+

WO2019173261A1 - Composition et procédé de traitement du cancer à l'aide d'acide hyaluronique - Google Patents

Composition et procédé de traitement du cancer à l'aide d'acide hyaluronique Download PDF

Info

Publication number
WO2019173261A1
WO2019173261A1 PCT/US2019/020642 US2019020642W WO2019173261A1 WO 2019173261 A1 WO2019173261 A1 WO 2019173261A1 US 2019020642 W US2019020642 W US 2019020642W WO 2019173261 A1 WO2019173261 A1 WO 2019173261A1
Authority
WO
WIPO (PCT)
Prior art keywords
immunotherapy
hyaluronic acid
cancer
toxic
daltons
Prior art date
Application number
PCT/US2019/020642
Other languages
English (en)
Inventor
Samuel Asculai
Ivor M. Hughes
Original Assignee
Samuel Asculai
Hughes Ivor M
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Samuel Asculai, Hughes Ivor M filed Critical Samuel Asculai
Publication of WO2019173261A1 publication Critical patent/WO2019173261A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • immunotherapy(ies) that employ and strengthen the cancer patient’s immune system to treat and eradicate the cancer cells and thus blood cancers and solid tumours comprised of those cells.
  • ACT adoptive cell transfer
  • TILs tumor infiltrating lymphocytes
  • TCRs specific T-cell receptors
  • CARs chimeric antigen receptors
  • CAR T- cell therapy has been recently approved by the FDA (March, 2017) for the treatment of children with acute lymphoblastic leukemia (ALL).
  • ALL acute lymphoblastic leukemia
  • Another CAR T-cell being developed is for adults with advanced lymphomas.
  • Research is also being carried out employing CAR T-cell therapy to treat solid tumours like breast and colorectal cancers.
  • tumour heterogeneity therefore must be considered when designing any cancer therapy such as ACT including CAR T-cell therapy for treatment of the cancer.
  • CAR T-cell therapy to treat solid tumours, the research has been to identify and project the specific cell surface antigens but the optimal selection has been severely hindered by the shortage of tumour surface antigens (TSA) because of high heterogeneity.
  • TSA tumour surface antigens
  • the posterior selection is tumour associated antigens (TAA) that are relatively over expressed on the tumour cell surface but for example, CAR T-cells targeting TAAs may cause collateral damage to normal cells.
  • CAR T-cell therapy has been demonstrated in research to be effective in the treatment of blood cancers such as lymphoma, leukemia, and multiple myeloma
  • its use to treat solid tumours has not been as successful.
  • binding sites on the solid tumours are also found in normal cells which may be collaterally damaged by the CAR T-cell therapy.
  • immunotherapy treatment such as ACT, such as CAR T-cell therapy or others (for example by TILs and TCRs)
  • any such treatment must penetrate into the tumour and cancer cells to eradicate the cancer cells and the tumour with minimal damage to normal tissue.
  • immunotherapy pharmaceutical formulations, compositions and formulations and the use and administration thereof to treat patients’ cancers not only blood cancers, but also, for example solid tumours, to address the collateral damage to normal cells caused by, for example, CAR T-cell therapy used to treat solid tumours and penetrate into the tumours to eradicate the tumours and cancer cells.
  • Suitable amounts determined of the non-toxic HA range generally from 10 mg and more, for example about 10 mg per 70 kg patient, for example between about 10 mg and about 1000 mg per 70 kg patient, or more of the exogenous HA in the dosage because of the minimal toxicity of HA, for example between about 200 and about 1000 mg of the exogenous HA in the dosage.
  • Optimal dosages range between about 50 and about 350 mg of HA per 70 kg person. “As there is no toxicity” of the HA, according to the patent,“the hyaluronic acid can obviously be administered in a dose excess (for example 3000 mg/70 kg individual) without any adverse effects” from the form of the HA.
  • the patent states that when ethyl alcohol is injected directly into a tumour, the ethyl alcohol is not dispersed throughout the tumour. However, when the ethyl alcohol is mixed with, and carried by, the HA, for example, the hyaluronic acid and or salts thereof, sonographic assessment of the tumour, demonstrates the dispersion of the ethyl alcohol throughout the tumour. (See also U.S. Patent 5767106 (Turley, Asculai).
  • CD44 which comes in several forms
  • RFIAMM receptors are expressed in greater numbers on cancer cells which offers an avenue of transporting and targeting anti-cancer agents to tumours, metastatic lesions and lymphatic tissues. She also discusses HA use by third parties. See also“The Hyaluronan Receptors CD44 and RHAMM (CD168) Form
  • RHAMM is localized inside the human cell and is unconventionally exported to the cell surface in response to certain defined stimuli. Extracellularly, RHAMM associates with CD44, and upon binding to hyaluronan, activates intracellular signalling pathways. RHAMM is over expressed in breast cancer. High RHAMM expression is associated with reduced metastasis-free survival. RHAMM is also associated with poor survival in pancreatic ductal adenocarcinoma. RHAMM is a non-integral cell surface receptor involved in the aggressive phenotype in a wide spectrum of human malignancies. (See J. Cancer 2015,6(1 1 ): 1093-1098.)
  • Hyaluronic Acid Synthases of HA plays roles in all stages of cancer metastasis.
  • HAS Hyaluronic Acid Synthases
  • tumour cells are able to release from tumour mass.
  • CD44 and RHAMM The interaction of HAS-produced HA with receptors CD44 and RHAMM, promotes the cell changes that allow the cancer cells to infiltrate the vascular and/or lymphatic system.
  • HA produced by HAS also protects cancer cells from physical damage while travelling in these systems.
  • CD44 and RHAMM have thus been studied in terms of their roles in cancer metastasis.
  • Increased clinical CD44 expression and RFIAMM expression have been positively correlated to metastasis.
  • RFIAMM can also cooperate with CD44 to promote angiogenesis toward the metastatic lesion.
  • HA can be tumour cells protectors from immune attack.
  • the tumour cells produced increased amounts of HA or induce the production of HA.
  • targeting HA-tumour cell receptor interactions may identify therapeutic approaches in cancer treatment, such as by depolymerizing HA.
  • the review article also provides that mast CD-expressing cells taken from normal animals, as well as from CD44 cell lines do not bind HA.
  • CAR T-cell therapy engineers the patients’ immune cells to treat their cancers. See CAR T-Ce!ls: Engineering
  • HA hyaluronic acid, its non-toxic salt forms and other non-toxic forms such as fragments and subunits thereof (such as described in U.S. Patents 5932560, 57767106, and 5827834, for example having a molecular weight between about 150,000 and about 750,000 Daltons)
  • ACT adoptive cell transfer
  • TILs TCRs
  • CARs chimeric antigen receptor
  • receptors for exogenous hyaluronic acid such as salts thereof, e.g. sodium hyaluronate
  • cancers such as the CD44 and
  • RHAMM receptors against the cancers to better target the cancer therapy e.g. ACT for example CAR T-cell therapy, to the cancer cells e.g. into solid tumours, to enable ACT, e.g. CAR T-cell, to eradicate the cancer - the HA binds to the cancer cells taking the CAR T-cell therapy into the cancer cells e.g. tumours, to eradicate them.
  • ACT e.g. CAR T-cell
  • the HA binds to the cancer cells taking the CAR T-cell therapy into the cancer cells e.g. tumours, to eradicate them.
  • normal tissue does not attract the exogenous non-toxic HA to the same extent so the therapy would not penetrate the healthy tissues and destroy them to the degree that the therapy penetrates (would penetrate) the cancer cells including tumours such as solid tumours.
  • the normal cells do not overly express the HA binding receptors CD44 and RHAMM.
  • CAR T-cell therapy For example, CAR T-cell therapy, even if normal cells have the same (or similar) binding proteins as the cancer cells. More CAR T-cell therapy penetrates the cancer cells because of their over expression of the CD44 and RHAMM for binding the exogenous HA.
  • this composition and combination enhances the safety of the use of the immunotherapy and minimizes the toxicity of such treatment to normal cells of the patients.
  • exogenous non-toxic HA not only as a carrier for the immunotherapy for delivery to and into the cancer cells, including solid tumours, but also to help reduce the toxicity of the immunotherapy on normal healthy cells.
  • compositions comprising effective amounts of immunotherapy such as ACT, for example CAR T-cell therapy suitable to treat cancer including solid tumours, together with effective amounts of exogenous nontoxic HA such as hyaluronic acid and non-toxic salts thereof and fragments and subunits thereof, having a molecular weight less than about 750,000 Daltons for example, between about 150,000 Daltons and about 750,000 Daltons thereby to minimize undesirable effects, such as toxic side effects on normal healthy tissue and healthy cells.
  • immunotherapy such as ACT
  • CAR T-cell therapy suitable to treat cancer including solid tumours
  • exogenous nontoxic HA such as hyaluronic acid and non-toxic salts thereof and fragments and subunits thereof
  • a pharmaceutical composition comprising immunotherapy medication such as ACT, for example TILs, TCRs, and CARs, suitable for treating cancer in a patient and non-toxic exogenous HA, such as hyaluronic acid and nontoxic salts thereof and/or fragments thereof and/or subunits of hyaluronic acid so that effective amounts of immunotherapy medication to treat the patient’s disease or condition and effective amounts of the form of HA, are provided to bind to, and to penetrate, for example cancer cells including solid cancerous tumours taking the immunotherapy medication with the HA but to bind minimally to normal healthy cells thereby to reduce damage to normal healthy cells by the immunotherapy medication.
  • immunotherapy medication such as ACT, for example TILs, TCRs, and CARs
  • immunotherapy medication to treat the disease or condition together with an effective amount of a non-toxic form of exogenous HA such as hyaluronic acid and non-toxic salt forms thereof such as sodium hyaluronate and combinations thereof, sufficient to facilitate the transport of the immunotherapy medication and facilitate its penetration of the immunotherapy medication into the diseased cells (such as cancer cells and solid cancerous tumours) but minimally damage normal healthy tissue, to reduce any detrimental effect on normal healthy tissue by the
  • HA has a molecular weight less than about 750,000 Daltons but greater then about 150,000 Daltons.
  • compositions using immunotherapy such as ACT, for example CAR T-cell therapy, suitable for the treatment of not only blood cancers but also solid cancerous tumours, in combination with forms of exogenous HA and non-toxic salt forms thereof having the aforesaid molecular weights whereby because the cancer cells express more receptors for the form of exogenous HA, for example forms of CD44 and RHAMM, than normal healthy cells, the majority of the form of the HA and CAR T-cell therapy when administered to a patient suffering from cancer, bind to the cancer and eradicate the cancer cells without injuring or destroying normal healthy cells to such an extent that the CAR T-cell therapy becomes overly toxic to the patient to prevent the continuous use of the composition for treating the patient whereby the composition enhances the safety of the use of the composition and minimally effects normal healthy tissue.
  • immunotherapy such as ACT, for example CAR T-cell therapy
  • ACT such as TILs, TCRs, and CARs
  • exogenous non toxic forms of HA by the form of HA binding to the over expressed receptors of the cancer cells, such as CD44 and RHAMM enabling the form of ACT to be carried to the cancer cells by the form of HA with minimal effects on the normal healthy tissue of the patient.
  • a pharmaceutical composition and effective uses of effective doses thereof comprising the combination of the effective amount of the aforesaid forms of exogenous non-toxic HA and effective amounts of the immunotherapy such as ACT, for example CARs, suitable to treat cancer, the HA for targeting, binding and penetrating the cancer cells (for example blood cancers and solid cancerous tumours, such as pancreatic cancer, cancer of the liver (from for example metastases) and breast cancer), whereby the combination of the effective amount of the aforesaid forms of exogenous non-toxic HA and effective amounts of the immunotherapy such as ACT, for example CARs, suitable to treat cancer, the HA for targeting, binding and penetrating the cancer cells (for example blood cancers and solid cancerous tumours, such as pancreatic cancer, cancer of the liver (from for example metastases) and breast cancer), whereby the cancer cells (for example blood cancers and solid cancerous tumours, such as pancreatic cancer, cancer of the liver (from for example metastases) and breast cancer), where
  • immunotherapy such as ACT, for example CARs
  • ACT for example CARs
  • the form of HA targeting the over expressed forms of CD44 and RHAMM receptors in and on the cancer cells taking the immunotherapy onto and into the cancer cells to treat reduce and eradicate them.
  • the form of HA minimally goes to the normal healthy tissue thus reducing and minimizing the effects and toxicity on normal healthy tissue and cells, thus increasing the safety of using the
  • Effective amounts of the form of HA for carrying medicine to tumours and penetrating cancerous tumour tissue with a medicinal agent and chemotherapy and chemo agents are known in the prior art (see or example U.S. Patents 5932560 and 5827834). These amounts would be adjusted up or down depending on the amount of immunotherapy, such as CAR T-cell therapy, being used.
  • the form of non-toxic HA will bind to the cancer cells’, and/or tumours’, over-expressed CD44 and RHAMM receptors much more extensively than the normal healthy cells (which express much less CD44 and RHAMM) thereby reducing the toxicity and increase the safety of infusing the immunotherapy with the form of HA into the patient.
  • the amount of the immunotherapy will be as known, and as continues to be determined in the art, and as according to a protocol prepared for each patient, and as has been approved by FDA, and as will be developed.
  • the amount of the exogenous, non-toxic form of the HA can then be adjusted up or down as needed.
  • HA transport chemical and medicinal agents to cancer cells and cancerous tumours - see U.S. Patent 5767106 (Falk, Asculai) discussed aforesaid and“Hyaluronic Acid (HA) & Cancer” by Christine White (aforesaid) - ‘The fact that CD44 and RHAMM receptors are expressed in greater numbers on cancer cells offers an avenue of transporting and targeting anti-cancer agents to tumors, metastatic lesions and lymphatic tissues.’
  • RHAMM associates with CD44 and upon binding to hyaluronan, activates intracellular signalling pathways’ -This hyaluronan is produced intracel 1 ularly (in the body and cancer cells).
  • CD44 is a broadly expressed, type 1 integral cell surface membrane glycoprotein that participates in cell-cell and cell-matrix adhesions, and in particular binds them to HA...”
  • Cell surface RHAMM (CD168) is an HA-binding protein/receptor that is not highly expressed in normal tissues but is commonly over-expressed in advanced cancers (18, 19), including breast cancer...”
  • CAR T-cell therapy a form of immunotherapy has been to date used to treat blood cancers, for example ALL, lymphoma and more recently, multiple myeloma.
  • This use of CAR T-cell therapy employs Beta-cell maturation antigen (BCMA).
  • BCMA Beta-cell maturation antigen
  • CAR T-Cells Expanding into Multiple Myeloma, supra.
  • the problem being addressed is whether they will ever be effective against solid tumours like breast and colorectal cancer, although slow progress and advances are being made in treating solid tumour, as discussed above, because the normal cells and cancerous cells have the same antigens, or the cancerous cells have the antigens within the cancer cells which hinders determining a suitable target for the CAR T-cell therapy.
  • a pharmaceutical composition comprising an effective amount of immunotherapy suitable to treat cancer including solid tumours, together with an effective amount of a form of exogenous non-toxic hyaluronic acid (HA) including non-toxic salts thereof and fragments and subunits thereof, having a molecular weight less than about 750,000 Daltons thereby to minimize undesirable effects, such as toxic side effects on normal healthy tissue of the immunotherapy when administered
  • HA non-toxic hyaluronic acid

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Composition pharmaceutique comprenant une quantité efficace d'immunothérapie appropriée pour traiter le cancer comprenant des tumeurs solides, avec une quantité efficace d'une forme d'acide hyaluronique (HA) non toxique exogène comprenant des sels non toxiques de ceux-ci et des fragments et des sous-unités de ceux-ci, ayant un poids moléculaire inférieur à environ 750 000 Daltons pour ainsi réduire au minimum les effets indésirables, tels que des effets secondaires toxiques sur un tissu sain normal de l'immunothérapie lors de son administration.
PCT/US2019/020642 2018-03-06 2019-03-05 Composition et procédé de traitement du cancer à l'aide d'acide hyaluronique WO2019173261A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862639077P 2018-03-06 2018-03-06
US62/639,077 2018-03-06

Publications (1)

Publication Number Publication Date
WO2019173261A1 true WO2019173261A1 (fr) 2019-09-12

Family

ID=67846309

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/020642 WO2019173261A1 (fr) 2018-03-06 2019-03-05 Composition et procédé de traitement du cancer à l'aide d'acide hyaluronique

Country Status (1)

Country Link
WO (1) WO2019173261A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6069135A (en) * 1989-09-21 2000-05-30 Hyal Pharmaceutical Corporation Use of hyaluronic acid or its derivatives to enhance delivery of therapeutic agents
US6136793A (en) * 1992-02-20 2000-10-24 Hyal Pharmaceutical Corporation Formulations containing hyaluronic acid
US20100173865A1 (en) * 2007-04-25 2010-07-08 Jim Klostergaard Anti-Cancer Agent-Hyaluronic Acid Conjugate Compositions and Methods

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6069135A (en) * 1989-09-21 2000-05-30 Hyal Pharmaceutical Corporation Use of hyaluronic acid or its derivatives to enhance delivery of therapeutic agents
US6136793A (en) * 1992-02-20 2000-10-24 Hyal Pharmaceutical Corporation Formulations containing hyaluronic acid
US20100173865A1 (en) * 2007-04-25 2010-07-08 Jim Klostergaard Anti-Cancer Agent-Hyaluronic Acid Conjugate Compositions and Methods

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JIN ET AL.: "Safe engineering of CAR T cells for adoptive cell therapy of cancer using long-term episomal gene transfer", EMBO MOLECULAR MEDICINE, vol. 8, no. 7, 6 May 2016 (2016-05-06) - 1 July 2016 (2016-07-01), pages 702 - 711, XP055400798 *
MISRA ET AL.: "Interactions between Hyaluronan and Its Receptors ( CD 44, RHAMM) Regulate the Activities of Inflammation and Cancer", FRONTIERS IN IMMUNOLOGY, vol. 6, 6 May 2015 (2015-05-06), pages 1 - 31, XP055635727 *

Similar Documents

Publication Publication Date Title
Locy et al. Immunomodulation of the tumor microenvironment: turn foe into friend
Hardacre et al. Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer: a phase 2 study
Anwer et al. Phase I trial of a formulated IL-12 plasmid in combination with carboplatin and docetaxel chemotherapy in the treatment of platinum-sensitive recurrent ovarian cancer
Granda et al. Experimental chronotherapy of mouse mammary adenocarcinoma MA13/C with docetaxel and doxorubicin as single agents and in combination
Dhar et al. Cancer immunotherapy: Recent advances and challenges
Murata et al. Improved tumor response by combining radiation and the vascular-damaging drug 5, 6-dimethylxanthenone-4-acetic acid
US20020037917A1 (en) Treatment of cancer using lipoic acid in combination with ascorbic acid
Morano et al. Intraperitoneal immunotherapy: historical perspectives and modern therapy
Le Naour et al. Trial watch: toll-like receptor ligands in cancer therapy
AU2001242581A1 (en) Combination therapies with vascular damaging activity
EP1272199A1 (fr) Therapies combinees induisant un effet de deterioration vasculaire
Krantz et al. Pancreas adenocarcinoma: novel therapeutics
Saluja et al. Evolution of novel therapeutic options for pancreatic cancer
Park et al. Enlightening the immune mechanism of the Abscopal effect in a murine HCC model and overcoming the late resistance with anti-PD-L1
He et al. Toxicities and therapeutic effect of 5-fluorouracil controlled release implant on tumor-bearing rats
Santosh et al. Cancer therapies: current scenario, management, and safety aspects
Crijnen et al. Emerging intravesical drugs for the treatment of non muscle-invasive bladder cancer
Skalickova et al. Injecting hope: the potential of intratumoral immunotherapy for locally advanced and metastatic cancer
Oratz et al. Intratumoral cisplatin/adrenaline injectable gel for the treatment of patients with cutaneous and soft tissue metastases of malignant melanoma
WO2019173261A1 (fr) Composition et procédé de traitement du cancer à l'aide d'acide hyaluronique
Laohavinij et al. Phase II study of paclitaxel and carboplatin for advanced non-small-cell lung cancer
Gutierrez et al. Augmenting chemotherapy with low-dose decitabine through an immune-independent mechanism
US11110303B2 (en) Hapten-enhanced chemoimmunotherapy by ultra-minimum incision personalized intratumoral chemoimmunotherapy
KR20220044310A (ko) 악성 종양을 치료하기 위한 병용약, 악성 종양을 치료하기 위한 의약 조성물 및 악성 종양 치료용 의약 조성물
Shi et al. Advances in tumor immunotherapy targeting macrophages

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19764474

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19764474

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载