WO2022093944A2 - Oncolytic virus boosts t cell response for effective til therapy - Google Patents

Oncolytic virus boosts t cell response for effective til therapy Download PDF

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Publication number
WO2022093944A2
WO2022093944A2 PCT/US2021/056829 US2021056829W WO2022093944A2 WO 2022093944 A2 WO2022093944 A2 WO 2022093944A2 US 2021056829 W US2021056829 W US 2021056829W WO 2022093944 A2 WO2022093944 A2 WO 2022093944A2
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WIPO (PCT)
Prior art keywords
ifn
cancer
infiltrating lymphocytes
tils
mils
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PCT/US2021/056829
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English (en)
French (fr)
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WO2022093944A3 (en
Inventor
Amer BEG
Mark J. Cantwell
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H. Lee Moffitt Cancer Center And Research Institute, Inc.
Memgen, Inc.
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Application filed by H. Lee Moffitt Cancer Center And Research Institute, Inc., Memgen, Inc. filed Critical H. Lee Moffitt Cancer Center And Research Institute, Inc.
Priority to JP2023526170A priority Critical patent/JP2023548831A/ja
Priority to EP21887430.3A priority patent/EP4237566A2/en
Priority to BR112023007922A priority patent/BR112023007922A2/pt
Priority to CA3196553A priority patent/CA3196553A1/en
Priority to AU2021368569A priority patent/AU2021368569A1/en
Priority to CN202180073895.XA priority patent/CN116710564A/zh
Priority to MX2023004780A priority patent/MX2023004780A/es
Publication of WO2022093944A2 publication Critical patent/WO2022093944A2/en
Publication of WO2022093944A3 publication Critical patent/WO2022093944A3/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • C12N5/0638—Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/761—Adenovirus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2510/00—Genetically modified cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/10011—Adenoviridae
    • C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
    • C12N2710/10341—Use of virus, viral particle or viral elements as a vector
    • C12N2710/10343—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/16043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • TIL tumor infiltrating lymphocyte
  • exogenous immunostimulatory molecules such as, for example, CD40-L, MEM40, B7-l(CD80)/B7-2(CD86), OX40L, 4-1BBL, CD70, GITRL, LIGHT, TIM-4, 1CAM-1, CD58 and/or SLAMF6
  • the oncolytic virus can further express one or more type 1 interferon (IFN) (such as, for example, IFN-a, IFN-p, IFN-K, IFN-5, IFN-e, IFN-T, IFN-co, and/or IFN-Q.
  • IFN type 1 interferon
  • the TILs generated are obtained in the tumor microenvironment at the site of the administration of the oncolytic virus; however TILs can also be obtained at tumor microenvironments not infected with the oncolytic virus.
  • TILs tumor infiltrating lymphocytes
  • MILs marrow infiltrating lymphocytes
  • a) harvesting TILs or MILs from a subject with a cancer b) culturing the harvested TILs or MILs in the presence of antigen presenting cells infected with an oncolytic virus expressing one or more exogenous immunostimulatory molecules (such as, for example, CD40-L, MEM40, B7- l(CD80)/B7-2(CD86), OX40L, 4-1BBL, CD70, GITRL, LIGHT, TIM-4, ICAM-1, CD58 and/or SLAMF6).
  • exogenous immunostimulatory molecules such as, for example, CD40-L, MEM40, B7- l(CD80)/B7-2(CD86), OX40L, 4-1BBL, CD70, GITRL, LIGHT, TIM-4, ICAM-1, CD58 and/or SLAMF6.
  • the oncolytic virus can further express one or more type 1 interferon (IFN) (such as, for example, IFN-a, IFN-P, IFN-K, IFN-5, IFN-e, IFN-T, IFN-CO, and/or IFN- .
  • IFN type 1 interferon
  • Also disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis in a subject comprising administering to a subject a therapeutically effective amount of the TILs or MILs of any of any preceding aspect.
  • a) administering an effective amount of an oncolytic virus expressing one or more exogenous immunostimulatory molecules such as, for example, CD40-L, MEM40, B7-l(CD80)/B7- 2(CD86), OX40L, 4-1BBL, CD70, GITRL, LIGHT, TIM-4, ICAM-1, CD58 andor SLAMF6 into a tumor cell; b) harvesting the tumor infiltrating lymphocytes (TILs) and/or marrow infiltrating lymphocytes (MILs); c) expanding the harvested TILs and/or MILs ex vivo; and d) administering a therapeutically effective amount of the expanded TILs and/or MILs to the subject.
  • an oncolytic virus expressing one or more exogenous immunostimulatory molecules (such as, for example, CD40-L, MEM40, B7-l(CD80)/B7- 2(CD86), OX40L, 4-1BBL, CD70, GIT
  • the cancerous or metastatic tumor being treated, reduced, inhibited, decreased, ameliorated, and/or prevented are abscopal to the tumor receiving any of the oncolytic viruses and/or TILs or MILs disclosed herein.
  • the oncolytic virus can further express one or more type 1 interferon (IFN) (such as, for example, IFN-a, IFN-P, IFN-K, IFN-5, IFN-e, IFN-T, IFN-CO, and/or IFN-Q.
  • IFN type 1 interferon
  • TILs tumor infiltrating lymphocytes
  • MILs marrow infiltrating lymphocytes
  • methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis in a subject comprising a) harvesting tumor infiltrating lymphocytes (TILs) and/or marrow infiltrating lymphocytes (MILs) from a subject with a cancer; culturing the harvested TILs or MILs in the presence of antigen presenting cells infected with an oncolytic virus expressing one or more exogenous immunostimulatory molecules; and administering a therapeutically effective amount of the expanded TILs and/or MILs to the subject.
  • TILs tumor infiltrating lymphocytes
  • MILs marrow infiltrating lymphocytes
  • the oncolytic virus can further express one or more type 1 interferon (IFN) (such as, for example, IFN-a, IFN-P, IFN-K, IFN-5, IFN-e, IFN- , IFN-CO, and/or IFN-Q.
  • IFN type 1 interferon
  • Fig. 2A Schematic representation of MEM40.
  • Fig. 2B Schematic representation of MEM-288.
  • Figures 4A, 4B, and 4C show that (4A) 344SQ (344), (4B) B16-F10 mouse cell lines and (4C) A549 human cell line were infected with indicated OVs AD-GFP (GFP), MEM- 188 (188) or MEM-288 (288) at different MOIs (1, 10, 100) for 2 days. Cell viability was determined by trypan blue staining assay 2 days after infection.
  • Figures 5A and 5B show that C57BL/6 mice were inoculated s.c. with 5e5 B16-OVA cells. On D12 and 16, these mice were subjected to two intratumoral injections of Ad- GFP, MEM-188 and MEM-288 (5 A) 10e8 or (5B) 10e9 IU. Significance of tumor size difference is indicated compared to untreated control mice at the last time-point.
  • Figure 5C shows the percentage of OVA-specific MHCII- and CD8+ cells in peripheral blood on D12 is shown after intratumoral injections of MEM-188 and MEM-288 atl0e9 IU in B16-OVA. Statistical analysis was done using two-way ANOVA for growth curves or a t test for OVAT evaluation. Statistical significance is indicated by p-values as *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001. NS: not significant.
  • Figure 5D shows the quantification of IFNy ELISPOT result from splenic CD8 T cells. C57BL/6 WT, IFNAR1 KO and CD40 KO mice (3 per group) were inoculated s.c.
  • FIG. 6A shows the treatment regimen in mice: C57BL/6 mice were inoculated s.c. with 5e5 B16-F10 cells on the primary site and with 2.5e5 B16-F10 cells on the contralateral site. As indicated, these mice were injected with MEM-288 at 10e9 IU on D12 and 16 into primary tumors and i.p. anti-PD-1 and CTLA-4 antibodies on D16, D19, D23 and 27.
  • FIG. 6B and 6C shows that tumor growth was determined on the primary site (6B) and contralateral site (6C) as indicated. Statistical analysis was done using two-way ANOVA for growth curves. Statistical significance is indicated by p-values or as *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001. NS: not significant.
  • Figure 6D shows Kaplan-Meier Survival Analysis showing overall survival of the mice. Statistical significance is indicated by p-values or as *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001. NS: not significant.
  • Figure 7A sows 129 mice were inoculated s.c. with 5e5 344 cells on the flank and subjected to Ad-GFP, MEM-188 or 288 injections at 10e9 IU on D12 and D16 into the tumors. Tumor growth was determined on the primary site as indicated. Significance is indicated compared to control UT group (PBS injection). Statistical significance is indicated by p-values or as *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001. NS: not significant. 24.
  • Figure 7B shows typical H&E staining of tumors in lungs of s.c. 344 tumor bearing mice in (7 A) on D38.
  • Figure 7C shows quantification of tumor mets of individual mice from different groups is shown as indicated. Statistical significance is indicated by p- values or as *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001. NS: not significant.
  • Figure 7D shows typical IHC staining of CD8 T cells in the lungs of mice in (7 A).
  • Figure 7E shows quantification of CD8 T cells density of individual mice from different groups is shown as indicated. Statistical significance is indicated by p- values or as *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001. NS: not significant.
  • Figures 8A and 8B show 129 mice were inoculated s.c. with 5e5 344 cells on the flank and subjected to MEM-288 injection at 10e9 IU on D12 and 16 into the tumors and i.p. anti-PD-1 antibody on D16, D19, D23 and 27.
  • Figure 8A shows IFNy ELISPOT from the splenic CD8 T cells of the mice and
  • Figure 8B shows quantification of ELISPOT results from (A).
  • Statistical analysis was done using t test. Statistical significance is indicated by p-values as *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001.
  • NS not significant.
  • Figure 9A shows flow cytometry analysis scheme of B16-OVA to detect populations of Macrophages, Neutrophils, Monocytes and DCs as indicated.
  • Figure 9B shows flow cytometry analysis scheme of B16-OVA to detect populations of B cells, CD4 T cells, CD8 T cells and OVA-specific CD8 T cells.
  • FIG. 10 shows C57BL/6 mice were inoculated s.c. with 5e5 B16-OVA or B16- OVA-ZsGreen cells on the flank. On D14, flow cytometry analysis of tumor B16-OVA to detect ZsGreen positive populations of macrophages and DCs identified as in Figure 9A. Percentage of positive cells is indicated.
  • Figure 11A shows C57BL/6 mice were inoculated s.c. with 5e5 B16-OVA or B16- OVA-ZsGreen cells on the flank. On D14, flow cytometry analysis was performed to detect ZsGreen + tumor cells in CD45" as indicated.
  • Figure 11B shows B16-OVA-ZsGreen tumors were subjected to PBS or MEM-288 injection at 10e9 IU on D12 into tumors.
  • Flow cytometry analysis of CD40L on ZsGreen + CD45" cells was performed from PBS and MEM-288 injected tumors.
  • Figure 12A shows flow cytometry analysis of CD80 and CD86 expression in MHC- II hlgh macrophages and DCs (CDllb + DC2) was performed on tumor in Figure 11b. Injection of CD80 and CD86 expression in MHC- II hlgh macrophages and DCs (CDllb + DC2) was performed on tumor in Figure 11b. Injection of CD80 and CD86 expression in MHC- II hlgh macrophages and DCs (CDllb + DC2) was performed on tumor in Figure 11b. Injection of
  • Figure 12B shows mean florescence intensity (MFI) of results (A).
  • Figure 13 shows DC populations in inguinal LNs. Two main populations of CDllc + MHC-II + DCs were detected.
  • the MHC-II high population comprises of migratory DC1 and DC2.
  • the MHC-II intermediate population comprises of resident DC1 and DC2. As expected, the migratory population has a higher proportion of CD103 + DC1 while the resident population has a higher proportion of CD8a + DC1.
  • FIG. 14 shows DC populations in LNs of WT, CD40 KO and IFNAR1 KO mice.
  • Two main populations of CD1 lc + MHC-II + DCs were detected in all genotype mice.
  • the MHC- II high population comprises of migratory DC1 and DC2.
  • the MHC-II intermediate population comprises of resident DC1 and DC2.
  • Figure 15A shows typical images of tumors for the 3 treatment groups.
  • Figure 15B shows scored values of the 3 treatment groups.
  • Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed.
  • the term "antigen presenting cell” refers to professional antigen presenting cell, which is selected from among dendritic cells, macrophages, and B cells.
  • the APC is a DC.
  • the APC is a mammalian cell.
  • the APC, such as DC, macrophage, or B cell is a human cell
  • An "increase” can refer to any change that results in a greater amount of a symptom, disease, composition, condition or activity.
  • An increase can be any individual, median, or average increase in a condition, symptom, activity, composition in a statistically significant amount.
  • the increase can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% increase so long as the increase is statistically significant.
  • a “decrease” can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity.
  • a substance is also understood to decrease the genetic output of a gene when the genetic output of the gene product with the substance is less relative to the output of the gene product without the substance.
  • a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed.
  • a decrease can be any individual, median, or average decrease in a condition, symptom, activity, composition in a statistically significant amount.
  • the decrease can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% decrease so long as the decrease is statistically significant.
  • “Inhibit,” “inhibiting,” and “inhibition” mean to decrease an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels.
  • reducing or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic (e.g., tumor growth). It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to. For example, “reduces tumor growth” means reducing the rate of growth of a tumor relative to a standard or a control.
  • prevent or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed.
  • the term “subject” refers to any individual who is the target of administration or treatment.
  • the subject can be a vertebrate, for example, a mammal.
  • the subject can be human, non-human primate, bovine, equine, porcine, canine, or feline.
  • the subject can also be a guinea pig, rat, hamster, rabbit, mouse, or mole.
  • the subject can be a human or veterinary patient.
  • patient refers to a subject under the treatment of a clinician, e.g., physician.
  • the term “therapeutically effective” refers to the amount of the composition used is of sufficient quantity to ameliorate one or more causes or symptoms of a disease or disorder. Such amelioration only requires a reduction or alteration, not necessarily elimination.
  • treatment refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
  • This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
  • this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
  • Biocompatible generally refers to a material and any metabolites or degradation products thereof that are generally non-toxic to the recipient and do not cause significant adverse effects to the subject.
  • compositions, methods, etc. include the recited elements, but do not exclude others.
  • Consisting essentially of' when used to define compositions and methods shall mean including the recited elements, but excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like.
  • Consisting of' shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions provided and/or claimed in this disclosure. Embodiments defined by each of these transition terms are within the scope of this disclosure.
  • a “control” is an alternative subject or sample used in an experiment for comparison purposes.
  • a control can be "positive” or “negative.”
  • Effective amount of an agent refers to a sufficient amount of an agent to provide a desired effect.
  • the amount of agent that is “effective” will vary from subject to subject, depending on many factors such as the age and general condition of the subject, the particular agent or agents, and the like. Thus, it is not always possible to specify a quantified “effective amount.” However, an appropriate “effective amount” in any subject case may be determined by one of ordinary skill in the art using routine experimentation. Also, as used herein, and unless specifically stated otherwise, an “effective amount” of an agent can also refer to an amount covering both therapeutically effective amounts and prophylactically effective amounts. An “effective amount” of an agent necessary to achieve a therapeutic effect may vary according to factors such as the age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a “pharmaceutically acceptable” component can refer to a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into a pharmaceutical formulation provided by the disclosure and administered to a subject as described herein without causing significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained.
  • the term When used in reference to administration to a human, the term generally implies the component has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.
  • “Pharmaceutically acceptable carrier” means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and/or human pharmaceutical or therapeutic use.
  • carrier or “pharmaceutically acceptable carrier” can include, but are not limited to, phosphate buffered saline solution, water, emulsions (such as an oil/water or water/oil emulsion) and/or various types of wetting agents.
  • carrier encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations and as described further herein.
  • “Pharmacologically active” (or simply “active”), as in a “pharmacologically active” derivative or analog, can refer to a derivative or analog (e.g., a salt, ester, amide, conjugate, metabolite, isomer, fragment, etc.) having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.
  • “Therapeutic agent” refers to any composition that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, e.g., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, e.g., prevention of a disorder or other undesirable physiological condition (e.g., a non-immunogenic cancer).
  • the terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, salts, esters, amides, proagents, active metabolites, isomers, fragments, analogs, and the like.
  • therapeutic agent when used, then, or when a particular agent is specifically identified, it is to be understood that the term includes the agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, proagents, conjugates, active metabolites, isomers, fragments, analogs, etc.
  • “Therapeutically effective amount” or “therapeutically effective dose” of a composition refers to an amount that is effective to achieve a desired therapeutic result.
  • a desired therapeutic result is the control of type I diabetes.
  • a desired therapeutic result is the control of obesity.
  • Therapeutically effective amounts of a given therapeutic agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the subject. The term can also refer to an amount of a therapeutic agent, or a rate of delivery of a therapeutic agent (e.g., amount over time), effective to facilitate a desired therapeutic effect, such as pain relief.
  • a desired therapeutic effect will vary according to the condition to be treated, the tolerance of the subject, the agent and/or agent formulation to be administered (e.g., the potency of the therapeutic agent, the concentration of agent in the formulation, and the like), and a variety of other factors that are appreciated by those of ordinary skill in the art.
  • a desired biological or medical response is achieved following administration of multiple dosages of the composition to the subject over a period of days, weeks, or years.
  • Type 1 IFNs can function as direct activators of the function of both dendritic cells (DCs) and T cells, in addition to their role in enhancing tumor immunogenicity by increasing expression of immune function genes in multiple cell types.
  • type 1 IFN This key immune stimulatory function of type 1 IFN has been recently exploited through use of stimulators of type 1 IFN expression, such as STING and TLR9 agonists.
  • stimulators of type 1 IFN expression such as STING and TLR9 agonists.
  • a synergistic relationship occurs between CD40 ligation and stimulators of type I IFN for robust CD8 T cell activation.
  • the combined systemic administration of CD40 agonists and activators of type 1 IFNs have high toxicity.
  • the tumor acts as the vaccine site leading to the activation of DCs and subsequent T cell stimulation to generate a systemic antitumoral immunity capable of controlling growth of distant non-treated tumors.
  • Such approaches aimed at avoiding systemic toxicity have been recently tested with STING and TLR9 agonists.
  • STING and TLR9 agonists have been recently tested with STING and TLR9 agonists.
  • TME tumor microenvironment
  • Oncolytic viruses have been developed for their ability to specifically replicate in cancer cells. Recent studies indicate that stimulation of host antitumor immunity is a key mechanism of action of OVs. OVs also allow the capacity to encode for transgenes which can be used to express powerful activators of the immune response to further enhance antitumor immunity. It is shown herein that an intralesionally delivered OV capable of activating an immunostimulatory molecule (such as, for example CD40) and/or type 1 IFN signaling in the TME can function as a potent activator of a systemic T cell response.
  • an immunostimulatory molecule such as, for example CD40
  • type 1 IFN signaling in the TME can function as a potent activator of a systemic T cell response.
  • a conditionally replicative type 5 adenovirus was developed that expresses a chimeric CD40L ligand (MEM40) and IFNP in collaboration with Memgen, Inc.
  • MEM-288 induces high level expression of CD40L and IFNP and induces a robust systemic T cell response that is capable of significantly curtailing distant tumor growth in mouse melanoma and lung tumor models.
  • a) administering an oncolytic virus expressing one or more type 1 interferon (IFN) such as, for example, IFN-a, IFN-P, IFN-K, IFN-5, IFN-e, IFN-T, IFN-CO, and/or IFN- and/or one or more exogenous immunostimulatory molecules (such as, for example, CD40-L, MEM40, B7-l(CD80)/B7-2(CD86), OX40L, 4-1BBL, CD70, GITRL, LIGHT, TIM-4, ICAM-1, CD58 and/or SLAMF6) into a tumor cell; and b) harvesting the tumor infiltrating lymphocytes.
  • IFN type 1 interferon
  • exogenous immunostimulatory molecules such as, for example, CD40-L, MEM40, B7-l(CD80)/B7-2(CD86), OX40L, 4-1BBL, CD70, GITRL, LIGHT, TIM-4, ICAM-1, CD
  • the onclolytic virus can be administered to the tumor by any means known in the art including, but not limited to intratumoral injection. While the above methods result in dramatically increased numbers of TILs and MILs at the tumor site, it is also recognized that TILs and Mils can be generated and/or increased at tumor sites outside the tumor microenvironment being treated (i.e., an abscopal effect).
  • TIL and MIL numbers increase at the target site of oncolytic virus administration and/or at abscopal tumor sites does not mean that further expansion cannot occur.
  • said TILs in MILs can be further expanded if cultured ex vivo.
  • methods of generating tumor infiltrating lymphocytes further comprising expanding the harvested TILs ex vivo.
  • TILs and MILs does not have to be limited to in vivo oncolytic virus methods where tumors receiving an infection of an oncolytic virus and harvested, but rather the expansion of TILs can occur ex vivo by harvesting TILs and MILs in a cancer site and then culturing the harvested cells in the presence of antigen presenting cells that are infected with the oncolytic virus. Thus, the expansion of TILs and/or MILs occurs entirely ex vivo.
  • TILs tumor infiltrating lymphocytes
  • MILs marrow infiltrating lymphocytes
  • methods of expanding a population of tumor infiltrating lymphocytes (TILs) or marrow infiltrating lymphocytes (MILs) comprising: a) harvesting TILs or MILs from a subject with a cancer; b) culturing the harvested TILs or MILs in the presence of antigen presenting cells infected with an oncolytic virus expressing one or more type 1 interferon (IFN) (such as, for example, IFN-a, IFN-P, IFN-K, IFN-5, IFN-e, IFN-T, IFN-CO, and/or IFN- and/or one or more exogenous immunostimulatory molecules (such as, for example, CD40-L, MEM40, B7- l(CD80)/B7-2(CD86), OX40L, 4-1BBL, CD70, GITRL, LIGHT, TIM-4,
  • the invention provides a viral vector, such as a lend virus, that expresses one or more type 1 interferon (IFN) (such as, for example, IFN-a, IFN-P, IFN-K, IFN-5, IFN-e, IFN-T, IFN-CO, and/or IFN- and/or one or more exogenous immunostimulatory molecule (such as, for example, CD40-L, MEM40, cluster of differentiation (CD) 80 and/or CD 86 (also known as B7-l(CD80) and B7-2(CD86)), OX40L, 4-1BB ligand (4-1BBL), CD70, LIGHT, glucocorticoid-induced TNFR-related protein ligand (GITRL), LIGHT, T-cell immunoglobulin and mucin domain 4 (TIM-4), intracellular adhesion molecule - 1 (ICAM-1), CD58, and/or signaling lymphocyte activation molecule (SLAM) family member 6 (SLA)
  • IFN type
  • Additional embodiments of the invention provide oncolytic viruses expressing any combination of a type I IFN, such as, IFN-a, IFN-P, IFN-e, IFN-K, and IFN-co, and an immunostimulatory molecule (such as, for example, CD40-L, MEM40, B7-l(CD80)/B7- 2(CD86), OX40L, 4-1BBL, CD70, GITRL, LIGHT, TIM-4, ICAM-1, CD58 and/or SLAMF6), for example, via one or more heterologous nucleic acid sequences encoding a combination of IFN-P and CD40-L. Any oncolytic virus may be utilized.
  • a type I IFN such as, IFN-a, IFN-P, IFN-e, IFN-K, and IFN-co
  • an immunostimulatory molecule such as, for example, CD40-L, MEM40, B7-l(CD80)/B7- 2(CD86), OX40L
  • the oncolytic virus can be adenovirus, reovirus, herpes virus, picornavirus (including coxsackievirus, poliovirus, and Seneca Valley virus), paramyxovirus (including measles virus and Newcastle disease virus (NDV)), parvovirus, rhabdovirus (including vesicular stomatitis virus (VSV)), or vaccinia virus.
  • the oncolytic virus is replication competent.
  • FIG. 72 Further embodiments of the invention provide methods of treating a malignancy in a subject by administering the oncolytic viruses disclosed herein, in combination by administering a checkpoint inhibitor to the subject.
  • IFN-a can be a human IFN-a represented by the sequence of SEQ ID NO: 1.
  • IFN-a can be a mammalian IFN-a, such as, mouse, rat, rabbit, pig, feline, canine, or bovine IFN-a. Additional embodiments of IFN-a from other mammals are known to a skilled artisan and such embodiments are within the purview of the invention.
  • IFN-a has between 80.00% and, up to, including 99.99% (e.g., 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence identity to the human wild-type IFN-a, for example, IFN-a of SEQ ID NO: 1.
  • IFN-P can be a human IFN-P represented by the sequence of SEQ ID NO: 2.
  • IFN-P can be a mammalian IFN-P, such as, mouse, rat, rabbit, pig, feline, canine, or bovine IFN-P- Additional embodiments of IFN-P from other mammals are known to a skilled artisan and such embodiments are within the purview of the invention. In certain embodiments, IFN-P has between 80.00% and, up to, including 99.99% ( e.g ., 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,
  • IFN-P lacks the first 22 amino acids of SEQ ID NO: 2 and optionally, further has a substitution of cysteine 17 of the resultant 165 amino acid peptide with serine.
  • IFN-e can be a human IFN-e represented by the sequence of SEQ ID NO: 3.
  • IFN-e can be a mammalian IFN-e, such as, mouse, rat, rabbit, pig, feline, canine, or bovine IFN-e. Additional embodiments of IFN-e from other mammals are known to a skilled artisan and such embodiments are within the purview of the invention. In certain embodiments, IFN-e has between 80.00% and, up to, including 99.99% (e.g., 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,
  • IFN-K can be a human IFN-K represented by the sequence of SEQ ID NO: 4.
  • IFN-K can be a mammalian IFN-K, such as, mouse, rat, rabbit, pig, feline, canine, or bovine IFN-k. Additional embodiments of IFN-K from other mammals are known to a skilled artisan and such embodiments are within the purview of the invention.
  • IFN-K has between 80.00% and, up to, including 99.99% (e.g, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence identity to the human wild-type IFN-K, for example, IFN-K of SEQ ID NO: 4.
  • IFN-co can be a human IFN-co represented by the sequence of SEQ ID NO: 5.
  • IFN-co can be a mammalian IFN-co, such as, mouse, rat, rabbit, pig, feline, canine, or bovine IFN-co. Additional embodiments of IFN-co from other mammals are known to a skilled artisan and such embodiments are within the purview of the invention.
  • IFN-co has between 80.00% and, up to, including 99.99% (e.g, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence identity to the human wild-type IFN-co, for example, IFN-co of SEQ ID NO: 5.
  • CD40-L can be a human CD40-L represented by the sequence of SEQ ID NO: 6.
  • CD40-L can be a mammalian CD40-L, such as, mouse, rat, rabbit, pig, feline, canine, or bovine CD40-L. Additional embodiments of CD40-L from other mammals are known to a skilled artisan and such embodiments are within the purview of the invention.
  • CD40-L has between 80.00% and, up to, including 99.99% (e.g ., 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence identity to the human wild-type CD40-L, for example, CD40-L of SEQ ID NO: 6.
  • the CD40-L can be a chimeric CD40-L or a non-chimeric CD40-L polypeptide.
  • the CD40-L expressed in an oncolytic virus of the invention is a chimeric CD40-L.
  • Such chimeric CD40-L polypeptides comprise CD40-L domains or subdomains from at least two different species, for example, human and mouse CD40-L.
  • chimeric CD40-L at least one domain or subdomain of CD40-L that contains a cleavage site of human CD40-L is replaced with a corresponding domain or subdomain of non-human CD40-L, preferably murine CD40-L.
  • a chimeric CD40-L can comprise a domain or subdomain of human CD40-L that binds to a CD40- L receptor. Domains I to IV of a human CD40-L (SEQ ID NO: 6) correspond to amino acid portions 1-14, 14-45, 46-110, and 111-261 of SEQ ID NO: 6.
  • a skilled artisan can determine domains I to IV of a non-human CD40-L based on sequence alignment of the non-human CD40- L with the human CD40-L. Certain domain positions of non-human CD40-L are provided in Table 1 of United States Patent No. 7,495,090, which is herein incorporated by reference in its entirety.
  • the chimeric CD40-L comprises a first subdomain of non human CD40-L, wherein the subdomain replaces a cleavage site of human CD40-L, and a second subdomain of human CD40-L that binds to a CD40-L receptor.
  • the first subdomain can comprise a subdomain of domain IV of a non-human CD40- L.
  • the first subdomain can further comprise domain III, or a subdomain or domain III, of a non-human CD40-L.
  • the first subdomain replaces a portion of a cleavage site of human CD40-L.
  • a chimeric CD40-L in addition to domain IV or a subdomain of domain IV, and optionally, domain III or a subdomain of domain III, a chimeric CD40-L further comprises domain II or a subdomain of domain II, of a non-human CD40-L.
  • the first subdomain of a chimeric CD40-L can comprise domain I or a subdomain or domain I, of non-human CD40-L.
  • the first subdomain comprises domains or subdomains of domain I, II, III and IV, of a non-human CD40-L.
  • the non-human CD40-L is a murine CD40-L.
  • the chimeric human/mouse CD40 ligand has 92% amino acid sequence homology with human CD40L (SEQ ID NO: 12) (See, US Patent No. 7,495,090, herein incorporated by reference and referred to herein as“MEM40”).
  • CD40 ligand” and“CD40-L” may be used interchangeably herein, and may also be referred to as“CD154”. Specifically, domains I, II and III - the regions that contain the intracellular, intra-membrane, and proximal extracellular domains, respectively, of this molecule - have been fully humanized.
  • domain IV which contains the CD40 binding portion of the molecule, only those murine domains necessary for optimum CD40 ligand expression in cells are retained.
  • MEM40 is fully humanized at the 3 ’ end of the molecule where antibody binding neutralizes the activity of the murine CD 154 (CD40 ligand) when administered to humans.
  • Non-limiting examples of chimeric CD40-L useful in the current invention comprise the following sequences:
  • SEQ ID NO: 8 MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKIEDERNLHE DFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETKKDEDPQIAAHVVSEA NSNAASVLQWAKKGYYTMKSNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREPSSQR PFIVGLWLKPSSGSERILLKAANTHSSSQLCEQQSVHLGGVFELQPGASVFVNVTDPSQV SHGTGFTSFGLLKL
  • SEQ ID NO: 9 MIETYSQPSPRSVATGLPASMKIFMYLLTVFLITQMIGSVLFAVYLHRRLDKVEEEVNLH EDFVFIKKLKRCNKGEGSLSLLNCEEMRRQFEDLVKDITLNKEEKKENSFEMQRGDEDP QIAAHVVSEANSNAASVLQWAKKGYYTMKSNLVTLENGKQLTVKRQGLYYIYAQVTF CSNREASSQAPFIVGLWLKPSSGSERILLKAANTHSSSQLCEQQSVHLGGVFELQPGASV
  • nucleotide sequences encoding the chimeric CD40-L of SEQ ID NOs: 7 to 18 are disclosed in United States patents 7,495,090, 7,928,213, and 8, 138,310. These nucleotide sequences are incorporated herein by reference and use of such nucleotide sequences is envisioned herein.
  • the oncolytic viruses of the invention can comprise a nucleic acid encoding IFN-a, wherein the IFN-a comprises the human wild-type IFN-a (SEQ ID NO: 1) or a IFN-a having between 80.00% and, up to, including 99.99% ( e.g ., 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,
  • the oncolytic viruses of the invention can comprise a nucleic acid encoding IFN-P, wherein the IFN-P comprises the human wild-type IFN-P (SEQ ID NO: 2) or a IFN-P having between 80.00% and, up to, including 99.99% (e.g., 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,
  • nucleotide sequence encodes for a IFN-P that lacks the first 22 amino acids of SEQ ID NO: 2 and optionally, further has a substitution of cysteine 17 of the resultant 165 amino acid peptide with serine.
  • the oncolytic viruses of the invention can comprise a nucleic acid encoding IFN-e, wherein the IFN-e comprises the human wild-type IFN-e (SEQ ID NO: 3) or a IFN-e having between 80.00% and, up to, including 99.99% (e.g, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence identity to the human wild-type IFN-e, for example, IFN-e of SEQ ID NO: 3.
  • the oncolytic viruses of the invention can comprise a nucleic acid encoding IFN-K, wherein the IFN-K comprises the human wild-type IFN-K (SEQ ID NO: 4) or a IFN-K having between 80.00% and, up to, including 99.99% (e.g, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence identity to the human wild-type IFN-K, for example, IFN-K of SEQ ID NO: 4.
  • the oncolytic viruses of the invention can comprise a nucleic acid encoding IFN-co, wherein the IFN-co comprises the human wild-type IFN-co (SEQ ID NO: 5) or a IFN-co having between 80.00% and, up to, including 99.99% (e.g, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence identity to the human wild-type IFN-co, for example, IFN-co of SEQ ID NO: 5.
  • the human wild-type IFN-co SEQ ID NO: 5
  • IFN-co having between 80.00% and, up to, including 99.99% e.g, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,
  • the oncolytic viruses of the invention can comprise a nucleic acid encoding CD40-L, wherein the CD40-L comprises the human wild-type CD40-L (SEQ ID NO:6) or a CD40-L having between 80.00% and, up to, including 99.99% (e.g, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence identity to the human wild-type CD40-L, for example, CD40-L of SEQ ID NO: 6.
  • the oncolytic viruses of the invention can also comprise a nucleic acid encoding a chimeric CD40-L, wherein the chimeric CD40-L has a sequence selected from SEQ ID NOs: 7 to 18 or a CD40-L having between 80.00% and, up to, including 99.99% ( e.g ., 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) sequence identity to a chimeric CD40-L having a sequence selected from SEQ ID NOs: 7 to 18.
  • the oncolytic virus of the invention can comprise a nucleic acid encoding MEM40.
  • the oncolytic viruses of the invention comprise IFNP comprising at least 80% sequence identity to the human IFNP (SEQ ID NO: 2) and the CD40-L comprises at least 80% sequence identity to a chimeric CD40-L having a sequence of SEQ ID NO: 12.
  • One or more heterologous nucleic acid sequences encoding the combination of type I IFN and CD40-L can be in one or more viral constructs.
  • the viral constructs include an adenoviral construct, adeno-associated viral construct (AAV), poxvirus construct, lentiviral construct, alphaviral construct, herpesviral construct, retroviral construct, vaccinia viral construct, vesicular stomatitis viral construct, or herpes simplex viral construct.
  • the oncolytic virus in accordance with the present invention can further include other modifications in its genome.
  • it can comprise additional DNA inserted into an already inactivated gene, or substituted for a deleted gene.
  • the oncolytic virus may also have incorporated therein one or more promoters that impart to the virus an enhanced level of tumor cell specificity. In this way, the oncolytic virus may be targeted to specific cancer types using cancer cell-specific promoters.
  • tumor cell-specific promoter or “tumor cell-specific transcriptional regulatory sequence” or “tumor-specific promoter” or “tumor-specific transcriptional regulatory sequence” indicates a transcriptional regulatory sequence, promoter and/or enhancer that is present at a higher level in the target cancer cell than in a normal cell.
  • the oncolytic virus for use in the invention may be under the control of an exogenously added regulator.
  • the oncolytic virus is an adenovirus (Ad).
  • Ad is a large (approximately 36 kb) DNA virus that infects humans, but which also display a broad host range.
  • adenovirus is an icosahedral virus containing a double- stranded, linear DNA genome.
  • serotypes of human adenoviruses There are approximately 50 serotypes of human adenoviruses, which are divided into six families based on molecular, immunological, and functional criteria. By adulthood, virtually every human has been infected with the more common adenovirus serotypes, the major effect being cold-like symptoms. 97.
  • Adenoviral infection of host cells results in adenoviral DNA being maintained episomally, which reduces the potential genotoxicity associated with integrating vectors.
  • adenoviruses are structurally stable, and no genome rearrangement has been detected after extensive amplification. Adenovirus can infect most epithelial cells regardless of their cell cycle stage. So far, adenoviral infection appears to be linked only to mild disease such as acute respiratory disease in humans.
  • the infectious cycle of the adenovirus takes place in 2 steps: the early phase which precedes initiation of the replication of the adenoviral genome, and which permits production of the regulatory proteins and proteins involved in the replication and transcription of the viral DNA, and the late phase which leads to the synthesis of the structural proteins.
  • the early genes are distributed in 4 regions that are dispersed in the adenoviral genome, designated El to E4 (“E” denotes "early”).
  • the early regions comprise at least-six transcription units, each of which possesses its own promoter.
  • the expression of the early genes is itself regulated, some genes being expressed before others.
  • Three regions, El, E2, and E4 are essential to replication of the virus. Thus, if an adenovirus is defective for one of these functions this protein will have to be supplied in trans, or the virus cannot replicate.
  • the El early region is located at the 5' end of the adenoviral genome, and contains 2 viral transcription units, E1A and E1B. This region encodes proteins that participate very early in the viral cycle and are essential to the expression of almost all the other genes of the adenovirus.
  • the El A transcription unit codes for a protein that transactivates the transcription of the other viral genes, inducing transcription from the promoters of the E IB, E2A, E2B, E3, and E4 regions and the late genes.
  • the adenovirus enters the permissive host cell via a cell surface receptor, and it is then internalized.
  • the viral DNA associated with certain viral proteins needed for the first steps of the replication cycle enters the nucleus of the infected cells, where transcription is initiated. Replication of the adenoviral DNA takes place in the nucleus of the infected cells and does not require cell replication. New viral particles or virions are assembled after which they are released from the infected cells, and can infect other permissive cells.
  • the adenovirus is an attractive delivery system.
  • Embodiments of the disclosure can utilize manufacturing process that can be free of or essentially free of protein, serum, and animal derived components making it suitable for a broad range of both prophylactic and therapeutic vaccine products.
  • helper cell lines may be derived from human cells such as human embryonic kidney cells, muscle cells, hematopoietic cells or other human embryonic mesenchymal or epithelial cells.
  • helper cells may be derived from the cells of other mammalian species that are permissive for human adenovirus. Such cells include, for example Vero cells or other monkey embryonic mesenchymal or epithelial cells.
  • a helper cell line is 293.
  • compositions can also be administered in vivo in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject, along with the nucleic acid or vector, without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
  • the carrier would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art.
  • compositions may be administered orally, parenterally (e.g., intravenously), by intramuscular injection, by intraperitoneal injection, transdermally, extracorporeally, topically or the like, including topical intranasal administration or administration by inhalant.
  • topical intranasal administration means delivery of the compositions into the nose and nasal passages through one or both of the nares and can comprise delivery by a spraying mechanism or droplet mechanism, or through aerosolization of the nucleic acid or vector.
  • Administration of the compositions by inhalant can be through the nose or mouth via delivery by a spraying or droplet mechanism. Delivery can also be directly to any area of the respiratory system (e.g., lungs) via intubation.
  • compositions required will vary from subject to subject, depending on the species, age, weight and general condition of the subject, the severity of the allergic disorder being treated, the particular nucleic acid or vector used, its mode of administration and the like. Thus, it is not possible to specify an exact amount for every composition. However, an appropriate amount can be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein. 105.
  • Parenteral administration of the composition, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions. A more recently revised approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained. See, e.g., U.S. Patent No. 3,610,795, which is incorporated by reference herein.
  • the materials may be in solution, suspension (for example, incorporated into microparticles, liposomes, or cells). These may be targeted to a particular cell type via antibodies, receptors, or receptor ligands.
  • the following references are examples of the use of this technology to target specific proteins to tumor tissue (Senter, et al., Bioconjugate Chem., 2:447-451, (1991); Bagshawe, K.D., Br. J. Cancer, 60:275-281, (1989); Bagshawe, et al., Br. J. Cancer, 58:700-703, (1988); Senter, et al., Bioconjugate Chem., 4:3-9, (1993); Battelli, et al., Cancer Immunol.
  • Vehicles such as "stealth” and other antibody conjugated liposomes (including lipid mediated drug targeting to colonic carcinoma), receptor mediated targeting of DNA through cell specific ligands, lymphocyte directed tumor targeting, and highly specific therapeutic retroviral targeting of murine glioma cells in vivo.
  • the internalization pathways serve a variety of functions, such as nutrient uptake, removal of activated proteins, clearance of macromolecules, opportunistic entry of viruses and toxins, dissociation and degradation of ligand, and receptor-level regulation. Many receptors follow more than one intracellular pathway, depending on the cell type, receptor concentration, type of ligand, ligand valency, and ligand concentration. Molecular and cellular mechanisms of receptor-mediated endocytosis has been reviewed (Brown and Greene, DNA and Cell Biology 10:6, 399-409 (1991)). a) Pharmaceutically Acceptable Carriers
  • compositions, including antibodies, can be used therapeutically in combination with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier e.g., a pharmaceutically-acceptable carrier
  • Suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton, PA 1995.
  • an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic.
  • the pharmaceutically-acceptable carrier include, but are not limited to, saline, Ringer's solution and dextrose solution.
  • the pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5.
  • Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of composition being administered.
  • compositions can be administered intramuscularly or subcutaneously. Other compounds will be administered according to standard procedures used by those skilled in the art.
  • compositions may include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice.
  • Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, antiinflammatory agents, anesthetics, and the like.
  • the pharmaceutical composition may be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Administration may be topically (including ophthalmically, vaginally, rectally, intranasally), orally, by inhalation, or parenterally, for example by intravenous drip, subcutaneous, intraperitoneal or intramuscular injection.
  • the disclosed antibodies can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
  • Formulations for topical administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids or binders may be desirable..
  • compositions may potentially be administered as a pharmaceutically acceptable acid- or base- addition salt, formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mono-, di-, trialkyl and aryl amines and substituted ethanolamines.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, glyco
  • Effective dosages and schedules for administering the compositions may be determined empirically, and making such determinations is within the skill in the art.
  • the dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms of the disorder are effected.
  • the dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like.
  • the dosage will vary with the age, condition, sex and extent of the disease in the patient, route of administration, or whether other drugs are included in the regimen, and can be determined by one of skill in the art.
  • the dosage can be adjusted by the individual physician in the event of any counterindications.
  • Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.
  • Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.
  • guidance in selecting appropriate doses for antibodies can be found in the literature on therapeutic uses of antibodies, e.g., Handbook of Monoclonal Antibodies, Ferrone et al., eds., Noges Publications, Park Ridge, N.J., (1985) ch. 22 and pp. 303-357; Smith et al., Antibodies in Human Diagnosis and Therapy, Haber et al., eds., Raven Press, New York (1977) pp. 365-389.
  • a typical daily dosage of the antibody used alone might range from about 1 pg/kg to up to 100 mg/kg of body weight or more per day, depending on the factors mentioned above.
  • the disclosed compositions can be used to treat any disease where uncontrolled cellular proliferation occurs such as cancers.
  • a representative but non-limiting list of cancers that the disclosed compositions can be used to treat is the following: lymphoma, B cell lymphoma, T cell lymphoma, mycosis fungoides, Hodgkin’s Disease, myeloid leukemia, bladder cancer, brain cancer, nervous system cancer, head and neck cancer, squamous cell carcinoma of head and neck, lung cancers such as small cell lung cancer and non-small cell lung cancer, neuroblastoma/glioblastoma, ovarian cancer, skin cancer, liver cancer, melanoma, squamous cell carcinomas of the mouth, throat, larynx, and lung, cervical cancer, cervical carcinoma, breast cancer, and epithelial cancer, renal cancer, genitourinary cancer, pulmonary cancer, esophageal carcinoma, head and neck carcinoma, large bowel cancer, hematopoietic cancers; testicular cancer; colon cancer,
  • a cancer and/or metastasis including abscopal tumors
  • methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis (including abscopal tumors) in a subject comprising administering to a subject any of the expanded TILs or MILs disclosed herein.
  • a) administering an oncolytic virus expressing one or more type 1 interferon (IFN) such as, for example, IFN-a, IFN-P, IFN-K, IFN-5, IFN-e, IFN-T, IFN-CO, and/or IFN- and/or one or more exogenous immunostimulatory molecules (such as, for example, CD40-L, MEM40, B7-l(CD80)/B7-2(CD86), OX40L, 4-1BBL, CD70, GITRL, LIGHT, TIM-4, 1CAM-1, CD58 and/or SLAMF6) into a tumor cell; b) harvesting the tumor infiltrating lymphocytes (TILs) and/or marrow infiltrating lymphocytes (MILs); c) expanding the harvested TILs and/
  • the TILs or MILs can be harvested first from the tumor and then expanded ex vivo in the presence of antigen presenting cells infected with oncolytic virus expressing one or more type 1 interferon (IFN) and/or one or more exogenous immunostimulatory molecules; and administering the expanded TILs and/or MILs to the subject.
  • the expanded TILs or MILs can then in-turn be administered (adoptively transferred) to the subject with the cancer.
  • TILs tumor infiltrating lymphocytes
  • MILs marrow infiltrating lymphocytes
  • IFN type 1 interferon
  • exogenous immunostimulatory molecules such as, for example, CD40-L, MEM40, B7-l(CD80)/B7-2(CD86), OX40L, 4-1BBL, CD70, GITRL, LIGHT, TIM-4, ICAM
  • successful treatment of a cancer in a subject is important and doing so may include the administration of additional treatments. Accordingly, it is intended herein that the disclosed methods of treating, inhibiting, reducing, and/or preventing cancer can augmented with any therapeutic treatment of a cancer including, but not limited surgical, radiological, and/or pharmaceutical treatments of a cancer.
  • the disclosed treatments can include and/or further include any anti-cancer therapy known in the art including, but not limited to Abemaciclib, Abiraterone Acetate, Abitrexate (Methotrexate), Abraxane (Paclitaxel Albumin- stabilized Nanoparticle Formulation), ABVD, ABVE, ABVE-PC, AC, AC-T, Adcetris (Brentuximab Vedotin), ADE, Ado-Trastuzumab Emtansine, Adriamycin (Doxorubicin Hydrochloride), Afatinib Dimaleate, Afinitor (Everolimus), Akynzeo (Netupitant and Palonosetron Hydrochloride), Aldara (Imiquimod), Aldesleukin, Alecensa (Alectinib), Alectinib, Alemtuzumab, Alimta (Pemetrexed Disodium), Aliqopa (Copanlisib Hydroch
  • chemotherapeutics that are PD1/PDL1 blockade inhibitors (such as, for example, lambrolizumab, nivolumab, pembrolizumab, pidilizumab, BMS-936559, Atezolizumab, Durvalumab, or Avelumab).
  • PD1/PDL1 blockade inhibitors such as, for example, lambrolizumab, nivolumab, pembrolizumab, pidilizumab, BMS-936559, Atezolizumab, Durvalumab, or Avelumab.
  • Example 1 Immunostimulatory activity of human IFNP in a mouse melanoma model
  • B16-F10 or B16-OVA melanoma expressing mouse IFNP functions as a powerful prophylactic vaccine, the protective effect of which is dependent on both CD8 and CD4 T cells (unpublished results).
  • This approach is functionally analogous to GM-CSF expressing tumor cells (GV AX).
  • B16-OVA cells were transduced with a pLenti-Puro control lentivirus or lentivirus expressing mouse or human IFNP followed by puromycin selection.
  • mice and human IFNP were highly effective in preventing tumor growth after challenge with live B16-OVA (Fig. 1C). These results indicate that in the setting of OV usage, human IFNP are also capable of inducing an antitumor T cell response in mice.
  • Example 3 Studies in a mouse melanoma model
  • a main premise of use of intralesional approaches is the potential for generation of a systemic antitumor immune response that can target non-injected lesions, i.e. trigger an abscopal effect.
  • a main goal of the studies has been to determine whether combined activation of CD40 and type 1 IFN signaling can generate a strong antitumor T cell response that is capable of curtailing growth of both injected and uninjected tumors.
  • Studies with a nononcolytic replication-incompetent adenovirus expressing MEM40/CD40L showed activity in the B16-F10 melanoma model. However, 4 injections of this virus were needed to observe activity as a single agent or in combination with ICI.
  • MEM-288 impact on systemic T cell responses: roles of CD40 and IFNAR1.
  • Example 4 Studies in a lung metastatic model
  • a virus expressing CD40L and IFNb (MEM-288) is capable of inducing a potent systemic antitumor T cell response which can control the growth of abscopal tumor lesions.
  • MEM-288 a virus that expresses human IFNb alone for the studies proposed here.
  • the studies include in-depth assessment of OV impact on DCs, macrophages and T cells with a key goal of defining the unique and synergistic contributions of CD40L and IFNb.
  • mice In addition to the above mentioned IFNAR1 and CD40 KO mice we can also use BATF3 KO mice, which lack DC1 (see below).
  • human IFNb triggers T cell activation in mice in an IFNAR1 -dependent manner (Fig. 1). However, it is possible that human IFNb can trigger a more substantive response in the setting of human IFNAR1/2 receptors in mouse cells.
  • Harari et al generated a transgenic mouse strain named HyBNAR (Hybrid IFNAR) with human IFNAR1/2 extracellular ligand binding domain and mouse IFNAR1/2 receptor signaling domains. It was shown in this study that while human IFNb induces signaling in wild-type mice, consistent with the results, this response is enhanced in HyBNAR mice.
  • the primary goal is to determine mechanisms of action of CD40L and IFNP in the TME for which we can use Ad-GFP, Ad-IFNP, MEM- 188 and MEM-288 OVs. These exploratory studies can help assess broad impact of above OVs on major populations of myeloid cells, DCs, T and B cells. As shown in Fig.
  • Tumor antigens are readily taken up by resident macrophages and DCs, which can be detected by using tumors that express GFP or ZsGreen. Recent studies have also demonstrated that antigen uptake functionally reprograms DCs.
  • ZsGreen + populations of macrophages and DCs were readily detected in ZsGreen expressing tumors compared to parental non-expressing tumors.
  • ZsGreen expression was used to identify tumor cells (ZsGreen + CD45 ) wherein we could also detect CD40E expression 2 days after a single MEM-288 injection (Fig. 11A-B).
  • mice can be digested to perform flow cytometry to determine differences in immune cells after injection of different OVs.
  • a specific focus can be on tumor antigen-specific CD8 T cells in B16-OVA tumors.
  • B16-OVA implanted mice that were treated with MEM-288 we readily detected increase in antitumor T cells in blood (Fig. 5C) and spleen (Fig 5D).
  • MEM-288 treatment results in the highest levels of total and OVA-specific CD8 T cells in tumors detected as in Fig. 9B).
  • IL- 12 p70 is a critical Thl-response promoting cytokine secreted by DCs, and a known target of CD40L. Furthermore, expression of IL-12 p70 by tumor DCs is crucial for T cell antitumor immune response.
  • OVs expressing different transgenes have varying effects on the broader TME and on T cell/DC activation.
  • MEM-288 has the most robust stimulatory effects because of the combined expression of CD40L and IFNP-
  • CD40L and IFNP Using a complementary approach, we can determine the individual roles of CD40L and IFNP on key phenotypes observed after MEM- 288 injection by using mice lacking CD40 and IFNAR1. While the above studies have shown that CD40 and IFNAR1 are important for T cell responses (Fig. 5D), we determine here the role of DCs in this response. This approach can help provide additional insights into the unique and overlapping functions of these two pathways in the context of MEM-288 treatment.
  • MHC-II + CD1 lc + cells are detected in inguinal DLNs.
  • the MHC hlgh population is thought to comprise of migratory DC1 and DC2, which as expected has the higher percentage of CD103 + DCs as well as CDllb + DCs.
  • a CDllc + population with intermediate levels of MHC-II (MHC int ) population comprises of resident DC1 and DC2 and has a lower percentage of CD103 + DCs.
  • the majority of ZsGreen+ DCs reside in the MHC hlgh population. We can determine here the impact of different OVs on the distribution and activation phenotype of these distinct populations.
  • MEM-288 administration can result in the highest DLN trafficking and that these DCs have the strongest activation phenotype.
  • LN populations of DCs do not appear to be impacted by absence of CD40 and IFNAR1. Nonetheless, it is not known whether CD40 and IFNAR1 absence impacts DC migration from tumor to DLNs.
  • mice bearing B16-OVA tumors for injection with all 4 OVs.
  • DC1 and DC2 sorted from DLN cells for co-culture with CFSE labeled naive OT-1 CD8 T cells to perform CFSE-dilution assays as described hereiin. These studies can determine whether MEM- 288 induced DC activation results in the highest levels of T cell proliferation.
  • Type I interferon is selectively required by dendritic cells for immune rejection of tumors.
  • Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. J Exp Med 202:637-650.
  • Macrophage IL-10 blocks CD8+ T celldependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26:623-637.
  • T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393:480-483.
  • PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568-571.
  • HDAC inhibitors enhance T cell chemokine expression and augment response to PD- 1 immunotherapy in lung adenocarcinoma. Clin Cancer Res 22:4119-4132.
  • SEQ ID NO: 1 is the amino acid sequence of the human wild-type interferon-a (UniProtKB Reference No. P05014):
  • SEQ ID NO: 2 is the amino acid sequence of the human wild-type interferon- 0(UniProtKB Reference No. P01574):
  • SEQ ID NO: 3 is the amino acid sequence of the human wild-type interferon-e (UniProtKB
  • SEQ ID NO: 5 is the amino acid sequence of the human wild-type interferon-co (UniProtKB
  • SEQ ID NO: 6 is the amino acid sequence of the human CD40-L (ETniProtKB Reference No. P29965):

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WO2022170219A1 (en) * 2021-02-05 2022-08-11 Iovance Biotherapeutics, Inc. Adjuvant therapy for cancer
CN116059260A (zh) * 2023-03-07 2023-05-05 华南农业大学 Sva病毒在制备肿瘤防治药物中的应用及抗肿瘤组合物
WO2023108003A3 (en) * 2021-12-07 2023-08-24 Memgen, Inc. Oncolytic virus boosts t cell response for effective til therapy

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EP3119477B1 (en) * 2014-03-20 2020-01-01 H. Lee Moffitt Cancer Center And Research Institute, Inc. Tumor-infiltrating lymphocytes for adoptive cell therapy
BR112020026045A2 (pt) * 2018-06-19 2021-03-23 H. Lee Moffitt Cancer Center And Research Institute, Inc. vírus oncolítico ou terapia do câncer mediada por célula que apresenta antígeno usando interferon tipo i e ligante de cd40

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WO2022170219A1 (en) * 2021-02-05 2022-08-11 Iovance Biotherapeutics, Inc. Adjuvant therapy for cancer
WO2023108003A3 (en) * 2021-12-07 2023-08-24 Memgen, Inc. Oncolytic virus boosts t cell response for effective til therapy
CN116059260A (zh) * 2023-03-07 2023-05-05 华南农业大学 Sva病毒在制备肿瘤防治药物中的应用及抗肿瘤组合物

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