WO2023172931A2

WO2023172931A2 - Methods of treating her2 cancer with a her2 t cell-antigen coupler

Info

Publication number: WO2023172931A2
Application number: PCT/US2023/063890
Authority: WO
Inventors: Deyaa ADIB
Original assignee: Triumvira Immunologics Usa, Inc.
Priority date: 2022-03-07
Filing date: 2023-03-07
Publication date: 2023-09-14
Also published as: WO2023172931A3

Abstract

A trifunctional molecule is provided, comprising (i) a target-specific ligand, (ii) a ligand that binds a protein associated with a TCR complex, and (iii) a T cell receptor signaling domain polypeptide. Variants of the molecule are provided, including variants that exhibit optimized surface expression, transduction efficiency, and effector functionality. Variations include, for example, different ligands that bind CD3 epsilon (e.g., OKT3, L2K, F6A, UCHT1 and humanized UCHT1), different signaling domains, and different linkers between domains.

Description

METHODS OF TREATING HER2 CANCER WITH A HER2 T CELL-ANTIGEN COUPLER CROSS-REFERENCE [0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No.63/268,976, filed March 7, 2022, and U.S. Provisional Patent Application No.63/374,830, filed September 7, 2022, each of which is incorporated by reference in its entirety herein. SUMMARY [0002] Disclosed herein, in certain embodiments, are methods of treating a HER2 positive cancer in an individual in need thereof. In some embodiments, the HER2-positive cancer is classified as 1+ by an immunohistochemistry (IHC) test. In some embodiments, the HER2- positive cancer is classified as 2+ by an immunohistochemistry (IHC) test. In some embodiments, the HER2-positive cancer is classified as 3+ by an immunohistochemistry (IHC) test. In some embodiments, the HER2-positive cancer is classified as HER2-positive by fluorescence in situ hybridization (FISH) analysis. In some embodiments, FISH analysis classifies the cancer as HER2-positive by identifying at least 1 copy of HER2 per cancer tumor cell. In some embodiments, FISH analysis classifies the cancer as HER2-positive by identifying at least 2 copies of HER2 per cancer tumor cell. In some embodiments, FISH analysis classifies the cancer as HER2-positive by identifying at least 3 copies of HER2 per cancer tumor cell. In some embodiments, FISH analysis classifies the cancer as HER2-positive by identifying at least 4 copies of HER2 per cancer tumor cell. In some embodiments, the HER2-positive cancer is classified as a triple negative breast cancer (for example, is HER2 negative, ER negative and PR negative). In some embodiments, the HER2-positive cancer has progressed after two lines of prior systemic therapy. In some embodiments, the method comprises administering to the individual a T cell expressing a nucleic acid encoding a HER2 TAC. In some embodiments, the HER2 TAC is encoded by a nucleic acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NO: 34, SEQ ID NO: 36, or SEQ ID NO: 38. In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NO: 35, SEQ ID NO: 37, or SEQ ID NO: 39. In some embodiments, the T cell comprises a vector comprising a nucleic acid sequence encoding the HER2. In some embodiments, the subject is a mammal. In some embodiments, the cancer is a metastatic HER2- positive cancer. In some embodiments, the HER-2 positive cancer is breast cancer, bladder cancer, pancreatic cancer, ovarian cancer, gastric cancer, salivary gland cancer, uterine cancer, cervical cancer, lung cancer, biliary tract cancer, colorectal cancer, prostate cancer, gastroesophageal junction cancer, or sarcoma. In some embodiments, the HER2-positive cancer is breast, lung, pancreatic, colorectal, gastric, endometrial, or ovarian cancer. In some embodiments, the HER2 positive cancer is rectosigmoid cancer, gastro-esophageal cancer, or gastric adenocarcinoma. In some embodiments, the pharmaceutical composition is administered to the individual transarterially, subcutaneously, intradermally, intratumorally, intranodally, intrameduliary, intramuscularly, intravenously or intraperitoneally. In some embodiments, the pharmaceutical composition is in a unit dose form. In some embodiments, the pharmaceutical composition comprises about 0.5 - 2 × 10⁹ T cells. In some embodiments, the pharmaceutical composition is administered daily, weekly, bi-weekly, monthly, bi-month or yearly. [0003] Described herein, in some embodiments, are methods of treating an individual having a HER2 low expressing cancer, comprising administering to the individual a T cell expressing a nucleic acid encoding a HER2 T cell Antigen Coupler (TAC) having an amino acid sequence at least 80% identical to the amino acid sequence: SEQ ID NO: 35, SEQ ID NO: 37, or SEQ ID NO: 39. In some embodiments, the HER2 low expressing cancer is classified as 0 by an immunohistochemistry (IHC) test. In some embodiments, the HER2 low expressing cancer is classified as 1+ by an immunohistochemistry (IHC) test. In some embodiments, the HER2 low expressing cancer is classified as 2+ by an immunohistochemistry (IHC) test. In some embodiments, the HER2 low expressing cancer is classified as a HER2 negative cancer. In some embodiments, the HER2 low expressing cancer is classified as a triple negative cancer. In some embodiments, the HER2 low expressing cancer is classified as low-expressing by fluorescence in situ hybridization (FISH). In some embodiments, the HER2 low expressing cancer is classified as having at most one copy of HER2 per cancer tumor cell. In some embodiments, the HER2 low expressing cancer is classified as having at most two copies of HER2 per cancer tumor cell. In some embodiments, the HER2 low expressing cancer is classified as having at most three copies of HER2 per cancer tumor cell. In some embodiments, the HER2 low expressing cancer is classified as having at most four copies of HER2 per cancer tumor cell. In some embodiments, the HER2 low expressing cancer has progressed after at least two lines of prior systemic therapy. In some embodiments, the HER2 TAC has an amino acid sequence at least 90% identical to the amino acid sequence: SEQ ID NO: 35, SEQ ID NO: 37, or SEQ ID NO: 39. In some embodiments, the HER2 TAC has an amino acid sequence 100% identical to the amino acid sequence: SEQ ID NO: 35, SEQ ID NO: 37, or SEQ ID NO: 39. In some embodiments, the HER2 TAC is encoded by a nucleic acid sequence having at least 80% sequence identity with the nucleic acid sequence: SEQ ID NO: 34, SEQ ID NO: 36, or SEQ ID NO: 38. In some embodiments, the HER2 TAC is encoded by a nucleic acid sequence having at least 90% sequence identity with the nucleic acid sequence: SEQ ID NO: 34, SEQ ID NO: 36, or SEQ ID NO: 38. In some embodiments, the HER2 TAC is encoded by a nucleic acid sequence having 100% sequence identity with the nucleic acid sequence: SEQ ID NO: 34, SEQ ID NO: 36, or SEQ ID NO: 38. In some embodiments, the nucleic acid sequence encoding the HER2 TAC is on a vector having a promoter that is expressed in mammalian cells. In some embodiments, the T cell comprises a vector comprising the nucleic acid sequence encoding the HER2 TAC. In some embodiments, the HER2 low expressing cancer is a metastatic cancer. In some embodiments, the HER2 low expressing cancer is breast cancer, bladder cancer, pancreatic cancer, ovarian cancer, gastric cancer, salivary gland cancer, uterine cancer, cervical cancer, lung cancer, biliary tract cancer, colorectal cancer, prostate cancer, gastroesophageal junction cancer, or sarcoma. In some embodiments, the HER2 low expressing cancer is breast, lung, pancreatic, colorectal, gastric, endometrial, or ovarian cancer. In some embodiments, the HER2 low expressing cancer is rectosigmoid cancer, gastro-esophageal cancer, or gastric adenocarcinoma. BRIEF DESCRIPTION OF THE DRAWINGS [0004] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which: [0005] Fig.1 shows a summary of adverse events by incidence. Adverse event is seen on the y- axis and frequency is seen on the x-axis. [0006] Fig.2A shows a graph of blood pharmacokinetic data. TAC copies per microgram (ug) of gDNA is on the y-axis and collection timepoint is seen on the x-axis. [0007] Fig.2B shows graphs of cytokine data including IFN-gamma (right panel), IL-12 (p70) (middle panel), and IL-6 (left panel). Fold difference versus pretreatment is seen on the y-axis and days is seen on the x-axis. [0008] Fig.3A shows CT with contrast images of the distal esophageal mass in Patient 2 at baseline day 0 (top image) as compared to day 29 (bottom image). At day 0, the tumor measured 30 mm. At day 29, the tumor mass completely regressed. [0009] Fig.3B shows CT and PET-CT images of a subject. Left panel of Fig.3B shows CT with contrast images of the gastrohepatic lymph node in Patient 1 at baseline day 0 (top image) as compared to day 29 (bottom image). At day 0, the tumor measured 20 mm. At day 29, the tumor measured 12.7 mm. The right panel of Fig.3B shows PET-CT images of gastrohepatic node and periportal mass reduction from baseline day 0 (top images) as compared to day 29 (bottom images). [0010] Fig.4 shows a graph of change in lesion size from baseline after 1 or 2 months in subjects after a dose of 6-8 x 10⁵ (Cohort 2), 1-3 x 10⁶ (Cohort 3), or 6-8 x 10⁶ (Cohort 4) cells per kg of body weight. Percent change in target lesions from baseline is seen on the y-axis. DETAILED DESCRIPTION [0011] Cancer is a major health challenge, with over 150,000 cases of cancer expected to be diagnosed in Canada alone. While patients with early stage disease are sometimes treated effectively by conventional therapies (surgery, radiation, chemotherapy), few options are available to patients with advanced disease, and those options are typically palliative in nature. Further, some patients, for example those having a HER2 low expressing cancer, do not respond well to HER2 therapies or are not even considered candidates for HER2 targeted therapies unless they have high expression of HER2 (e.g., 3+ by immunohistochemistry). [0012] One option for treating cancers is treatment with engineered T cells. Engineered T cells can be genetically modified to yield: (i) forced expression of T cell receptor (TCR); or (ii) a chimeric antigen receptor (CAR) specific for antigen targets on the tumor. To date, the chimeric antigen receptors used for engineering T cells consist of: (i) a targeting domain, usually a single- chain fragment variable (scFv); (ii) a transmembrane domain; and (iii) a cytosolic domain that contains signaling elements from the T cell receptor and associated proteins. Such chimeric antigen receptors have also been referred to as “T-body” or “Chimeric Immune Receptor” (CIR), but currently, most researchers use the term “CAR”. One advantage of the CAR approach is that it allows any patient’s immune cells to be targeted against any desirable target in a major histocompatibility complex (MHC) independent manner. This is appealing as MHC presentation is often defective in tumor cells. [0013] CARs are considered in modular terms and scientists have spent considerable time investigating the influence of different cytoplasmic signaling domains on CAR function. Conventional CARs generally share two main components: (i) the CD3 zeta cytoplasmic domain, which contains immunotyrosine activation motifs (ITAMs) critical for T cell activation; and (ii) components of costimulatory receptors that trigger important survival pathways such as the Akt pathway. [0014] The first-generation CARs employed a single signaling domain from either CD3ȗ or FcİRIȖ. Second-generation CARs combined the signaling domain of CD3ȗ with the cytoplasmic domain of costimulatory receptors from either the CD28 or TNFR family of receptors. Most CAR-engineered T cells that are currently being tested in the clinic employ second-generation CARs where CD3ȗ is coupled to the cytoplasmic domain of either CD28 or CD137. These second generation CARs have demonstrated anti-tumor activity in CD19-positive tumors. Third- generation CARs combined multiple costimulatory domains, but there is concern that third- generation CARs may lose antigen-specificity. [0015] While CAR-engineered T cells have shown considerable promise in clinical application, they rely on a synthetic method for replacing the native activation signal that is provided by the T cell receptor (TCR). Since this synthetic receptor does not deliver all of the signaling components associated with the TCR (ex. ITAMs on CD3Ȗ, CD3į, CD3İ), it remains unclear whether the T cells are optimally activated by the CAR or how the CAR activation affects T cell differentiation (ex. progression to memory). Furthermore, since the CAR signaling domains are disconnected from their natural regulatory partners by the very nature of the CAR structure, there is an inherent risk that CARs may lead to a low-level of constitutive activation, which could result in off-target toxicities. Therefore, the synthetic nature of the prototypic CAR may disrupt canonical mechanisms that limit TCR activation, and may underpin the severe toxicity often associated with therapeutic doses of conventional CAR T cells. [0016] Given these limitations, it is preferable to re-direct T cells to attack tumors via their natural TCR. To this end, a class of recombinant proteins termed “Bispecific T-cell Engagers” (BiTEs) has been created. These proteins employ bispecific antibody fragments to crosslink T- cell TCR receptors with target antigens. This leads to efficient T-cell activation, triggering cytotoxicity. Similarly, bi-specific antibodies have been generated that accomplish this goal and some scientists have simply linked anti-CD3 antibodies to tumor-specific antibodies employing chemical linkage. While these bi-specific proteins have demonstrated some activity in vitro, GMP production, short biological half-lives, and limited bioavailability represent significant challenges to the successful use of these molecules in cancer treatment. Additionally, these molecules also fail to properly recapitulate natural TCR signaling because they do not engage the TCR co-receptors (CD8 and CD4). [0017] An alternate chimeric receptor, termed a T cell Antigen Coupler (TAC) receptor, has been developed which employs a distinct biology to direct the T cell to attack tumors. While the CAR is a fully synthetic receptor that stitches together components of T cell receptor (TCR) signaling complex, the TAC receptor re-directs the TCR towards tumor targets and recapitulates the native TCR signaling structure. For example, in some embodiments, the TACs disclosed herein activate natural Major Histocompatibility complex (MHC) signaling through the T-cell receptor (TCR), while retaining MHC-unrestricted targeting. Further, the TACs disclosed herein recruit the T-Cell Receptor (TCR) in combination with co-receptor stimulation. Moreover, in some embodiments, TACs disclosed herein show enhanced activity and safety. Certain terminology [0018] The term “antigen-binding domain,” refers to any substance or molecule that binds, directly or indirectly, to a target (e.g., HER2). Antigen-binding domains include antibodies or fragments thereof, peptides, peptidomimetics, proteins, glycoproteins, proteoglycans, carbohydrates, lipids, nucleic acids, or small molecules that bind to a target. [0019] As used herein, unless otherwise indicated, the term “antibody” is understood to mean an intact antibody (e.g., an intact monoclonal antibody), or a fragment thereof, such as a Fc fragment of an antibody (e.g., an Fc fragment of a monoclonal antibody), or an antigen-binding fragment of an antibody (e.g., an antigen-binding fragment of a monoclonal antibody), including an intact antibody, antigen-binding fragment, or Fc fragment that has been modified, engineered, or chemically conjugated. In general, antibodies are multimeric proteins that contain four polypeptide chains. Two of the polypeptide chains are called immunoglobulin heavy chains (H chains), and two of the polypeptide chains are called immunoglobulin light chains (L chains). The immunoglobulin heavy and light chains are connected by an interchain disulfide bond. The immunoglobulin heavy chains are connected by interchain disulfide bonds. A light chain consists of one variable region (VL) and one constant region (CL). The heavy chain consists of one variable region (VH) and at least three constant regions (CH1, CH2 and CH3). The variable regions determine the binding specificity of the antibody. Each variable region contains three hypervariable regions known as complementarity determining regions (CDRs) flanked by four relatively conserved regions known as framework regions (FRs). The extent of the FRs and CDRs has been defined (Kabat, E.A., et al. (1991) SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST, FIFTH EDITION, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; and Chothia, C. et al. (1987) J. MOL. BIOL.196:901-917). The three CDRs, referred to as CDR₁, CDR₂, and CDR₃, contribute to the antibody binding specificity. Naturally occurring antibodies have been used as starting material for engineered antibodies, such as chimeric antibodies and humanized antibodies. Examples of antibody-based antigen-binding fragments include Fab, Fab’, (Fab’)₂, Fv, single chain antibodies (e.g., scFv), minibodies, and diabodies. Examples of antibodies that have been modified or engineered include chimeric antibodies, humanized antibodies, and multispecific antibodies (e.g., bispecific antibodies). An example of a chemically conjugated antibody is an antibody conjugated to a toxin moiety. [0020] The term “T cell” as used herein refers to a type of lymphocyte that plays a central role in cell-mediated immunity. T cells, also referred to as T lymphocytes, are distinguished from other lymphocytes, such as B cells and natural killer cells, by the presence of a T-cell receptor (TCR) on the cell surface. There are several subsets of T cells with distinct functions, including but not limited to, T helper cells, cytotoxic T cells, memory T cells, regulatory T cells and natural killer T cells. [0021] The term “Ȗį T cell” or “gamma delta T cell” or “gd T cell “as used herein refers to any lymphocyte having a Ȗį T cell receptor (TCR) on its surface, including one Ȗ-chain and one į- chain. [0022] The term “T cell antigen coupler” or TAC is used interchangeably with “trifunctional T cell antigen coupler” or Tri-TAC and refers to an engineered nucleic acid construct or polypeptide comprising (a) an antigen-binding domain that binds a target, (b) an antigen-binding domain that binds a protein associated with a T cell receptor (TCR) complex, and (c) a T cell receptor signaling domain. [0023] The term “polynucleotide” and/or “nucleic acid sequence” and/or “nucleic acid” as used herein refers to a sequence of nucleoside or nucleotide monomers consisting of bases, sugars and intersugar (backbone) linkages. The term also includes modified or substituted sequences comprising non-naturally occurring monomers or portions thereof. The nucleic acid sequences of the present application may be deoxyribonucleic acid sequences (DNA) or ribonucleic acid sequences (RNA) and may include naturally occurring bases including adenine, guanine, cytosine, thymidine and uracil. The sequences may also contain modified bases. Examples of such modified bases include aza and deaza adenine, guanine, cytosine, thymidine and uracil; and xanthine and hypoxanthine. The nucleic acids of the present disclosure may be isolated from biological organisms, formed by laboratory methods of genetic recombination or obtained by chemical synthesis or other known protocols for creating nucleic acids. [0024] The term “isolated polynucleotide” or “isolated nucleic acid sequence” as used herein refers to a nucleic acid substantially free of cellular material or culture medium when produced by recombinant DNA techniques, or chemical precursors, or other chemicals when chemically synthesized. An isolated nucleic acid is also substantially free of sequences which naturally flank the nucleic acid (i.e. sequences located at the 5ƍ and 3ƍ ends of the nucleic acid) from which the nucleic acid is derived. The term “nucleic acid” is intended to include DNA and RNA and is either double stranded or single stranded, and represents the sense or antisense strand. Further, the term “nucleic acid” includes the complementary nucleic acid sequences. [0025] The term “recombinant nucleic acid” or “engineered nucleic acid” as used herein refers to a nucleic acid or polynucleotide that is not found in a biological organism. For example, recombinant nucleic acids may be formed by laboratory methods of genetic recombination (such as molecular cloning) to create sequences that would not otherwise be found in nature. Recombinant nucleic acids may also be created by chemical synthesis or other known protocols for creating nucleic acids. [0026] The terms “peptide”, “polypeptide,” and “protein” as used herein mean a chain of amino acids. The term protein as used herein further means a large molecule comprising one or more chains of amino acids and, in some embodiments, is a fragment or domain of a protein or a full length protein. Furthermore, as used herein, the term protein either refers to a linear chain of amino acids or to a chain of amino acids that has been processed and folded into a functional protein. The protein structure is divided into four distinct levels: (1) primary structure – referring to the sequence of amino acids in the polypeptide chain, (2) secondary structure – referring to the regular local sub-structures on the polypeptide backbone chain, such as Į-helix and ȕ-sheets, (3) tertiary structure – referring to the three-dimensional structure if monomeric and multimeric protein molecules, and (4) quaternary structure – referring to the three-dimensional structure comprising the aggregation of two or more individual polypeptide chains that operate as a single functional unit. The use of peptide or polypeptide herein does not mean that the chain of amino acids is not also a protein (i.e., a chain of amino acids having a secondary, tertiary or quaternary structure). [0027] The term “isolated polypeptide” refers to a polypeptide substantially free of cellular material or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. [0028] The term “vector” as used herein refers to a polynucleotide that is used to deliver a nucleic acid to the inside of a cell. In some embodiments, a vector is an expression vector comprising expression control sequences (for example, a promoter) operatively linked to a nucleic acid to be expressed in a cell. Vectors known in the art include, but are not limited to, plasmids, phages, cosmids and viruses. [0029] The term “tumor antigen” or “tumor associated antigen” as used herein refers to an antigenic substance produced in tumor cells that triggers an immune response in a host (e.g. which is presented by MHC complexes). In some embodiments, a tumor antigen is on the surface of a tumor cell. [0030] As used herein, the term “transmembrane and cytosolic domain” refers to a polypeptide that comprises a transmembrane domain and a cytosolic domain of a protein associated with the T cell receptor (TCR) complex. In some embodiments, such transmembrane and cytosolic domain may include, but is not limited to, protein domains that (a) associate with the lipid raft and/or (b) bind Lck. [0031] A “TCR co-receptor” as used herein, refers to a molecule that assists the T cell receptor (TCR) in communicating with an antigen-presenting cell and may be considered part of the first signal that leads to the activation of the TCR. Examples of TCR co-receptors include, but are not limited to, CD4, LAG3, and CD8. [0032] A “TCR co-stimulator” or “co-stimulatory domain” as used herein, refers to a molecule that enhances the response of a T cell to an antigen and may be considered as the second signal that leads to the activation of the TCR. Examples of TCR co-stimulators include, but are not limited to, ICOS, CD27, CD28, 4-1BB (CD 137), OX40 (CD134), CD30, CD40, lymphocyte fiction-associated antigen 1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds CD83. [0033] The terms “recipient”, “individual”, “subject”, “host”, and “patient”, are used interchangeably herein and in some embodiments, refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and laboratory, zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys etc. In some embodiments, the mammal is human. None of these terms require the supervision of medical personnel. [0034] As used herein, the terms “treatment,” “treating,” and the like, in some embodiments, refer to administering an agent, or carrying out a procedure, for the purposes of obtaining an effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of affecting a partial or complete cure for a disease and/or symptoms of the disease. “Treatment,” as used herein, may include treatment of a disease or disorder (e.g. cancer) in a mammal, particularly in a human, and includes: (a) preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (e.g., including diseases that may be associated with or caused by a primary disease; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease. Treating may refer to any indicia of success in the treatment or amelioration or prevention of a cancer, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms; or making the disease condition more tolerable to the patient; slowing in the rate of degeneration or decline; or making the final point of degeneration less debilitating. The treatment or amelioration of symptoms is based on one or more objective or subjective parameters; including the results of an examination by a physician. Accordingly, the term "treating" includes the administration of the compounds or agents of the present invention to prevent, delay, alleviate, arrest or inhibit development of the symptoms or conditions associated with diseases (e.g. cancer). The term "therapeutic effect" refers to the reduction, elimination, or prevention of the disease, symptoms of the disease, or side effects of the disease in the subject. [0035] As used herein, singular forms “a”, “and,” and “the” include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to “an antibody” includes a plurality of antibodies and reference to “an antibody” in some embodiments includes multiple antibodies, and so forth. [0036] As used herein, all numerical values or numerical ranges include whole integers within or encompassing such ranges and fractions of the values or the integers within or encompassing ranges unless the context clearly indicates otherwise. Thus, for example, reference to a range of 90-100%, includes 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. In another example, reference to a range of 1-5,000 fold includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5, fold, etc., 2.1, 2.2, 2.3, 2.4, 2.5, fold, etc., and so forth. [0037] “About” a number, as used herein, refers to range including the number and ranging from 10% below that number to 10% above that number. “About” a range refers to 10% below the lower limit of the range, spanning to 10% above the upper limit of the range. [0038] “Percent (%) identity” refers to the extent to which two sequences (nucleotide or amino acid) have the same residue at the same positions in an alignment. For example, “an amino acid sequence is X% identical to SEQ ID NO: Y” refers to % identity of the amino acid sequence to SEQ ID NO: Y and is elaborated as X% of residues in the amino acid sequence are identical to the residues of sequence disclosed in SEQ ID NO: Y. Generally, computer programs are employed for such calculations. Exemplary programs that compare and align pairs of sequences, include ALIGN (Myers and Miller, 1988), FASTA (Pearson and Lipman, 1988; Pearson, 1990) and gapped BLAST (Altschul et al., 1997), BLASTP, BLASTN, or GCG (Devereux et al., 1984). [0039] As used herein, the term “selective binding” refers to the higher affinity with which a molecule (e.g. protein such as an antigen-binding domain of TAC) binds its target molecule (e.g. target antigen such as HER2) over other molecules. Unless indicated otherwise, the terms “selective binding” and “specific binding” are used interchangeably herein. [0040] The term “HER2 positive” refers to HER2 overexpression in a cancer. A cancer is classified as “HER2 positive” by an immunohistochemistry (IHC) assay score of 3+ or an immunohistochemistry (IHC) assay score of 2+ with HER2 amplification. Having at least 4 copies of HER2 per tumor cell can also be used to classify a cancer as “HER2 positive” and can be determined using an insitu hybridization (ISH) assay. [0041] The term “HER2 low expressing” refers to low HER2 expression in a cancer. A cancer is classified as “HER2 low expressing” by an immunohistochemistry (IHC) assay score of 0, an immunohistochemistry (IHC) assay score of 1+, or an immunohistochemistry (IHC) assay score of 2+ with no HER2 amplification. “HER2 low expressing” cancer can refer to HER2 negative cancers and HER2 triple negative cancers (estrogen receptor (ER) negative, progesterone receptor (PR) negative, and HER2 negative). Having at most 4 (e.g., at most 3, at most 2, at most 1) copies of HER2 per tumor cell can also be used to classify a cancer as “HER2 low expressing” and can be determined using an insitu hybridization (ISH) assay. HER2 T cell antigen coupler (HER2-TAC) HER2 Ligand [0042] The HER2 ligand refers to any substance or molecule that binds, directly or indirectly, to a HER2 protein. In some embodiments, the HER2 is expressed on a cancer/tumor cell. In some embodiments, the HER is expressed on a breast cancer cell. In some embodiments, the HER2 is expressed on a metastatic cancer cell. [0043] Target-specific ligands include, but are not limited to, antibodies and fragments thereof, for example single chain antibodies such as single-chain antibodies (scFvs), single domain antibodies, peptides, peptidomimetics, proteins, glycoproteins, or proteoglycans that bind to the target cell and/or antigen. In some embodiments, the target-specific ligands include, but are not limited to, designed ankyrin repeat proteins (DARPins), lectins, knottins, centryrins, anticalins, or naturally occurring ligands for the tumor antigen, such as growth factors, enzyme substrates, receptors or binding proteins. In some embodiments, target specific ligands include non-protein compounds that bind to target cells and/or antigens, including but not limited to carbohydrates, lipids, nucleic acids, or small molecules. In some embodiments, a target-specific ligand is a designed ankyrin repeat (DARPin) targeted to a specific cell and/or antigen. In some embodiments, a target-specific ligand is a single-chain variable fragment (ScFv) targeted to a specific cell and/or antigen. [0044] In some embodiments, the HER-2 ligand comprises an antigen binding domain of an antibody selected from the group consisting of Trastuzumab, Pertuzumab, Lapatinib, Neratinib, Ado-trastuzmab Emtansine, Gancotamab, Margetuximab, Timigutuzumab, and Ertumaxomab. In some embodiments, the HER2 ligand is a DARPin that selectively binds a HER-2 (erbB-2) antigen. In some embodiments, the DARPin targeted to HER-2 (erb-2) comprises SEQ ID NO: 1 or SEQ ID NO: 2. [0045] In some embodiments, the first polynucleotide comprises a nucleotide sequence having at least 70% sequence identity with SEQ ID NO: 1. In some embodiments, the first polynucleotide comprises a nucleotide sequence having at least 75% sequence identity with SEQ ID NO: 1. In some embodiments, the first polynucleotide comprises a nucleotide sequence having at least 80% sequence identity with SEQ ID NO: 1. In some embodiments, the first polynucleotide comprises a nucleotide sequence having at least 85% sequence identity with SEQ ID NO: 1. In some embodiments, the first polynucleotide comprises a nucleotide sequence having at least 90% sequence identity with SEQ ID NO: 1. In some embodiments, the first polynucleotide comprises a nucleotide sequence having at least 95% sequence identity with SEQ ID NO: 1. In some embodiments, the first polynucleotide comprises a nucleotide sequence of SEQ ID NO: 1. [0046] In some embodiments, the target-specific ligand comprises an amino acid sequence having at least 70% sequence identity with SEQ ID NO: 2. In some embodiments, the target- specific ligand comprises an amino acid sequence having at least 75% sequence identity with SEQ ID NO: 2. In some embodiments, the target-specific ligand comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 2. In some embodiments, the target-specific ligand comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 2. In some embodiments, the target-specific ligand comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 2. In some embodiments, the target-specific ligand comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 2. In some embodiments, the target-specific ligand comprises an amino acid sequence of SEQ ID NO: 2. Ligand that binds a TCR complex [0047] In some embodiments, the TAC comprises a ligand that binds a protein associated with the TCR complex. In some embodiments, the ligand that binds a protein associated with a TCR complex comprises a substance that binds, directly or indirectly, to a protein of the TCR. In some embodiments, the ligand that binds a protein associated with a TCR complex comprises a substance that selectively binds to a protein of the TCR. In some embodiments, the ligand that binds a protein associated with a TCR complex comprises a substance that specifically binds to a protein of the TCR. Proteins associated with the TCR include, but are not limited, to the TCR alpha (Į) chain, TCR beta (ȕ) chain, TCR gamma (Ȗ) chain, TCR delta (į) chain, CD3Ȗ chain, CD3į chain and CD3İ chains. In some embodiments, a ligand that binds a protein associated with the TCR complex is an antibody to the TCR alpha (Į) chain, TCR beta (ȕ) chain, TCR gamma (Ȗ) chain, TCR delta (į) chain, CD3Ȗ chain, CD3į chain and/or CD3İ chain. In some embodiments, the protein associated with a TCR complex is CD3. In some embodiments, the protein associated with a TCR complex is CD3İ. Examples of CD3 antibodies, include, but are not limited to, for. In some embodiments, the antibody that binds CD3 is a single chain antibody, for example a single-chain variable fragment (scFv). In some embodiments, the ligand that binds a TCR is anti-CD3 antibody, or a fragment thereof, such as muromonab, otelixizumab, teplizumab, visilizumab, CD3-12, MEM-57, 4D10A6, CD3D, or TR66. [0048] In some embodiments, the CD3 is of a TCR complex on a cell expressing the second polynucleotide. In some embodiments, the binding of the CD3 induces activation of a cell expressing the second polynucleotide. [0049] In some embodiments, the ligand that binds a TCR complex is UCHT1, or a variant thereof. In some embodiments, the ligand that binds a TCR complex is UCHT1 (SEQ ID NO: 3, SEQ ID NO: 4 or homologs thereof). In some embodiments, the UCHT1 ligand binds CD3. In some embodiments, the UCHT1 ligand selectively binds CD3. In some embodiments, the UCHT1 ligand specifically binds CD3. In some embodiments, the UCHT1 ligand binds CD3İ. In some embodiments, the UCHT1 ligand selectively binds CD3İ. In some embodiments, the UCHT1 ligand specifically binds CD3İ. In some embodiments, the UCHT1 ligand is encoded by SEQ ID NO: 3. In some embodiments, the UCHT1 ligand comprises SEQ ID NO: 4. In some embodiments, the UCHT1 ligand is mutated. In some embodiments, the UCHT1 ligand comprises a Y182T mutation (also referred to as UCHT1 (Y182T)) (SEQ ID NO: 5 and SEQ ID NO: 6). In some embodiments, the UCHT1 (Y182T) ligand binds CD3. In some embodiments, the UCHT1 (Y182T) ligand selectively binds CD3. In some embodiments, the UCHT1 (Y182T) ligand specifically binds CD3. In some embodiments, the UCHT1 (Y182T) ligand binds CD3İ. In some embodiments, the UCHT1 (Y182T) ligand selectively binds CD3İ. In some embodiments, the UCHT1 (Y182T) ligand specifically binds CD3İ. In some embodiments, the UCHT1 (Y182T) ligand is encoded by SEQ ID NO: 5. In some embodiments, the UCHT1 (Y182T) ligand comprises SEQ ID NO: 6. In some embodiments, the ligand that binds a TCR complex is a humanized UCHT1 (huUCHT1). In some embodiments, the ligand that binds a TCR complex is huUCHT1 (SEQ ID NO: 7, SEQ ID NO: 8 or homologs thereof). In some embodiments, the huUCHT1 ligand binds CD3. In some embodiments, the huUCHT1 ligand selectively binds CD3. In some embodiments, the huUCHT1 ligand specifically binds CD3. In some embodiments, the huUCHT1 ligand binds CD3İ. In some embodiments, the huUCHT1 ligand selectively binds CD3İ. In some embodiments, the huUCHT1 ligand specifically binds CD3İ. In some embodiments, the huUCHT1 ligand is encoded by SEQ ID NO: 7. In some embodiments, the huUCHT1 ligand comprises SEQ ID NO: 8. In some embodiments, the huUCHT1 has a Y177T mutation (also referred to as huUCHT1 (Y177T)) (SEQ ID NO: 9 and SEQ ID NO: 10). In some embodiments, the huUCHT1 (Y177T) ligand binds CD3. In some embodiments, the huUCHT1 (Y177T) ligand selectively binds CD3. In some embodiments, the huUCHT1 (Y177T) ligand specifically binds CD3. In some embodiments, the huUCHT1 (Y177T) ligand binds CD3İ. In some embodiments, the huUCHT1 (Y177T) ligand selectively binds CD3İ. In some embodiments, the huUCHT1 (Y177T) ligand specifically binds CD3İ. In some embodiments, the huUCHT1 (Y177T) ligand is encoded by SEQ ID NO: 9. In some embodiments, the huUCHT1 ligand comprises SEQ ID NO: 10. [0050] In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 70% sequence identity with SEQ ID NO: 3. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 75% sequence identity with SEQ ID NO: 3. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 80% sequence identity with SEQ ID NO: 3. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 85% sequence identity with SEQ ID NO: 3. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 90% sequence identity with SEQ ID NO: 3. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 95% sequence identity with SEQ ID NO: 3. In some embodiments, the second polynucleotide comprises a nucleotide sequence of SEQ ID NO: 3. [0051] In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 70% sequence identity with SEQ ID NO: 4. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 75% sequence identity with SEQ ID NO: 4. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 4. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 4. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 4. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 4. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence of SEQ ID NO: 4. [0052] In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 70% sequence identity with SEQ ID NO: 5. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 75% sequence identity with SEQ ID NO: 5. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 80% sequence identity with SEQ ID NO: 5. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 85% sequence identity with SEQ ID NO: 5. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 90% sequence identity with SEQ ID NO: 5. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 95% sequence identity with SEQ ID NO: 5. In some embodiments, the second polynucleotide comprises a nucleotide sequence of SEQ ID NO: 5. [0053] In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 70% sequence identity with SEQ ID NO: 6. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 75% sequence identity with SEQ ID NO: 6. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 6. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 6. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 6. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 6. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence of SEQ ID NO: 6. [0054] In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 70% sequence identity with SEQ ID NO: 7. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 75% sequence identity with SEQ ID NO: 7. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 80% sequence identity with SEQ ID NO: 7. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 85% sequence identity with SEQ ID NO: 7. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 90% sequence identity with SEQ ID NO: 7. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 95% sequence identity with SEQ ID NO: 7. In some embodiments, the second polynucleotide comprises a nucleotide sequence of SEQ ID NO: 7. [0055] In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 70% sequence identity with SEQ ID NO: 8. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 75% sequence identity with SEQ ID NO: 8. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 8. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 8. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 8. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 8. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence of SEQ ID NO: 8. [0056] In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 70% sequence identity with SEQ ID NO: 9. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 75% sequence identity with SEQ ID NO: 9. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 80% sequence identity with SEQ ID NO: 9. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 85% sequence identity with SEQ ID NO: 9. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 90% sequence identity with SEQ ID NO: 9. In some embodiments, the second polynucleotide comprises a nucleotide sequence having at least 95% sequence identity with SEQ ID NO: 9. In some embodiments, the second polynucleotide comprises a nucleotide sequence of SEQ ID NO: 9. [0057] In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 70% sequence identity with SEQ ID NO: 10. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 75% sequence identity with SEQ ID NO: 10. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 10. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 10. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 10. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 10. In some embodiments, the ligand that binds a TCR complex comprises an amino acid sequence of SEQ ID NO: 10. Transmembrane domain and Cytosolic domain [0058] In some embodiments, the HER2 T cell antigen coupler includes a T cell receptor signaling domain polypeptide. In some embodiments, the TCR signaling domain polypeptide comprises a transmembrane domain. In some embodiments, the TCR signaling domain polypeptide comprises a cytosolic domain. In some embodiments, the TCR signaling domain polypeptide comprises a transmembrane domain and a cytosolic domain. In some embodiments, the cytosolic domain and transmembrane domains are optionally joined by a linker. In some embodiments, the T cell receptor signaling domain polypeptide comprises a TCR co-receptor domain. In some embodiments, the T cell receptor signaling domain polypeptide does not comprise a TCR co-stimulator domain. In some embodiments, the TCR signaling domain polypeptide comprises a transmembrane domain and/or a cytosolic domain of a TCR co- receptor. In some embodiments, the TCR co-receptor is CD4, CD8, LAG3, or a chimeric variation thereof. [0059] In some embodiments, the TCR co-receptor is CD4. In some embodiments, the TCR signaling domain polypeptide comprises the transmembrane and cytosolic domains of the CD4 co-receptor encoded by SEQ ID NO: 11. In some embodiments, the TCR signaling domain polypeptide comprises the transmembrane and cytosolic domains of the CD4 co-receptor comprising SEQ ID NO: 12. [0060] In some embodiments, the third polynucleotide comprises a nucleotide sequence having at least 70% sequence identity with SEQ ID NO: 11. In some embodiments, the third polynucleotide comprises a nucleotide sequence having at least 75% sequence identity with SEQ ID NO: 11. In some embodiments, the third polynucleotide comprises a nucleotide sequence having at least 80% sequence identity with SEQ ID NO: 11. In some embodiments, the third polynucleotide comprises a nucleotide sequence having at least 85% sequence identity with SEQ ID NO: 11. In some embodiments, the third polynucleotide comprises a nucleotide sequence having at least 90% sequence identity with SEQ ID NO: 11. In some embodiments, the third polynucleotide comprises a nucleotide sequence having at least 95% sequence identity with SEQ ID NO: 11. In some embodiments, the third polynucleotide comprises a nucleotide sequence of SEQ ID NO: 11. [0061] In some embodiments, the transmembrane domain and cytosolic domain comprise an amino acid sequence having at least 70% sequence identity with SEQ ID NO: 12. In some embodiments, the transmembrane domain and cytosolic domain comprise an amino acid sequence having at least 75% sequence identity with SEQ ID NO: 12. In some embodiments, the transmembrane domain and cytosolic domain comprise an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 12. In some embodiments, the transmembrane domain and cytosolic domain comprise an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 12. In some embodiments, the transmembrane domain and cytosolic domain comprise an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 12. In some embodiments, the transmembrane domain and cytosolic domain comprise an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 12. In some embodiments, the transmembrane domain and cytosolic domain comprise an amino acid sequence of SEQ ID NO: 12. Linkers, Connectors, and Configurations [0062] In some embodiments, a nucleic acid disclosed herein is in an order of (1) a polynucleotide encoding a HER2 ligand; (2) a polynucleotide encoding a UCHT1 (e.g., huUCHT1); (3) a polynucleotide encoding a CD4 transmembrane domain and a cytosolic domain. In some embodiments, a nucleic acid disclosed herein is in an order of (1) a HER2 ligand; (2) a polynucleotide encoding a UCHT1 (e.g., huUCHT1); (3) a polynucleotide encoding a CD4 transmembrane domain and a cytosolic domain, wherein the order is 5’ end to 3’ end. In some embodiments, a nucleic acid disclosed herein is in an order of (1) a HER2 ligand; (2) a polynucleotide encoding a UCHT1 (e.g., huUCHT1); (3) a polynucleotide encoding a CD4 transmembrane domain and a cytosolic domain, wherein the order is 3’ end to 5’ end. [0063] In some embodiments, a nucleic acid described herein is in an order of (1) a polynucleotide encoding a UCHT1 (e.g., huUCHT1); (2) a HER2 ligand; (3) a polynucleotide encoding a CD4 transmembrane domain and a cytosolic domain. In some embodiments, a nucleic acid described herein is in an order of (1) a polynucleotide encoding a UCHT1 (e.g., huUCHT1); (2) a HER2 ligand; (3) a polynucleotide encoding a CD4 transmembrane domain and a cytosolic domain, wherein the order is 5’ end to 3’ end. In some embodiments, a nucleic acid described herein is in an order of (1) a polynucleotide encoding a UCHT1 (e.g., huUCHT1); (2) a HER2 ligand; (3) a polynucleotide encoding a CD4 transmembrane domain and a cytosolic domain, wherein the order is 3’ end to 5’ end. [0064] In some embodiments, the HER2 ligand, the UCHT1 (e.g., huUCHT1), and CD4 transmembrane domain and a cytosolic domain polypeptides are directly fused. For example, the HER2 ligand and the CD4 transmembrane domain and a cytosolic domain polypeptide are both fused to the UCHT1 (e.g., huUCHT1). In some embodiments, the HER2 ligand, the UCHT1 (e.g., huUCHT1), and CD4 transmembrane domain and a cytosolic domain polypeptides are joined by at least one linker. In some embodiments, the first polypeptide and the second polypeptide are directly fused, and joined to the third polypeptide by a linker. In some embodiments, the second polypeptide and the third polypeptide are directly fused, and joined to the first polypeptide by a linker. [0065] In some embodiments, the linker is a peptide linker. In some embodiments, the peptide linker comprises 1 to 40 amino acids. In some embodiments, the peptide linker comprises 1 to 30 amino acids. In some embodiments, the peptide linker comprises 1 to 15 amino acids. In some embodiments, the peptide linker comprises 1 to 10 amino acids. In some embodiments, the peptide linker comprises 1 to 6 amino acids. In some embodiments, the peptide linker comprises 30 to 40 amino acids. In some embodiments, the peptide linker comprises 32 to 36 amino acids. In some embodiments, the peptide linker comprises 5 to 30 amino acids. In some embodiments, the peptide linker comprises 5 amino acids. In some embodiments, the peptide linker comprises 10 amino acids. In some embodiments, the peptide linker comprises 15 amino acids. In some embodiments, the peptide linker comprises 20 amino acids. In some embodiments, the peptide linker comprises 25 amino acids. In some embodiments, the peptide linker comprises 30 amino acids. [0066] In some embodiments, the peptide linker comprises a G4S3 linker (SEQ ID NO: 13). In some embodiments, the peptide linker comprises SEQ ID NOs: 14, 15, 16, 17, 18, 19, or variants or fragments thereof. [0067] In some embodiments, the peptide linker that joins the HER2 ligand to the UCHT1 (e.g., huUCHT1) is known as the connector to distinguish this protein domain from other linkers in the TAC. The connector is of any size. In some embodiments, the connector between UCHT1 (e.g., huUCHT1) and the HER2 ligand is a short helix comprising SEQ ID NO ID: 20. In some embodiments, the connector between UCHT1 (e.g., huUCHT1) and the HER2 ligand is a short helix encoded by SEQ ID NO ID: 21. In some embodiments, the connector between UCHT1 (e.g., huUCHT1) and the HER2 ligand is a long helix comprising SEQ ID NO ID: 22. In some embodiments, the connector between UCHT1 (e.g., huUCHT1) and the HER2 ligand is a long helix encoded by SEQ ID NO ID: 23. In some embodiments, the connector between UCHT1 (e.g., huUCHT1) and the HER2 ligand is a large domain comprising SEQ ID NO ID: 24. In some embodiments, the connector between UCHT1 (e.g., huUCHT1) and the HER2 ligand is a large domain encoded by SEQ ID NO ID: 25. [0068] In some embodiments, a nucleic acid disclosed herein comprises a leader sequence. In some embodiments, the leader sequence comprises a nucleotide sequence having at least 70% sequence identity with SEQ ID NO: 26, 28, or 30. In some embodiments, the leader sequence comprises a nucleotide sequence having at least 75% sequence identity with SEQ ID NO: 26, 28, or 30. In some embodiments, the leader sequence comprises a nucleotide sequence having at least 80% sequence identity with SEQ ID NO: 26, 28, or 30. In some embodiments, the leader sequence comprises a nucleotide sequence having at least 85% sequence identity with SEQ ID NO: 26, 28, or 30. In some embodiments, the leader sequence comprises a nucleotide sequence having at least 90% sequence identity with SEQ ID NO: 26, 28, or 30. In some embodiments, the leader sequence comprises a nucleotide sequence having at least 95% sequence identity with SEQ ID NO: 26, 28, or 30. In some embodiments, the leader sequence comprises a nucleotide sequence of SEQ ID NO: 26, 28, or 30. [0069] In some embodiments, a nucleic acid disclosed herein comprises a leader sequence. In some embodiments, the leader sequence comprises an amino acid sequence having at least 70% sequence identity with SEQ ID NO: 27, 29, or 31. In some embodiments, the leader sequence comprises an amino acid sequence having at least 75% sequence identity with SEQ ID NO: 27, 29, or 31. In some embodiments, the leader sequence comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 27, 29, or 31. In some embodiments, the leader sequence comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 27, 29, or 31. In some embodiments, the leader sequence comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 27, 29, or 31. In some embodiments, the leader sequence comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 27, 29, or 31. In some embodiments, the leader sequence comprises an amino acid sequence of SEQ ID NO: 27, 29, or 31. [0070] In some embodiments, the TAC disclosed herein is the anti-HER-2 DARPin TAC (also referred to as configuration 1; SEQ ID NO: 34 and 35) includes, in order: i) the leader sequence (secretion signal) (SEQ ID NO: 26 and 27) ii) DARPin specific for HER-2 antigen (SEQ ID NO: 1 and 2) iii) Myc tag (SEQ ID NO: 32 and 33) iv) Connector (SEQ ID NO: 14 and 15) v) UCHT1 (SEQ ID NO: 3 and 4) vi) Linker (SEQ ID NO: 16 and 17) vii) CD4 (SEQ ID NO: 11 and 12). [0071] In some embodiments, the TAC disclosed herein is a HER2-TAC. In some embodiments, the HER2-TAC comprises a nucleotide sequence having at least 70% sequence identity with SEQ ID NO: 34. In some embodiments, the HER2-TAC comprises a nucleotide sequence having at least 75% sequence identity with SEQ ID NO: 34. In some embodiments, the HER2- TAC comprises a nucleotide sequence having at least 80% sequence identity with SEQ ID NO: 34. In some embodiments, the HER2-TAC comprises a nucleotide sequence having at least 85% sequence identity with SEQ ID NO: 34. In some embodiments, the HER2-TAC comprises a nucleotide sequence having at least 90% sequence identity with SEQ ID NO: 34. In some embodiments, the HER2-TAC comprises a nucleotide sequence having at least 95% sequence identity with SEQ ID NO: 34. In some embodiments, the HER2-TAC comprises a nucleotide sequence of SEQ ID NO: 34. [0072] In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 70% sequence identity with SEQ ID NO: 35. In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 75% sequence identity with SEQ ID NO: 35. In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 35. In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 35. In some embodiments, the HER2-TAC an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 35. In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 35. In some embodiments, the HER2-TAC comprises an amino acid sequence of SEQ ID NO: 35. [0073] In some embodiments, the TAC disclosed herein is a HER2-TAC. In some embodiments, the HER2-TAC comprises a nucleotide sequence having at least 70% sequence identity with SEQ ID NO: 36. In some embodiments, the HER2-TAC comprises a nucleotide sequence having at least 75% sequence identity with SEQ ID NO: 36. In some embodiments, the HER2- TAC comprises a nucleotide sequence having at least 80% sequence identity with SEQ ID NO: 36. In some embodiments, the HER2-TAC comprises a nucleotide sequence having at least 85% sequence identity with SEQ ID NO: 36. In some embodiments, the HER2-TAC comprises a nucleotide sequence having at least 90% sequence identity with SEQ ID NO: 36. In some embodiments, the HER2-TAC comprises a nucleotide sequence having at least 95% sequence identity with SEQ ID NO: 36. In some embodiments, the HER2-TAC comprises a nucleotide sequence of SEQ ID NO: 36. [0074] In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 70% sequence identity with SEQ ID NO: 37. In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 75% sequence identity with SEQ ID NO: 37. In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 37. In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 37. In some embodiments, the HER2-TAC an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 37. In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 37. In some embodiments, the HER2-TAC comprises an amino acid sequence of SEQ ID NO: 37. [0075] In some embodiments, the TAC disclosed herein is a HER2-TAC. In some embodiments, the HER2-TAC comprises a nucleotide sequence having at least 70% sequence identity with SEQ ID NO: 38. In some embodiments, the HER2-TAC comprises a nucleotide sequence having at least 75% sequence identity with SEQ ID NO: 38. In some embodiments, the HER2- TAC comprises a nucleotide sequence having at least 80% sequence identity with SEQ ID NO: 38. In some embodiments, the HER2-TAC comprises a nucleotide sequence having at least 85% sequence identity with SEQ ID NO: 38. In some embodiments, the HER2-TAC comprises a nucleotide sequence having at least 90% sequence identity with SEQ ID NO: 38. In some embodiments, the HER2-TAC comprises a nucleotide sequence having at least 95% sequence identity with SEQ ID NO: 38. In some embodiments, the HER2-TAC comprises a nucleotide sequence of SEQ ID NO: 38. [0076] In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 70% sequence identity with SEQ ID NO: 39. In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 75% sequence identity with SEQ ID NO: 39. In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 39. In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 39. In some embodiments, the HER2-TAC an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 39. In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 39. In some embodiments, the HER2-TAC comprises an amino acid sequence of SEQ ID NO: 39. Polypeptides and Vector Constructs [0077] In some embodiments, the HER2 TACS disclosed herein are delivered to a T cell via a vector. In some embodiments, the vectors further comprise a promoter. In some embodiments, the promoter is functional in a mammalian cell. Promoters, regions of DNA that initiate transcription of a particular nucleic acid sequence, are well known in the art. A “promoter functional in a mammalian cell” refers to a promoter that drives expression of the associated nucleic acid sequence in a mammalian cell. A promoter that drives expression of a nucleic acid sequence is referred to as being “operably connected” to the nucleic acid sequence. [0078] A variety of delivery vectors and expression vehicles are employed to introduce nucleic acids described herein into a cell. [0079] In some embodiments, the HER TAC coding sequence is operably connected to the promoter. [0080] In some embodiments, the vector is designed for expression in mammalian cells such as T cells. In some embodiments, the vector is a viral vector. In some embodiments, the viral vector is a retroviral vector. [0081] In some embodiments, vectors that are useful comprise vectors derived from lentiviruses, Murine Stem Cell Viruses (MSCV), pox viruses, oncoretroviruses, adenoviruses, and adeno- associated viruses. Other delivery vectors that are useful comprise vectors derived from herpes simplex viruses, transposons, vaccinia viruses, human papilloma virus, Simian immunodeficiency viruses, HTLV, human foamy virus and variants thereof. Further vectors that are useful comprise vectors derived from spumaviruses, mammalian type B retroviruses, mammalian type C retroviruses, avian type C retroviruses, mammalian type D retroviruses and HTLV/BLV type retroviruses. One example of a lentiviral vector useful in the disclosed compositions and methods is the pCCL4 vector. Expression in T cells [0082] In some embodiments, the T cell is transduced or transfected with a nucleic acid sequence encoding a HER2 T cell antigen coupler, for example a vector comprising a nucleic acid sequence encoding a HER2. In some embodiments, the T cell is an isolated T cell. [0083] T cells are obtained from a number of sources, including, but not limited to blood (for example, peripheral blood mononuclear cells), bone marrow, thymus tissue, lymph node tissue, cord blood, thymus tissue, tissue from an infection site, spleen tissue, or tumors. [0084] In some embodiments, the T cells are autologous T cells. In some embodiments, the T cells are allogenic. In some embodiments, the T cells are Įȕ (alpha beta) T cells (i.e., T cell with a TCR composed of one Į (alpha) chain and ȕ (beta) chain. In some embodiments, the T cells are gamma delta (Ȗį) T cells (i.e., T cells with a TCR composed of one Ȗ (gamma) chain and one į (delta) chain. [0085] In some embodiments, the T cells are obtained from a cell line of T cells. In some embodiments, the T cells are obtained from donors (allogeneic T cells). In some embodiments, the T cells are obtained by differentiation of embryonic or adult stem cells or from induced pluripotent stem cells. In some embodiments, regardless of the source of T cells, the T cells have been modified so that they lack expression of an endogenous TCR and/or permanently or transiently lack expression of MHC/HLA molecules (universal donor T cells). In some embodiments, the T cells are autologous with respect to the subject. In some embodiments, the cells are allogeneic, syngeneic, or xenogeneic with respect to the subject. [0086] In some embodiments, once obtained, the T cells are optionally enriched in vitro. In some embodiments, a population of cells is enriched by positive or negative selection. Further, the T cells are optionally frozen or cryopreserved and then thawed at a later date. [0087] In some embodiments, T cells are activated and/or expanded before or after introducing the TAC to the T cells. In some embodiments, the T cells are expanded by contact with a surface having attached thereto an agent that stimulates a CD3/TCR complex associated signal and a ligand that stimulates a co-stimulator molecule on the surface of the T cells. In some embodiments, the T cells are expanded by contact with one or more soluble agents that stimulate CD3/TCR complex signaling and co-stimulator molecule signaling. [0088] In some embodiments, the T cells are transduced or transfected with nucleic acid sequences. The transduced or transfected T cells express proteins coded for by the transfected or transduced nucleic acid sequences. A nucleic acid may be introduced into a cell by physical, chemical, or biological means. Physical means include, but are not limited to, microinjection, electroporation, particle bombardment, lipofection and calcium phosphate precipitation. Biological means include the use of DNA and RNA vectors. [0089] Viral vectors, including retroviral vectors, are used to introduce and express a nucleic acid into a T cell. Viral vectors include vectors derived from lentivirus, Murine Stem Cell Viruses (MSCV), pox viruses, herpes simplex virus I, adenovirus and adeno-associated viruses. The vector optionally includes a promoter that drives expression of the transduced nucleic acid molecule in a T cell (e.g., a CMV promoter, eF1a promoter, or MSCV promoter). [0090] Any suitable assay is used to confirm the presence and/or expression of the transduced nucleic acid sequence and/or the polypeptide encoded by the nucleic acid in the T cell. Assays include, but are not limited to, Southern and Northern blotting, RT-PCR and PCR, ELISA, Western blotting, and flow cytometry. [0091] A T cell expressing a TAC has increased T cell activation in the presence of an antigen compared to a T cell not expressing a TAC and/or as compared to a T cell expressing a traditional CAR. Increased T cell activation is ascertained by numerous methods, including but not limited to, increased tumor cell line killing, increased cytokine production, increased cytolysis, increased degranulation and/or increased expression of activation markers such as CD107Į, IFNȖ, IL2 or TNFĮ. In some embodiments, increases are measured in an individual cell or in a population of cells. [0092] The terms “increased” or “increasing” as used herein refer to at least a 1%, 2%, 5%, 10%, 25%, 50%, 100% or 200% increase in a T cell or population of T cells expressing a TAC compared to a T cell or population of T cells not expressing a TAC and/or as compared to a T cell or population of T cells expressing a traditional CAR. Pharmaceutical Compositions [0093] In some embodiments, the T cell expressing the HER2 TAC is administered to an individual in need in a pharmaceutical compositions comprising a HER2 TAC T cell disclosed herein (transduced with and/or expressing a TAC), and a pharmaceutically acceptable carrier. [0094] Pharmaceutically acceptable carriers include, but are not limited to, buffers such as neutral buffered saline, phosphate buffered saline 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); or preservatives. In some embodiments, the engineered T cells are formulated for intravenous administration. [0095] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). The quantity and frequency of administration is determined by such factors as the condition of the patient, and the type and severity of the patient’s disease, although appropriate dosages are determined by clinical trials. When “an immunologically effective amount,” “an anti-tumor effective amount,” “a tumor-inhibiting effective amount,” or “therapeutic amount” is indicated, the precise amount of the compositions of the present invention to be administered is determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient (subject). [0096] In some embodiments, the modified T cells and/or pharmaceutical compositions described herein are administered at a dosage of 10¹ to 10¹⁵ cells per kg body weight, 10⁴ to 10⁹ cells per kg body weight, optionally 10⁵ to 10⁸ cells per kg body weight, 10⁶ to 10⁷ cells per kg body weight or 10⁵ to 10⁶ cells per kg body weight, including all integer values within those ranges. In some embodiments, the modified T cells and/or pharmaceutical compositions described herein are administered at a dosage of greater than 10¹ cells per kg body weight. In some embodiments, the modified T cells and/or pharmaceutical compositions described herein are administered at a dosage of less than 10¹⁵ cells per kg body weight. In some embodiments, the modified T cells and/or pharmaceutical compositions described herein are administered at a dosage of at least or about 0.05 x 10⁶, 0.08 x 10⁶, 0.1 x 10⁶, 0.2 x 10⁶, 0.3 x 10⁶, 0.4 x 10⁶, 0.5 x 10⁶, 0.6 x 10⁶, 0.7 x 10⁶, 0.8 x 10⁶, 0.9 x 10⁶, 1 x 10⁶, 2 x 10⁶, 3 x 10⁶, 4 x 10⁶, 5 x 10⁶, 6 x 10⁶, 7 x 10⁶, 8 x 10⁶, 9 x 10⁶, 10 x 10⁶ cells per kg body weight. In some embodiments, the modified T cells and/or pharmaceutical compositions described herein are administered at a dosage in a range of about 0.05 x 10⁶ to about 10 x 10⁶, 0.05 x 10⁶ to about 9 x 10⁶, 0.05 x 10⁶ to about 8 x 10⁶, 0.05 x 10⁶ to about 7 x 10⁶, 0.05 x 10⁶ to about 6 x 10⁶, 0.05 x 10⁶ to about 5 x 10⁶, 0.05 x 10⁶ to about 4 x 10⁶, 0.05 x 10⁶ to about 3 x 10⁶, 0.05 x 10⁶ to about 2 x 10⁶, 0.05 x 1⁶ to about 10 x 10⁶, 0.1 x 10⁶ to about 10 x 10⁶, 0.1 x 10⁶ to about 9 x 10⁶, 0.1 x 10⁶ to about 8 x 10⁶, 0.1 x 10⁶ to about 7 x 10⁶, 0.1 x 10⁶ to about 6 x 10⁶, 0.1 x 10⁶ to about 5 x 10⁶, 0.1 x 10⁶ to about 4 x 10⁶, 0.1 x 10⁶ to about 3 x 10⁶, 0.1 x 10⁶ to about 2 x 10⁶, 0.1 x 1⁶ to about 1 x 10⁶, or 0.1 x 1⁶ to about 0.5 x 10⁶, 1 x 10⁶ to about 10 x 10⁶, 1 x 10⁶ to about 9 x 10⁶, 1 x 10⁶ to about 8 x 10⁶, 1 x 10⁶ to about 7 x 10⁶, 1 x 10⁶ to about 6 x 10⁶, 1 x 10⁶ to about 5 x 10⁶, 1 x 10⁶ to about 4 x 10⁶, 1 x 10⁶ to about 3 x 10⁶, or 1 x 10⁶ to about 2 x 10⁶ cells per kg body weight. [0097] In some embodiments, the modified T cells and/or pharmaceutical compositions described herein are administered at a dosage of 0.5 x10⁶ cells, 2 x10⁶ cells, 4 x10⁶ cells, 5 x10⁶ cells, 1.2 x10⁷ cells, 2 x10⁷ cells, 5 x10⁷ cells, 2 x10⁸ cells, 5 x10⁸ cells, 2 x10⁹ cells, 0.5-2000 x10⁶ cells, 0.5-2 x10⁶ cells, 0.5-2 x10⁷ cells, 0.5-2 x10⁸ cells, or 0.5-2 x10⁹ cells, including all integer values within those ranges. [0098] In some embodiments, T cell compositions are administered multiple times at these dosages. In some embodiments, the dosage is administered a single time or multiple times, for example daily, weekly, biweekly, or monthly, hourly, or is administered upon recurrence, relapse or progression of the cancer being treated. The cells, in some embodiments, are administered by using infusion techniques that are commonly known in immunotherapy (see, e.g., Rosenberg et al., New Eng. J. of Med.319:1676, 1988). [0099] The pharmaceutical composition is substantially free of, e.g., there are no detectable levels of a contaminant, e.g., selected from the group consisting of endotoxin, mycoplasma, replication competent lentivirus (RCL), p24, VSV-G nucleic acid, HIV gag, residual anti- CD3/anti-CD28 coated beads, mouse antibodies, pooled human serum, bovine serum albumin, bovine serum, culture media components, vector packaging cell or plasmid components, a bacterium a fungus, mycoplasma, IL-2, and IL-7. [00100] In some embodiments, engineered T-cells disclose herein are administered to a subject and blood is subsequently redrawn (or apheresis performed), T-cells therefrom are activated and reinfused into the patient with engineered T cells. This process, in some embodiments, is carried out multiple times every few weeks. T-cells are activated from blood draws of from 10 cc to 400 cc. T-cells are activated from blood draws of 20 cc, 30 cc, 40 cc, 50 cc, 60 cc, 70 cc, 80 cc, 90 cc, or 100 cc. [00101] The modified/engineered T cells and/or pharmaceutical compositions are administered by methods including, but not limited to, aerosol inhalation, injection, infusion, ingestion, transfusion, implantation or transplantation. The modified T cells and/or pharmaceutical compositions are administered to a subject transarterially, subcutaneously, intradermally, intratumorally, intranodally, intrameduliary, intramuscularly, by intravenous (i.v.) injection, by intravenous (i.v.) infusion, or intraperitoneally. The modified/engineered T cells and/or pharmaceutical compositions thereof are administered to a patient by intradermal or subcutaneous injection. The modified/engineered T cells and/or pharmaceutical compositions thereof are administered by i.v. injection. The modified/engineered T cells and/or pharmaceutical compositions thereof are injected directly into a tumor, lymph node, or site of infection. [00102] The modified/engineered T cells T cells and/or pharmaceutical compositions are administered in a volume of about 5 mL, 10 mL, 15 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, 50 mL, 60 mL, 70 mL, 80 mL, 90 mL, 100 mL, 110 mL, 120 mL, 130 mL, 140 mL, 150 mL, 200 mL, 300 mL, 400 mL, or 500 mL. [00103] The modified/engineered T cells T cells and/or pharmaceutical compositions are administered in a volume of at greater than at most about 5 mL, 10 mL, 15 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, 50 mL, 60 mL, 70 mL, 80 mL, 90 mL, 100 mL, 110 mL, 120 mL, 130 mL, 140 mL, 150 mL, 200 mL, 300 mL, 400 mL, or 500 mL. [00104] The modified/engineered T cells T cells and/or pharmaceutical compositions are administered in a volume of at least about 5 mL, 10 mL, 15 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, 50 mL, 60 mL, 70 mL, 80 mL, 90 mL, 100 mL, 110 mL, 120 mL, 130 mL, 140 mL, 150 mL, 200 mL, 300 mL, 400 mL, or 500 mL. [00105] A pharmaceutical composition is prepared by per se known methods for the preparation of pharmaceutically acceptable compositions that are administered to subjects, such that an effective quantity of the T cells is combined in a mixture with a pharmaceutically acceptable carrier. Suitable carriers are described, for example, in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, 20^th ed., Mack Publishing Company, Easton, Pa., USA, 2000). On this basis, the compositions include, albeit not exclusively, solutions of the substances in association with one or more pharmaceutically acceptable carriers or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids. [00106] Suitable pharmaceutically acceptable carriers include essentially chemically inert and nontoxic compositions that do not interfere with the effectiveness of the biological activity of the pharmaceutical composition. Examples of suitable pharmaceutical carriers include, but are not limited to, water, saline solutions, glycerol solutions, N-(1(2,3-dioleyloxy)propyl)N,N,N- trimethylammonium chloride (DOTMA), diolesylphosphotidyl-ethanolamine (DOPE), and liposomes. In some embodiments, such compositions contain a therapeutically effective amount of the compound, together with a suitable amount of carrier so as to provide the form for direct administration to the patient. [00107] Pharmaceutical compositions include, without limitation, lyophilized powders or aqueous or non-aqueous sterile injectable solutions or suspensions, which may further contain antioxidants, buffers, bacteriostats and solutes that render the compositions substantially compatible with the tissues or the blood of an intended recipient. Other components that may be present in such compositions include water, surfactants (such as Tween), alcohols, polyols, glycerin and vegetable oils, for example. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, tablets, or concentrated solutions or suspensions. [00108] A pharmaceutical composition disclosed herein is formulated into a variety of forms and administered by a number of different means. A pharmaceutical formulation is administered orally, rectally, or parenterally, in formulations containing conventionally acceptable carriers, adjuvants, and vehicles as desired. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, or intrasternal injection and infusion techniques. Administration includes injection or infusion, including intra-arterial, intracardiac, intracerebroventricular, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration. In some exemplary embodiments, a route of administration is via an injection such as an intramuscular, intravenous, subcutaneous, or intraperitoneal injection. [00109] Liquid formulations include an oral formulation, an intravenous formulation, an intranasal formulation, an ocular formulation, an otic formulation, an aerosol, and the like. In certain embodiments, a combination of various formulations is administered. In certain embodiments a composition is formulated for an extended release profile. Methods of Treatment [00110] Described herein, in some embodiments, are methods of treating a HER2 low expressing cancer in an individual in need thereof comprising administering a HER2 T cell Antigen Coupler (TAC) described herein. In some embodiments, the individual is not responsive to a cancer therapy. In some embodiments, the individual has received a cancer therapy but the cancer therapy does not improve the cancer, prevent cancer regression, control the cancer, or combinations thereof. In some embodiments, the individual has a HER2 low expressing cancer that is advanced, metastatic, unresectable, or combinations thereof. In some embodiments, the individual has a HER2 low expressing cancer that is advanced, metastatic, unresectable, or combinations thereof after at least 1, 2, 3, 4, or more than 4 cancer therapies. [00111] In some embodiments, the individual has a HER2 low expressing cancer and has received at least one cancer therapy (e.g., chemotherapy, radiation). In some embodiments, the individual has a HER2 low expressing cancer and has received at least two cancer therapies. Anticancer therapies include, but are not limited to, surgical therapy, chemotherapy, radiation therapy, cryotherapy, hormonal therapy, immunotherapy, cytokine therapy, and combinations thereof. In some embodiments, the cancer therapy comprises an antibody selected from the group consisting of Trastuzumab, Pertuzumab, Lapatinib, Neratinib, Ado-trastuzmab Emtansine, Gancotamab, Margetuximab, Timigutuzumab, and Ertumaxomab. In some embodiments, the cancer therapy comprises an antibody drug conjugate (e.g., Trastuzumab Deruxtecan), wherein the antibody is selected from the group consisting of Trastuzumab, Pertuzumab, Lapatinib, Neratinib, Ado-trastuzmab Emtansine, Gancotamab, Margetuximab, Timigutuzumab, and Ertumaxomab [00112] Various HER2 positive cancers for treatment are contemplated herein. In some embodiments, the HER2 positive cancer is a metastatic HER2-positive cancer. In some embodiments, the HER2 positive cancer comprises a solid tumor. In some embodiments, the HER2 positive cancer is breast cancer, bladder cancer, pancreatic cancer, ovarian cancer, gastric cancer, salivary gland cancer, uterine cancer, cervical cancer, lung cancer, biliary tract cancer, colorectal cancer, prostate cancer, gastroesophageal junction cancer, or sarcoma. In some embodiments, the HER2 positive cancer is breast, lung, pancreatic, colorectal, gastric, endometrial, or ovarian cancer. In some embodiments, the HER2 positive cancer is rectosigmoid cancer, gastro-esophageal cancer, or gastric adenocarcinoma. [00113] Various HER2 low expressing cancers for treatment are contemplated herein. In some embodiments, the HER2 low expressing cancer is a metastatic cancer. In some embodiments, the HER2 low expressing cancer comprises a solid tumor. In some embodiments, the HER2 low expressing cancer is breast cancer, bladder cancer, pancreatic cancer, ovarian cancer, gastric cancer, salivary gland cancer, uterine cancer, cervical cancer, lung cancer, biliary tract cancer, colorectal cancer, prostate cancer, gastroesophageal junction cancer, or sarcoma. In some embodiments, the HER2 low expressing cancer is breast, lung, pancreatic, colorectal, gastric, endometrial, or ovarian cancer. In some embodiments, the HER2 low expressing cancer is rectosigmoid cancer, gastro-esophageal cancer, or gastric adenocarcinoma. [00114] In some embodiments, the HER2 low expressing cancer is classified as a HER2 negative cancer. In some embodiments, the HER2 low expressing cancer is classified as a triple negative breast cancer (for example, is HER2 negative, ER negative and PR negative). In some embodiments, the HER2 low expressing cancer has progressed after two lines of prior systemic therapy. [00115] HER-2 cancers, in some embodiments, are classified as 0, 1+, 2+, or 3+ by various methods. In some embodiments, the method comprises immunohistochemistry, immunocytochemistry (ICC), in situ hybridization (ISH), flow cytometry, enzyme immuno- assays (EIA), enzyme linked immuno-assays (ELISA), blotting methods (e.g. Western, Southern, and Northern), or labeling inside electrophoresis systems or on surfaces or arrays. In some embodiments, the method comprises immunohistochemistry. In some embodiments, the method comprises immunohistochemistry in situ hybridization including, but not limited to, fluorescence in situ hybridization (FISH). In some embodiments, the method comprises sequencing including, but not limited to, next generation sequence (NGS), single molecule real- time sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, and sequencing by synthesis. [00116] In some embodiments, a HER2-positive cancer is classified as 3+ by an immunohistochemistry (IHC) test. In some embodiments, a HER2-positive cancer is classified as 2+ by an immunohistochemistry (IHC) test. In some embodiments, the HER2-positive cancer is classified as HER2-positive by FISH analysis. In some embodiments, FISH analysis classifies the cancer as HER2-positive expressing by identifying at least 4 copies of HER2 per cancer tumor cell. In some embodiments, FISH analysis classifies the cancer as HER2-positive by identifying at least 5 copies of HER2 per cancer tumor cell. In some embodiments, FISH analysis classifies the cancer as HER2-positive by identifying at least 6 copies of HER2 per cancer tumor cell. [00117] In some embodiments, a HER2 low expressing cancer is classified as 0 by an immunohistochemistry (IHC) test. In some embodiments, a HER2 low expressing cancer is classified as 1+ by an immunohistochemistry (IHC) test. In some embodiments, the HER2 low expressing cancer is classified as 2+ by an immunohistochemistry (IHC) test. In some embodiments, the HER2 low expressing cancer is classified as HER2 negative by an immunohistochemistry (IHC) test. In some embodiments, the HER2 low expressing cancer is classified as triple negative by an immunohistochemistry (IHC) test. In some embodiments, the HER2 low expressing cancer is classified as HER2 low expressing by FISH analysis. In some embodiments, FISH analysis classifies the cancer as HER2 low expressing by identifying at most 1 copy of HER2 per cancer tumor cell. In some embodiments, FISH analysis classifies the cancer as HER2 low expressing by identifying at most 2 copies of HER2 per cancer tumor cell. In some embodiments, FISH analysis classifies the cancer as HER2 low expressing by identifying at most 3 copies of HER2 per cancer tumor cell. In some embodiments, FISH analysis classifies the cancer as HER2 low expressing by identifying at most 4 copies of HER2 per cancer tumor cell. [00118] Prior to administration of the modified T cells and/or pharmaceutical compositions described herein, the individual, in some embodiments, undergoes additional preparation for treatment. In some embodiments, the individual undergoes an apheresis procedure. In some embodiments, the individual undergoes leukapheresis. In some embodiments, the individual undergoes a lymphodepletion chemotherapy. [00119] In some embodiments, the methods for treating a HER2 cancer (e.g., a HER2 positive cancer or a HER2 low expressing cancer) described herein comprises administering to the individual a T cell expressing a nucleic acid encoding a HER2 TAC. In some embodiments, the HER2 TAC is encoded by a nucleic acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NO: 34, SEQ ID NO: 36, or SEQ ID NO: 38. In some embodiments, the HER2-TAC comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NO: 35, SEQ ID NO: 37, or SEQ ID NO: 39. In some embodiments, the T cell comprises a vector comprising a nucleic acid sequence encoding the HER2. [00120] In some embodiments, the methods for treating a HER2 positive cancer or HER2 low expressing cancer described herein comprises administering to the individual the modified T cells and/or pharmaceutical compositions described herein at a dosage of 10¹ to 10¹⁵ cells per kg body weight, 10⁴ to 10⁹ cells per kg body weight, optionally 10⁵ to 10⁸ cells per kg body weight, 10⁶ to 10⁷ cells per kg body weight or 10⁵ to 10⁶ cells per kg body weight, including all integer values within those ranges. In some embodiments, the modified T cells and/or pharmaceutical compositions described herein are administered at a dosage of greater than 10¹ cells per kg body weight. In some embodiments, the modified T cells and/or pharmaceutical compositions described herein are administered at a dosage of less than 10¹⁵ cells per kg body weight. In some embodiments, the modified T cells and/or pharmaceutical compositions described herein are administered at a dosage of at least or about 0.05 x 10⁶, 0.08 x 10⁶, 0.1 x 10⁶, 0.2 x 10⁶, 0.3 x 10⁶, 0.4 x 10⁶, 0.5 x 10⁶, 0.6 x 10⁶, 0.7 x 10⁶, 0.8 x 10⁶, 0.9 x 10⁶, 1 x 10⁶, 2 x 10⁶, 3 x 10⁶, 4 x 10⁶, 5 x 10⁶, 6 x 10⁶, 7 x 10⁶, 8 x 10⁶, 9 x 10⁶, 10 x 10⁶ cells per kg body weight. In some embodiments, the modified T cells and/or pharmaceutical compositions described herein are administered at a dosage in a range of about 0.05 x 10⁶ to about 10 x 10⁶, 0.05 x 10⁶ to about 9 x 10⁶, 0.05 x 10⁶ to about 8 x 10⁶, 0.05 x 10⁶ to about 7 x 10⁶, 0.05 x 10⁶ to about 6 x 10⁶, 0.05 x 10⁶ to about 5 x 10⁶, 0.05 x 10⁶ to about 4 x 10⁶, 0.05 x 10⁶ to about 3 x 10⁶, 0.05 x 10⁶ to about 2 x 10⁶, 0.05 x 1⁶ to about 10 x 10⁶, 0.1 x 10⁶ to about 10 x 10⁶, 0.1 x 10⁶ to about 9 x 10⁶, 0.1 x 10⁶ to about 8 x 10⁶, 0.1 x 10⁶ to about 7 x 10⁶, 0.1 x 10⁶ to about 6 x 10⁶, 0.1 x 10⁶ to about 5 x 10⁶, 0.1 x 10⁶ to about 4 x 10⁶, 0.1 x 10⁶ to about 3 x 10⁶, 0.1 x 10⁶ to about 2 x 10⁶, 0.1 x 1⁶ to about 1 x 10⁶, or 0.1 x 1⁶ to about 0.5 x 10⁶, 1 x 10⁶ to about 10 x 10⁶, 1 x 10⁶ to about 9 x 10⁶, 1 x 10⁶ to about 8 x 10⁶, 1 x 10⁶ to about 7 x 10⁶, 1 x 10⁶ to about 6 x 10⁶, 1 x 10⁶ to about 5 x 10⁶, 1 x 10⁶ to about 4 x 10⁶, 1 x 10⁶ to about 3 x 10⁶, or 1 x 10⁶ to about 2 x 10⁶ cells per kg body weight. [00121] In some embodiments, the methods for treating a HER2 positive cancer or HER2 low expressing cancer described herein comprises administering to the individual the modified T cells and/or pharmaceutical compositions described herein at a dosage of 0.5 x10⁶ cells, 2 x10⁶ cells, 4 x10⁶ cells, 5 x10⁶ cells, 1.2 x10⁷ cells, 2 x10⁷ cells, 5 x10⁷ cells, 2 x10⁸ cells, 5 x10⁸ cells, 2 x10⁹ cells, 0.5-2000 x10⁶ cells, 0.5-2 x10⁶ cells, 0.5-2 x10⁷ cells, 0.5-2 x10⁸ cells, or 0.5- 2 x10⁹ cells, including all integer values within those ranges. [00122] In some embodiments, T cell compositions are administered multiple times at these dosages. In some embodiments, the dosage is administered a single time or multiple times, for example daily, weekly, biweekly, or monthly, hourly, or is administered upon recurrence, relapse or progression of the cancer being treated. The cells, in some embodiments, are administered by using infusion techniques that are commonly known in immunotherapy (see, e.g., Rosenberg et al., New Eng. J. of Med.319:1676, 1988). [00123] In some embodiments, the pharmaceutical composition is administered to the individual transarterially, subcutaneously, intradermally, intratumorally, intranodally, intrameduliary, intramuscularly, intravenously or intraperitoneally. [00124] In some embodiments, the individual is a mammal. [00125] The methods for treating a HER2 positive cancer or HER2 low expressing cancer described herein, in some embodiments, improve or prevent worsening of cancer progression. In some embodiments, the methods described herein result in disease control. In some embodiments, the methods described herein decrease tumor size. In some embodiments, the methods described herein decrease tumor size by at least about 10% to about 25%, about 10% to about 50%, about 20% to 100%. In some instances, tumor size decreases by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or greater than 95%. In some embodiments, the methods described herein decrease tumor size by 5-95%, 10-90%, 20-80%, 30-70%, 40-60%, 50-95%, 65-85%, or 75-95%. In some embodiments, the methods described herein decrease tumor size by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or greater than 95%. In some embodiments, the methods described herein decrease tumor size is at least about 5%. In some embodiments, the methods described herein decrease tumor size is by at least about 10%. In some embodiments, the methods described herein decrease tumor size is at least about 20%. In some embodiments, the methods described herein decrease tumor size is at least about 30%. In some embodiments, the methods described herein decrease tumor size is at least about 40%. In some embodiments, the methods described herein decrease tumor size is at least about 50%. In some embodiments, the methods described herein decrease tumor size is at least about 60%. In some embodiments, the methods described herein decrease tumor size is at least about 70%. In some embodiments, the methods described herein decrease tumor size is at least about 80%. [00126] The methods for treating a HER2 positive cancer or HER2 low expressing cancer described herein, in some embodiments, reduce or eliminate symptoms associated with cancer. Exemplary symptoms include, but are not limited to, fatigue, weight loss, fever, pain, constipation, diarrhea, unusual bleeding, and other signs and symptoms of cancer, including early death. [00127] In some embodiments, the methods for treating a HER2 positive cancer or HER2 low expressing cancer described herein increase long term survival compared to individuals not treated with the modified T cells and/or pharmaceutical compositions described herein alone or in combination with surgery, chemotherapy, or radiation. In some embodiments, long term survival increases by 5-95%, 10-90%, 20-80%, 30-70%, 40-60%, 50-95%, 65-85%, or 75-95%. Long term survival, in some embodiments, increases by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or greater than 95%. [00128] In some embodiments, the methods for treating a HER2 positive cancer or HER2 low expressing cancer described herein decreases cancer metastases. In some embodiments, the cancer metastases decreases by about 5-95%, 10-90%, 20-80%, 30-70%, 40-60%, 50-95%, 65- 85%, or 75-95%. The decrease in cancer metastases may by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or greater than 95%. In some embodiments, the cancer metastases decreases by at least 5%. In some embodiments, the cancer metastases decreases by at least 10%. In some embodiments, the cancer metastases decreases by at least 30%. In some embodiments, the cancer metastases decreases by at least 50%. [00129] In some embodiments, the methods for treating a HER2 positive cancer or HER2 low expressing cancer described herein result in stable disease (SD) for a certain period of time. In some embodiments, the period of time is at least 1 month. In some embodiments, the period of time is at least 2 months. In some embodiments, the period of time is at least 3 months. In some embodiments, the period of time is at least 4 months. In some embodiments, the period of time is at least 5 months. In some embodiments, the period of time is at least 6 months. In some embodiments, the period of time is at least 7 months. In some embodiments, the period of time is at least 8 months. In some embodiments, the period of time is at least 9 months. In some embodiments, the period of time is at least 10 months. In some embodiments, the period of time is at least 11 months. In some embodiments, the period of time is at least 1 year. In some embodiments, the period of time is at least 11 months. In some embodiments, the period of time is at least 2 years. In some embodiments, the period of time is at least 11 months. In some embodiments, the period of time is at least 5 years. In some embodiments, the period of time is at least 11 months. In some embodiments, the period of time is at least 10 years. [00130] In some embodiments, the methods for treating a HER2 positive cancer or HER2 low expressing cancer described herein result in a disease control rate (DCR) of at least about 10% to about 25%, about 10% to about 50%, about 20% to 100%. In some instances, the methods for treating a HER2 positive cancer or HER2 low expressing cancer described herein result in a DCR of at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or greater than 95%. In some embodiments, the methods for treating a HER2 positive cancer or HER2 low expressing cancer described herein result in a DCR of 20-80%, 30-70%, 40-60%, 50-95%, 65-85%, or 75- 95%. In some embodiments, the methods for treating a HER2 positive cancer or HER2 low expressing cancer described herein result in a DCR at least about 30%. In some embodiments, the methods for treating a HER2 positive cancer or HER2 low expressing cancer described herein result in a DCR of at least about 40%. the methods for treating a HER2 positive cancer or HER2 low expressing cancer described herein result in a DCR of at least about 50%. In some embodiments, the methods for treating a HER2 positive cancer or HER2 low expressing cancer described herein result in a DCR of at least about 60%. In some embodiments, the methods for treating a HER2 positive cancer or HER2 low expressing cancer described herein result in a DCR of at least about 70%. In some embodiments, the methods for treating a HER2 positive cancer or HER2 low expressing cancer described herein result in a DCR of at least about 80%. Table 1. Table of Sequences

EXAMPLES [00131] The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art. Example 1. Clinical Trial of HER2 TAC [00132] Study Rationale: T cell antigen-coupler (TAC) technology is a novel way to genetically modify T cells and to redirect them to target cancer antigens by co-opting the natural T cell receptor. TAC HER2-targeted T cells use HER2 on the cancer cell surface as a docking station and lead to tumor cell killing through T cell activation. Murine models show TAC T cells can persist for extended periods of time and protect the host from tumor regrowth. TAC T cells also accumulate within solid tumors and lead to robust anti-tumor efficacy while yielding a favorable safety profile. It is hypothesized TAC T cell monotherapy will be safe and effective in treating patients with HER2+ solid tumors and provide significant therapeutic benefit in an area of high unmet medical need. [00133] The dose finding portion of this trial will evaluate increasing dose levels of TAC T cells used as a monotherapy to identify recommended doses in patients with solid tumors who are HER2+ (with expression levels of 3+, 2+, and 1+) and have progressed after 2 lines of systemic therapy. [00134] The following dose expansion groups will further evaluate the safety, efficacy, and pharmacokinetics (PK) of TAC T cell monotherapy: breast, lung, pancreatic, colorectal, gastric, endometrial, ovarian, and all others. [00135] In summary, HER2 amplification is known to occur in breast, gastric, salivary, vaginal, endometrial, bladder, colorectal, and cervical cancers, activating numerous oncogenic signaling axes (e.g., PI3K/AKT and Ras/Raf/ERK) resulting in improved malignant cell survival, proliferation, migration, and resistance to immunotherapy. [00136] Primary Study Objectives: [00137] To evaluate the safety and tolerability of TAC T cell monotherapy in patients with HER2+ solid tumors. [00138] To determine recommended doses for TAC T cell monotherapy. [00139] Endpoints for Primary Objectives: Incidence of dose limiting toxicities (DLTs) over the first 28 days. Frequency, severity, and duration of treatment-emergent adverse events (TEAEs) and laboratory abnormalities. [00140] Secondary Study Objectives: [00141] To characterize PK profiles of TAC T cell monotherapy. Endpoints: Cmax, Tmax, and AUC, and duration of persistence. [00142] To evaluate the efficacy of TAC T cell monotherapy. Endpoints: Investigator Assessment of the Following Response Evaluation Criteria in Solid Tumors (RECIST) – Overall Response Rate (ORR), Duration of Response (DOR), Disease Control Rate (DCR), Overall Survival (OS), and Progression-Free Survival (PFS) [00143] To evaluate the immunogenicity of TAC T cell monotherapy, and to assess potential impacts on PK exposure and biological activity. Endpoint: Immunogenicity of TAC T cells. [00144] Study Design: [00145] This is a first-in-human, open-label multicenter trial. The safety and tolerability of increasing dose levels of TAC T cell monotherapy will be investigated first (Dose Levels -1, 1, 2, 3, 4; beginning with Dose Level 1).

[00146] HER2+ tumor types allowed will include, but are not limited to, salivary gland, breast, stomach, ovary, uterus, cervix, lung, biliary tract, pancreas, colorectum, bladder, and prostate. HER2 expression levels of 1+, 2+, and 3+ will be allowed. [00147] The following dose expansion groups will further evaluate the safety, efficacy, and pharmacokinetics (PK) of TAC T cell monotherapy at or near the RP2Ds: breast, lung, pancreatic, colorectal, gastric, endometrial, ovarian, and all others. [00148] Duration: [00149] Patients in the monotherapy dose cohort will continue participation in the trial for up to 2 years, or until progressive disease (PD), or unacceptable toxicity is reported, whichever occurs first. [00150] Methodology: [00151] Upon enrollment, patients will undergo leukapheresis to obtain T cells for the manufacture of TAC T Cells. Patients may receive bridging anticancer therapy, after leukapheresis and before lymphodepleting chemotherapy, if deemed necessary by the Investigator. Bridging therapies must be discontinued at least 14 days prior to initiation of lymphodepletion, patients must continue to meet eligibility criteria pertaining to adequate organ function (except hematologic parameters), active infections, pregnancy, measurable disease confirmed by imaging and medication washout before initiation of lymphodepletion. If TAC T cells cannot be manufactured from the first leukapheresis product, additional leukapheresis may be allowed after consultation with the Sponsor. [00152] Upon the successful manufacture of TAC T cells, patients will enter the treatment phase. It includes lymphodepleting chemotherapy, followed by a single dose of TAC T cells administered intravenously (IV) approximately 48 hours (± 24 hours) after completion of lymphodepleting chemotherapy, unless clinical or logistical circumstances require modification of this timing. Any dose adjustments to the lymphodepleting chemotherapy must be discussed in advance with the Medical Monitor. A post-treatment tumor biopsy (in patients with accessible disease) will be obtained approximately 8 days following the TAC T cell dose. [00153] Follow-up Periods: [00154] Patients treated with TAC T cell monotherapy will continue to be followed for up to 2 years, or until PD, or unacceptable toxicity is reported, whichever occurs first. After trial completion, patients may be enrolled in a separate long-term follow-up (LTFU) protocol recording survival, long-term toxicity, and viral vector safety for up to 15 years. [00155] Assessments: [00156] Safety, PK, PD, and biomarker values will be closely assessed over the first month; after which, assessments will occur during visits every 3 months for up to 2 years, or until PD, or unacceptable toxicity is reported, whichever occurs first. Radiographic disease assessments will be performed pre-treatment and approximately at 1, 3, 6, 9, 12, 18 and 24 months following the TAC T cells dose. [00157] General Inclusion Criteria [00158] Patients must meet all the following criteria to participate in this study: [00159] Signed, written informed consent obtained prior to any study procedures. Participation in pharmacogenomics (PGx) testing is optional . [00160] Age ^ 18 years at the time of informed consent. [00161] Either a fresh tumor sample or the most recent archival tumor sample available with corresponding pathology report for histological disease diagnosis to confirm HER2-protein expression on tumor cell surface by central analysis. The most recent archival tissue available is an acceptable alternative regardless of when it was obtained during prior treatment or lines of therapy. Tumor samples will be screened centrally for HER2 status by both fluorescent in-situ hybridization (FISH) and immunohistochemistry (IHC) assays. If a subject’s fresh or archival tumor sample can be obtained for central confirmation and is HER2+ on local laboratory results by one of the following 3 methods: IHC, FISH, or NGS, Screening and enrollment may proceed, and the central confirmation can be completed retrospectively after the subject has enrolled in the trial. [00162] Histologically or cytologically confirmed diagnosis of a solid tumor that is currently metastatic or locally advanced for which the patient has received at least 2 prior lines of therapy. For breast cancer patients, both prior lines of therapy must have included HER2 targeted agents. Patients with solid tumors with genetic alterations and mutations (such as BRAF, BRCA, EGFR mutations, and ALK translocation) where approved targeted therapies were available to their specific cancers must have been treated with such approved therapies prior to being enrolled in this trial, or refused such approved targeted therapy for their cancers prior to enrollment. [00163] Measurable disease on imaging per RECIST Criteria Version 1.1 at time of enrollment [00164] Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening. [00165] Life expectancy of at least 12 weeks. [00166] Adequate organ and bone marrow reserve function, as defined in the table below, prior to leukapheresis. [00167] Recovery to ^ Grade 1 or baseline of any toxicities due to previous therapy, except alopecia, anemia, thrombocytopenia, and neutropenia. [00168] If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. [00169] Toxicity that has not recovered to ^ Grade 1 is allowed if it meets the inclusion requirements for laboratory parameters. [00170] Adequate vascular access for leukapheresis as per institutional guidelines. [00171] For women physiologically capable of becoming pregnant, agreement to use highly effective methods of contraception starting 28 days prior to study treatment and for 1 year after the last TAC01-HER2 dose. For men who have partners physiologically capable of becoming pregnant, agreement to use an effective barrier contraceptive method during study treatment and for 1 year after the last TAC01-HER2 dose Example 2. Clinical Trial of HER2-TAC in Relapsed or Refractory Solid Tumors [00172] This clinical trial was an open^label, multicenter phase I/II study aimed to establish safety, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetic profile, and efficacy of TAC01-HER2 in patients with HER2^positive and HER2 low expressing solid tumors including breast, lung, pancreatic, colorectal, gastric, endometrial, ovarian, and others who have progressed on prior anti^cancer therapies including HER2 targeted anti-cancer therapies. [00173] The study completed enrollment and treatment of three cohorts of 11 patients in Cohorts 1-3, and an additional 7 patients in Cohort 4, for a total of 18 patients treated. Patients underwent leukapheresis, bridging therapy, if needed, while their TAC T cells were engineered, lymphodepletion chemotherapy (LDC), and then TAC01-HER2 infusion. Patients in Cohort 1 received single TAC01-HER2 infusions of 0.3 x 10⁶ cells/kg; patients in Cohort 2 received single TAC01-HER2 infusions of 0.8 x 10⁶ (Cohort 2) cells/kg, patients in Cohort 3 received single TAC01-HER2 infusions of 3 x 10⁶ cells/kg; and 7 patients in Cohort 4 received single TAC01-HER2 infusions of 6-8 x 10⁶ cells/kg and one patient in Cohort 4 received 2 doses of the same dose level. Single TAC01-HER2 infusions of 0.3 x 10⁶ (Cohort 1), 0.8 x 10⁶ (Cohort 2), and 3 x 10⁶ (Cohort 3) cells/kg in adult patients were determined to be safe with no dose limiting toxicities (DLT). Only one DLT of Grade 3 pneumonitis was reported in one Cohort 4 patient (6-8 x 10⁶ cells/kg) that resolved after hospitalization. Patients enrolled included those with advanced, metastatic, unresectable solid tumors which express HER2 after at least 2 lines of therapy, at least 1 measurable lesion per RECIST version 1.1, ECOG performance score 0^1, and grade 1 or baseline for any prior treatment related toxicities. DLTs were assessed up to 28 days after TAC01-HER2 infusion. Demographic and tumor-intrinsic characteristics of the patients are seen in Table 2 below. Table 2. Demographic and Tumor-Intrinsic Characteristics

[00174] Safety data was measured as seen in Fig.1. As seen in the data, only Grade 1 or 2 cytokine release syndrome (CRS) events were observed. No immune effector cell-associated neurotoxicity (ICANS) was observed. Except for the Grade 3 pneumonitis, one Grade 1 and two Grade 2 CRS events, the rest of the reported serious adverse events (SAEs) were confirmed to be unrelated to the TAC01-HER2 infusions. [00175] Blood pharmacokinetics and cytokine expression were measured in a first patient (“Patient 1”) of Cohort 2. Patient 1 is a 42 year old male with IHC 3+, HER2+ stage IVb metastatic gastric adenocarcinoma who was previously treated with 2 lines of HER2^directed targeted chemotherapy and palliative radiation. Blood pharmacokinetic and cytokine expression data is seen in Figs.2A-2B. Fig.2A shows the number of TAC copies over time, demonstrating low but definitive presence of TAC01-HER2 cells. Fig.2B shows graphs of IFN-gamma, IL-12 (p70), and IL-6 levels. Patient 1 had slightly elevated levels of the various cytokines and absence of IL-6 confirms lack of CRS. [00176] Response to TAC01-HER2 treatment was further determined for Cohort 2-4 patients, 1 or 2 months after receiving the engineered cell infusion. Patient 2 (2+ IHC equivocal, HER2+ gastroesophageal cancer where HER2 targeted therapies are not indicated until HER2 status is confirmed), treated in Cohort 4, had a baseline distal esophageal tumor mass 30 mm in size, which completely regressed at the time of tumor assessment (Fig.3A). Due to the presence of new sub-cm non-target lymphatic lesions and residual pelvic ascites, the patient was assessed as having a partial response according to RECIST 1.1 Tumor Response Assessments. Patient 1 (IHC 3+, HER2+ gastric cancer), treated in Cohort 2, had a baseline tumor size of 20 mm, which shrunk to 12.7 mm, corresponding to a 36.5% reduction in tumor size and assessed as a partial response (Fig.3B). The response data for Patient 1, Patient 2, and the other patients in Cohorts 2-4 are seen in Fig.4 and Table 3. Patient 3 had IHC 3+, HER2 colorectal cancer. Patient 4 had IHC 3+, Her2+ gall bladder cancer. Patient 5 had 2+ IHC, equivocal HER2 colorectal cancer where HER2 targeted therapies are not indicated until HER2 status is confirmed. Patients 4 and 5 exhibited 0.0% change in tumor volume from baseline, indicating stable disease which constitutes significant clinical benefit as HER2 targeted therapies in equivocal HER2 status are not indicated and the response rates in this treatment refractory settings are below 5% in these patients in later lines of anti-neoplastic therapy. See STIVARGA USPI, LONSURF USPI, 2016 HER2 GEA HER2 CAP/ASCO Guidelines. In summary Table 3 demonstrates clinical benefit in 5 patients (Patient 2, Patient 5, Patient 7, Patient 12, and Patient 14) out of 14 with low HER 2 expression, +1 and +2 HER2 expressing tumors that are considered negative or equivocal and by clinical standards they are not considered candidates for HER2 targeted therapies. See ASCO/CAP Guidelines 2016, 2018. Table 3. Patient Best Response to TAC01-HER2 Treatment

SOD: Sum of Dimensions; GEJ: GastroEsophageal Junction; PR: Partial Response; PD: Progressive Disease; SD: Stable Disease [00177] Tumor regression was also measured in Patient 1. As seen in the right panel of Fig.3B and Table 4, there was an overall interval decreased size of previously noted metabolically active lymph nodes associated with the mass observed. However, persistent intense metabolic activity in most of them was noted. Despite SUVmax increase the lesions showed more extensive photopenic areas, representing cystic/necrotic change (cancer cell death). There was also a stable cystic/necrotic node (cancer cell death) observed. Table 4. Patient 1 PET Scan Results (Evaluable Disease)

*Despite SUVmax increase the lesion shows more extensive photopenic areas, representing cystic/necrotic change (cancer cell death). [00178] The data so far show that TAC01-HER2 was safe and well tolerated, supported by the absence of immune effector cell-associated neurotoxicity, CRS events that resolved after standard therapy, and only a single DLT at the highest dose, which resolved after hospitalization and administration of standard of care therapies. The TAC01-HER2 exhibited clinical efficacy and a disease control rate (DCR) of 64% in Cohorts 2-4. Clinical efficacy was highest in subjects with 3+ HER2+ tumors, with a DCR of 83%. Even in subjects with 2+ and 1+ HER2+ tumors, the DCR was 50% in each group, an impressive result in a heavily pre-treated population with metastatic disease and no alternative therapies. [00179] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS WHAT IS CLAIMED IS: 1. A method of treating an individual having a HER2 low expressing cancer, comprising administering to the individual a T cell expressing a nucleic acid encoding a HER2 T cell Antigen Coupler (TAC) having an amino acid sequence at least 80% identical to the amino acid sequence: SEQ ID NO: 35, SEQ ID NO: 37, or SEQ ID NO: 39.

2. The method of claim 1, wherein the HER2 low expressing cancer is classified as 0 by an immunohistochemistry (IHC) test.

3. The method of claim 1, wherein the HER2 low expressing cancer is classified as 1+ by an immunohistochemistry (IHC) test.

4. The method of claim 1, wherein the HER2 low expressing cancer is classified as 2+ by an immunohistochemistry (IHC) test.

5. The method of claim 1, wherein the HER2 low expressing cancer is classified as a HER2 negative cancer.

6. The method of claim 1, wherein the HER2 low expressing cancer is classified as a triple negative cancer.

7. The method of claim 1, wherein the HER2 low expressing cancer is classified as low- expressing by fluorescence in situ hybridization (FISH).

8. The method of claim 1, wherein the HER2 low expressing cancer is classified as having at most one copy of HER2 per cancer tumor cell.

9. The method of claim 1, wherein the HER2 low expressing cancer is classified as having at most two copies of HER2 per cancer tumor cell.

10. The method of claim 1, wherein the HER2 low expressing cancer is classified as having at most three copies of HER2 per cancer tumor cell.

11. The method of claim 1, wherein the HER2 low expressing cancer is classified as having at most four copies of HER2 per cancer tumor cell.

12. The method of claim 1, wherein the HER2 low expressing cancer has progressed after at least two lines of prior systemic therapy.

13. The method of claim 1, wherein the HER2 TAC has an amino acid sequence at least 90% identical to the amino acid sequence: SEQ ID NO: 35, SEQ ID NO: 37, or SEQ ID NO: 39.

14. The method of claim 1, wherein the HER2 TAC has an amino acid sequence 100% identical to the amino acid sequence: SEQ ID NO: 35, SEQ ID NO: 37, or SEQ ID NO: 39.

15. The method of claim 1, wherein the HER2 TAC is encoded by a nucleic acid sequence having at least 80% sequence identity with the nucleic acid sequence: SEQ ID NO: 34, SEQ ID NO: 36, or SEQ ID NO: 38.

16. The method of claim 1, wherein the HER2 TAC is encoded by a nucleic acid sequence having at least 90% sequence identity with the nucleic acid sequence: SEQ ID NO: 34, SEQ ID NO: 36, or SEQ ID NO: 38.

17. The method of claim 1, wherein the HER2 TAC is encoded by a nucleic acid sequence having 100% sequence identity with the nucleic acid sequence: SEQ ID NO: 34, SEQ ID NO: 36, or SEQ ID NO: 38.

18. The method of claim 1, wherein the nucleic acid sequence encoding the HER2 TAC is on a vector having a promoter that is expressed in mammalian cells.

19. The method of claim 1, wherein the T cell comprises a vector comprising the nucleic acid sequence encoding the HER2 TAC.

20. The method of claim 1, wherein the HER2 low expressing cancer is a metastatic cancer.

21. The method of claim 1, wherein the HER2 low expressing cancer is breast cancer, bladder cancer, pancreatic cancer, ovarian cancer, gastric cancer, salivary gland cancer, uterine cancer, cervical cancer, lung cancer, biliary tract cancer, colorectal cancer, prostate cancer, gastroesophageal junction cancer, or sarcoma.

22. The method of claim 1, wherein the HER2 low expressing cancer is breast, lung, pancreatic, colorectal, gastric, endometrial, or ovarian cancer.

23. The method of claim 1, wherein the HER2 low expressing cancer is rectosigmoid cancer, gastro-esophageal cancer, or gastric adenocarcinoma.