WO1998016246A9 - Immunotherapie amelioree par cytokine pour tumeurs cerebrales - Google Patents

Immunotherapie amelioree par cytokine pour tumeurs cerebrales

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Publication number
WO1998016246A9
WO1998016246A9 PCT/US1997/018455 US9718455W WO9816246A9 WO 1998016246 A9 WO1998016246 A9 WO 1998016246A9 US 9718455 W US9718455 W US 9718455W WO 9816246 A9 WO9816246 A9 WO 9816246A9
Authority
WO
WIPO (PCT)
Prior art keywords
cytokine
tumor
cells
csf
days
Prior art date
Application number
PCT/US1997/018455
Other languages
English (en)
Other versions
WO1998016246A1 (fr
Filing date
Publication date
Application filed filed Critical
Priority to AU48182/97A priority Critical patent/AU4818297A/en
Priority to EP97910921A priority patent/EP0930892A1/fr
Priority to JP10518504A priority patent/JP2001502331A/ja
Priority to CA002267977A priority patent/CA2267977A1/fr
Publication of WO1998016246A1 publication Critical patent/WO1998016246A1/fr
Publication of WO1998016246A9 publication Critical patent/WO1998016246A9/fr

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Definitions

  • systemic chemotherapy has had minor success in the treatment of cancer of the colon- rectum, esophagus, liver, pancreas, and kidney.
  • a major problem with systemic chemotherapy for the treatment of these types of cancer is that the systemic doses required to achieve control of tumor growth frequently result in unacceptable systemic toxicity.
  • Efforts to improve delivery of chemotherapeutic agents to the tumor site have resulted in advances in organ- directed chemotherapy, as by continuous systemic infusion, for example.
  • continuous infusions of anticancer drugs generally have not shown a clear benefit over pulse or short-term infusions.
  • Implantable elastomer access ports with self-sealing silicone diaphragms have also been tried for continuous infusion, but extravasation remains a problem.
  • Portable infusion pumps are now available as delivery devices and are being evaluated for efficacy.
  • Controlled release biocompatible polymers have been used successfully for local drug delivery and have been utilized for contraception, insulin therapy, glaucoma treatment, asthma therapy, prevention of dental related disorders, and certain types of cancer chemotherapy.
  • Laser, R. , and Wise, D. , eds, Medical Applications of Controlled Release, Vol. I and II, Boca Raton, CRC Press (1986) ).
  • the design and development of effective anti-tumor agents for treatment of patients with malignant neoplasms of the central nervous system have been influenced by two major factors: 1) the blood-brain barrier provides an anatomic obstruction, limiting access of drugs to these tumors; and 2) the drugs given at high systemic levels are generally cytotoxic.
  • Efforts to improve drug delivery to the tumor bed in the brain have included transient osmotic disruption of the blood brain barrier, cerebrospinal fluid perfusion, and direct infusion into a brain tumor using catheters. Each technique has had significant limitations. Disruption of the blood brain barrier increased the uptake of hydrophilic substances into normal brain, but did not significantly increase substance transfer into the tumor.
  • the examples demonstrate that systemic administration (vaccination) with GM-CSF transduced tumor cells or microencapsulated GM-CSF protects against growth of intracranial melanoma.
  • the examples also demonstrate that local intracranial delivery of IL-2 transduced tumor cells or microencapsulated IL-2 generates immediate anti-tumor responses within the central nervous system as well as long term memory capable of generating potent anti-tumor responses against multiple subsequent tumor challenges, including challenges outside the central nervous system.
  • the examples further demonstrate that combination immunotherapy using systemic vaccination with GM-CSF transductants and local intracranial administration of IL-2 transductants produces an anti-tumor effect that is significantly enhanced as compared to treatment with either treatment alone.
  • a therapy for treatment of tumors has been developed which relies on the combination of an initial systemic "priming" of the immune system, most preferably through the combination of administration of a cytokine such as GM-CSF and tumor antigen such as replication incompetent tumor cells along with local release at the tumor site (or site of resection following tumor removal) of a cytokine such as IL-2 which enhances the immune response against the tumor cells.
  • Local release can be obtained using any of several means, but a preferred method is using microparticles to release cytokine over a period of at least days or transduced cells, most preferably replication incompetent tumor cells which are transduced with the gene encoding the cytokine to be released. The latter is shown to release for at least five days after implantation. Microparticles can be designed to release for between hours and weeks or even months, as required.
  • GM-CSF Granulocyte-macrophage colony stimulating factor
  • GM-CSF Granulocyte-macrophage colony stimulating factor
  • GM-CSF has been shown to prime systemic immune responses via stimulation of bone marrow derived antigen presenting cells. See Inaba, K.
  • Interleukin-2 is produced by CD4+ T cells, and in lesser quantities by CD8+ T cells.
  • Secreted IL-2 is a 14 to 17 kD glycoprotein encoded by a single gene on chromosome 4 in humans.
  • IL- 2 acts on the same cells that produce it, i.e., it functions as an autocrine growth factor.
  • IL-2 also acts on other T lymphocytes, including both CD4 + and CD8+ cells.
  • IL-2 induces a local inflammatory response leading to activation of both helper and cytotoxic subsets of T cells.
  • IL-2 also stimulates the growth of natural killer cells and enhances their cytolytic function.
  • Tumor necrosis factor was originally identified as a mediator of tumor necrosis present in the serum of animals exposed to bacterial lipopolysaccharide (LPS) such as endotoxin.
  • LPS lipopolysaccharide
  • the major endogenous source of TNF is the LPS-activated mononuclear phagocyte, although antigen-stimulated T cells, activated natural killer cells, and activated mast cells can also secrete this protein.
  • TNF is initially synthesized as a nonglycosylated transmembrane protein of approximately 25 kD. TNF has potent anti-tumor effects in vitro, although clinical trials of TNF in advanced cancer patients have been discontinued due to toxicity.
  • TNF- ⁇ has a diverse range of biological properties including inducing expression of a number of cytokines such as interleukin-6, interleukin-8, GM-CSF, and granulocye-colony stimulating factor, as well as causing hemorrhagic necrosis in established tumors. TNF has been reported to generate tumor suppression after tumor cell-targeted TNF- ⁇ gene transfer. Blankenstein, T. , et al., J. Exp. Med. , 173:1047-52 (1991). iv. Interleukin-4.
  • Interleukin-4 is a helper T cell- derived cytokine of approximately 20 kD which stimulates the proliferation of mouse B cells in the presence of anti-Ig antibody (an analog of antigen) and causes enlargement of resting B cells as well as increased expression of class II MHC molecules.
  • the principal endogenous source of IL-4 is from CD4+ T lymphocytes. Activated mast cells and basophils, as well as some CD8+ T cells, are also capable of producing IL-4.
  • Gamma interferon is a homodimeric glycoprotein containing approximately 21 to 24 kD subunits. IFN- ⁇ is produced by some CD4+ helper T cells and nearly all CD8+ T cells. Transcription is directly initiated as a consequence of antigen activation and is enhanced by IL-2 and interleukin-12. IFN- ⁇ is also produced by natural killer cells.
  • IFN- ⁇ acts as a potent activator of mononuclear phagocytes, acts directly on T and B lymphocytes to promote their differentiation and acts to stimulate the cytolytic activity of natural killer cells.
  • IFN- ⁇ transduced non-immunogenic sarcoma has been reported to elicit CD8+ T cells against wild type tumor cells. Restifo, N. , et al., J. Exp. Med. , 175: 1423-28 (1992). vi. Interleukin-3.
  • Interleukin-3 also known as multilineage colony-stimulating factor, is a 20 to 26 kD product of CD4+ T cells that acts on the most immature marrow progenitors and promotes the expansion of cells that differentiate into all known mature cell types. IL-3 has been reported to enhance development of tumor reactive cytotoxic T cells by a CD4-dependent mechanism. Pulaski, B. A. , et al., Cancer Res. , 53:2112-57 (1993). vii. Interleukin-6.
  • Interleukin-7 is a cytokine secreted by marrow stromal cells that acts on hematopoietic progenitors committed to the B lymphocyte lineage. IL-7 has been reported to induce CD42+ T cell dependent tumor rejection. Hock, H. , et al., J. Exp. Med. , 174: 1291-99 (1991). ix. Granulocyte-colony stimulating factor. Granulocyte- colony stimulating factor (G-CSF) is made by the same cells that make GM- CSF. The secreted polypeptide is approximately 19 kD. G-CSF gene transfer has been reported to suppress tumorgenicity of murine adenocarcinoma.
  • cytokines are known in the art to have an anti-tumor effect and can be used in the pharmaceutical compositions described herein. Moreover, since cytokines are known to have an effect on other cytokines, one can admimster the cytokine which elicits one of the cytokines described above, or directly administer one of the cytokines which is elicited. Additional cytokines are known to those skilled in the art and are described in Abbas, et al., "Cytokines", chapter 12, pp. 239-61, Cellular and Molecular Immunology. 2nd Ed., W.B.
  • dexamefhasone a synthetic corticosteroid used systemically to control cerebral edema
  • Other compounds which can be included are preservatives, antioxidants, and fillers, coatings or bulking agents which may also be utilized to alter polymeric release rates.
  • Cytokine Formulations The cytokines can be administered in a pharmaceutically acceptable carrier such as saline, phosphate buffered saline, cells transduced with a gene encoding the cytokine, microparticles, or other conventional vehicles, i.
  • the cytokines can be encapsulated into a biocompatible polymeric matrix, most preferably biodegradable, for use in the treatment of solid tumors.
  • the cytokine is preferably released by diffusion and/or degradation over a therapeutically effective time, usually eight hours to five years, preferably one week to one year.
  • microencapsulated includes incorporated onto or into or on microspheres, microparticles, or microcapsules.
  • Microcapsules is used interchangeably with microspheres and microparticles, although it is understood that those skilled in the art of encapsulation will recognize the differences in formulation methods, release characteristics, and composition between these various modalities.
  • the microspheres can be directly implanted or delivered in a physiologically compatible solution such as saline.
  • Buffers, acids and bases are used to adjust the pH of the composition.
  • Agents to increase the diffusion distance of agents released from the implanted polymer can also be included.
  • Surfactants may be necessary in implant formulations to enhance wettability of poorly soluble or hydrophobic materials.
  • Surfactants such as polysorbates or sodium lauryl sulfate are, if necessary, used in low concentrations, generally less than 5%.
  • Controlled release devices are typically prepared in one of several ways.
  • the polymer can be melted, mixed with the substance to be delivered, and then solidified by cooling.
  • Such melt fabrication processes require polymers having a melting point that is below the temperature at which the substance to be delivered and polymer degrade or become reactive.
  • the device can be prepared by solvent casting, where the polymer is dissolved in a solvent, and the substance to be delivered dissolved or dispersed in the polymer solution. The solvent is then evaporated, leaving the substance in the polymeric matrix. Solvent casting requires that the polymer be soluble in organic solvents and that the agents to be encapsulated be soluble or dispersible in the solvent. Similar devices can be made by phase separation or emulsification or even spray drying techniques. In still other methods, a powder of the polymer is mixed with the cytokine and then compressed to form an implant.
  • TNF gene transfer is described in Blankenstein, T., et al., J. Exp. Med., 73:1047-52 (1991).
  • IL-6 transfection into lung carcinoma tumor cells is described in Progador, A, et al., Cancer Res. , 52:3679-87 (1992).
  • ⁇ lFN cDNA transduced into non-immunogenic sarcoma is described in Restifo, N., I. Exp. Med. , 175: 1423-28 (1992).
  • G-CSF gene transfer is described in Colombo, M., et al., Cancer Res., 52:4853-57 (1991).
  • Suitable pharmaceutical vehicles are known to those skilled in the art.
  • Inducers can also be used to produce cells which secrete cytokines.
  • Inducers may be used alone in some cases or in combination with transforming agents, and include tumor necrosis factor (TNF), endotoxin, and other agents known to those skilled in the art.
  • TNF tumor necrosis factor
  • the cultured cells are exposed to an amount effective to activate the cells, as determined by cytokine expression, immunoglobulin secretion, and/or other indicators such as proliferation or alteration of cell surface properties or markers.
  • cells are initially exposed to a small amount to "prime" the cells, then to a subsequent dose to elicit greater activation of the cells.
  • Cells can be admimstered in medium or washed and administered in saline. Alternatively, cells can be encapsulated in a polymeric matrix and administered. II. Administration to Patients
  • Animals were then placed in a stereotactic frame and cells were delivered by a 26 gauge needle to a depth of 3 mm over a period of 3 minutes.
  • the total volume of injected cells was 10 ⁇ l.
  • the needle was removed, the site irrigated with sterile 0.9% NaCl solution, and the skin was sutured closed with 4.0 vicryl.
  • mice Development of an intracranial B16-F10 melanoma model in C57BL/6 mice.
  • animals were divided into five groups of at least eight animals and received stereotactic intracranial injections of either 10 2 , 10 3 , 10 4 , or 10 5 wild type B16-F10 melanoma cells into the left parietal region by the method described above.
  • Control animals received similar intracranial injections of 0.9% NaCl solution. Animals were assessed daily for survival.
  • brains were removed at the time of death and fixed in 10% formalin for at least 5 days, sectioned, embedded in paraffin, and stained with hematoxylin and eosin.
  • This study demonstrates that a significant anti-tumor immune response is generated using a systemic vaccination with GM-CSF microspheres. This response is comparable to that generated by GM-CSF transduced tumor cells and represents a practical method for delivering GM-CSF in treatments employing GM-CSF immunotherapy.
  • IL-2 transduced cells were found to be highly effective in treating intracranial tumor when they were delivered directly to the brain.
  • Initial studies showed that the IL-2 effect was dose-dependent.
  • the results are shown in Figure 3.
  • Doses of 0.08 ng per day of IL-2 (10 3 IL-2 producing cells) showed no enhanced survival compared, to controls, whereas a dose of 0.8 ng per day (10 4 IL-2 producing cells) showed a trend toward prolonged survival that did not reach statistical significance.
  • a dose of 8.0 ng per day (10 5 IL-2 producing cells) a significant prolongation in survival was seen.
  • B16-F10 melanoma cells were used for systemic delivery of GM-CSF or intracranial delivery of IL-2. Forty-nine C57B16 mice were vaccinated in the flank with either GM-CSF producing B16-F10 cells or medium followed by intracranial delivery of IL-2 or medium 2 weeks later. Every animal received an intracranial co-injection of wild-type melanoma at a dose uniformly fatal to untreated animals. Initial survivors and a new control group were rechallenged with a second intracranial dose of wild-type B16-F10 melanoma 134 days after their first challenge.

Abstract

La présente invention concerne une thérapie permettant de traiter des patients atteints de cancer en combinant l'administration par voie générale d'une cytokine et d'un véhicule pharmaceutiquement acceptable avec l'administration locale d'une cytokine et d'un véhicule pharmaceutiquement acceptable. Dans le mode de réalisation préféré, les tumeurs cérébrales sont traitées au moyen d'une cytokine telle que le GM-CSF administré par voie générale, de préférence en combinaison avec un antigène tumoral tel que des cellules tumorales incapables de se répliquer, et d'une cytokine telle que l'IL-2 ou l'IL-4 administrée localement, de préférence dans un véhicule assurant sa libération lente tel que des cellules transduites, et de préférence des cellules tumorales incapables de se répliquer, ou incorporée dans des véhicules microparticulaires tels que des microsphères polymères.
PCT/US1997/018455 1996-10-16 1997-10-15 Immunotherapie amelioree par cytokine pour tumeurs cerebrales WO1998016246A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU48182/97A AU4818297A (en) 1996-10-16 1997-10-15 Cytokine enhanced immunotherapy for brain tumors
EP97910921A EP0930892A1 (fr) 1996-10-16 1997-10-15 Immunotherapie amelioree par cytokine pour tumeurs cerebrales
JP10518504A JP2001502331A (ja) 1996-10-16 1997-10-15 脳腫瘍に対するサイトカインで増強した免疫療法
CA002267977A CA2267977A1 (fr) 1996-10-16 1997-10-15 Immunotherapie amelioree par cytokine pour tumeurs cerebrales

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US73159796A 1996-10-16 1996-10-16
US08/731,597 1996-10-16

Publications (2)

Publication Number Publication Date
WO1998016246A1 WO1998016246A1 (fr) 1998-04-23
WO1998016246A9 true WO1998016246A9 (fr) 1998-08-13

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EP (1) EP0930892A1 (fr)
JP (1) JP2001502331A (fr)
AU (1) AU4818297A (fr)
CA (1) CA2267977A1 (fr)
WO (1) WO1998016246A1 (fr)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
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WO1995016464A1 (fr) * 1993-12-14 1995-06-22 Johns Hopkins University School Of Medicine Liberation controlee de substances pharmaceutiquement actives pour l'immunotherapie
US6277368B1 (en) 1996-07-25 2001-08-21 The Regents Of The University Of California Cancer immunotherapy using autologous tumor cells combined with cells expressing a membrane cytokine
ATE412418T1 (de) * 1998-04-02 2008-11-15 Univ California Zusammensetzungen zur erhöhung der zahl antigen präsentierender zellen und der antitumoralen antwort in menschlichen patienten
US20020110538A1 (en) * 1999-12-28 2002-08-15 Health Research, Inc. Methods and products for tumor immunotherapy using cytokines
CA2412845C (fr) * 2000-06-29 2014-07-22 Lexigen Pharmaceuticals Corp. Renforcement des reponses immunitaires dont la mediation est assuree par une proteine de fusion anticorp-cytokine via le traitement combine a base d'agents ameliorant la fixation des immunocytokines
US6911204B2 (en) 2000-08-11 2005-06-28 Favrille, Inc. Method and composition for altering a B cell mediated pathology
DE60331725D1 (de) * 2002-03-25 2010-04-29 Technologie Biolactis Inc Therapeutische mittel als antikrebs impfstoffadjuvantien und deren therapeutische verfahren
EP1374893A1 (fr) 2002-06-17 2004-01-02 NovImmune S.A. Vaccination au moyen de cellules immuno-isolées produisant un immunomodulateur
US7695723B2 (en) * 2002-12-31 2010-04-13 Sygnis Bioscience Gmbh & Co. Kg Methods of treating neurological conditions with hematopoietic growth factors
CN108289942A (zh) 2015-09-25 2018-07-17 迈斯免疫公司 用生产免疫调节剂的免疫-分离的细胞接种疫苗
EP3806888B1 (fr) 2018-06-12 2024-01-31 Obsidian Therapeutics, Inc. Constructions régulatrices dérivées de pde5 et procédés d'utilisation en immunothérapie
WO2020123716A1 (fr) 2018-12-11 2020-06-18 Obsidian Therapeutics, Inc. Il12 liée à la membrane, compositions et procédés de régulation accordable
CN113966397A (zh) 2019-03-08 2022-01-21 黑曜石疗法公司 人碳酸酐酶2组合物和用于可调调节的方法
US20220267398A1 (en) 2019-06-12 2022-08-25 Obsidian Therapeutics, Inc. Ca2 compositions and methods for tunable regulation
CN114450308A (zh) 2019-06-12 2022-05-06 黑曜石疗法公司 用于调节性调控的ca2组合物和方法
US20230092895A1 (en) 2019-08-30 2023-03-23 Obsidian Therapeutics, Inc. Tandem cd19 car-based compositions and methods for immunotherapy
US11058725B2 (en) 2019-09-10 2021-07-13 Obsidian Therapeutics, Inc. CA2 compositions and methods for tunable regulation

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