antigen-binding molecule that binds specifically to DLL3, wherein the heavy chain of the antigen-binding molecule comprises CDR1 (SEQ ID No.: 42), CDR2 (SEQ ID No.: 43) and CDR3 (SEQ ID No.: 44) and the light chain of the antigen-binding molecule comprises CDR1 (SEQ ID No.: 47), CDR2 (SEQ ID No.: 48) and CDR3 (SEQ ID No.: 49).

70. An isolated polynucleotide encoding a chimeric antigen receptor (CAR) or a T cell receptor (TCR) comprising an antigen-binding molecule that binds specifically to DLL3, wherein the heavy chain of the antigen-binding molecule comprises CDR1 (SEQ ID No.: 52), CDR2 (SEQ ID No.: 53) and CDR3 (SEQ ID No.: 54) and the light chain of the antigen-binding molecule comprises CDR1 (SEQ ID No.: 57), CDR2 (SEQ ID No.: 58) and CDR3 (SEQ ID No.: 59).

71. An isolated polynucleotide encoding a chimeric antigen receptor (CAR) or a T cell receptor (TCR) comprising an antigen-binding molecule that binds specifically to DLL3, wherein the heavy chain of the antigen-binding molecule comprises CDR1 (SEQ ID No.: 62), CDR2 (SEQ ID No.: 63) and CDR3 (SEQ ID No.: 64) and the light chain of the antigen-binding molecule comprises CDR1 (SEQ ID No.: 67), CDR2 (SEQ ID No.: 68) and CDR3 (SEQ ID No.: 69).

72. A method of treating a disease or disorder in a subject in need, comprising administering the polynucleotide to the subject according to claim 15, 47, 60, 69, 70 or 71.

73. A method of treating a disease or disorder in a subject in need, comprising administering the polypeptide to the subject according to claim 41.

74. A method of treating a disease or disorder in a subject in need, comprising administering to the subject the chimeric antigen receptor according to claim 1 or 25.

75. A method of treating a disease or disorder in a subject in need, comprising administering the cell to the subject according to claim 18, 30, 37, 43 or 56.

76. A method of treating a disease or disorder in a subject who needs it, comprising administering to the subject the pharmaceutical composition according to claim 24 or 34.

77. The method according to any of claims 72, 73, 74, 75 or 76, wherein the disease or disorder is cancer.

78. The method according to claim 77, wherein the cancer is adrenal, liver, kidney, bladder, breast, gastric, ovarian, cervical, uterine, esophageal, colorectal, prostate (e.g., prostate adenocarcinoma), pancreatic, lung (both small cell and non-small cell), thyroid, carcinomas, sarcomas, glioblastomas, head and neck tumors, large cell neuroendocrine carcinoma (LCNEC), medullary thyroid cancer, glioblastoma, neuroendocrine prostate cancer (NEPO), high-grade gastroenteropancreatic (GEP) cancer, and malignant melanoma.

79. The method of claim 77, wherein the cancer is small cell lung cancer.

80. The lentiviral vector according to claim 17, wherein the lentiviral vector is a pGAR vector.