WO2005079581A1 - Distribution intratumorale de cellules dendritiques - Google Patents

Distribution intratumorale de cellules dendritiques Download PDF

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Publication number
WO2005079581A1
WO2005079581A1 PCT/US2004/001612 US2004001612W WO2005079581A1 WO 2005079581 A1 WO2005079581 A1 WO 2005079581A1 US 2004001612 W US2004001612 W US 2004001612W WO 2005079581 A1 WO2005079581 A1 WO 2005079581A1
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tumor
dendritic cells
mammal
cells
administering
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PCT/US2004/001612
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English (en)
Inventor
John S. Yu
Keith Black
Moneeb Ehtesham
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Cedars-Sinai Medical Center
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Priority to EP04703716A priority Critical patent/EP1705992A1/fr
Priority to PCT/US2004/001612 priority patent/WO2005079581A1/fr
Publication of WO2005079581A1 publication Critical patent/WO2005079581A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4614—Monocytes; Macrophages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4615—Dendritic cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
    • A61K39/4622—Antigen presenting cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated

Definitions

  • the present invention relates to methods of treating a tumor by administering dendritic cells and compositions effective for the same. More specifically, the method involves administering dendritic cells directly into a tumor or its surrounding tissue, the tumor being located in the body of a mammal.
  • the compositions are dendritic cell-based.
  • BACKGROUND OF THE INVENTION Cancer remains one of the leading causes of death in the United States and around the world.
  • Various forms of cancer are differentially treated, depending in part on the location of a tumor targeted for treatment.
  • One particularly difficult group of tumors to treat are those that reside in and near the brain.
  • Treatment of brain tumors presents a number of problems, not the least of which being the dangers inherent in any surgical procedure involving regions of the brain and the tissue located nearby. There is little room for error and the consequences of even a minor surgical mishap can be devastating to a patient; brain damage, or even death may result.
  • surgery remains the preferred method of treatment for most brain tumors and is often performed in conjunction with radiation therapy and chemotherapy.
  • Glioblastoma multiforme and anaplastic astrocytomas are classified in the category of brain tumors commonly known as malignant gliomas. Although not particularly common tumors themselves, they represent a class of tumors associated with significant rates of mortality and morbidity.
  • Current treatment for malignant glioma consists of surgical resection followed by radiation therapy and chemotherapy. However, this treatment generally fails in substantially changing the outcome for a patient; median survival remains less than one year even with medical intervention. Inducing the body's immune system to specifically combat tumor cells may ultimately be the only means of completely eliminating these cells.
  • T-cells recognize the digested fragments and bind to the APCs; this activates the T-cells and triggers the immune response.
  • Some studies suggest that tumor cells themselves may contain immunogeneic antigens. However, these studies further note that tumor cells are poor APCs; they do not efficiently internalize and process/present tumor antigens to T-cells. S. Constant et al., "Peptide and protein antigens require distinct antigen-presenting cell subsets for the priming of CD4+ T cells," J. Immunol. 154:4915-4923 (1995); D. Levin et al. , "Role of dendritic cells in the priming of CD4+ lymphocytes to peptide antigen in vivo," J.
  • IL-4 interleukin-4
  • TGF- ⁇ transforming growth factor- ⁇
  • GM-CSF granulocyte- macrophage colony-stimulating factor
  • Dendritic cells are "professional APCs," as they are uniquely capable of activating both primed T-cells (as in the case of macrophages and B-cells) and na ⁇ ve T-cells (i.e., those that have not previously encountered antigens). In fact, dendritic cells are the only APCs known to process exogenous antigen through the class I pathway. Thus, efforts have been directed toward determining whether dendritic cells presenting tumor- associated antigens can mediate a significant anti-tumor response; potentially an anti- tumor response stronger than that induced by cytokine-presenting cells.
  • cytokine-stimulated dendritic cells have been pulsed ex vivo with tumor antigens and used successfully as anti-tumor vaccines for extracranial tumor models.
  • J. Mayorodomo et al. "Bone marrow-derived dendritic cells pulsed with synthetic tumor peptides elicit protective and therapeutic antitumor immunity," Nature Med. 1 :1297-1302 (1995); J. Young and K. Inaba, "Dendritic cells and adjuvants for class I major histocompatability complex-restricted antitumor immunity," J. Exp. Med. 183:7-11 (1996); L.
  • a tumor may be surgically inaccessible, or the surgical manipulation thereof may present unreasonable danger to the health and safety of a patient. Even in instances where tumor tissue can be readily accessed and sampled, the surgical harvest required to obtain that tissue subjects a patient to yet another procedure, the avoidance of which is likely desirable.
  • a system and method of implementing a dendritic cell-based vaccination strategy that obviates, for practical purposes, the above- mentioned limitations. More specifically, there is a need in the art for a composition including and method for implementing a dendritic cell-based vaccination strategy to treat a tumor without the need for ex vivo priming of the dendritic cells prior to administration of the same to a patient.
  • the present invention provides a method and dendritic cell-based composition for treating a tumor.
  • the method may include administering dendritic cells directly into the tumor itself or into the tissue surrounding or located nearby the tumor, and may be effective in the treatment of a tumor disposed in any location throughout the body of a mammal.
  • the method and composition do not require the dendritic cells used therein to be primed ex vivo prior to inclusion in the composition or administration to a patient.
  • the methods of the present invention may induce immune cell infiltration into a tumor.
  • Figure 1 depicts a phenotypic profile of dendritic cells in accordance with an embodiment of the present invention. Bone marrow cultures yielded cells expressing cell surface phenotypic markers that dendritic cells commonly express.
  • Figure 2 depicts an inhibition of tumor growth owing to intratumoral dendritic cell vaccination in accordance with an embodiment of the present invention.
  • Dendritic cells (Column B) and a saline control (Column A) were vaccinated into subcutaneous 9L glioma tumors on the dorsum of the foot. Tumor volume was markedly lower when treated with dendritic cells.
  • Figure 3 depicts an intratumoral vaccination with dendritic cells inducing T-cell infiltration into brain tumors in accordance with an embodiment of the present invention. Dendritic cells vaccinated into brain tumors induce increased CD4+ T-cell infiltration (Fig. 3A) as compared to saline-treated controls (Fig. 3B).
  • Figure 4 depicts an intracranial dendritic cell vaccination prolonging survival in accordance with an embodiment of the present invention.
  • FIG. 5 depicts an intracranial dendritic cell vaccination prolonging survival in animals with established intracranial gliomas in accordance with an embodiment of the present invention.
  • 9L glioma-bearing rats survived longer than monocyte-inoculated controls.
  • Figure 6 depicts a promotion of T-cell infiltration in 9L intracranial gliomas inoculated with dendritic cells in accordance with an embodiment of the present invention. Strong T-cell infiltration was observed in animals vaccinated with dendritic cells (Fig. 6A) and weak infiltration was observed in monocyte-treated (Fig. 6B) and saline-treated (Fig. 6C) controls. R2 indicates region of CD8+ staining and R3 indicates region of CD4+ staining.
  • Figure 7 is executed in color and depicts a migration of dendritic cells into systemic lymph nodes in accordance with an embodiment of the present invention. Dendritic cells expressing green fluorescent protein (GFP) were found dispersed within the main tumor mass (Fig.
  • GFP green fluorescent protein
  • FIG. 7A depicts an enhancement of tumor-specific cytotoxic T-cell activity by intratumoral inoculation of dendritic cells into intracranial brain tumors in accordance with an embodiment of the present invention.
  • T-cells from animals inoculated with dendritic cells demonstrated a 1.48-fold increase in IFN-gamma RNA message compared to monocyte-treated (1.12-fold) and saline-treated (1.20-fold) controls.
  • Figure 9 depicts an enhancement of tumor-specific cytotoxic T-cell activity by intratumoral inoculation of dendritic cells into intracranial brain tumors in accordance with an embodiment of the present invention.
  • T-cells from animals inoculated with dendritic cells demonstrated a 1.31 -fold increase in secreted IFN-gamma compared to monocyte- treated (0.70-fold) and saline-treated (1.10-fold) controls.
  • the present invention is based upon a composition for and method of treating a tumor by injecting or otherwise administering dendritic cells into the tumor or its immediately surrounding tissue (hereinafter, a tumor and its immediately surrounding tissue are collectively included in the term "tumor region"). More specifically, the method involves injecting or otherwise administering the dendritic cells directly into a solid tumor. Treating a tumor in accordance with the embodiments of the present invention provides dendritic cells with more direct access to the tumor than that which is possible with conventional methods; especially those conventional methods wherein dendritic cells are administered peripherally.
  • the techniques of the present invention may be particularly advantageous in instances where a tumor is surgically inoperable, where surgery is otherwise undesirable, or where no portion of the tumor can be retrieved for priming dendritic cells ex vivo against the tumor; although such factors need not be indicated in order for the methods of the present invention to be effective.
  • the methods of the present invention may be especially advantageous in the treatment of tumors located in the brain of a mammal; particularly in treating high- or low-grade malignant gliomas, and, even more particularly, in treating anaplastic astrocytoma or glioblastoma multiforme.
  • composition and methods of the present invention are based, in part, on the inventors' surprising discovery that unprimed dendritic cells may be delivered to the tumor region of a patient and may thereafter be effective in the treatment of the tumor. Dendritic cells administered in this manner essentially prime themselves in vivo upon coming into contact or otherwise establishing biochemical communication with the target tumor cells, and, correspondingly, their antigen proteins.
  • Unprimed dendritic cells include those dendritic cells that do not rely upon the acquisition of tumor tissue as a protein source, and the subsequent culturing therewith.
  • dendritic cells are primed ex vivo. This generally involves culturing the dendritic cells with the tumor cells against which they will subsequently be utilized. This process provides the dendritic cells access to the tumor proteins, thereby allowing the cells to process the associated tumor antigens and prepare to present the digested antigens to T-cells upon introduction of the dendritic cells to the body of a patient.
  • dendritic cells may be delivered directly into a tumor bed or tumor region without first being primed ex vivo; the dendritic cells process the tumor antigens only in vivo.
  • Dendritic cells suitable for use in accordance with the present invention may be isolated or obtained from any tissue in which such cells are found, or may be otherwise cultured and provided.
  • antigen-presenting dendritic cells are preferred for use in accordance with the methods of the present invention.
  • dendritic cells may be found, by way of example, in the bone marrow or peripheral blood mononuclear cells (PBMCs) of a mammal, in the spleen of a mammal, or in the skin of a mammal (i.e., Langerhan's cells, which possess certain qualities similar to that of dendritic cells, may be found in the skin and may further be employed in conjunction with the methods of the present invention, and are included within the scope of the term "dendritic cells” as used herein).
  • PBMCs peripheral blood mononuclear cells
  • Langerhan's cells which possess certain qualities similar to that of dendritic cells
  • bone marrow may be harvested from a mammal and cultured in a medium.
  • Any suitable medium that promotes the growth of dendritic cells may be used in accordance with the present invention, and may be readily ascertained by one of skill in the art without undue experimentation.
  • GM-CSF and/or IL-4 may be included in the above-described medium.
  • Media may be at least partially replenished every few (e.g., two to four) days during the culturing process. After a suitable amount of time, clusters of dendritic cells may be apparent in the medium, and may be retrieved therefrom, either in individual clusters or in any other convenient amount.
  • Dendritic cells used in conjunction with the methods of the present invention may be delivered to a tumor region (e.g., a brain tumor, or the surrounding brain tissue) in a recipient by any suitable means. Such means of delivery may include, but are in no way limited to, injection, infusion, inoculation, direct surgical delivery, or any combination thereof.
  • dendritic cells may be administered to a mammal by direct inoculation via stereotactic surgery; a standard inoculation procedure known to those of skill in the art of neurosurgery.
  • the composition of the present invention may include unprimed dendritic cells in a pharmaceutical carrier.
  • Any conventional pharmaceutical carrier may be used in accordance with the composition or methods of the present invention, and an appropriate carrier may be selected by one of skill in the art without undue experimentation.
  • the pharmaceutical carrier is saline, although other carriers may be utilized depending upon the desired characteristics of the composition.
  • the dendritic cells administered to a patient in accordance with the composition and methods of the present invention may be delivered in combination with any of a variety of additional substances and compounds.
  • the dendritic cells of the present invention may be administered to a patient along with any suitable carrier, vehicle, additive, excipient, pharmaceutical adjunct, or other suitable product, as will be readily ascertained and appreciated by one of skill in the art.
  • the dendritic cells of the present invention may be administered in conjunction with other therapeutic compounds or agents useful in the treatment of the tumor or the relief of pain associated with the tumor or treatment thereof.
  • the quantity of dendritic cells appropriate for administration to a patient to effect the methods of the present invention and the most convenient route of such administration may be based upon a variety of factors, as may the formulation of the composition of the present invention .
  • a patient may be administered with from about 10 5 to about 10 7 dendritic cells in from about 0.05 mL to about 0.30 mL saline in a single administration.
  • a mammal is treated with dendritic cells following or in conjunction with radiotherapy. While not wishing to be bound by any theory, it is believed that prior or simultaneous treatment with radiotherapy renders a dendritic cell vaccination more effective as is allows the dendritic cells to better process dying tumor cells. Similarly, a chemotherapy regimen administered either prior to or simultaneous with dendritic cell vaccination therapy that induces tumor cells to undergo apoptosis (i.e., programmed cell death) may be beneficial.
  • treating includes, but is not limited to, ameliorating the tumor, lessening the severity of its complications, causing it to decrease in mass and/or size, preventing it from manifesting, preventing it from recurring, merely preventing it from worsening, or a therapeutic effort to effect any of the aforementioned, even if such therapeutic effort is ultimately unsuccessful.
  • EXAMPLES The Examples discussed herein demonstrate that dendritic cells may inhibit the growth of brain tumors when implanted directly into the tumors, and that this treatment may prolong the life of a patient with a brain tumor. The Examples further illustrate that dendritic cell vaccination may induce immune cell infiltration into brain tumors and systemic lymph nodes. Moreover, the Examples show that the implantation of dendritic cells directly into tumors disposed in locations throughout the body of a mammal is effective in the treatment of the same.
  • EXAMPLE 2 Dendritic Cells Inhibit Tumor Growth when Inoculated Intratum orally Dendritic cells were inoculated subcutaneously along with a mixture of irradiated and viable 9L glioma cells into the dorsum of the right foot of adult Fisher rats . Two weeks following this procedure, a second dose of dendritic cells was inoculated into each growing tumor. Eight weeks following t ie second dendritic cell vaccination, tumor sizes were measured using a precision caliper. Tumors were markedly smaller in animals that had received intratumoral dendritic cell as compared to the control animals that received only saline inoculations (Fig. 2).
  • E.XAMPLE 3 Dendritic Cell Vaccination Induces Immune Cell (T-cell) Infiltration into Brain Tumors
  • Dendritic cells were inoculated intracranially along with a mixture of irradiated and viable 9L glioma cells into the right corpus striatum (basal ganglia) of adult Fisher rats. Two weeks following this procedure, a second dose of dendritic cells was inoculated into each growing tumor. Two weeks following the second dendritic cell vaccination, animals were euthanized and their brains harvested. The brains were immediately frozen and sectioned on a cryostat (available from Janis Research Company, Inc.; Wilmington, MA).
  • T-cell markers i.e., CD4 and CD8.
  • Tumors from dendritic cell vaccinated animals displayed increased quantities of infiltrating T-cells as compared to tumors from control animals that received only saline inoculations (Fig. 3).
  • Dendritic cells were inoculated intracranially along with a mixture of irradiated and viable 9L glioma cells into the right corp us striatum (basal ganglia) of adult Fisher rats. Two weeks following this procedure, a second dose of dendritic cells was inoculated into each growing tumor. Control animals were treated at similar time points with intracranial saline inoculations. Animals were followed for survival. Rats treated with intracranial dendritic cell vaccination survived longer than saline treated controls, with 75% of dendritic cell-treated animals surviving beyond 90 days after the initial tumor implantation compared to 5% of the control group (Fig.
  • EXAMPLE 5 Dendritic Cell Vaccinations Prolong Survival in Rats with Established Brain Tumors
  • a mixture of irradiated and viable 9L glioma cells was introduced into the right corpus striatum (basal ganglia) of adult Fisher rats. Two days later, rats were inoculated intracranially with dendritic cells. Control animals were treated at similar time points with intracranial monocyte/macrophage inoculations. Animals were followed for survival. Rats treated with intracranial dendritic cell vaccination survived longer than monocyte/macrophage-treated controls, with 60% of dendritic cell-treated animals surviving beyond 90 days after the initial tumor implantation compared to 10% of the control group (Fig. 5). Moreover, surviving rats were immune to intracranial tumor re- challenge.
  • a mixture of irradiated and viable 9L glioma cells was introduced into the right corpus striatum (basal ganglia) of adult Fisher rats. Rats were vaccinated with intratumoral inoculations of immature dendritic cells, monocytes, or saline on days 2 and 16 following tumor implantation. One week following the second intratumoral inoculation, tumors were harvested and stained for CD4+ and CD8+ T-cell content. Results indicated strong T-cell infiltration in animals vaccinated with dendritic cells (Fig. 6A) and weak infiltration in monocyte (Fig. 6B) and saline (Fig. 6C) treated controls.
  • EXAMPLE 7 Dendritic Cells Migrate to Systemic Lymph Nodes To assess whether dendritic cells inoculated into intracranial brain tumors could drain to the lymphatic system, deep cervical lymph nodes were harvested from rats that had received intracranial co-implantations of partially irradiated 9L glioma cells and green fluorescent protein (GFP) expressing dendritic cells four days earlier. Tumor bearing brain sections from these animals demonstrated GFP positive dendritic cells interspersed within the main tumor mass (Fig. 7A). Deep cervical lymph nodes ipsilateral to the site of implantation were infiltrated with numerous GFP expressing cells (Fig. 7B). In contrast, contralateral cervical lymph node tissue (not shown) or lymph nodes from 9L glioma bearing rats not inoculated with dendritic cells (Fig. 7C) did not reveal any GFP positivity.
  • GFP green fluorescent protein
  • EXAMPLE 8 Enhancement of Tumor-Specific Cytotoxic T-cell Activity with Dendritic Cell Inoculation, Measured by Increased IFN-gamma Message
  • T-cells were isolated from their spleens two weeks following the second intratumoral inoculation. Harvested T-cells were re-stimulated in quadruplicate in vitro with irradiated 9L glioma cells.
  • PCR polymerase chain reaction
  • a cycle difference of 1 was assumed to indicate a two-fold difference in the message.
  • a fold-increase in IFN-gamma message for each treatment group was calculated by comparing target with no target.
  • T-cells from animals inoculated with dendritic cells demonstrated a 1.48-fold increase in IFN-gamma RNA message compared to monocyte (1.12-fold) and saline (1.20-fold) treated controls.
  • EXAMPLE 9 Enhancement of Tumor-Specific Cytotoxic T-cell Activity with Dendritic Cell Inoculation, Measured by Increased IFN-gamma Secretion
  • T-cells were isolated from their spleens two weeks following the second intratumoral inoculation. Harvested T-cells were re-stimulated in quadruplicate in vitro with irradiated 9L glioma cells.
  • a fold-increase in IFN-gamma levels for each treatment group was calculated by comparing target with no target.
  • T-cells from animals inoculated with dendritic cells demonstrated a 1.31-fold increase in secreted IFN-gamma compared to monocyte (0.70-fold) and saline (1.10-fold) treated controls.
  • the protease inhibitors of the present invention may be used in the treatment of any number of conditions where inflammation is observed, as would be readily recognized by one skilled in the art and without undue experimentation.

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Abstract

L'invention concerne des méthodes pour traiter une tumeur. Ces méthodes consistent à administrer des cellules dendritiques, soit directement dans la tumeur, ou indirectement, dans le tissu entourant cette tumeur. D'autres méthodes de l'invention consistent à induire une infiltration cellulaire immunitaire dans les tumeurs, et à traiter les tumeurs au moyen de cellules dendritiques non sensibilisées, par l'administration de cellules dendritiques, de manière analogue. Les méthodes de l'invention sont particulièrement avantageuses pour le traitement de tumeurs au cerveau, et d'autres tumeurs solides situées dans le corps d'un mammifère, qui sont difficiles ou impossibles à traiter par des moyens chirurgicaux classiques. Les compositions à base de cellules dendritiques de l'invention sont efficaces pour traiter les cellules susmentionnées.
PCT/US2004/001612 2004-01-20 2004-01-20 Distribution intratumorale de cellules dendritiques WO2005079581A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
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US7939090B2 (en) 2003-10-21 2011-05-10 Cedars-Sinai Medical Center System and method for the treatment of cancer, including cancers of the central nervous system
US8097256B2 (en) 2006-09-28 2012-01-17 Cedars-Sinai Medical Center Cancer vaccines and vaccination methods
US8129184B2 (en) 2006-09-26 2012-03-06 Cedars-Sinai Medical Center Cancer stem cell antigen vaccines and methods
US8383768B2 (en) 2009-05-07 2013-02-26 Immunocellular Therapeutics, Ltd. CD133 epitopes
US9068020B2 (en) 2008-09-02 2015-06-30 Cedars-Sinai Medical Center CD133 epitopes
EP3033417A4 (fr) * 2012-06-27 2017-06-14 Hasumi International Research Foundation Thérapie et procédé pour l'introduction intra-tumorale d'un lymphocyte t cytotoxique et/ou d'une cellule nkt avec un anti-tnf et/ou anti-il-10
US10137182B2 (en) 2013-02-14 2018-11-27 Immunocellular Therapeutics, Ltd. Cancer vaccines and vaccination methods
US11472856B2 (en) 2016-06-13 2022-10-18 Torque Therapeutics, Inc. Methods and compositions for promoting immune cell function
US11524033B2 (en) 2017-09-05 2022-12-13 Torque Therapeutics, Inc. Therapeutic protein compositions and methods of making and using the same
US11781111B2 (en) 2018-06-29 2023-10-10 Breakthrough Tech Llc Activation of immune cells

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EHTESHAM M ET AL: "Intratumoral dendritic cell vaccination elitics potent tumroicidal immunity against malignant glioma in rats", JOURNAL OF IMMUNOTHERAPY, vol. 26, no. 2, March 2003 (2003-03-01), pages 107 - 116, XP002983473 *
YU J S ET AL: "Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration", vol. 61, 1 February 2001 (2001-02-01), pages 842 - 847, XP002983453 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7939090B2 (en) 2003-10-21 2011-05-10 Cedars-Sinai Medical Center System and method for the treatment of cancer, including cancers of the central nervous system
US8129184B2 (en) 2006-09-26 2012-03-06 Cedars-Sinai Medical Center Cancer stem cell antigen vaccines and methods
US9023338B2 (en) 2006-09-26 2015-05-05 Cedars-Sinai Medical Center Cancer stem cell antigen vaccines and methods
US9433667B2 (en) 2006-09-28 2016-09-06 Cedars-Sinai Medical Center Cancer vaccines and vaccination methods
US8097256B2 (en) 2006-09-28 2012-01-17 Cedars-Sinai Medical Center Cancer vaccines and vaccination methods
US10226519B2 (en) 2006-09-28 2019-03-12 Cedars-Sinai Medical Center Cancer vaccines and vaccination methods
US8871211B2 (en) 2006-09-28 2014-10-28 Cedars-Sinai Medical Center Cancer vaccines and vaccination methods
US9095538B2 (en) 2006-09-28 2015-08-04 Cedars-Sinai Medical Center Cancer vaccines and vaccination methods
US9068020B2 (en) 2008-09-02 2015-06-30 Cedars-Sinai Medical Center CD133 epitopes
US9382308B2 (en) 2008-09-02 2016-07-05 Cedars-Sinai Medical Center CD133 epitopes
US8604167B2 (en) 2009-05-07 2013-12-10 Immunocellular Therapeutics, Ltd. CD133 epitopes
US8383768B2 (en) 2009-05-07 2013-02-26 Immunocellular Therapeutics, Ltd. CD133 epitopes
EP3033417A4 (fr) * 2012-06-27 2017-06-14 Hasumi International Research Foundation Thérapie et procédé pour l'introduction intra-tumorale d'un lymphocyte t cytotoxique et/ou d'une cellule nkt avec un anti-tnf et/ou anti-il-10
US10137182B2 (en) 2013-02-14 2018-11-27 Immunocellular Therapeutics, Ltd. Cancer vaccines and vaccination methods
US11096996B2 (en) 2013-02-14 2021-08-24 Precision Lifesciences Group Llc Cancer vaccines and vaccination methods
US11472856B2 (en) 2016-06-13 2022-10-18 Torque Therapeutics, Inc. Methods and compositions for promoting immune cell function
US11524033B2 (en) 2017-09-05 2022-12-13 Torque Therapeutics, Inc. Therapeutic protein compositions and methods of making and using the same
US11781111B2 (en) 2018-06-29 2023-10-10 Breakthrough Tech Llc Activation of immune cells

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