WO2008091643A2 - Système de culture in vitro pour évaluer la synergie du ciblage de voies immunosuppressives concomitantes à une immunothérapie - Google Patents

Système de culture in vitro pour évaluer la synergie du ciblage de voies immunosuppressives concomitantes à une immunothérapie Download PDF

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WO2008091643A2
WO2008091643A2 PCT/US2008/000890 US2008000890W WO2008091643A2 WO 2008091643 A2 WO2008091643 A2 WO 2008091643A2 US 2008000890 W US2008000890 W US 2008000890W WO 2008091643 A2 WO2008091643 A2 WO 2008091643A2
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antibody
monoclonal antibody
alt
chemotherapeutic drug
antigen
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PCT/US2008/000890
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WO2008091643A3 (fr
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Birgit C. Schultes
Antoine A. Noujaim
Christopher F. Nicodemus
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Altarex Medical Corp.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/208—IL-12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2086—IL-13 to IL-16
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • cancer recurrence remains a concern.
  • typical treatment includes surgery followed by high doses of chemotherapy.
  • a majority of these patients relapse and do not respond to other chemotherapeutic treatments. These patients then avail themselves to experimental or salvage treatments.
  • tumor-induced immune suppression is an obstacle to cancer immunotherapy, and it involves many different pathways exploited by the tumor.
  • the invention relates to immunology. More particularly, the invention relates to the use of agents targeting / antagonizing immune suppressive pathways concurrent to immunotherapy, or concurrent to immunotherapy in combination with chemotherapy.
  • the agents block one or more dominant suppressive pathways to improve outcomes of tumor immunotherapi es .
  • One aspect of the invention provides a method for treating cancer, comprising concurrently administering a binding agent, such as a monoclonal antibody (e.g., a xenotypic monoclonal antibody), a chemotherapeutic drug, and an agent that antagonizes one or more immune suppressive pathways to a patient suffering from cancer.
  • a binding agent such as a monoclonal antibody (e.g., a xenotypic monoclonal antibody), a chemotherapeutic drug, and an agent that antagonizes one or more immune suppressive pathways to a patient suffering from cancer.
  • Another aspect of the invention provides a method for treating cancer, comprising concurrently administering a binding agent, such as a monoclonal antibody (e.g., a xenotypic monoclonal antibody), and an agent that antagonizes one or more immune suppressive pathways to a patient suffering from cancer.
  • a binding agent such as a monoclonal antibody (e.g., a xenotypic monoclonal antibody)
  • an agent that antagonizes one or more immune suppressive pathways to a patient suffering from cancer.
  • the binding agent is a monoclonal antibody, such as a xenotypic monoclonal antibody.
  • the xenotypic monoclonal antibody is murine.
  • Exemplary xenotypic monoclonal antibody is AIt-I , Alt-2, Alt-3, Alt-4, Alt-5, or Alt-6.
  • the patient is a human.
  • the agent comprises a cytokine.
  • the agent comprises IL-15, TNF-alpha, FLT-3L, IL- 12, IL- 21 , IL-23, or combination thereof. In certain embodiments, the agent comprises an antibody.
  • the antibody blocks an immune regulatory mechanism (e.g., blocks one or more inhibitory receptors), or inhibits, inactivates, or removes T 1 eg .
  • an immune regulatory mechanism e.g., blocks one or more inhibitory receptors
  • the antibody is effective at increasing T-cell reactivity particularly to the tumor.
  • the antibody comprises an anti-CD25 antibody, an anti-GITR antibody, an anti-B7-Hl antibody, an anti-TGF- ⁇ antibody, or a combination thereof.
  • the agent comprises an inhibitor of IDO or an Arginase inhibitor.
  • the agent comprises NOHA or 1 -MT.
  • the agent comprises a cytokine, an antibody, an inhibitor of IDO or an Arginase inhibitor, or a combination thereof.
  • the agent comprises one or more of IL- 15, TNF-alpha, FLT- 3L, IL-12, IL-21, IL-23, an anti-CD25 antibody, an anti-GITR antibody, an anti-B7-Hl antibody, an anti-TGF- ⁇ antibody, NOHA or 1-MT, or a combination thereof; wherein the chemotherapeutic drug is Gemcitabine or Topotecan; and wherein the xenotypic monoclonal antibody is an anti-CA 125 antibody (such as OVAREX ® MAb or MAb B43.13) or an anti- MUC-I antibody (such as BREV AREX ® MAb or MAb-AR20.5).
  • the chemotherapeutic drug is Gemcitabine or Topotecan
  • the xenotypic monoclonal antibody is an anti-CA 125 antibody (such as OVAREX ® MAb or MAb B43.13) or an anti- MUC-I antibody (such as BREV AREX ® MAb or
  • the chemotherapeutic drug is administered within a week before the monoclonal antibody. In certain embodiments, the chemotherapeutic drug is administered within a week after the monoclonal antibody. In certain embodiments, the chemotherapeutic drug is administered simultaneously (e.g., concurrently or at about the same time or within the same day) with the monoclonal antibody.
  • the monoclonal antibody is administered in a dose of less than or equal to 10 mg, 5 mg, 2 mg, 1 mg, 0.5 mg.
  • the monoclonal antibody is administered in a dose of about 0.1 ⁇ g to 2 mg per kg of body weight, or about about 0.2 ⁇ g to 1 mg per kg of body weight, or about 0.5 ⁇ g to 500 ⁇ g per kg of body weight, or about 1 ⁇ g to 250 ⁇ g per kg of body weight, or about 2 ⁇ g to 100 ⁇ g per kg of body weight, or about 5 ⁇ g to 50 ⁇ g per kg of body weight, etc.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being highly toxic to the patient.
  • the method further comprises surgical removal of the cancer.
  • the cancer is surgically removed concurrent with the administration of the chemotherapeutic drug and the monoclonal antibody in a dose (1) equal to or less than 10 mg, 5 mg, 2 mg, 1 mg, 0.5 mg; or (2) about 0.1 ⁇ g to 2 mg per kg of body weight, or about about 0.2 ⁇ g to 1 mg per kg of body weight, or about 0.5 ⁇ g to 500 ⁇ g per kg of body weight, or about 1 ⁇ g to 250 ⁇ g per kg of body weight, or about 2 ⁇ g to 100 ⁇ g per kg of body weight, or about 5 ⁇ g to 50 ⁇ g per kg of body weight, etc.
  • the monoclonal Ab is Alt- 1 , Alt-2, Alt-3, Alt-4, Alt-5, or AIt- 6.
  • administration of the monoclonal antibody comprises a 20 minute intravenous infusion.
  • the chemotherapeutic drug is administered within seven days prior to the administration of the monoclonal antibody.
  • the chemotherapeutic drug is administered within seven days following the administration of the monoclonal antibody.
  • the chemotherapeutic drug is administered every four weeks for six cycles.
  • the method further comprises the step of administering the monoclonal antibody every twelve weeks for up to two years.
  • the monoclonal antibody and chemotherapeutic drug are administered at weeks 1, 4, and 8, followed by further administration of the chemotherapeutic drug alone at weeks 12 and 16, followed by concurrent administration of the chemotherapeutic drug and xenotypic monoclonal antibody at week 20.
  • the concurrent administration of the monoclonal antibody and the chemotherapeutic drug occurs at week 1, followed by administration of the chemotherapeutic drug at week 4, wherein the concurrent administration is repeated for six cycles and followed by administration of the monoclonal antibody every twelve weeks for up to two years.
  • the monoclonal antibody is administered at weeks 1, 3, 5, 7 and 9, followed by concurrent administration of the chemotherapeutic drug and the monoclonal antibody in a dose less than or equal to 2 mg at week 12.
  • the dosage level may be varied asindicated herein above, or be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being highly toxic to the patient.
  • the concurrent administration of the chemotherapeutic drug and monoclonal antibody is repeated every four weeks for up to 6 cycles.
  • the method further comprises administering the monoclonal antibody every twelve weeks for up to two years.
  • the method comprises administering the monoclonal antibody and the chemotherapeutic agents according to the schemes shown in Figure 13 or described in Example IV.
  • the method comprises administering the chemotherapeutic drug at Weeks 0, 4, 8, 12, 16, and 20 (Cycles 1-6, respectively), and administering the monoclonal antibody either concurrently with, or about one week after administering the chemotherapeutic agent (e.g., carboplatin/paclitaxel for ovarian cancer), at Day 1 of Week 0 (Cycle 1), Week 8 (cycle 3), and Week 16 (cycle 5), (about 4 weeks between cycles), followed by administering the monoclonal antibody every twelve weeks for up to two years or until disease progression.
  • the chemotherapeutic agent e.g., carboplatin/paclitaxel for ovarian cancer
  • Another aspect of the invention provides a method for inducing a host immune response in a patient against a multi-epitopic in vivo tumor antigen, which antigen does not elicit an effective host immune response, comprising concurrently administering to the patient: (1) an agent that antagonizes one or more immune suppressive pathways to a patient suffering from cancer; (2) a chemotherapeutic drug; and, (3) a composition comprising a binding agent that specifically binds to a first epitope on the antigen and allowing the binding agent to form a binding agent/antigen pair, wherein a host immune response is elicited against a second epitope on the antigen.
  • the binding agent is a murine monoclonal antibody.
  • the murine MAb is AIt-I, Alt-2, Alt-3, Alt-4, Alt-5, or Alt-6.
  • the patient is human.
  • the chemotherapeutic drug is administered within a week before the binding agent. In certain embodiments, the chemotherapeutic drug is administered within a week after the binding agent. In certain embodiments, the chemotherapeutic drug is administered simultaneously ⁇ e.g., concurrently or at about the same time or within the same day) with the binding agent.
  • the binding agent is administered in a dose (1) equal to or less than 10 mg, 5 mg, 2 mg, 1 mg, 0.5 mg; or (2) about 0.1 ⁇ g to 2 mg per kg of body weight, or about about 0.2 ⁇ g to 1 mg per kg of body weight, or about 0.5 ⁇ g to 500 ⁇ g per kg of body weight, or about 1 ⁇ g to 250 ⁇ g per kg of body weight, or about 2 ⁇ g to 100 ⁇ g per kg of body weight, or about 5 ⁇ g to 50 ⁇ g per kg of body weight, etc.
  • the method further comprises surgical removal of the cancer.
  • Another aspect of the invention provides a method for treating cancer, comprising concurrent administration to a patient suffering from cancer a chemotherapeutic drug, a binding agent, an antigen, and an agent that antagonizes one or more immune suppressive pathways.
  • the binding agent is a murine monoclonal antibody, such as AIt-I, Alt-2, Alt-3, Alt-4, Alt-5, or Alt-6.
  • the patient is human.
  • the chemotherapeutic is administered within a week before the murine monoclonal antibody. In certain embodiments, the chemotherapeutic is administered within a week after the murine monoclonal antibody. In certain embodiments, the chemotherapeutic is administered simultaneously (e.g., concurrently or at about the same time or within the same day) with the murine monoclonal antibody.
  • the murine monoclonal antibody is administered in a dose (1) equal to or less than 10 mg, 5 mg, 2 mg, 1 mg, 0.5 mg; or (2) about 0.1 ⁇ g to 2 mg per kg of body weight, or about about 0.2 ⁇ g to 1 mg per kg of body weight, or about 0.5 ⁇ g to 500 ⁇ g per kg of body weight, or about 1 ⁇ g to 250 ⁇ g per kg of body weight, or about 2 ⁇ g to 100 ⁇ g per kg of body weight, or about 5 ⁇ g to 50 ⁇ g per kg of body weight, etc.
  • Another aspect of the invention provides a method for inducing a host immune response in a patient against a multi-epitopic in vivo tumor antigen, which antigen does not elicit an effective host immune response, comprising concurrently administering to the patient: (1) an agent that antagonizes one or more immune suppressive pathways; (2) a chemotherapeutic drug; (3) a composition comprising a binding agent present in an amount of from 0.1 ⁇ g to 2 mg per kg of body weight of the host, and wherein the binding agent specifically binds to an epitope on the antigen and an effective host immune response is elicited against a second epitope on the antigen.
  • Another aspect of the invention provides a method for treating cancer, comprising administering a xenotypic antibody, a chemotherapeutic drug, and an agent that antagonizes one or more immune suppressive pathways to a patient suffering from cancer.
  • Another aspect of the invention provides a therapeutic composition
  • a therapeutic composition comprising: (a) at least one monoclonal antibody, each specific for an antigen associated with a disease; and, (b) at least one antagonist of an inhibitory component of the immune system, such as an agent that antagonizes one or more immune suppressive pathways, reduces immune suppression, or inhibits or removes T reg .
  • the therapeutic composition further comprises a chemotherapeutic drug.
  • the antagonist is an antibody. In certain embodiments, the antagonist is a cytokine.
  • the antagonist is selected from the group consisting of: IL- 15, TNF-alpha, FLT-3L, IL- 12, IL-21 , IL-23, an anti-CD25 antibody, an anti-GITR antibody, an anti-B7-Hl antibody, an anti-TGF- ⁇ antibody, NOHA or 1-MT, and a combination thereof.
  • At least one of said monoclonal antibody is specific for a cancer antigen (e.g., specifically binding to an epitope on a cancer antigen and an effective host immune response is elicited against a second epitope on the antigen).
  • the antigens are associated with the same disease.
  • At least one of said monoclonal antibody is an anti-CA 125 antibody, an anti-MUC-1 antibody, an anti-PSA antibody, an anti-CA 19.9 antibody, or a combination thereof.
  • At least one of said monoclonal antibody is selected from the group consisting of: AIt-I, Alt-2, Alt-3, Alt-4, Alt-5, and Alt-6.
  • the antigens are cancer antigens.
  • kits comprising: (a) at least one monoclonal antibody each specific for an antigen associated with a disease; and, (b) at least one antagonist of an inhibitory component of the immune system, such as an agent that antagonizes one or more immune suppressive pathways, reduces immune suppression, or inhibits or removes T reg .
  • an inhibitory component of the immune system such as an agent that antagonizes one or more immune suppressive pathways, reduces immune suppression, or inhibits or removes T reg .
  • the kit further comprises a chemotherapeutic drug.
  • Figure 1 is a diagram showing a non-limiting embodiment of the invention. Patients can continue chemotherapy up to 6 cycles and OVAREX ® MAb up to 2 years. Endpoints: Time to progression, QOL, Safety, Survival.
  • Figure 2 is a graph showing the difference in the numbers between Ab2 responders (open squares, effective immune response) and Ab2 non-responders (black squares, ineffective immune response) over time in ovarian cancer patients.
  • Figure 3 is a schematic representation of an exemplary experimental set up for the experiment described in Example II.
  • Figures 4A-4D show the cytokine results described in Example II.
  • Figures 5A-5D show the antibody results described in Example II.
  • Figures 6A-6D show the IDO/Arginase inhibitor results described in Example II.
  • Figure 7 shows the result of a successful combinations therapy in Example II.
  • Figure 8 shows that IC could induce CD4 + T helper cells, and CD8 + IFN- ⁇ producing CTL cells, whereas PSA alone or PSA in complex with a non-specific antibody mainly stimulated CD4 + T cells, using human immune cells.
  • FIG. 9A shows that immune complexes of PSA and MAb-AR47.47 induce CTL specific for PSA in PSA-transgenic mice.
  • Figure 9B shows that immune complexes of PSA and MAb-AR47.47 also induce ThI and Th2 helper responses to PSA (based on cytokine ELISA assay and ICC assay) in PSA-transgenic mice.
  • Figures 1OA and 1OB show that cross-linking MAb-AR47.47 increased humoral but not cellular responses.
  • Figures 1 IA &1 IB show that increasing the immunogenicity of MAb-AR47.47 enhanced T helper but not CTL responses.
  • Figures 1 1 C & 1 1 D show that increasing the immunogenicity of the anti-PSA antibody in form of a goat antibody in mice enhanced T helper 2 but not T helper 1 or CTL responses.
  • Figures 12A and 12B show that MAb-AR47.47 is able to control tumor growth, and that MAb-AR47.47 in combination with cyclophosphamide is able to reject tumors more so than AR47.47 or cyclophosphamide alone.
  • Figure 13 shows the study design for OVA-Gy-18 described in Example IV.
  • Figure 14 shows certain results of the experiment described in Example IV.
  • ELISPOT analysis of the immune response to CA 125 autologous dendritic cells (DCs) were pulsed with CA 125 4 hours prior to maturation. Pulsed and non-pulsed DC were incubated with PBMCs from each time point in triplicate on anti-IFN- ⁇ coated ELISPOT plates, which were stained after 18 hrs. The pre-immunization and maximum response measured post immunization are displayed. The ELISPOT assay was conducted at SBI.
  • T regulatory cells and TCR zeta T cells in peripheral blood were characterized by flow cytometry using phycoerythrin-labeled anti-human CD25 and phycoerythrin-cyanine 5-labeled CD4, both purchased from Beckman Coulter (Fullerton, CA) and fluorescein isothiocyanate-labeled FoxP3 (eBiosciences, San Diego, CA).
  • Figure 15 shows certain results of the experiment described in Example IV.
  • FIG. 1 Kaplan-Meier graph of PFS, ITT Population. Twelve month PFS estimate from Kaplan-Meier analysis. Kaplan-Meier graph of (B) PFS and (C) overall survival dichotomized by treatment emergent CA 125 specific T-cell response (responder or non- responder).
  • the invention relates to immunology. More particularly the invention relates to the use of immunotherapy in combination with chemotherapy.
  • the present invention partly stems from the discovery that a combination of immunotherapy with traditional chemotherapy and/or radiotherapy alleviates and/or prevents the recurrence of cancer, or improves the treatment of cancer.
  • the presence of a host anti- xenotypic antibody response in a patient will stimulate an immune response, and the administration of an agent that antagonizes one or more immune suppressive pathways promotes host immune response.
  • the inventors have exploited this discovery to develop therapeutics containing binding agents and agents that antagonize one or more immune suppressive pathways useful in immunotherapy, and chemotherapeutic or radiotherapeutic drugs, as well as methods for using these therapeutics.
  • the patents and publications cited herein reflect the level of skill in this field and are hereby incorporated by reference in their entirety to the same extent as if each was specifically and individually indicated to be incorporated by reference.
  • the invention provides a method for treating cancer, comprising concurrently administering a binding agent, such as a monoclonal antibody (e.g., a xenotypic monoclonal antibody), a chemotherapeutic drug, and an agent that antagonizes one or more immune suppressive pathways to a patient suffering from cancer.
  • a binding agent such as a monoclonal antibody (e.g., a xenotypic monoclonal antibody), a chemotherapeutic drug, and an agent that antagonizes one or more immune suppressive pathways to a patient suffering from cancer.
  • the invention relates to a method for treating cancer, comprising concurrently administering a binding agent, such as a monoclonal antibody (e.g., a xenotypic monoclonal antibody), and an agent that antagonizes one or more immune suppressive pathways to a patient suffering from cancer.
  • a binding agent such as a monoclonal antibody (e.g., a xenotypic monoclonal antibody)
  • an agent that antagonizes one or more immune suppressive pathways to a patient suffering from cancer.
  • such agent may comprise a cytokine.
  • the cytokine can be IL-15, TNF-alpha, FLT-3L, IL-12, IL-21 , IL-23, or combination thereof.
  • the agent comprises an antibody.
  • the antibody blocks an immune regulatory mechanism, e.g., blocks one or more inhibitory receptors, or inhibits, inactivates, or removes T reg (regulatory T cells).
  • the antibody is effective at increasing T-cell reactivity particularly to the tumor.
  • exemplary such antibodies include an anti-CD25 antibody, an anti- GITR antibody, an anti-B7-Hl antibody, an anti-TGF- ⁇ antibody, or a combination thereof.
  • the agent comprises an inhibitor of IDO or an Arginase inhibitor.
  • the agent may comprise NOHA or 1-MT.
  • the agent comprises a cytokine, an antibody, an inhibitor of IDO or an Arginase inhibitor, or a combination thereof.
  • the agent comprises one or more of IL- 15, TNF- alpha, FLT-3L, IL-12, IL-21, IL-23, an anti-CD25 antibody, an anti-GITR antibody, an anti- B7-H1 antibody, an anti-TGF- ⁇ antibody, NOHA or 1-MT, or a combination thereof; wherein the chemotherapeutic drug is gemcitabine or topotecan; and wherein the xenotypic monoclonal antibody is an anti-CA 125 antibody (such as OVAREX ® MAb or MAb B43.13) or an anti-MUC-1 antibody (such as BREV AREX ® MAb or MAb-AR20.5).
  • the binding agent is an antibody, such as a monoclonal antibody.
  • the monoclonal antibody may be a xenotypic monoclonal antibody, such as a murine monoclonal antibody when, for example, the patient is a human.
  • the binding by the (xenotypic) monoclonal antibody of a first epitope exposes a second distinct epitope on the antigen or enables an immune response to such second distinct epitope.
  • the (xenotypic) monoclonal antibody when bound to the antigen, forms an immunogenic complex.
  • exemplary (xenotypic) monoclonal antibodies (“MAb"), preferably include IgGl antibodies; chimeric monoclonal antibodies (“C-MAb”); humanized antibodies; genetically engineered monoclonal antibodies ("G- MAb”); fragments of monoclonal antibodies (including but not limited to "F(ab) 2 ", "F(ab)” and “Dab”); and single chains representing the reactive portion of monoclonal antibodies (“SC-MAb”).
  • the binding agent may be labeled or unlabeled.
  • preferred xenotypic monoclonal antibodies include, without limitation, murine monoclonal antibodies.
  • Particularly preferred murine monoclonal antibodies include those with the same binding specificity, or those binding to the same epitope as that bound by: AIt-I (murine IgGl , specifically binds to MUC-I ; ATCC No. PTA-975; American Type Culture Collection, Manassas, Va.), Alt-2 (OVAREX ® MAb B43.13, murine IgGl, specifically binds to CA 125; ATCC No. PTA-1883), Alt3 (murine IgG3, specifically binds to CA 19.9; ATCC No.
  • Alt-4 murine IgM, specifically binds to CA 19.9; ATCC No. PTA-2692
  • Alt-5 murine IgGl, specifically binds to CA 19.9; ATCC No. PTA-2690
  • Alt-6 murine IgGl, specifically binds to prostate specific antigen (PSA); ATCC No. HBl 2526.
  • the chemotherapeutic drug used is commercially available.
  • the chemotherapeutic can be an inhibitor of chromatin function, a topoisomerase inhibitor, a microtubule inhibiting drug, a DNA damaging agent, an antimetabolite (such as folate antagonists, pyrimidine analogs, purine analogs, and sugar-modified analogs), a DNA synthesis inhibitor, a DNA interactive agent (such as an intercalating agent), and/or a DNA repair inhibitor.
  • Some non limiting examples include carboplatin, cisplatin, docetaxel, paclitaxel, doxorubicin, HCl liposome injection, topotecan, hydrochloride, gemcitabine, cyclophosphamide, and etoposide or any combination thereof.
  • preferred chemotherapeutic drug is gemcitabine, topotecan and cyclophosphamide.
  • Chemotherapeutic agents may be categorized by their mechanism of action into, for example, the following groups: anti-metabolites/anti-cancer agents, such as pyrimidine analogs (5-fluorouracil, floxuridine, capecitabine, gemcitabine and cytarabine) and purine analogs, folate antagonists and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine (cladribine)); antiproliferative/antimitotic agents including natural products such as vinca alkaloids (vinblastine, vincristine, and vinorelbine), microtubule disruptors such as taxane (paclitaxel, docetaxel), vincristin, vinblastin, nocodazole, epothilones and navelbine, epidipodophyllotoxins (etoposide, teniposide), DNA damaging agents (actinomycin, amsacrine, anthracyclines,
  • the chemotherapeutic drug is administered within a week before or after the murine monoclonal antibody (as binding agent).
  • cancer is used to mean a condition in which a cell in a patient's body undergoes abnormal, uncontrolled proliferation.
  • the abnormal cell may proliferate to form a solid tumor, or may proliferate to form a multitude of cells (e.g., leukemia).
  • leukemia e.g., leukemia
  • a patient suffering from cancer is treated where additional metastasis either do not occur, or are reduced in number as compared to a patient who does not receive treatment.
  • a patient is treated where the patient's solid cancer either becomes reduced in size or does not increase in size as compared to a patient who does not receive treatment.
  • the number of cancer cells e.g., leukemia cells
  • the patient is human.
  • a "patient suffering from cancer” of the invention may express the mutant protein and not yet be symptomatic for the disease.
  • the cancer is colon cancer (which is associated with the mutant K-ras protein)
  • a patient with a mutant K-ras protein in some cells of the colon is a patient according to the invention even though that patient may not yet be symptomatic for colon cancer.
  • Associated with a mutant protein means signs or symptoms of illness in a majority of patients are present when the mutant protein is present in the patient's body, but in which signs or symptoms of illness are absent when the mutant protein is absent from the patient's body.
  • “Signs or symptoms of illness” are clinically recognized manifestations or indications of disease.
  • the patient in need of treatment is suffering from cancer of the prostate, ovaries, breast, stomach, lung, colon, and skin.
  • the patient in need of treatment is a human.
  • the therapeutic compositions of the invention further comprise a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is meant a carrier that is physiologically acceptable to the administered patient.
  • One exemplary pharmaceutically acceptable carrier is physiological saline.
  • Other pharmaceutically- acceptable carriers and their formulations are well-known and generally described in, for example, Remington's Pharmaceutical Sciences (18th Ed., ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990).
  • administering means providing the composition to the patient in a manner that results in the composition being inside the patient's body.
  • Such an administration can be by any route including, without limitation, parenteral, sub-cutaneous, intradermal, intravenous, intra-arterial, intraperitoneal, and intramuscular.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the subject pharmaceutical compositions, are formulated into pharmaceutically acceptable dosage forms such as described below or by other conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being highly toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular composition employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • the method further comprises surgery, administration of a chemotherapeutic drug, and administration of a (xenotypic) monoclonal antibody in a dose equal to or less than 2 mg given by intravenous infusion over 20 minutes during weeks 1, 3, 5, 9, then every 8 weeks, followed by administration of a chemotherapeutic drug within 5 days of the administration of the binding agent.
  • the xenotypic antibody e.g., Alt-2
  • the xenotypic antibody is administered as a 2 mg dose dissolved in 50 mL saline and infused slowly preferably over approximately 20 minutes. If an allergic or other reaction occurs that may limit the completion of the dose, then a lower dose may be employed at that time or with subsequent treatments, so that the expected dose range would be 1 -2 mg per treatment.
  • Premedication with oral or intravenous dyphenhydramine (25 to 50 mg) is usually administered to lessen the risk of allergic reaction to the protein.
  • the schedule used for combined Alt-2 and chemotherapy for example, comprises administering Alt-2 at the dose above at weeks 1, 3, 5, 7, 9 with chemotherapy administered with Alt-2 on weeks 12 through 26.
  • Alt-2 may be started after recovery from any required surgery that is done prior to the chemotherapy and then continued up to, and during, the chemotherapy treatment period.
  • the chemotherapy can be given in 3-4 week cycles or other schedules according to the treating physician and common clinical practice.
  • Chemotherapy may continue for up to six cycles followed by the xenotypic antibody administration every twelve weeks for up to two years.
  • the method comprises surgery, followed within seven days by administration of a (xenotypic) monoclonal antibody in a dose equal to or less than 2 mg given by intravenous infusion over 20 minutes during weeks 1 , 3, 5, 9, then every 8 weeks with concurrent administration of a chemotherapeutic drug at week 3 and thereafter.
  • the murine antibody is administered at week 1 after completing standard surgery but has not yet begun chemotherapy.
  • the murine antibody is administered in a dose equal to or less than 2 mg via a 20 minute intravenous infusion followed by a second treatment and concurrent administration of a chemotherapeutic drug on weeks 6 and beyond.
  • Concurrent Administration means administration within a relatively short time period from each other. Preferably such time period is less than 2 weeks, more preferably less than 7 days, most preferably less than 1 day and could even be administered simultaneously.
  • the method comprises administering the chemotherapeutic drug at Weeks 0, 4, 8, 12, 16, and 20 (Cycles 1-6, respectively), and administering the monoclonal antibody either concurrently with, or about one week after administering the chemotherapeutic agent (e.g., carboplatin/paclitaxel for ovarian cancer), at Day 1 of Week 0 (Cycle 1), Week 8 (cycle 3), and Week 16 (cycle 5), (about 4 weeks between cycles), followed by administering the monoclonal antibody every twelve weeks for up to two years or until progression.
  • the chemotherapeutic agent e.g., carboplatin/paclitaxel for ovarian cancer
  • the expected progression-free survival times may be measured in months to years, depending on prognostic factors including the number of relapses, stage of disease, and other factors. Overall survival is also measured in months to years.
  • the addition of the xenotypic monoclonal antibody, Alt-2 is expected to increase the time to recurrence or progression, and may also prolong the survival time. Any improvement of 2 months or longer is usually considered to be clinically meaningful.
  • the invention provides a method for inducing a host immune response in a patient against a multi-epitopic in vivo tumor antigen present in the host's serum, which antigen does not elicit a host immune response, comprising administering to the patient an agent that antagonizes one or more immune suppressive pathways, a chemotherapeutic drug, and a composition comprising a binding agent that specifically binds to a first epitope on the antigen and allowing the binding agent to form a binding agent/antigen pair, wherein a host immune response is elicited against a second epitope on the antigen.
  • binding agent refers to one member of a binding pair, including an immunologic pair, e.g., a binding moiety that is capable of binding to an antigen, preferably a single epitope expressed on the antigen, such as a predetermined tumor antigen.
  • an immunologic pair e.g., a binding moiety that is capable of binding to an antigen, preferably a single epitope expressed on the antigen, such as a predetermined tumor antigen.
  • the binding of a first single epitope exposes a second distinct epitope on the antigen.
  • the binding agent when bound to the antigen, forms an immunogenic complex.
  • Exemplary binding agents include, but are not limited to: antibodies, monoclonal antibodies ("MAb”), preferably IgGl antibodies; chimeric monoclonal antibodies (“C-MAb”); humanized antibodies; genetically engineered monoclonal antibodies (“G-MAb”); fragments of monoclonal antibodies (including but not limited to "F(Ab).
  • MAb monoclonal antibodies
  • C-MAb chimeric monoclonal antibodies
  • G-MAb genetically engineered monoclonal antibodies
  • fragments of monoclonal antibodies including but not limited to "F(Ab).
  • binding agent may be labeled or unlabeled.
  • Preferred binding agents of the invention are monoclonal antibodies.
  • these xenotypic monoclonal antibodies include, without limitation, murine monoclonal antibodies.
  • Particularly preferred murine monoclonal antibodies include those with the same binding specificity, or those binding to the same epitope as that bounds by: AIt-I (murine IgGl, specifically binds to MUC-I; ATCC No. PTA-975; American Type Culture Collection, Manassas, Va.), Alt-2 (OVAREX ® Mab-B43.13, murine IgGl, specifically binds to CA 125; ATCC No. PTA-1883), Alt3 (murine IgG3, specifically binds to CA 19.9; ATCC No.
  • Alt-4 murine IgM, specifically binds to CA 19.9; ATCC No. PTA-2692
  • Alt-5 murine IgGl , specifically binds to CA 19.9; ATCC No. PTA-2690
  • Alt-6 murine IgGl, specifically binds to prostate specific antigen (PSA); ATCC No. HB-12526.
  • a "multi-epitopic in vivo tumor antigen” is an antigen that presents multiple epitopes on its surface.
  • Some non-limiting examples of such antigens include CA 125, MUC-I, PSA, CA 19.9, and TAG-72. Although they are called antigens, these molecules, while aberrant, are frequently tolerated in cancer patients and as such their presence does not by itself evoke a remedial immune reaction.
  • “Inducing a host immune response” means that the patient experiences alleviation or reduction of signs or symptoms of illness, and specifically includes, without limitation, prolongation of survival.
  • a CD8 + IFN- ⁇ producing T cell is activated to induce a cytotoxic T lymphocyte (CTL) immune response in the patient administered the murine monoclonal antibody.
  • CTL cytotoxic T lymphocyte
  • a CD4 + IFN- ⁇ producing T cell is activated to induce a helper T cell immune response in the patient administered with the composition.
  • a CD4 + IL-4 or IL-5 producing T cell is activated to induce a helper T cell immune response in the patient administered with the composition.
  • Activated CD4 + IL-4 or IL-5 producing T cells i.e., helper T cells
  • provide necessary immunological help e.g. by release of cytokines
  • a humoral response to the antigen is activated in the patient administered with the composition.
  • Activation of a CD8 + and/or CD4 + IFN- ⁇ or IL-4, producing T cells means causing T cells that have the ability to produce IFN- ⁇ or IL-4 to actually produce IFN- ⁇ or IL-4, or to increase their production of IFN- ⁇ or IL-4.
  • “Induction of CTL” means causing potentially cytotoxic T lymphocytes to exhibit antigen specific cytotoxicity.
  • Antigen specific cytotoxicity means cytotoxicity against a cell presenting an epitope that is associated with the antigen associated with the cancer that is greater than an antigen that is not associated with the cancer.
  • Cytotoxicity refers to the ability of the cytotoxic T lymphocyte to kill the target cell. Preferably, such antigen-specific cytotoxicity is at least 3-fold, more preferably 10-fold greater, more preferably more than 100-fold greater than cytotoxicity against a cell not presenting the antigen not associated with the cancer.
  • the method comprises concurrent administration of a chemotherapeutic drug, a binding agent, an antigen, and an agent that antagonizes one or more immune suppressive pathways.
  • the invention provides a method for inducing a host immune response in a patient against a multi-epitopic in vivo tumor antigen, which antigen does not elicit an effective host immune response, comprising concurrently administering to the patient an agent that antagonizes one or more immune suppressive pathways, a chemotherapeutic drug, and a composition comprising a binding agent present in an amount of from 0.1 ⁇ g to 2 mg per kg of body weight of the host, and wherein the binding agent specifically binds to an epitope on the antigen and an effective host immune response is elicited against a second epitope on the antigen.
  • Alt-2 was administered by 20-minute infusion in weeks 1, 3, 5, and 9 prior to initiation of chemotherapy, and then an option to continue every 8 weeks x 2 doses concurrent with chemotherapy on weeks 12 and 26.
  • Humoral immune responses including HAMA, Ab2 and anti-CA 125 antibody, were assessed at baseline and serially.
  • ELISPOT assay T cell responses were evaluated for activation by Alt-2, CA 125, or autologous tumor.
  • Applicants have developed an in vitro system for ovarian cancer using human dendritic cells (DC), T cells, and HLA-A2 matched live NIH:OVCAR-3 tumor cells to assess the presence of tumor-induced regulatory pathways and to study agents that impact such mechanisms.
  • the system generates regulatory T cells (T reg ), non-responsive T cells, DC with an immature phenotype, and high levels of TGF- ⁇ .
  • the co-cultures were treated with antibodies to neutralize soluble factors such as TGF- ⁇ or VEGF, antibodies to block immune suppressive cell surface molecules like GITR and B7-H1, cytokines that promote T cell activation (IL-2, IL-7, IL-12, IL-15, IL-21, IL-23) or DC recruitment or activation (GM-CSF, TNF- ⁇ , Flt-3L), antibodies to reduce T reg (rat and human anti-CD25), or inhibitors of indolamine-2,3-dioxygenase (IDO) or arginase (1-MT, NOHA, L-NMMA) for 7 days in the presence or absence of the immune activating antibodies, oregovomab (OVAREX MAb- B43.13, anti-CA 125) or BREV AREX ® MAb-AR20.5 (anti-MUC-1).
  • TGF- ⁇ or VEGF antibodies to block immune suppressive cell surface molecules like GITR and B7-H1, cytokines that promote T cell
  • DC maturation could be improved by addition of anti-CD25 antibodies and TNF- ⁇ .
  • a reduction in the number of T ieg (CD4 + CD25brightFoxP3 + ) in the co-culture was achieved most potently with anti-CD25 antibodies, but also with anti-TGF- ⁇ , anti-GITR, anti-B7-Hl, as well as Flt-3L, IL-12, IL-15, IL-15+IL-21, IL-7, TNF- ⁇ , and inhibitors of IDO and arginase.
  • tumor-specific T cell responses were only restored with anti-TGF- ⁇ , anti-CD25, anti-B7-Hl, anti- GITR, Flt-3L, IL-15, 1-MT and L-NMMA.
  • DC were generated from monocytes for 7 days in GM-CSF and IL-4 in 12-well plates (5x10 5 cells/well). Immature DC were washed, and NIH:OVCAR-3 tumor cells (5x10 4 cells/well) were added on Day 7. The cultures were treated with cytokines, antibodies to regulatory molecules, inhibitors to IDO and arginase, or multiple combinations of effective biologies with each other or with chemotherapeutics, with or without addition of MAb-B43.13, MAb-AR20.5 or control IgGl (5 ⁇ g/mL) for 1 h. T cells isolated from the same donor as the DC were added (2x10 6 cells/well) and the cultures incubated for 7 days. Controls included cultures without drug or tumor cells, cultures with antibodies alone, and tumor cells grown separated from DC and T cells by a semi-permeable membrane.
  • T cells were harvested and stained for CD4-FITC, CD25-PE/Cy5 (CyC) and intracellular FoxP3-PE (eBiosciences) and tested for T cell proliferation against media (background), anti-CD3/CD28 beads, or apoptotic tumor cells (BrdU ELISA, EMD- Calbiochem).
  • DC were harvested and stained with anti-CD40-FITC, CD86-PE and CD83- CyC.
  • Supernatants were tested for TGF-b by ELISA. The averages of 3-5 experiments are shown. The experimental lay-out is described in Figure 3 and the results described herein are shown in Figures 4-7.
  • Cytokines with reported effects in cancer immunotherapy were tested at different concentrations in the co-culture system. Cytokines effective at increasing T cell reactivity particularly to the tumor were tested further in combination with anti-CA 125 and anti-MUC- 1 antibodies at optimum concentrations.
  • IL-15, TNF- ⁇ , FLT-3L, IL-12, IL-21 and IL-23 were able to enhance non-specific and tumor-specific T cell proliferation in a concentration dependent manner.
  • cytokines were tested in combination with tumor specific antibodies (MAb- B43.13 and MAb-AR20.5) and an isotype control (MOPC-21).
  • the specific antibodies showed some enhancement of tumor specific T cell response alone and showed particularly strong responses in combination with IL- 15, TNF- ⁇ , Flt-3L and IL-23).
  • IL- 12 was the only cytokine that affected DC maturation (upregulated CD40 and CD86), but it didn't translate into enhanced T cell activation.
  • IL-15, TNF- ⁇ , FLT-3L, IL- 12, IL-21, and IL-23 were able to enhance T cell proliferation to non-specific stimuli (anti-CD3/CD28) as well as to the co-cultured tumor cells.
  • the effect was enhanced in combination with MAb-B43.13 and MAb-AR20.5 for IL- 15, TNF- ⁇ , FLT-3L and IL-23.
  • Antibodies that block known regulatory mechanisms or remove T ieg were tested at different concentrations in the in vitro system. Antibodies effective at increasing T cell reactivity particularly to the tumor were tested further in combination with anti-CA 125 and anti-MUC-1 antibodies under optimized conditions.
  • Antibodies that block TGF- ⁇ , GITR or B7-H1 or that remove/ inactivate T reg were able to enhance non-specific and tumor-specific T cell proliferation in a concentration dependent manner.
  • anti-CD25 antibodies at low cone.
  • anti-GITR or anti-B7-Hl at blocking cone.
  • the monoclonal and polyclonal anti-GITR antibodies enhanced DC maturation (upregulated CD40, CD86 and CD83; further increased when combined with the tumor- specific antibodies), whereas the humanized anti-CD25 antibody (ZENAPAX ) down- regulated CD83 on co-cultured DC.
  • Antibodies to TGF- ⁇ , CD25, GITR and B7-H1 could enhance T cell stimulation to the co-cultured tumor.
  • Anti-CD25, -GITR and -B7-H1 also showed additive effects in combination with the studied anti-CA 125 and anti-MUC-1 antibodies. Results described herein are shown in Figures 5A-5D.
  • Inhibitors for IDO and arginase were tested in the co-culture system alone and in combination at several concentrations. Effective doses were tested further in combination with anti-CA 125 and anti-MUC-1 antibodies.
  • Inhibitors of IDO and arginase showed a small but statistically significant effect in enhancing T cell responses in the co-culture system.
  • the arginase inhibitor NOHA enhanced CD40 expression on co-cultured DC, IDO inhibitor 1-MT in combination with MAb-B43.13 and MAb-AR20.5 increased CD40 and CD83.
  • the data presented herein demonstrates that co-cultures of iDCs, live tumor cells and T cells showed induction of T reg and inhibition of T cell responses and DC maturation, compared to T cells cultured without tumor cells.
  • Tumor cells separated by a semipermeable membrane induced less T reg and did not inhibit T cell proliferation.
  • Some of the immune suppressive pathways could be reversed by adding certain cytokines (IL- 15, TNF- ⁇ , FLT-3L, IL-23), or antibodies that block inhibitory receptors or T reg (anti-CD25, anti-GITR, anti-B7-Hl).
  • cytokines IL- 15, TNF- ⁇ , FLT-3L, IL-23
  • antibodies that block inhibitory receptors or T reg anti-CD25, anti-GITR, anti-B7-Hl
  • OVAREX ® MAb or BREVAREX ® MAb with chemotherapy (particularly gemcitabine or topotecan) and anti-CD25 antibodies (which are commercially available). Schedules can be further optimized in vivo, in view of specific patient parameters.
  • MAb-B43.13 and MAb-AR20.5 are murine monoclonal IgGl antibodies to CA 125 and MUC-I, respectively (AltaRex Medical Corp.). MOPC21 (Biolegend) was used as isotype control antibody.
  • Anti-TGF- ⁇ , anti-B7-Hl and anti-GITR antibodies were purchased from R&D Systems.
  • Rat anti-CD25 was from Abeam and humanized anti-CD25 (ZENAP AX ® ) was supplied by Roche.
  • Cytokines All cytokines were acquired from Biosource with the exception of Flt-3L, IL- 12 and IL-23 (R&D Systems).
  • NIH:OVCAR-3 ovarian tumor cells were purchased from ATCC.
  • PBL Human PBL: Leukaphoresis samples from healthy normal donors were obtained from SeraCare Life Science Inc. (Oceanside, CA). Peripheral Blood Leukocytes (PBL) were purified on Ficoll (Histopaque 1.077, Sigma).
  • Human DC were prepared from PBL by negative selection with anti-CD3, CD 16 and CD 19, followed by anti-mouse-Ig-magnetic beads (Dynal, Monocyte Isolation Kit). Cells were cultured in GM-CSF and IL-4 (1000 U/ml each, BioSource) for 4- 6 days. Human T cells were isolated using Dynal's Negative T Cell Isolation kit.
  • Chemotherapeutic Drugs Paclitaxel and topotecan were purchased from LKT labs; gemcitabine was obtained from Lilly.
  • PSA is shed into the blood, and is accessible for immune complex formation, but it is not expressed on the cell-surface.
  • PSA-derived peptides are expressed on MHC class I and II for T cell recognition.
  • CTL and T helper 1 responses are considered to be most important, while antibodies to PSA are not expected to have direct effects.
  • the murine MAb-AR47.47 recognizes all circulating forms of PSA, and targets the epitope EPEEFLT (SEQ ID NO: 1). While not wishing to be bound by any particular theory, MAb-AR47.47 is thought to bind PSA and forms an immune complex (IC). The IC is then taken up by antigen processing cells (APCs), such as DCs, via Fc Receptor and MMR. In vitro studies showed that human and murine dendritic cells process PSA more efficiently in immune complex (IC) form with MAb-AR47.47. IC could induce CD4 + T helper cells, and CD8 + IFN- ⁇ producing CTL cells, whereas PSA alone or PSA in complex with a non-specific antibody mainly stimulated CD4 + T cells (see Figure 8).
  • APCs antigen processing cells
  • mice which are tolerant to human PSA (as a self-antigen) on the CD4 and CD8 T cell level.
  • the mice were generated by, and provided as a gift from Dr. Frelinger (U. of Rochester).
  • expression of the full-length human PSA is driven by the murine PSA promoter.
  • the expression is restricted to prostate.
  • B and T cell compartments are tolerant to human PSA.
  • PSA-transfected tumor cells are thus available as excellent transplanted tumor models useful for studying anti-tumor effect of vaccines as well as combination therapies because they are not being spontaneously rejected. These tumor models feature secreted PSA.
  • mice Nine PSA-transgenic mice (3 groups with 3 mice/group) were immunized s.c. at weeks 0, 3, 6 and 9 with PSA (10 ⁇ g/mouse), MAb-AR47.47 alone (50 ⁇ g/mouse), or IC consisting of MAb-AR47.47 and PSA (10 ⁇ g of PSA + 50 ⁇ g of MAb), respectively, at various concentrations.
  • PBS was used as control.
  • B cell and cytokine responses were analyzed at baseline, weeks 4, 7 and 10.
  • T cell responses were analyzed at week 10. That is, test bleeds for antibody and cytokine responses were taken after 2, 3 and 4 immunizations.
  • mice were sacrificed and spleen cells isolated for analysis of T cell responses (CTL and ICC).
  • mice were immunized 3-times s.c. with PSA (2, 10 and 50 ⁇ g/mouse), MAb-AR47.47 (50 ⁇ g/mouse), PSA + MAb-AR47.47 (2, 10, and 50 + 50 ⁇ g/mouse), PSA + MAb-AR47.47 + rabbit anti-mouse IgG (2, 10, and 50 + 50 + 50 ⁇ g/mouse), or PBS.
  • Test bleeds for antibody responses were taken after 2 and 3 immunizations.
  • mice were sacrificed and spleen cells isolated for analysis of T cell responses by IFN- ⁇ ICC.
  • Serum samples were analyzed for antibodies to PSA.
  • mice were immunized 4-times s.c. with PSA + MAb-AR47.47 (10 and 50 ⁇ g/mouse), PSA + MAb-AR47.47-OVA (10 and 50 ⁇ g/mouse), or PBS.
  • PSA + MAb-AR47.47 (10 and 50 ⁇ g/mouse)
  • PSA + MAb-AR47.47-OVA 10 and 50 ⁇ g/mouse
  • PBS PBS
  • mice were immunized 4-times s.c. with PSA (0.4, 2, and 10 ⁇ g/mouse), MAb-AR47.47 (10 ⁇ g/mouse), PSA + MAb-AR47.47 (0.4, 2, and 10 ⁇ g/mouse + 10 ⁇ g/mouse), goat anti-PSA (10 ⁇ g/mouse), PSA + goat-anti-PSA (0.4, 2, and 10 ⁇ g/mouse + 10 ⁇ g/mouse), PSA-KLH (10 ⁇ g/mouse in RIBI adjuvant) or PBS.
  • Test bleeds for antibody responses were taken after 3 and 4 immunizations.
  • mice were sacrificed and spleen cells isolated for analysis of T cell responses by IFN- ⁇ and IL-10 ICC. Serum samples were analyzed for antibodies to PSA.
  • cross-linking MAb-AR47.47 increased humoral but not cellular responses (see Figures 1OA and 10B). Specifically, T cells specific for PSA were highest in the PSA-AR47.47 group. PSA concentration of about 2-10 ⁇ g/mL were found to be effective in complex (equimolar concentration or slight Ab excess). Cross-linking Ab by using rabbit anti-mouse IgG made the IC less effective than the non-cross-linked Ab-PSA complexes. In contrast, increased antibody responses were observed with PSA-AR47.47 IC and IC cross- linked with anti-mouse IgG compared to PSA alone. Cross-linking also enabled antibody responses at lower immunogen concentrations.
  • mice are largely non-responsive to immunizations with PSA or PSA-KLH; particularly on the T cell level, IC (such as AR47.47- PSA IC) can reverse unresponsiveness to PSA and prime antibodies, T helper cells and CTL against this self tumor antigen in vivo.
  • T helper 1 and CTL responses could be induced by immunization with IC but not with PSA or Ab alone. Attempts to make the antibody more foreign in the mice (conjugation to KLH, cross-linking with rabbit Ab, goat anti-PSA, etc.) resulted in better T helper 2 responses, but not T helper 1 or CTL responses.
  • mice were transplanted at Day 0 with 2 x 10 5 CT26.PSA tumor cells (which expresses PSA) at the dorsal flank. When tumors reached about 4-6 mm in diameter (about Day 10), mice were immunized weekly five times with: PSA (2 ⁇ g/mouse), AR47.47 (10 ⁇ g/mouse), PSA+AR47.47 (2+10 ⁇ g/mouse) or PBS (s.c.) control. Tumors were measured every other day and volumes calculated. Mice were sacrificed when tumors reached about 1.5 cm 3 .
  • mice were transplanted at Day 0 with 2 x 10 5 CT26.PSA tumor cells (which expresses PSA) at the dorsal flank.
  • tumors reached about 4-6 mm in diameter (about Day 10)
  • mice were treated i.p. with the chemotherapeutic drug cyclophosphamide or "Cy" (100 mg/kg), followed by immunization 2 days later with: PSA (2 ⁇ g/mouse), AR47.47 (10 ⁇ g/mouse), or PBS (s.c.) control. Cy treatment was repeated once and immunizations 4 times on a weekly schedule. Tumors were measured every other day and volumes calculated.
  • mice treated with AR47.47 in combination with Cy rejected the transplanted tumors in 7 of 8 animals (about 88% remission rate), while PBS control with Cy is only about 50% successful.
  • mice used are PSA-transgenic mice developed by J. Frelinger (see Wei et al., Tissue-specific expression of the human prostate-specific antigen gene in transgenic mice: implications for tolerance and immunotherapy. Proc Nat'l Acad Sci U.S.A. 94: 6369-6374, 1997).
  • These BALB/c mice express human PSA under the probasin promotor in the mouse prostate. Since the human PSA protein is expressed from a transgene in a normal mouse tissue, it is treated as a "self-antigen" by the transgenic mice. As a result, the mice are tolerant to human PSA on the CD4 and CD8 T cell level.
  • AR47.47 can (1) significantly reduce tumor growth in mice transplanted with PSA-expressing prostatic tumor cells; (2) significantly prolong survival of mice transplanted with PSA-expressing prostatic tumor cells; and (3) more effectively reject tumor in combination therapy in mice transplanted with PSA- expressing prostatic tumor cells.
  • MAb-AR47.47 (murine IgGl ; AltaRex Medical Corp.) recognizes free and complexed PSA at the linear epitope EPEEFLT (SEQ ID NO: xxx, see Berlyn et al., Generation of CD4(+) and CD8(+) T lymphocyte responses by dendritic cells armed with PSA/anti-PSA (antigen/antibody) complexes. Clin Immunol 101 : 276-283, 2001), which is involved in the induction of cellular immune response.
  • the antibody is a mouse IgG l ⁇ , and has an affinity of approximately 3 x 10 9 M 1 to all soluble forms of PSA.
  • PSA purified from seminal fluid was purchased from Scripps or Maine Biotechnology Associates.
  • PSA-transgenic mice The mice (BALB/c) were developed by J.F. Frelinger (Wei et al., Tissue-specific expression of the human prostate-specific antigen gene in transgenic mice: implications for tolerance and immunotherapy. Proc Natl Acad Sci USA. 94: 6369- 6374, 1997), which express human PSA under the probasin promotor in the mouse prostate. The mice are tolerant to hu PSA on the CD4 and CD8 T cell level.
  • Immunizations Mice were immunized with PSA, MAb-AR47.47 or IC consisting of MAb-AR47.47 and PSA as well as appropriate controls. Immunizations were given s.c. or i.v. every 2 weeks for a total of 4-5 doses. Mice were monitored for antibodies to PSA and cytokines (IL-4, IFN- ⁇ ) by ELISA, and for T cell responses by IFN- ⁇ ICC, IL-10 ICC, T cell proliferation assay, or CTL assay.
  • PSA PSA
  • cytokines IL-4, IFN- ⁇
  • CT26.PSA tumor cells were transplanted s.c. into the rear flank of the mice at 2x10 5 cells/mouse. When tumors reached approximately 5 mm in diameter, mice were treated with docetaxel, irinotecan, topotecan, or cyclophosphamide (Cy). Only Cy showed an anti-tumor effect in this model.
  • Ovarian cancer is the most lethal gynecological cancer in the US. Modest increases in median survival have occurred in the past 20 years, but patients with advanced disease still have disappointing long term survival. Thus, there is a medical need to explore alternative treatment approaches such as combination therapy.
  • Alt-2 is a CA 125-specific MAb that stimulates immune responses to CA 125.
  • C-IT chemo-immunotherapy
  • Qualifying patients were randomized to concurrent chemotherapy (carboplatin/paclitaxel) with MAb administered at cycles 1, 3, and 5 (Arm A) or 1 week following cycles 1 , 3, and 5 (Arm B) of C. Both arms received oregovomab every 12 weeks until progression; response to C-IT was assessed at 36 weeks.
  • the study design is shown in Figure 13.
  • C-IT was assessed by serial measurements of CA 125, as well as clinical parameters for progression-free survival and survival.
  • Immunological endpoints included development of humoral responses to the MAb (HAMA, Ab2) and cellular immune responses to CA 125 (IFN- ⁇ ELISPOT). Patients were assessed for baseline and on-study immune status including quantitation of tumor infiltrating lymphocytes (TIL), phenotype of PBMC including TCR- ⁇ chain expression and plasma cytokines levels.
  • TIL tumor infiltrating lymphocytes
  • TCR- ⁇ chain expression a marker of functionality of T cells, was decreased in these patients; however, there was a treatment-emergent increase in TCR- ⁇ chain expression on CD4 + cells in both treatment arms (54% and 53% Arms A and B respectively). Patients in both treatment arms had elevated VEGF, IL-10, IL-2R, and TNF- ⁇ at baseline.
  • the immune response to Alt-2 was not abrogated by concurrent administration of chemotherapy or by potential immunosuppression associated with tumor burden present during treatment in the front-line setting. In fact, surgery and front-line C appeared to have an immune-adjuvant effect on both humoral and cellular responses.
  • the results of the experiment are represented in Figures 14 & 15.
  • Chemo-immunotherapy had a similar safety profile to chemotherapy alone.
  • a randomized front-line efficacy study of Alt-2-carboplatin-paclitaxel chemo-immunotherapy administered on the same day is justified to further explore use of Alt-2 beyond maintenance mono-immunotherapy.

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Abstract

L'invention concerne l'immunologie. Plus particulièrement, l'invention concerne l'utilisation d'agents ciblant / antagonisant des voies immunosuppressives concomitantes à une immunothérapie, ou concomitantes à une immunothérapie en combinaison avec une chimiothérapie.
PCT/US2008/000890 2007-01-23 2008-01-23 Système de culture in vitro pour évaluer la synergie du ciblage de voies immunosuppressives concomitantes à une immunothérapie WO2008091643A2 (fr)

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US8217149B2 (en) 2008-12-09 2012-07-10 Genentech, Inc. Anti-PD-L1 antibodies, compositions and articles of manufacture
US8652465B2 (en) 2005-06-08 2014-02-18 Emory University Methods and compositions for the treatment of persistent infections
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US8652465B2 (en) 2005-06-08 2014-02-18 Emory University Methods and compositions for the treatment of persistent infections
US11359013B2 (en) 2005-06-08 2022-06-14 Emory University Methods and compositions for the treatment of persistent infections and cancer by inhibiting the programmed cell death 1 (PD-1) pathway
US9457080B2 (en) 2005-06-08 2016-10-04 Emory University Methods and compositions for the treatment of persistent infections and cancer by inhibiting the programmed cell death 1 (PD-1) pathway
US10370446B2 (en) 2005-06-08 2019-08-06 Emory University Methods and compositions for the treatment of persistent infections and cancer by inhibiting the programmed cell death 1 (PD-1) pathway
EP2331130A4 (fr) * 2008-04-09 2012-11-07 Advanced Immune Therapeutics Inc Anticorps d'ige pour le traitement du cancer
US8697079B2 (en) 2008-04-09 2014-04-15 Quest Pharma Tech Inc. IgE antibodies for the treatment of cancer
EP2331130A2 (fr) * 2008-04-09 2011-06-15 Advanced Immune Therapeutics, Inc. Anticorps d'ige pour le traitement du cancer
US9598491B2 (en) 2008-11-28 2017-03-21 Emory University Methods for the treatment of infections and tumors
US9920123B2 (en) 2008-12-09 2018-03-20 Genentech, Inc. Anti-PD-L1 antibodies, compositions and articles of manufacture
US8217149B2 (en) 2008-12-09 2012-07-10 Genentech, Inc. Anti-PD-L1 antibodies, compositions and articles of manufacture
CN106794246A (zh) * 2014-08-08 2017-05-31 昂奎斯特有限公司 肿瘤抗原特异性抗体和tlr3刺激以增强检查点干扰癌症疗法的性能
EP3177321A4 (fr) * 2014-08-08 2018-02-07 Oncoquest Inc. Anticorps specifique d'antigenes tumoraux et de stimulation de tlr3 pour ameliorer la performance de la therapie par interference du point de contrôle du cancer
US10392444B2 (en) 2014-08-08 2019-08-27 Oncoquest, Inc. Tumor antigen specific antibodies and TLR3 stimulation to enhance the performance of checkpoint interference therapy of cancer
WO2016019472A1 (fr) 2014-08-08 2016-02-11 Quest Pharmatech Inc. Anticorps specifique d'antigenes tumoraux et de stimulation de tlr3 pour ameliorer la performance de la therapie par interference du point de contrôle du cancer
US20180221477A1 (en) * 2017-02-06 2018-08-09 Oncoquest, Inc. Treatment of cancer with therapeutic monoclonal antibody specific for a tumor associated antigen and an immune adjuvant
JP2018127439A (ja) * 2017-02-06 2018-08-16 オンコクエスト インコーポレイテッドＯｎｃｏｑｕｅｓｔ Ｉｎｃ． 腫瘍関連抗原に対し特異的な治療用モノクローナル抗体および免疫アジュバントを用いたがん治療
US10537636B2 (en) * 2017-02-06 2020-01-21 Oncoquest Inc. Treatment of cancer with therapeutic monoclonal antibody specific for a tumor associated antigen and an immune adjuvant
JP6999286B2 (ja) 2017-02-06 2022-01-18 オンコクエスト ファーマシューティカルズ インコーポレイテッド 腫瘍関連抗原に対し特異的な治療用モノクローナル抗体および免疫アジュバントを用いたがん治療
US11351255B2 (en) 2017-02-06 2022-06-07 Oncoquest Inc. Treatment of cancer with therapeutic monoclonal antibody specific for a tumor associated antigen and an immune adjuvant

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