WO2017184534A1

WO2017184534A1 - Methods and compositions for improving safety and efficacy of natural killer cell immunotherapy

Info

Publication number: WO2017184534A1
Application number: PCT/US2017/028016
Authority: WO
Inventors: Michael Callahan
Original assignee: The Gorlin Companies
Priority date: 2016-04-18
Filing date: 2017-04-17
Publication date: 2017-10-26

Abstract

Described herein are compositions for improving cancer treatment by combining, in vitro, NK-92 cells expressing a high affinity antibody binding moiety on the cell surface with an antibody that recognizes a tumor epitope such that the moiety is bound to the antibody before administration to a patient. Optionally, such modified NK-92 cells are also bound to an anti-fugetatic agent. Also provided are methods for making and using the same. Further provided are methods for treating cancer by co-administering the modified NK-92 cells with an antibody-albumin-chemotherapy complex.

Description

METHODS AND COMPOSITIONS FOR IMPROVING SAFETY AND EFFICACY OF NATURAL KILLER CELL IMMUNOTHERAPY

BACKGROUND

[0001] Natural killer (NK) cells are cytotoxic lymphocytes that are involved in the innate immune system. NK cells can target multiple aberrant cell types and stressed cells, including cancer cells, virus-infected cells, microorganisms, and microorganism-infected cells. NK cells are cytotoxic and can induce apoptosis or osmotic cell lysis in target cells.

[0002] There is considerable interest in the use of NK cells for immunotherapy, particularly for the treatment of cancer. NK cells may be isolated from the patient (autologous) or from a different source (allogenic). The cells may be expanded and optionally modified before administration to the patient, e.g. by insertion of a gene that confers an advantage on the NK cells, such as a gene expressing a cytokine, Fc receptor, and/or chimeric antigen receptor.

[0003] In addition, NK cell lines have been developed that have shown potential in immunotherapy for numerous diseases, including the NK-92 cell line. NK-92 cells were derived from a patient having NK cell lymphoma. The NK-92 cell line is an immortalized cell line that is capable of genetic modification as well as expansion in vitro. Further information on NK-92 cells, modifications thereof, and uses thereof can be found, for example, in U.S. Patent Nos. 8,313,943; 8,034,332; and U.S. Patent Pub. Nos. 2006/0110360; 2016/0075784; each of which is incorporated herein by reference in its entirety.

[0004] There remains a need for safe and efficacious immunotherapy compositions for treatment of diseases, including cancer.

SUMMARY OF THE INVENTION

[0005] This invention relates to compositions and methods of making or using of NK-92 cells expressing a high affinity Fc receptor (e.g., high-affinity CD16) or other antibody binding moiety (referred to herein as haNK-92) and bound to an antibody having a high affinity for the Fc receptor (or other moiety), where the antibody is bound to the antibody binding moiety in vitro (i.e., prior to administration to a patient) to produce modified haNK- 92 cells. The cells are optionally pretreated with AMD3100 or other anti-fugetactic agent prior to or after forming the antibody- K-92 complex, such that the anti-fugetactic agent is bound to the cells, e.g. via CXCR4 receptors on the surface of the haNK-92 cells. Without being bound by theory, it is contemplated that binding of the antibody to the haNK-92 cells prior to administration to a patient reduces the risk of undesired endogenous antibody binding to the haNK-92 cell, for example by autoimmune antibodies produced by the patient.

Preferably, the haNK-92 cells are irradiated (before or after modification).

[0006] haNK-92 cells have a finite half-life in vivo due to required irradiation prior to administration to a patient. This limits their potential for sustained efficacy even when used contemporaneously or sequentially with an additional agent, such as the modified haNK-92 described herein, with or without the anti-fugetactic agent. The half-life is measured as the time period during which modified haNK-92 cells exhibit antibody-dependent cell-mediated cytotoxicity (ADCC) activity. As the irradiated modified haNK-92 cells succumb to the irradiation, they lose their ability to coordinate ADCC prior to dying. Therefore, haNK-92 cell half-life is really two different times - a first half-life during which the cells exhibit ADCC properties (half-life with ADCC) and a second half-life measured from the time of injection to cell death including the period extending from loss of ADCC properties to cell death (half-life with ADCC and without ADCC). It is contemplated that during the haNK-92 half-life with ADCC, the extent of ADCC exhibited by these cells is declining as they approach the stage where these cells no longer exhibit ADCC. This means that the efficacy of these cells is front-loaded, with tailing properties during their short lifespan.

[0007] This invention is further directed to a contemplated synergy between using an albumin complex of an antibody (such as rituximab) and optionally a chemotherapeutic agent associated with the albumin, and the same antibody bound to the modified haNK-92 cells. These cells are optionally pretreated with AMD3100 or other anti-fugetactic agent prior to or after forming the antibody-haNK complex. Preferably, the haNK-92 cells are irradiated (before or after modification).

[0008] In one embodiment is provided an aqueous composition suitable for in vivo injection into a subject, said composition comprising an effective amount of NK-92 cells, wherein said cells comprise a monoclonal antibody bound thereto through an antibody binding motif on the surface of said cells, and further wherein said cells have been exposed to a sufficient amount of irradiation so as to have a finite lifespan, thereby rendering said composition suitable for in vivo injection. Preferably, the antibody has a high affinity for the antibody binding motif.

[0009] In one embodiment, an anti-fugetactic agent is bound to a receptor on the cells. In one embodiment, the anti-fugetactic agent is AMD3100, KRH-1636, T-20, T-22, T-140, TE- 14011, T-14012, TN14003, TAK-779, AK602, SCH-351125, Tannic acid, NSC 651016, thalidomide, GF 10923 OX, an antibody that interferes with dimerization of a fugetactic chemokine, or an antibody that interferes with dimerization of a receptor for a fugetactic chemokine. In one embodiment, the receptor is a CXCR4 receptor or a CXCR7 receptor.

[0010] In one embodiment, the antibody binding motif is CD 16 or CD 19. In one

embodiment, the CD 16 is a high-affinity CD 16.

[0011] In one embodiment, the antibody has an affinity for the antibody binding motif of at least 10⁵ M^"1. In one embodiment, the antibody has an affinity for the antibody binding motif of at least 10⁶ M^"1. In one embodiment, the antibody has an affinity for the antibody binding motif of at least 10⁷ M^"1. In one embodiment, the antibody has an affinity for the antibody binding motif of at least 10⁸ M^"1. In one embodiment, the antibody has an affinity for the antibody binding motif of at least 10⁹ M^"1. In one embodiment, the antibody has an affinity for the antibody binding motif of at least 10¹⁰ M^"1.

[0012] In one embodiment, the antibody is not a therapeutic antibody. That is, in some embodiments, the antibody bound to the haNK-92 cells has no effect on a target cell on its own, but rather serves to direct the modified haNK-92 cells to the target cell. Without being bound by theory, it is contemplated that antibodies with proven safety and antigen binding, but little to no therapeutic effect, may be used in the compositions and methods described herein.

[0013] In one embodiment, the composition further comprises antibody that is not bound to the antibody binding motif. That is, the composition includes excess antibody beyond what is required to fully occupy the antibody binding motifs on the surfaces of the K-92 cells within the composition. Without wishing to be bound by any theory, it is contemplated that the haNK-92 cells may proliferate between the time of binding the antibody to the cells and administration to the patient, e.g., during transport. The presence of excess antibody allows antibody-binding moieties on the progeny haNK-92 cells to bind the antibody and reduces the occurrence of unbound moiety. In addition, the presence of unbound antibody in the composition may allow for steady-state binding of the antibody to the cells.

[0014] In one aspect is provided a method for treating cancer in a patient in need thereof, said method comprising administering to said patient an effective amount of an NK-92 cell composition, said composition comprising NK-92 cells comprising a monoclonal antibody bound thereto through an antibody binding motif on the surface of said cells, and further wherein said cells have been exposed to a sufficient amount of irradiation so as to have a finite lifespan, thereby rendering said composition suitable for in vivo injection. Preferably, the antibody has a high affinity for the antibody binding motif.

[0015] In one aspect is provide a method for treating cancer in a patient which method comprises administering to said patient a combination of immunotherapy and chemotherapy, wherein said immunotherapy comprises administering to said patient an effective amount of an NK-92 cell composition, said composition comprising NK-92 cells comprising a monoclonal antibody bound thereto through an antibody binding motif on the surface of said cells, and further wherein said cells have been exposed to a sufficient amount of irradiation so as to have a finite lifespan, thereby rendering said composition suitable for in vivo injection; and said chemotherapy comprises administering to said patient a protein carrier having a plurality of said monoclonal antibodies complexed thereto, said protein carrier further comprising a chemotherapeutic agent associated therewith. Preferably, the antibody has a high affinity for the antibody binding motif. In one embodiment, the combination is administered concurrently. In one embodiment, the combination is administered sequentially. In a preferred embodiment, the chemotherapeutic agent is paclitaxel. In another preferred embodiment, the protein carrier is albumin. [0016] In one embodiment, the method further comprises administering an anti -fugetactic agent to the patient. In one embodiment, the anti-fugetactic agent is administered prior to, concurrently with, and/or after administration of the modified NK-92 cells. In one embodiment, the anti-fugetactic agent is bound to a receptor on the cells prior to

administration to the patient. In one embodiment, the anti-fugetactic agent is AMD3100, KRH-1636, T-20, T-22, T-140, TE-14011, T-14012, TN14003, TAK-779, AK602, SCH- 351125, Tannic acid, NSC 651016, thalidomide, GF 109230X, an antibody that interferes with dimerization of a fugetactic chemokine, or an antibody that interferes with dimerization of a receptor for a fugetactic chemokine.

[0017] In one embodiment, the method further comprises administering a particle comprising a carrier protein core having the monoclonal antibody associated with the protein core, and optionally comprising a chemotherapeutic agent associated with the core. In one

embodiment, the carrier protein is albumin. In one embodiment, the albumin is human serum albumin (HSA). In one embodiment, the chemotherapeutic agent is paclitaxel.

[0018] In one embodiment, at least a subset of the antibody is bound to the antibody binding motif. In one embodiment, the antibody binding motif is a cell surface receptor. In one embodiment, the cell surface receptor is CD 16 or CD 19. In one embodiment, the CD 16 is a high-affinity CD 16.

[0019] In one embodiment, the antibody has an affinity for the antibody binding motif of at least 10⁶ M^"1.

[0020] In one embodiment, the antibody recognizes a tumor-associated epitope.

[0021] In one aspect is provided a method of making an NK-92 composition that is suitable for in vivo injection into a patient, the method comprising:

providing a population of NK-92 cells having an antibody binding motif on the surface of said cells;

contacting the NK-92 cell population with a monoclonal antibody having a high avidity for the antibody binding motif under conditions to bind the antibody to the antibody binding motif; optionally contacting the K-92 cell population with an anti-fugetactic agent under conditions to bind the anti-fugetactic agent to the NK-92 cells; and

exposing the NK-92 cell population to a sufficient amount of irradiation so as to have a finite lifespan, thereby rendering said composition suitable for in vivo injection.

[0022] In one embodiment, a first subset of the antibody is bound to the antibody binding motif and a second subset of the antibody is not bound to the antibody binding motif.

DETAILED DESCRIPTION

[0023] After reading this description it will become apparent to one skilled in the art how to implement the invention in various alternative embodiments and alternative applications. However, all the various embodiments of the present invention will not be described herein. It will be understood that the embodiments presented here are presented by way of an example only, and not limitation. As such, this detailed description of various alternative embodiments should not be construed to limit the scope or breadth of the present invention as set forth below.

[0024] Before the present invention is disclosed and described, it is to be understood that the aspects described below are not limited to specific compositions, methods of preparing such compositions, or uses thereof as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0025] The detailed description of the invention is divided into various sections only for the reader's convenience and disclosure found in any section may be combined with that in another section. Titles or subtitles may be used in the specification for the convenience of a reader, which are not intended to influence the scope of the present invention.

Definitions

[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings:

[0027] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0028] "Optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0029] The term "about" when used before a numerical designation, e.g., temperature, time, amount, concentration, and such other, including a range, indicates approximations which may vary by ( + ) or ( - ) 10%, 5%, 1%, or any subrange or subvalue there between.

Preferably, the term "about" when used with regard to a dose amount means that the dose may vary by +/- 10%.

[0030] "Comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements, but not excluding others. "Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention.

"Consisting of shall mean excluding substantial method steps and more than trace elements of other ingredients. Embodiments defined by each of these transition terms are within the scope of this invention.

[0031] "Pharmaceutically acceptable" excipients (vehicles, additives) are those which can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient employed.

[0032] The term "antibody" or "antibodies" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules (i.e., molecules that contain an antigen binding site that immuno-specifically bind an antigen). The term also refers to antibodies comprised of two immunoglobulin heavy chains and two immunoglobulin light chains as well as a variety of forms including full length antibodies and portions thereof; including, for example, an immunoglobulin molecule, a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, a Fab, a Fab', a F(ab')2, a Fv, a disulfide linked Fv, a scFv, a single domain antibody (dAb), a diabody, a multispecific antibody, a dual specific antibody, an anti -idiotypic antibody, a bispecific antibody, a functionally active epitope-binding fragment thereof, bifunctional hybrid antibodies (e.g., Lanzavecchia et al., Eur. J. Immunol. 17, 105 (1987)) and single chains (e.g., Huston et al., Proc. Natl. Acad. Sci. U.S.A., 85, 5879-5883 (1988) and Bird et al., Science 242, 423-426 (1988), which are incorporated herein by reference). (See, generally, Hood et al., Immunology, Benjamin, N.Y., 2ND ed. (1984); Harlow and Lane, Antibodies. A

Laboratory Manual, Cold Spring Harbor Laboratory (1988); Hunkapiller and Hood, Nature, 323, 15-16 (1986), which are incorporated herein by reference). The antibody may be of any type (e.g., IgG, IgA, IgM, IgE or IgD). Preferably, the antibody is IgG. More preferably, the antibody contains a Fc domain. An antibody may be non-human (e.g., from mouse, goat, or any other animal), fully human, humanized, or chimeric.

[0033] The term "antigen" is well understood in the art and includes substances which are immunogenic. As used herein, the term "antigen" may also refer to a substance to which a binding agent other than an antibody (e.g., an aptamer) can bind.

[0034] The term "biosimilar" as used herein refers to a biopharmaceutical which is deemed to be comparable in quality, safety, and efficacy to a reference product marketed by an innovator company.

[0035] The term "carrier protein" as used herein refers to proteins that function to transport therapeutic agents, antibodies, or both. Examples of carrier proteins are discussed in more detail below. Where albumin is recited herein as the carrier protein, it is contemplated that a different carrier protein can be substituted.

[0036] The term "dose" and "dosage" refer to an amount of therapeutic agent (e.g., cells, binding agent, or chemotherapeutic agent) given to a patient in need thereof. The attending clinician will select an appropriate dose from the range based on the patient's weight, age, health, stage of cancer, level of circulating antigen, and other relevant factors, all of which are well within the skill of the art. The term "unit dose" refers to a dose of the agent that is given to the patient to provide a desired result. In some instances, the unit dose is sold in a sub-therapeutic formulation (e.g., 10% of the therapeutic dose). The unit dose may be administered as a single dose or a series of subdoses.

[0037] An "effective amount" intends to indicate the amount of a compound or agent (e.g., modified haNK-92 cells) administered or delivered to the patient which is most likely to result in the desired treatment outcome. The amount is empirically determined by the patient's clinical parameters including, but not limited to the stage of disease, age, gender, histology, and likelihood for recurrence. In addition, the level of circulating antigen can be used to empirically determine the effective amount of the chemotherapeutic and/or binding agent to administer to a patient.

[0038] The term "nanoparticle" as used herein refers to particles with at least one dimension less than 5 microns. In some embodiments, the nanoparticle is less than 1 micron. For direct administration, the nanoparticle may be larger. Even larger particles are expressly

contemplated by the invention. The terms "conjugate" and "complex" as used herein are synonymous with "nanoparticle." The term "nanoparticle" may also encompass discrete multimers of smaller unit nanoparticles.

[0039] In a population of particles, the size of individual particles is distributed about a mean. Particle sizes for the population can therefore be represented by an average, and also by percentiles. D50 is the particle size below which 50% of the particles fall. 10% of particles are smaller than the D 10 value and 90% of particles are smaller than D90. Where unclear, the "average" size is equivalent to D50.

[0040] As used herein, the term "therapeutic effect" refers to achievement of the desired and/or beneficial consequences of a medical treatment. A non-limiting example of a therapeutic effect of the present disclosure is the shrinkage and/or eradication of a tumor and/or killing of cancer cells in a patient. [0041] The term "treating" or "treatment" covers the treatment of a disease or disorder (e.g., cancer), in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, i.e., arresting its development; (ii) relieving a disease or disorder, i.e., causing regression of the disease or disorder; (iii) slowing progression of the disease or disorder; and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder. In some embodiments "treating" or "treatment" refers to the killing of cancer cells. In some embodiments "treating" or "treatment" refers to increasing progression-free survival of the patient(s). In some embodiments "treating" or "treatment" refers to increasing survival rates.

[0042] "Cytokine" is a generic term for non-antibody, soluble proteins which are released from one cell subpopulation and which act as intercellular mediators, for example, in the generation or regulation of an immune response. See Human Cytokines: Handbook for Basic & Clinical Research (Agrawal, et al. eds., Blackwell Scientific, Boston, Mass. 1991) (which is hereby incorporated by reference in its entirety for all purposes).

[0043] "CXCR4/CXCL12 antagonist" refers to a compound that antagonizes CXCL12 binding to CXCR4 or otherwise reduces the fugetactic effect of CXCL12.

[0044] "Fugetactic activity" or "fugetactic effect" refers to the ability of an agent to repel (or chemorepel) a eukaryotic cell with migratory capacity {i.e., a cell that can move away from a repellant stimulus). Accordingly, an agent with fugetactic activity is a "fugetactic agent." Such activity can be detected using any of a variety of systems well known in the art {see, e.g., U.S. Pat. No. 5,514,555 and U.S. Patent Application Pub. No. 2008/0300165, each of which is incorporated by reference herein in its entirety). A preferred system for use herein is described in US Patent 6,448,054, which is incorporated herein by reference in its entirety. Usually, the fugetactic effect is present in an area around the cell wherein the concentration of the chemokine is sufficient to provide the fugetactic effect. The term "fugetactic wall" also may be used to describe such an effect. Some chemokines, including interleukin 8 and CXCL12, may exert fugetactic activity at high concentrations {e.g., over about 100 nM), whereas lower concentrations exhibit no fugetactic effect and may even be chemoattractant. [0045] The term "anti-fugetactic effect" refers to the effect of the anti-fugetactic agent to attenuate or eliminate the fugetactic effect of the chemokine. Accordingly, an agent with anti-fugetactic effect is a "anti-fugetactic agent."

Compositions and Methods

Modified high affinity K-92 Cells

[0046] NK-92 cells can be modified by any method to produce haNK-92 cells, i.e., NK-92 cells expressing a high-affinity antibody binding motif on the surface of the cells. See, e.g., U.S. Patent Nos. 8,313,943; 8,034,332; and U.S. Patent Pub. Nos. 2006/0110360;

2016/0075784; each of which is incorporated herein by reference in its entirety.

[0047] In preferred embodiments, the haNK-92 cells express CD 16, and particularly high affinity CD 16. In some embodiments, the haNK-92 cells express CD 19.

[0048] The haNK-92 cells are modified by contacting the cells with the antibody under conditions to allow binding of the antibody to the antibody binding motif.

[0049] The haNK-92 cells are optionally contacted with an anti-fugetactic agent under conditions to allow binding of the anti-fugetactic agent to a receptor (e.g., CXCR4 or CXCR7) on the surface of the haNK-92 cell. This step may be performed before or after contacting the cells with the antibody.

[0050] In some embodiments, the anti-fugetactic agent is administered to the patient in conjunction with the modified haNK-92 cells. In some embodiments, the anti-fugetactic agent is administered prior to administration of the modified haNK-92 cells. In some embodiments, the anti-fugetactic agent is administered at the same time (but not necessarily via the same route of administration) as the modified haNK-92 cells.

[0051] Preferably, before administration to the patient, the haNK-92 cells are irradiated. Such irradiation may occur prior to or after contacting the cells with the antibody. Such irradiation may occur prior to or after contacting the cells with the anti-fugetactic agent.

[0052] Table 1 depicts a list of non-limiting list of antibodies for cancer targets. Table 1 : Antibodies for cancer targets

[0053] In some embodiments, the antibody is selected from the group consisting of ado- trastuzumab emtansine, alemtuzumab, bevacizumab, blinatumomab, brentuximab vedotin, cetuximab, denosumab, dinutuximab, ibritumomab tiuxetan, ipilimumab, nivolumab, obinutuzumab, ofatumumab, panitumumab, pembrolizumab, pertuzumab, rituximab, trastuzumab, or any biosimilar thereof.

[0054] In some embodiments, the antibody is a non-therapeutic and non-endogenous human antibody. In some embodiments, the antibody is a chimeric antibody, a non-endogenous human antibody, a humanized antibody, or non-human antibody.

[0055] Before administering modified haNK-92 cells as provided herein to a mammal, the mammal can be assessed to determine whether or not the mammal has a cancer or disease expressing the relevant antigen (e.g., the antigen recognized by the antibody bound to the haNK-92 cells). Any appropriate method can be used to determine whether or not a mammal has a cancer or disease expressing the relevant antigen. For example, a mammal (e.g., human) can be identified using standard diagnostic techniques. In some cases, a tissue biopsy can be collected and analyzed to determine whether or not a mammal has a cancer or disease expressing the antigen.

[0056] After identifying a mammal as having the disease or cancer, the mammal can be administered modified haNK-92 cells as provided herein. For example, the cells can be administered prior to or in lieu of surgical resection of a tumor. In some cases, the cells as provided herein can be administered following resection of a tumor.

[0057] The modified haNK-92 cells as provided herein can be administered to a mammal in any appropriate amount, at any appropriate frequency, and for any appropriate duration effective to achieve a desired outcome (e.g., to increase progression-free survival). In some cases, cells as provided herein can be administered to a mammal having a cancer or disease to reduce the progression rate of the cancer or disease by 5, 10, 25, 50, 75, 100, or more percent. For example, the progression rate can be reduced such that no additional cancer progression is detected. [0058] The modified ha K-92 cells (and any other agent as described herein) may be provided as a pharmaceutically acceptable composition. A pharmaceutically acceptable composition may comprise one or more pharmaceutically acceptable excipients. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. Liquid pharmaceutical compositions include, for example, solutions, suspensions, and emulsions suitable for intradermal, subcutaneous, parenteral, or intravenous administration. Sterile water solutions of the modified NK cell compositions or sterile solutions of the modified NK cell compositions in solvents comprising water, buffered water, saline, PBS, ethanol, or propylene glycol are examples of liquid compositions suitable for parenteral administration. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, detergents, and the like.

[0059] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

[0060] Pharmaceutical compositions of the invention are suitable for use in a variety of drug delivery systems. Suitable formulations for use in the present invention are found in

Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed. (1985). For a brief review of methods for drug delivery, see, Langer, Science 249: 1527-1533 (1990). The pharmaceutical compositions of the present invention can be administered by various routes, e.g., subcutaneous, intradermal, transdermal, intramuscular, intravenous, or intraperitoneal.

Albumin-Antibody Complexes

[0061] Antibody complexes with albumin particles carrying a cytotoxic agent have tumor targeting capacity that translates into better delivery of the cytotoxic agent to the tumor. These complexes are not irradiated. As such, these complexes are not subject to loss of activity due to cellular death. Antibody complexes remaining in the body during their half- life are contemplated to be as active as those immediately after injection.

[0062] These two different approaches to treating the tumor have the ability to be used together or sequentially. In the latter approach, the modified haNK-92 cells are administered either before or after the albumin-antibody complex. In the case where modified haNK-92 cells are administered first, one can either contemporaneously administered the albumin- antibody complex or wait for a period of time after modified haNK-92 cells have been administered. In one embodiment, the period of time is within hours so that as the modified haNK-92 lose efficacy, the albumin-antibody complex replaces that lost efficacy. In another embodiment, the albumin-antibody complex is administered 3 or more days after modified haNK-92 so that there is little to no contribution from one therapy with the other. Which therapy that is initiated first is within the decision of the attending clinician. One

consideration is that the modified haNK-92 cells as described herein may advantageously be administered after the albumin-antibody complex so as to reduce the risk of renal damage due to clearance of dead cells arising from both dead tumor cells and dead haNK-92 cells. The combined treatment also provides an additional challenge to the tumor and reduces the ability of the tumor to become resistant to the combined treatment.

[0063] The combination of modified haNK-92 (plus the fugetactic agent) with the antibody- albumin complexes allow for both high initial tumor cell killing by the components (e.g., because the AMD-bound modified haNK-92 can pass the fugetactic wall) and long-term tumor cell killing with the antibody-albumin complex, thereby providing a one-two punch to the tumor. This binary approach is contemplated to result in a synergy between the two components as it allows for the short term killing by AMD-bound modified haNK-92 coupled with both the short term and long term killing of the antibody-albumin complex (e.g., AR160) against tumors (e.g., CD20+ lymphomas).

[0064] In some embodiments, the antibody is one of the antibodies listed in Table 1.

[0065] In some embodiments, the chemotherapeutic is selected from the group consisting of abiraterone, bendamustine, bortezomib, carboplatin, cabazitaxel, cisplatin, chlorambucil, dasatinib, docetaxel, doxorubicin, epirubicin, erlotinib, etoposide, everolimus, gefitinib, idarubicin, imatinib, hydroxyurea, imatinib, lapatinib, leuprorelin, melphalan, methotrexate, mitoxantrone, nedaplatin, nilotinib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, picoplatin, romidepsin, satraplatin, sorafenib, vemurafenib, sunitinib, teniposide, triplatin, vinblastine, vinorelbine, vincristine, and cyclophosphamide. Preferably, the chemotherapeutic agent is paclitaxel.

[0066] Both ABRAXANE® and albumin particles comprising other chemotherapeutic agents are disclosed by U.S. Patent Nos. 7,758,891; 7,820,788; 7,923,536; 8,034,375; 8,138,229; 8,268,348; 8,314, 156; 8,853,260; and 9, 101,543, each of which is incorporated herein by reference in its entirety. In addition, carrier protein, chemotherapeutic, antibody conjugates, or combinations thereof are disclosed by PCT Publication Nos. WO2016/057554,

WO2014/055415, and U.S. Publication No. 2014/0178486, each of which is incorporated herein by reference in its entirety.

[0067] Table 2 depicts a list of non-limiting list of chemotherapeutic agents. It should be understood, that while targets are limited, the use of the agents is not limited only to the listed targets. It is contemplated that each individually can be used for any type of cancer, including those listed throughout the disclosure.

Table 2: Cancer therapeutic

ABVD (Adriamycin, bleomycin, vinblastine Hodgkin lymphoma

sulfate, dacarbazine)

ABVE (Adriamycin, bleomycin, vincristine Hodgkin lymphoma (in children)

sulfate, etoposide)

ABVE-PC(Adriamycin, bleomycin, Hodgkin lymphoma (in children)

vincristine sulfate, etoposide, prednisone,

cyclophosphamide)

AC (Adriamycin cyclophosphamide) Breast cancer

AC-T (Adriamycin, cylclophosphamide, Breast cancer

Taxol)

Adcetris (Brentuximab Vedotin) Anaplastic large cell lymphoma; Hodgkin lymphoma

ADE (Cytarabine (Ara-C), Daunorubicin Acute myeloid leukemia (in children) Hydrochloride, Etoposide)

Ado-Trastuzumab Emtansine Breast cancer

Adriamycin (Doxorubicin Hydrochloride) Acute lymphoblastic leukemia; acute myeloid leukemia; breast cancer, gastric (stomach) cancer; Hodgkin lymphoma; neuroblastoma; non-Hodgkin lymphoma; ovarian cancer; small cell lung cancer; soft tissue and bone sarcomas; thyroid cancer; transitional cell bladder cancer; Wilms tumor

Adrucil (Fluorouracil) Basal cell carcinoma; breast cancer; colorectal cancer; gastric (stomach) adenocarcinoma; pancreatic cancer; squamous cell carcinoma of the head and neck

Afatinib Dimaleate Non-small cell lung cancer

Afinitor (Everolimus) Breast cancer, pancreatic cancer; renal cell carcinoma; subependymal giant cell astrocytoma

Alimta (Pemetrexed Disodium) Malignant pleural mesothelioma; non-small cell lung cancer

Ambochlorin (Chlorambucil) Chronic lymphocytic leukemia; Hodgkin lymphoma; non-Hodgkin lymphoma

Anastrozole Breast cancer

Aredia (Pamidronate Disodium) Breast cancer; multiple myeloma

Arimidex (Anastrozole) Breast cancer

Aromasin (Exemestane) Advanced breast cancer; early-stage breast cancer and estrogen receptor positive

Arranon (Nelarabine) T-cell acute lymphoblastic leukemia; T-cell lymphoblastic lymphoma

Azacitidine Myelodysplastic syndromes

BEACOPP Hodgkin lymphoma

Becenum (Carmustine) Brain tumors; Hodgkin lymphoma; multiple myeloma; non-Hodgkin lymphoma

Beleodaq (Belinostat) Peripheral T-cell lymphoma BEP Ovarian germ cell tumors; testicular germ cell tumors

Bicalutamide Prostate cancer

BiCNU (Carmustine) Brain tumors; Hodgkin lymphoma; multiple myeloma; non-Hodgkin lymphoma

Bleomycin Hodgkin lymphoma; non-Hodgkin

lymphoma; penile cancer; squamous cell carcinoma of the cervix; squamous cell carcinoma of the head and neck; squamous cell carcinoma of the vulva; testicular cancer

Bosulif (Bosutinib) Chronic myelogenous leukemia

Brentuximab Vedotin Anaplastic large cell lymphoma; Hodgkin lymphoma

Busulfan Chronic myelogenous leukemia

Busulfex (Busulfan) Chronic myelogenous leukemia

C ab ozanti nib - S -Mai ate Medullary thyroid cancer

CAF Breast cancer

Camptosar (Irinotecan Hydrochloride) Colorectal cancer

CAPOX Colorectal cancer

Carfilzomib Multiple myeloma

Casodex (Bicalutamide) Prostate cancer

CeeNU (Lomustine) Brain tumors; Hodgkin lymphoma

Ceritinib Non-small cell lung cancer

Cerubidine (Daunorubicin Hydrochloride) Acute lymphoblastic leukemia; acute myeloid leukemia

Chlorambucil Chronic lymphocytic leukemia; Hodgkin lymphoma; non-Hodgkin lymphoma

CHLORAMBUCIL-PREDNISONE Chronic lymphocytic leukemia

CHOP Non-Hodgkin lymphoma

Cisplatin Bladder cancer; cervical cancer; malignant mesothelioma; non-small cell lung cancer; ovarian cancer; squamous cell carcinoma of the head and neck; testicular cancer

Clafen (Cyclophosphamide) Acute lymphoblastic leukemia; acute myeloid leukemia; breast cancer; chronic lymphocytic leukemia; chronic myelogenous leukemia; Hodgkin lymphoma; multiple myeloma; mycosis fungoides; neuroblastoma; non- Hodgkin lymphoma; ovarian cancer;

retinoblastoma

Clofarex (Clofarabine) Acute lymphoblastic leukemia

CMF Breast cancer

Cometriq (Cabozantinib-S-Malate) Medullary thyroid cancer

COPP Hodgkin lymphoma; non-Hodgkin lymphoma

COPP-ABV Hodgkin lymphoma

Cosmegen (Dactinomycin) Ewing sarcoma; gestational trophoblastic disease; rhabdomyosarcoma; solid tumors;

testicular cancer; Wilms tumor

CVP Non-Hodgkin lymphoma; chronic

lymphocytic leukemia

Cyclophosphamide Acute lymphoblastic leukemia; acute myeloid leukemia; breast cancer; chronic lymphocytic leukemia; chronic myelogenous leukemia; Hodgkin lymphoma; multiple myeloma; mycosis fungoides; neuroblastoma; non- Hodgkin lymphoma; ovarian cancer;

retinoblastoma.

Cyfos (Ifosfamide) Testicular germ cell tumors

Cyramza (Ramucirumab) Adenocarcinoma; colorectal cancer; non- small cell lung cancer

Cytarabine Acute lymphoblastic leukemia; acute myeloid leukemia; chronic myelogenous leukemia; meningeal leukemia

Cytosar-U (Cytarabine) Acute lymphoblastic leukemia; acute myeloid leukemia; chronic myelogenous leukemia; meningeal leukemia

Cytoxan (Cyclophosphamide) Acute lymphoblastic leukemia; acute myeloid leukemia; breast cancer; chronic lymphocytic leukemia; chronic myelogenous leukemia; Hodgkin lymphoma; multiple myeloma; mycosis fungoides; neuroblastoma; non- Hodgkin lymphoma; ovarian cancer;

retinoblastoma

Dacarbazine Hodgkin lymphoma; melanoma

Dacogen (Decitabine) Myelodysplastic syndromes

Dactinomycin Ewing sarcoma; gestational trophoblastic disease; rhabdomyosarcoma; solid tumors; testicular cancer; Wilms tumor

Daunorubicin Hydrochloride Acute lymphoblastic leukemia; acute myeloid leukemia

Degarelix Prostate cancer

Denileukin Diftitox Cutaneous T-cell lymphoma

Denosumab Giant cell tumor of the bone; breast cancer, prostate cancer

DepoCyt (Liposomal Cytarabine) Lymphomatous meningitis

DepoFoam (Liposomal Cytarabine) Lymphomatous meningitis

Docetaxel Breast cancer; adenocarcinoma of the

stomach or gastroesophageal junction; non- small cell lung cancer; prostate cancer;

squamous cell carcinoma of the head and neck

Doxil (Doxorubicin Hydrochloride AIDS-related Kaposi sarcoma; multiple Liposome) myeloma; ovarian cancer

Doxorubicin Hydrochloride Acute lymphoblastic leukemia; acute myeloid leukemia; breast cancer; gastric (stomach) cancer; Hodgkin lymphoma; neuroblastoma; non-Hodgkin lymphoma; ovarian cancer; small cell lung cancer; soft tissue and bone sarcomas; thyroid cancer; transitional cell bladder cancer; Wilms tumor.

Dox-SL (Doxorubicin Hydrochloride AIDS-related Kaposi sarcoma; multiple

Liposome) myeloma; ovarian cancer

DTIC-Dome (Dacarbazine) Hodgkin lymphoma; melanoma

Efudex (Fluorouracil) Basal cell carcinoma; breast cancer; colorectal cancer; gastric (stomach) adenocarcinoma; pancreatic cancer; squamous cell carcinoma of the head and neck

Ellence (Epirubicin Hydrochloride) Breast cancer

Eloxatin (Oxaliplatin) Colorectal cancer; stage III colon cancer

Emend (Aprepitant) Nausea and vomiting caused by

chemotherapy and nausea and vomiting after surgery

Enzalutamide Prostate cancer

Epirubicin Hydrochloride Breast cancer

EPOCH Non-Hodgkin lymphoma

Erbitux (Cetuximab) Colorectal cancer; squamous cell carcinoma of the head and neck

Eribulin Mesylate Breast cancer

Erivedge (Vismodegib) Basal cell carcinoma

Erlotinib Hydrochloride Non-small cell lung cancer; pancreatic cancer

Erwinaze (Asparaginase Erwinia Acute lymphoblastic leukemia

chrysanthemi)

Etopophos (Etoposide Phosphate) Small cell lung cancer; testicular cancer

Evacet (Doxorubicin Hydrochloride AIDS-related Kaposi sarcoma; multiple

Liposome) myeloma; ovarian cancer

Everolimus Breast cancer; pancreatic cancer; renal cell carcinoma; subependymal giant cell astrocytoma

Evista (Raloxifene Hydrochloride) Breast cancer

Exemestane Breast cancer

Fareston (Toremifene) Breast cancer

Farydak (Panobinostat) Multiple myeloma

Faslodex (Fulvestrant) Breast cancer

FEC Breast cancer

Femara (Letrozole) Breast cancer

Filgrastim Neutropenia

Fludara (Fludarabine Phosphate) Chronic lymphocytic leukemia Fluoroplex (Fluorouracil) Basal cell carcinoma; breast cancer; colorectal cancer; gastric (stomach) adenocarcinoma; pancreatic cancer; squamous cell carcinoma of the head and neck

Folex (Methotrexate) Acute lymphoblastic leukemia; breast cancer;

gestational trophoblastic disease; head and neck cancer; lung cancer; mycosis fungoides; non-Hodgkin lymphoma; osteosarcoma

FOLFIRI Colorectal cancer

FOLFIRI-BEVACIZUMAB Colorectal cancer

FOLFIRI-CETUXIMAB Colorectal cancer

FOLFIRINOX Pancreatic cancer

FOLFOX Colorectal cancer

Folotyn (Pralatrexate) Peripheral T-cell lymphoma

FU-LV Colorectal cancer; esophageal cancer; gastric cancer

Fulvestrant Breast cancer

Gefitinib Non-small cell lung cancer

Gemcitabine Hydrochloride Breast cancer; non-small cell lung cancer;

ovarian cancer; pancreatic cancer

GEMCITABINE-CISPLATIN Biliary tract cancer; bladder cancer; cervical cancer; malignant mesothelioma; non-small cell lung cancer; ovarian cancer; pancreatic cancer

GEMCITABINE-OXALIPLATIN Pancreatic cancer

Gemtuzumab Ozogamicin (antibody drug Acute myeloid leukemia

conjugate)

Gemzar (Gemcitabine Hydrochloride) Breast cancer; non-small cell lung cancer;

ovarian cancer; pancreatic cancer

Gilotrif (Afatinib Dimaleate) Non-small cell lung cancer

Gleevec (Imatinib Mesylate) Acute lymphoblastic leukemia; chronic

eosinophilic leukemia or hypereosinophilic syndrome; chronic myelogenous leukemia; dermatofibrosarcoma protuberans;

gastrointestinal stromal tumor;

myelodysplastic/myeloproliferative neoplasms; systemic mastocytosis.

Gliadel (Carmustine Implant) Glioblastoma multiforme; malignant glioma

Goserelin Acetate Breast cancer; prostate cancer

Halaven (Eribulin Mesylate) Breast cancer

Hycamtin (Topotecan Hydrochloride) Cervical cancer; ovarian cancer; small cell lung cancer

Hyper-CVAD Acute lymphoblastic leukemia; non-Hodgkin lymphoma

Ibrance (Palbociclib) Breast cancer

Ibrutinib Chronic lymphocytic leukemia; mantel cell lymphoma;

ICE Hodgkin lymphoma; non-Hodgkin lymphoma

Iclusig (Ponatinib Hydrochloride) Acute lymphoblastic leukemia; Chronic myelogenous leukemia

Idamycin (Idarubicin Hydrochloride) Acute myeloid leukemia

Imatinib Mesylate Acute lymphoblastic leukemia; chronic

gastrointestinal stromal tumor;

myelodysplastic/myeloproliferative neoplasms; systemic mastocytosis.

Imbruvica (Ibrutinib) Chronic lymphocytic leukemia; mantle cell lymphoma; Waldenstrom macroglobulinemia

Inlyta (Axitinib) Renal cell carcinoma

Iressa (Gefitinib) Non-small cell lung cancer

Irinotecan Hydrochloride Colorectal cancer

Istodax (Romidepsin) Cutaneous T-cell lymphoma

Ixempra (Ixabepilone) Breast cancer

Jevtana (Cabazitaxel) Prostate cancer

Keoxifene (Raloxifene Hydrochloride) Breast cancer

Kyprolis (Carfilzomib) Multiple myeloma

Lenvima (Lenvatinib Mesylate) Thyroid cancer

Letrozole Breast cancer

Leucovorin Calcium Colorectal cancer

Leukeran (Chlorambucil) Chronic lymphocytic leukemia; Hodgkin lymphoma; non-Hodgkin lymphoma

Leuprolide Acetate Prostate cancer

Linfolizin (Chlorambucil) Chronic lymphocytic leukemia; Hodgkin lymphoma; non-Hodgkin lymphoma

LipoDox (Doxorubicin Hydrochloride AIDS-related Kaposi sarcoma; multiple Liposome) myeloma; ovarian cancer

Lomustine Brain tumors; Hodgkin lymphoma

Lupron (Leuprolide Acetate) Prostate cancer

Lynparza (Olaparib) Ovarian cancer

Marqibo (Vincristine Sulfate Liposome) Acute lymphoblastic leukemia

Matulane (Procarbazine Hydrochloride) Hodgkin lymphoma

Mechlorethamine Hydrochloride Bronchogenic carcinoma; chronic

lymphocytic leukemia; chronic myelogenous leukemia; Hodgkin lymphoma; malignant pleural effusion, malignant pericardial effusion, and malignant peritoneal effusion; mycosis fungoides; non-Hodgkin lymphoma

Megace (Megestrol Acetate) Breast cancer; endometrial cancer

Mekinist (Trametinib) Melanoma Mercaptopurine Acute lymphoblastic leukemia

Mesnex (Mesna) Hemorrhagic cystitis

Methazolastone (Temozolomide) Anaplastic astrocytoma; glioblastoma

multiforme

Mexate (Methotrexate) Acute lymphoblastic leukemia; breast cancer;

Mexate-AQ (Methotrexate) Acute lymphoblastic leukemia; breast cancer;

Mitoxantrone Hydrochloride Acute myeloid leukemia; prostate cancer

Mitozytrex (Mitomycin C) Gastric (stomach) and pancreatic

adenocarcinoma

MOPP Hodgkin lymphoma

Mozobil (Plerixafor) Multiple myeloma; non-Hodgkin lymphoma

Mustargen (Mechlorethamine Bronchogenic carcinoma; chronic

Hydrochloride) lymphocytic leukemia; chronic myelogenous leukemia; Hodgkin lymphoma; malignant pleural effusion, malignant pericardial effusion, and malignant peritoneal effusion; mycosis fungoides; non-Hodgkin lymphoma

Myleran (Busulfan) Chronic myelogenous leukemia

Mylotarg (Gemtuzumab Ozogamicin) Acute myeloid leukemia

Nanoparticle Paclitaxel (Paclitaxel Albumin- Breast cancer; Non-small cell lung cancer; stabilized Nanoparticle Formulation) Pancreatic cancer

Navelbine (Vinorelbine Tartrate) Non-small cell lung cancer

Nelarabine T-cell acute lymphoblastic leukemia

Neosar (Cyclophosphamide) Acute lymphoblastic leukemia; Acute

myeloid leukemia; Breast cancer; Chronic lymphocytic leukemia; Chronic myelogenous leukemia; Hodgkin lymphoma; Multiple myeloma; Mycosis fungoides;

Neuroblastoma; Non-Hodgkin lymphoma; Ovarian cancer; Retinoblastoma

Nexavar (Sorafenib Tosylate) Hepatocellular carcinoma; Renal cell

carcinoma; Thyroid cancer

Nilotinib Chronic myelogenous leukemia

Nivolumab Melanoma; Squamous non-small cell lung cancer

Nolvadex (Tamoxifen Citrate) Breast cancer

Odomzo (Sonidegib) Basal cell carcinoma

OEPA Hodgkin lymphoma

OFF Pancreatic cancer

Olaparib Ovarian cancer Oncaspar (Pegaspargase) Acute lymphoblastic leukemia

OPPA Hodgkin lymphoma

Oxaliplatin Colorectal cancer; Stage III colon cancer

Paclitaxel AIDS-related Kaposi sarcoma; Breast cancer;

Non-small cell lung cancer; Ovarian cancer

Paclitaxel Albumin-stabilized Nanoparticle Breast cancer; Non-small lung cancer;

Formulation Pancreatic cancer

PAD Multiple myeloma

Palbociclib Breast cancer

Pamidronate Disodium Breast cancer; Multiple myeloma

Panitumumab Colorectal cancer

Panobinostat Multiple myeloma

Paraplat (Carboplatin) Non-small cell lung cancer; Ovarian cancer

Paraplatin (Carboplatin) Non-small cell lung cancer; Ovarian cancer

Pazopanib Hydrochloride Renal cell carcinoma; Soft tissue sarcoma

Pegaspargase Acute lymphoblastic leukemia

Pemetrexed Disodium Malignant pleural mesothelioma; Non-small cell lung cancer

Platinol (Cisplatin) Bladder cancer; Cervical cancer; Malignant mesothelioma; Non-small cell lung cancer; Ovarian cancer; Squamous cell carcinoma of the head and neck; Testicular cancer

Platinal-AQ (Cisplatin) Bladder cancer; Cervical cancer; Malignant mesothelioma; Non-small cell lung cancer; Ovarian cancer; Squamous cell carcinoma of the head and neck; Testicular cancer

Plerixafor Multiple myeloma; Non-Hodgkin lymphoma

Pomalidomide Multiple myeloma

Pomalyst (Pomalidomide) Multiple myeloma

Pontinib Hydrochloride Acute lymphoblastic leukemia; Chronic

myelogenous leukemia

Pralatrexate Peripheral T-cell lymphoma

Prednisone Acute lymphoblastic leukemia; Chronic

lymphocytic leukemia; Hodgkin lymphoma; Multiple myeloma; Non-Hodgkin lymphoma; Prostate cancer; Thymoma and thymic carcinoma

Procarbazine Hydrochloride Hodgkin lymphoma

Provenge (Sipuleucel-T) Prostate cancer

Purinethol (Mercaptopurine) Acute lymphoblastic leukemia

Radium 223 Dichloride Prostate cancer

Raloxifene Hydrochloride Breast cancer

R-CHOP Non-Hodgkin lymphoma

R-CVP Non-Hodgkin lymphoma

Regorafenib Colorectal cancer; Gastrointestinal stromal tumor

R-EPOCH B-cell non-Hodgkin lymphoma

Revlimid (Lenalidomide) Mantle cell lymphoma; Multiple myeloma;

Anemia

Rheumatrex (Methotrexate) Acute lymphoblastic leukemia; Breast cancer;

Gestational trophoblastic disease; Head and neck cancer; Lung cancer; Non-Hodgkin lymphoma; Osteosarcoma

Romidepsin Cutaneous T-cell lymphoma

Rubidomycin (Daunorubicin Hydrochloride) Acute lymphoblastic leukemia; Acute

myeloid leukemia

Sipuleucel-T Prostate cancer

Somatuline Depot (Lanreotide Acetate) Gastroenteropancreatic neuroendocrine

tumors

Sonidegib Basal cell carcinoma

Sorafenib Tosylate Hepatocellular carcinoma; Renal cell

carcinoma; Thyroid cancer

Sprycel (Dasatinib) Acute lymphoblastic leukemia; Chronic

myelogenous leukemia

STANFORD V Hodgkin lymphoma

Stivarga (Regorafenib) Colorectal cancer; Gastrointestinal stromal tumor

Sunitnib Mai ate Gastronintestinal stromal tumor; Pancreatic cancer; Renal cell carcinoma

Sutent (Sunitinib Malate) Gastronintestinal stromal tumor; Pancreatic cancer; Renal cell carcinoma

Synovir (Thalidomide) Multiple myeloma

Synribo (Omacetaxine Mepesuccinate) Chronic myelogenous leukemia

TAC Breast cancer

Tafinlar (Dabrafenib) Melanoma

Tamoxifen Citrate Breast cancer

Tarabine PFS (Cytarabine) Acute lymphoblastic leukemia; Acute

myeloid leukemia; Chronic myelogenous leukemia

Tarceva (Erlotinib Hydrochloride) Non-small cell lung cancer; Pancreatic cancer

Targretin (Bexarotene) Skin problems caused by cutaneous T-cell lymphoma

Tasigna (Niltinib) Chronic myelogenous leukemia

Taxol (Paclitaxel) AIDS-related Kaposi sarcoma; Breast cancer;

Non-small cell lung cancer; Ovarian cancer

Taxotere (Docetaxel) Breast cancer; Adenocarcinoma; Non-small cell lung cancer; Prostate cancer; Squamous cell carcinoma of the head and neck

Temodar (Temozolomide) Anaplastic astrocytoma; Glioblastoma

multiforme

Temozolomide Anaplastic astrocytoma; Glioblastoma multiforme

Thiotepa Bladder cancer; Breast cancer; Malignant pleural effusion, malignant pericardial effusion, and malignant peritoneal effusion; Ovarian cancer

Toposar (Etoposide) Small cell lung cancer; Testicular cancer

Topotecan Hydrochloride Cervical cancer; Ovarian cancer; Small cell lung cancer

Toremifene Breast cancer

Torisel (Temsirolimus) Renal cell carcinoma

TPF Squamous cell carcinoma of the head and neck; Gastric (stomach) cancer

Trastuzumab Adenocarcinoma; Breast cancer

Treanda (Bendamustine Hydrochloride) B-cell non-Hodgkin lymphoma; Chronic lymphocytic leukemia

Trisenox (Arsenic Trioxide) Acute promyelocytic leukemia

Tykerb (Lapatinib Ditosylate) Breast cancer

Vandetabib Medullary thyroid cancer

VAMP Hodgkin lymphoma

VelP Ovarian germ cell; Testicular cancer

Velban (Vinblastine Sulfate) Breast cancer; Choriocarcinoma; Hodgkin lymphoma; Kaposi sarcoma; Mycosid fungoides; Non-Hodgkin lymphoma;

Testicular cancer

Velcade (Bortezomib) Mulitple myeloma; Mantle cell lymphoma

Velsar (Vinblastine Sulfate) Breast cancer; Choriocarcinoma; Hodgkin lymphoma; Kaposi sarcoma; Mycosis fungoides; Non-Hodgkin lymphoma;

Testicular cancer

VePesid (Etoposide) Small cell lung cancer; Testicular cancer

Viadur (Leuprolide Acetate) Prostate cancer

Vidaza (Azacitidine) Myelodysplastic syndromes

Vincasar PFS (Vincristine Sulfate) Acute leukemia; Hodgkin lymphoma;

Neuroblastoma; Non-Hodgkin lymphoma; Rhabdomyosarcoma; Wilms tumor

Vincristine Sulfate Liposome Acute lymphoblastic leukemia

Vinorelbine Tartrate Non-small cell lung cancer

VIP Testicular cancer

Visbodegib Basal cell carcinoma

Voraxaze (Glucarpidase) Toxic blood levels of the anticancer drug methotrexate

Votrient (Pazopanib Hydrochloride) Renal cell carcinoma; Soft tissue sarcoma

Wellcovorin (Leucovorin Calcium) Colorectal cancer; Anemia

Xalkori (Crizotinib) Non-small cell lung cancer

Xeloda (Capecitabine) Breast cancer; Colorectal cancer XELIRI Colorectal cancer; Esophageal cancer; Gastric

(stomach) cancer

XELOX Colorectal cancer

Xofigo (Radium 223 Dichloride) Prostate cancer

Xtandi (Enzalutamide) Prostate cancer

Zaltrap (Ziv-Aflibercept) Colorectal cancer

Zelboraf (Vemurafenib) Melanoma

Ziv-Aflibercept Colorectal cancer

Zoladex (Goserelin Acetate) Breast cancer; Prostate cancer

Zolinza (Vorinostat) Cutaneous T-cell lymphoma

Zometa (Zoledronic Acid) Multiple myeloma

Zydelig (Idelalisib) Chronic lymphocytic leukemia; Non-Hodgkin lymphoma (Follicula B-cell non Hodgkin lymphoma and Small lymphocytic

lymphoma)

Zykadia (Certinib) Non-small cell lung cancer

Zytiga (Abiraterone Acetate) Prostate cancer

[0068] In some embodiments, the chemotherapeutic agent is associated with a carrier protein. [0069] In some embodiments, the effective amount of the chemotherapeutic is about 100 mg/m 2 , about 105 mg/m 2 , about 110 mg/m 2 , about 115 mg/m 2 , about 120 mg/m 2 , about 125 mg/m 2 , about 130 mg/m 2 , about 135 mg/m 2 , about 140 mg/m 2 , about 145 mg/m 2 , about 150 mg/m 2 , about 155 mg/m 2 , about 160 mg/m 2 , about 165 mg/m 2 , about 170 mg/m 2 , about 175 mg/m 2 , about 180 mg/m 2 , about 185 mg/m 2 , about 190 mg/m 2 , about 195 mg/m 2 , or about 200 mg/m² of the chemotherapeutic agent.

[0070] It is to be understood that the therapeutic agent (i.e., chemotherapeutic) may be located inside the nanoparticle, on the outside surface of the nanoparticle, or both. The nanoparticle may contain more than one different therapeutic agents, for example, two therapeutic agents, three therapeutic agents, four therapeutic agents, five therapeutic agents, or more. Furthermore, a nanoparticle may contain the same or different therapeutic agents inside and outside the nanoparticle.

[0071] In some embodiments any antibody, aptamer, therapeutic agent, or any combination thereof is expressly excluded. [0072] In some cases, complexes as described herein can be designed to have an average diameter that is less than 1 μιη. For example, appropriate concentrations of carrier protein and antibody (or other binding agent) can be used such that complexes having an average diameter that is less than 1 μιη are formed. In some cases, the complexes provided herein can have an average diameter that is between 0.1 μιη and 1 μιη (e.g., between 0.1 μιη and 0.95 μιη, between 0.1 μιη and 0.9 μιτι, between 0.1 μιη and 0.8 μιτι, between 0.1 μιη and 0.7 μιτι, between 0.1 μιη and 0.6 μιτι, between 0.1 μιη and 0.5 μιτι, between 0.1 μιη and 0.4 μιτι, between 0.1 μιη and 0.3 μιτι, between 0.1 μιη and 0.2 μιτι, between 0.2 μιη and 1 μιτι, between 0.3 μιη and 1 μιτι, between 0.4 μιη and 1 μιτι, between 0.5 μιη and 1 μιτι, between 0.2 μιη and 0.6 μιη, between 0.3 μιη and 0.6 μιτι, between 0.2 μιη and 0.5 μm, or between 0.3 μιη and 0.5 μιη). Complexes provided herein having an average diameter that is between 0.1 μιη and 0.9 μιη can be administered systemically (e.g., intravenously) to treat cancer or other disease located within a mammal's body.

[0073] In some cases, a complex as provided herein can have greater than 60 percent (e.g., greater than 65, 70, 75, 80, 90, 95, or 99 percent) of the complexes having a diameter that is between 0.1 μιη and 0.9 μιη (e.g., between 0.1 μιη and 0.95 μιτι, between 0.1 μιη and 0.9 μιτι, between 0.1 μιη and 0.8 μιτι, between 0.1 μιη and 0.7 μιτι, between 0.1 μιη and 0.6 μιτι, between 0.1 μιη and 0.5 μιτι, between 0.1 μιη and 0.4 μιτι, between 0.1 μιη and 0.3 μιτι, between 0.1 μιη and 0.2 μιτι, between 0.2 μιη and 1 μιτι, between 0.3 μιη and 1 μιτι, between 0.4 μιη and 1 μιτι, between 0.5 μιη and 1 μm, between 0.2 μιη and 0.6 μm, between 0.3 μιη and 0.6 μιτι, between 0.2 μm and 0.5 μιτι, or between 0.3 μιη and 0.5 μm). Complexes provided herein having greater than 60 percent (e.g., greater than 65, 70, 75, 80, 90, 95, or 99 percent) of the complexes with a diameter that is between 0.1 μιη and 0.9 μιη can be administered systemically (e.g., intravenously) to treat cancer or other disease expressing the relevant antigen located within a mammal's body.

[0074] In general, any appropriate combination of carrier protein, chemotherapy agent, and binding agent can be used as described herein. For example, an appropriate amount of carrier protein (e.g., with a chemotherapeutic), and an appropriate amount of binding agent can be mixed together in the same container. This mixture can be incubated at an appropriate temperature (e.g., room temperature, between 5 °C and 60 °C, between 23 °C and 60 °C, between 15 °C and 30 °C, between 15 °C and 25 °C, between 20 °C and 30 °C, or between 20 °C and 25 °C) for a period of time (e.g., about 30 minutes, or between about 5 minutes and about 60 minutes, between about 5 minutes and about 45 minutes, between about 15 minutes and about 60 minutes, between about 15 minutes and about 45 minutes, between about 20 minutes and about 400 minutes, or between about 25 minutes and about 35 minutes) before being administered to a patient having a cancer.

[0075] Optionally, the antibody-carrier protein-chemotherapy agent complex is lyophilized. Where the complex is lyophilized, it is reconstituted in a pharmaceutically acceptable excipient prior to administration to the patient.

[0076] In some cases, carrier protein nanoparticles comprising a chemotherapy agent can be contacted with a binding agent to form complexes that are stored prior to being administered to a patient. For example, a composition can be formed as described herein and stored for a period of time (e.g., days or weeks) prior to being administered to a patient.

[0077] Any appropriate method can be used to obtain complexes as described herein. Any appropriate method can be used to administer a complex as provided herein to a mammal. For example, a composition containing carrier protein/binding agent/chemotherapeutic complexes can be administered via injection (e.g., subcutaneous injection, intramuscular injection, intravenous injection, or intrathecal injection).

[0078] In some embodiments, the carrier protein is albumin, gelatin, elastin, gliadin, legumin, zein, a soy protein, a milk protein, an antibody -binding protein, or a whey protein. Preferably, the carrier protein is albumin. In one embodiment, the albumin is human serum albumin. In one embodiment, the albumin is recombinant albumin.

Anti-fugetactic Agent

[0079] Without being bound by theory, the addition of anti-fugetactic agent to the cells prior to administration is contemplated to aid in penetration of the "fugetactic wall" surrounding the tumor as a result of chemokine (e.g., CXCL12) over-expression by the tumor. Anti- fugetactic agents are agents with the ability to attenuate or eliminate the fugetactic effect of fugetactic agents. Known agents with anti-fugetactic effect include AMD3100 (mozobil/plerixafor), KRH-1636, T-20, T-22, T-140, TE-14011, T-14012, TN14003, TAK- 779, AK602, SCH-351125, Tannic acid, NSC 651016, thalidomide, GF 109230X. Preferably, the anti-fugetactic agent is AMD3100.

[0080] The anti-fugetactic agent may be any such agent known in the art. In one

embodiment, the anti-fugetactic agent is an anti-fugetactic agent as described in U.S. Patent Application Publication No. 2008/0300165, which is hereby incorporated by reference in its entirety. In a preferred embodiment, the anti-fugetactic agent is AMD3100

(mozobil/plerixafor; 1 , 1 '-[ 1 ,4-phenylenebis(methylene)]bis [1,4,8, 11- tetraazacyclotetradecane]), KRH-1636, T-20, T-22, T-140, TE-14011, T-14012, TN14003, TAK-779, AK602, SCH-351125, Tannic acid, NSC 651016, thalidomide, GF 109230X, an antibody that interferes with dimerization of a fugetactic chemokine, or an antibody that interferes with dimerization of a receptor for a fugetactic chemokine. For example, the antibody may inhibit dimerization of CXCL12, IL-8, CXCR3, or CXCR4. In one

embodiment, the anti-fugetactic agent is an antibody that interferes with binding of the chemokine to its receptor. In a preferred embodiment, the anti-fugetactic agent is AMD3100.

[0081] Anti-fugetactic agents include any agents that specifically inhibit chemokine and/or chemokine receptor dimerization, thereby blocking the chemorepellent response to a fugetactic agent. Certain chemokines, including IL-8 and CXCL12 can also serve as chemorepellents at high concentrations (e.g., above 100 nM) where much of the chemokine exists as a dimer. Dimerization of the chemokine elicits a differential response in cells, causing dimerization of chemokine receptors, an activity which is interpreted as a

chemorepellent signal. Blocking the chemorepellent effect of high concentrations of a chemokine secreted by a tumor can be accomplished, for example, by anti-fugetactic agents that inhibit chemokine dimer formation or chemokine receptor dimer formation. For example, antibodies that target and block chemokine receptor dimerization, e.g., by interfering with the dimerization domains or ligand binding, can be anti-fugetactic agents. Anti-fugetactic agents that act via other mechanisms of action, e.g., that reduce the amount of fugetactic cytokine secreted by the cells, inhibit dimerization, and/or inhibit binding of the chemokine to a target receptor, are also encompassed by the present invention. Where desired, this effect can be achieved without inhibiting the chemotactic action of the monomeric chemokine. [0082] In other embodiments, the anti-fugetactic agent is a CXCR4 antagonist, CXCR3 antagonist, CXCR4/CXCL12 antagonist or selective PKC inhibitor.

[0083] The CXCR4 antagonist can be but is not limited to AMD3100, KRH-1636, T-20, T- 22, T-140, TE-14011, T-14012, or TN14003, or an antibody that interferes with the dimerization of CXCR4.

[0084] The CXCR3 antagonist can be but is not limited to TAK-779, AK602, or SCH- 351125, or an antibody that interferes with the dimerization of CXCR3.

[0085] The CXCR4/ CXCL12 antagonist can be but is not limited to Tannic acid, NSC 651016, or an antibody that interferes with the dimerization of CXCR4 and/or CXCL12.

[0086] The selective PKC inhibitor can be but is not limited to thalidomide or GF 10923 OX.

[0087] In a preferred embodiment, the anti-fugetactic agent is AMD3100 (plerixafor).

AMD3100 is described in U.S. Patent No. 5,583, 131, which is incorporated by reference herein in its entirety.

[0088] In one embodiment, the anti-fugetactic agent is coupled with a molecule that allows targeting of a tumor or cancer. In one embodiment, the anti-fugetactic agent is coupled with (e.g., bound to) an antibody specific for the tumor to be targeted. In one embodiment, the anti-fugetactic agent is coupled to the molecule that allows targeting of the tumor or cancer.

[0089] In one embodiment, the anti-fugetactic agent is bound to the modified haNK-92 cells in vitro (prior to administration to a patient). See, e.g., PCT Pub. No. WO2017/049228, which is incorporated herein by reference in its entirety. In one embodiment, the anti-fugetactic agent, e.g. AMD3100, is bound to the haNK cells via CXCL4 expressed on the cell surface.

Cancers

[0090] Cancers or tumors that can be treated by the compositions and methods described herein include, but are not limited to cancers listed in the above tables and: biliary tract cancer; brain cancer, including glioblastomas and medulloblastomas; breast cancer; uterine cancer; tubal cancer; cervical cancer; choriocarcinoma; colon cancer; bladder cancer; endometrial cancer; vaginal cancer; vulvar cancer; esophageal cancer; mouth cancer; gastric cancer; kidney cancer; hematological neoplasms, including acute lymphocytic and myelogenous leukemia; multiple myeloma; AIDS associated leukemias and adult T-cell leukemia lymphoma; intraepithelial neoplasms, including Bowen's disease and Paget's disease; liver cancer (hepatocarcinoma); lung cancer; head or neck cancers or oral cancers (mouth, throat, esophageal, nasopharyngeal, jaw, tonsil, nasal, lip, salivary gland, tongue, etc.); lymphomas, including Hodgkin's disease and lymphocytic lymphomas;

neuroblastomas; neuroendocrine tumors; oral cancer, including squamous cell carcinoma; adrenal cancer; anal cancer; angiosarcoma; appendix cancer; bile duct cancer; bone cancer; carcinoid tumors; soft tissue sarcoma; rhabdomyosarcoma; eye cancer; ovarian cancer, including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells, and fallopian tube cancer; gallbladder cancer; pancreas cancer; prostate cancer; rectal cancer; sarcomas, including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma; skin cancer, including melanoma, Kaposi's sarcoma, basocellular cancer and squamous cell cancer; testicular cancer, including germinal tumors (seminoma, non- seminoma[teratomas, choriocarcinomas]), stromal tumors and germ cell tumors; penile cancer; hemangioendothelioma; gastrointestinal cancer; ureteral cancer; urethral cancer; spinal cancer; pituitary gland cancer; primary central nervous system (CNS) lymphoma; thyroid cancer, including thyroid adenocarcinoma and medullar carcinoma; and renal cancer including adenocarcinoma and Wilms tumor. In important embodiments, cancers or tumors include breast cancer, prostate cancer, colorectal cancer, lymphoma, multiple myeloma, and melanoma.

Claims

WHAT IS CLAIMED IS:

1. An aqueous composition suitable for in vivo injection into a subject, said composition comprising an effective amount of K-92 cells, wherein said cells comprise a high avidity monoclonal antibody bound thereto through an antibody binding motif on the surface of said cells, and further wherein said cells have been exposed to a sufficient amount of irradiation so as to have a finite lifespan, thereby rendering said composition suitable for in vivo injection.

2. The composition of claim 1, further comprising an anti-fugetactic agent bound to a receptor on the cells.

3. The composition of claim 2, wherein the anti-fugetactic agent is AMD3100, KRH- 1636, T-20, T-22, T-140, TE-14011, T-14012, TN14003, TAK-779, AK602, SCH-351125, Tannic acid, NSC 651016, thalidomide, GF 109230X, an antibody that interferes with dimerization of a fugetactic chemokine, or an antibody that interferes with dimerization of a receptor for a fugetactic chemokine.

4. The composition of claim 2, wherein the receptor is a CXCR4 receptor or a CXCR7 receptor.

5. The composition of any one of the above claims, wherein the antibody binding motif is CD16 or CD19.

6. The composition of claim 5, wherein the CD 16 is a high-affinity CD 16.

7. The composition of any one of the above claims, wherein the antibody has an affinity for the antibody binding motif of at least 10⁶ M^"1.

8. The composition of any one of the above claims, wherein the antibody is not a therapeutic antibody.

9. The composition of any one of claims 1-7, wherein the antibody is selected from the group consisting of ado-trastuzumab emtansine, alemtuzumab, bevacizumab, blinatumomab, brentuximab vedotin, cetuximab, denosumab, dinutuximab, ibritumomab tiuxetan, ipilimumab, nivolumab, obinutuzumab, ofatumumab, panitumumab, pembrolizumab, pertuzumab, rituximab, trastuzumab, or any biosimilar thereof.

10. The composition of any one of the above claims, further comprising antibody that is not bound to the antibody binding motif.

11. A method for treating cancer in a patient in need thereof, said method comprising administering to said patient an effective amount of an K-92 cell composition, said composition comprising NK-92 cells comprising a high avidity monoclonal antibody bound thereto through an antibody binding motif on the surface of said cells, and further wherein said cells have been exposed to a sufficient amount of irradiation so as to have a finite lifespan, thereby rendering said composition suitable for in vivo injection.

12. The method of claim 11, further comprising administering an anti-fugetactic agent to the patient.

13. The method of claim 12, wherein the anti-fugetactic agent is administered prior to, concurrently with, and/or after administration of the modified NK-92 cells.

14. The method of claim 12, wherein the anti-fugetactic agent is bound to a receptor on the cells prior to administration to the patient.

15. The method of any one of claims 11-14, further comprising administering a particle comprising a carrier protein core having an antibody associated with the core, and optionally comprising a chemotherapeutic agent associated with the core.

16. The method of claim 15, wherein the carrier protein is albumin.

17. The method of claim 15 or claim 16, wherein the antibody is selected from the group consisting of ado-trastuzumab emtansine, alemtuzumab, bevacizumab, blinatumomab, brentuximab vedotin, cetuximab, denosumab, dinutuximab, ibritumomab tiuxetan, ipilimumab, nivolumab, obinutuzumab, ofatumumab, panitumumab, pembrolizumab, pertuzumab, rituximab, trastuzumab, or any biosimilar thereof.

18. The method of any one of claims 15-17, wherein the chemotherapeutic agent is selected from the group consisting of abiraterone, bendamustine, bortezomib, carboplatin, cabazitaxel, cisplatin, chlorambucil, dasatinib, docetaxel, doxorubicin, epirubicin, erlotinib, etoposide, everolimus, gefitinib, idarubicin, imatinib, hydroxyurea, imatinib, lapatinib, leuprorelin, melphalan, methotrexate, mitoxantrone, nedaplatin, nilotinib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, picoplatin, romidepsin, satraplatin, sorafenib,

vemurafenib, sunitinib, teniposide, triplatin, vinblastine, vinorelbine, vincristine, and cyclophosphamide.

19. The method of any one of claims 12-18, wherein the anti -fugetactic agent AMD3100, KRH-1636, T-20, T-22, T-140, TE-14011, T-14012, TN14003, TAK-779, AK602, SCH- 351125, Tannic acid, NSC 651016, thalidomide, GF 109230X, an antibody that interferes with dimerization of a fugetactic chemokine, or an antibody that interferes with dimerization of a receptor for a fugetactic chemokine.

20. The method of any one of claims 11-19, wherein a subset of the antibody is not bound to the antibody binding motif.

21. The method of any one of claims 11-20, wherein the antibody binding motif is CD 16 or CD 19.

22. The method of claim 21, wherein the CD 16 is a high-affinity CD 16.

23. The method of any one of claims 11-22, wherein the antibody has an affinity for the antibody binding motif of at least 10⁶ M^"1.

24. The method of any claims 11-23, wherein the antibody recognizes a tumor-associated epitope.

25. A method for treating cancer in a patient which method comprises administering to said patient a combination of immunotherapy and chemotherapy, wherein said

immunotherapy comprises administering to said patient an effective amount of an NK-92 cell composition, said composition comprising NK-92 cells comprising a high avidity monoclonal antibody bound thereto through an antibody binding motif on the surface of said cells, and further wherein said cells have been exposed to a sufficient amount of irradiation so as to have a finite lifespan, thereby rendering said composition suitable for in vivo injection; and said chemotherapy comprises administering to said patient a protein carrier having a plurality of said monoclonal antibodies complexed thereto, said protein carrier further comprising a chemotherapeutic agent associated therewith.

26. The method of claim 25, wherein said combination is administered concurrently.

27. The method of claim 25, wherein said combination is administered sequentially.

28. The method of any one of claims 25-27, wherein the antibody binding motif is CD16 or CD 19.

29. The method of claim 28, wherein the CD 16 is a high-affinity CD 16.

30. A method of making an NK-92 composition that is suitable for in vivo injection into a patient, the method comprising:

contacting the NK-92 cell population with a monoclonal antibody having a high avidity for the antibody binding motif under conditions to bind the antibody to the antibody binding motif;

optionally contacting the NK-92 cell population with an anti -fugetactic agent under conditions to bind the anti-fugetactic agent to the NK-92 cells; and

31. The method of claim 30, wherein the anti-fugetactic agent is AMD3100, KRH-1636, T-20, T-22, T-140, TE-14011, T-14012, TN14003, TAK-779, AK602, SCH-351125, Tannic acid, NSC 651016, thalidomide, GF 109230X, an antibody that interferes with dimerization of a fugetactic chemokine, or an antibody that interferes with dimerization of a receptor for a fugetactic chemokine.

32. The method of claim 30 or claim 31, wherein the antibody binding motif is CD16 or CD 19.

33. The method of claim 32, wherein the CD16 is a high-affinity CD16.

34. The method of any one of claims 30-33 wherein a first subset of the antibody is bound to the antibody binding motif and a second subset of the antibody is not bound to the antibody binding motif.

35. An aqueous pharmaceutical composition comprising antibodies and K-92 cells which express a high-affinity receptor on the cell surface, wherein at least a portion of the antibodies are bound to the high-affinity receptor; and a pharmaceutically acceptable excipient.

36. The composition of claim 35, wherein the cells have been exposed to a sufficient amount of irradiation so as to have a finite lifespan, thereby rendering said composition suitable for in vivo injection.

37. The composition of claim 35 or 36, wherein the high-affinity receptor is high-affinity CD 16.

38. The composition of claim 35 or 36, further comprising an anti-fugetactic agent.

39. The composition of claim 38, wherein at least a portion of the anti-fugetactic agent is bound to CXCL4 on the cell surface.

40. A method for treating a patient having a cancer which expresses an antigen, the method comprising administering to the patient a therapeutically effective amount of the composition of claim 35, wherein the antibody recognizes the antigen.

41. The method of claim 40, further comprising administering to the patient a

therapeutically effective amount of an anti-fugetactic agent.

42. The method of claim 41, wherein the anti-fugetactic agent was bound to the ha K-92 cells in vitro.

43. The method of claim 42, wherein the anti-fugetactic agent is AMD-3100.

44. The method of claim 40 or 41, further comprising administering to the patient a nanoparticle complex comprising albumin-bound paclitaxel complexed to a second antibody, wherein the second antibody recognizes an epitope expressed by the cancer.