Thanks, hmuney. I've cut and pasted some of the more relevant parts of the translated Russian Patent. It does a good job of explaining the basics of Dendritic Cell therapeutic technology. I removed references and less material text.
(24) Starting date of the patent validity period:
09/14/2016
Date of registration:
16.06.2021
Priority (s):
(30) Convention priority: ;
15.09.2015 US 62 / 219.058
(43) Date of publication of the application: 10/16/2019 Byull. No. 29
(45) Published: 16.06.2021 Bul. No. 17
(56) List of documents cited in the search report: DATTAA J. et al., Optimizing Dendritic Cell-Based Approaches for Cancer Immunotherapy, YALE JOURNAL OF BIOLOGY AND MEDICINE, 2014, V. 87, N. 4, p.491- 518. HAEGEL-KRONENBERGER H. et al., Adhesive and / or signaling functions of CD44 isoforms in human dendritic cells, The Journal of Immunology, 1998, V. 161, N. 8, p. 3902-3911. EP 2199793, 23.06.2010.
RU 2348418, 10.03.2009.
(85) Commencement date for consideration of the PCT national phase application: 04/16/2018
(86) PCT Application:
US 2016/051781 (14.09.2016)
(87) Publication of the PCT Application:
WO 2017/048875 (23.03.2017)
Correspondence address:
129090, Moscow, st. B. Spasskaya, 25, building 3, LLC "Law Firm Gorodissky and Partners"
(72) Author (s): BOSCH Marnix L. (US)
(73) Patentee (s): NORTVEST BAYOTHERAPYUTICS, INC. (US)
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(54) METHODS RELATING TO COMPOSITIONS OF ACTIVATED DENDRITIC CELLS AND TO IMMUNOTHERAPEUTIC TREATMENT OF INDIVIDUALS WITH PROGRESSIVE CANCER
(57) Abstract:
The invention relates to the field of biotechnology, specifically to a method for determining the immunotherapeutic activity of a composition of activated dendritic cells (DC), and can be used in medicine. The proposed method, including determining the relative amounts of IL-6, IL-8, IL-12 and TNFa and comparing them with threshold values, can be used to increase the immunotherapeutic activity of a population of activated dendritic cells and to determine the effectiveness of immunotherapy in a patient.
CROSS-REFERENCE TO RELATED APPLICATION (S)
This application claims the priority of US Provisional Application Serial No. 62/219058, filed September 15, 2015, the contents of which are incorporated herein by reference in their entirety and for all purposes.
Patients with inoperable, locally progressive, or metastatic solid tumors have a poor prognosis and limited therapeutic options, especially after unsuccessful standard therapy... Recently, there has been some progress in cancer immunotherapy... however, to achieve an effective immune response against cancer, the immune system must first be stimulated to attack cancer cells... In particular, tumor-specific antigens must be presented to "untrained" T cells by antigen presenting cells, which, in turn, will lead to the induction of T cell differentiation into activated cytotoxic T cells...
Dendritic cells (DC) are involved in the initiation of adaptive immune responses through the absorption of antigenic compounds and their subsequent presentation to the immune system. DCs stimulate B cells and T cells and generate costimulatory molecules such as cytokines to trigger CTL expansion... In recent years, there have been many studies on DC-based immunotherapy, since DC are known to have the ability to induce a broad immune response. Clinical trials using a DC-based cancer vaccine have produced various encouraging results, and some of these results have come from recent, advanced clinical trials. (Anguille et al. ,Pharmacol. Rev. 67: 731-753, 2015). It is known that various DCs present in the blood are involved in efficient cross-presentation of antigen and have the ability to efficiently migrate to draining lymph nodes. However, DCs contain less than 1% of peripheral blood mononuclear cells, which means that such cellular material is insufficient to obtain a composition that initiates and maintains a tumor-specific immune response.
...
As a result, ex vivoDCs have been generated from monocytes taken from an individual being treated, for example by leukapheresis, however, strategies using other types of DCs are currently being explored. After DC production, these cells are usually pulsed with antigen and reintroduced to the patient as infected. Selection and source of antigen (eg, purified tumor-specific or tumor-associated antigen).
Preclinical studies have shown that activated DCs (aDCs; DCVax®-Direct) are more effective than immature DCs at clearing tumors in mice after intratumoral injection.
Dendritic cells (DC) are professional antigen-presenting cells of the immune system that are likely to have the ability to activate untrained T cells and memory T cells. Dendritic cells derived ex vivo , are increasingly being used in immunotherapy, and in particular in cancer immunotherapy.
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The activation of dendritic cells initiates the transformation of immature DCs, which, in their phenotype, are similar to Langerhans skin cells, into mature antigen-presenting cells that can migrate to the lymph nodes. This process leads to a gradual and progressive loss of the effective ability to absorb antigens inherent in immature dendritic cells, and to the activation of the expression of costimulatory cell surface molecules and various cytokines. DC maturation can be initiated by various stimuli. This process is complex, and the complete maturation of dendritic cells, in particular monocytic dendritic cells, at least in vitro,depends on the dendritic cell maturation agent used and can be resolved in 48 hours. One of the consequences of maturation is a change in the migratory properties of cells in vivo.... For example, inducing the maturation of immature dendritic cells leads to the stimulation of several chemokine receptors, including CCR7, which directs cells to T-cell regions of draining lymph nodes, where mature DCs activate T cells directed against antigens presented on the DC surface surrounded by MHC molecules class I and class II.
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Therefore, DC maturation can be stimulated or initiated by many different factors that act by signaling the host. Consequently, there is no single path of maturation or the result of such maturation, but in fact there is a set of stages of DC maturation, each of which has its own functional properties. Conceptually, this makes some sense, since many different attack strategies are needed to suppress various factors that pose a threat to the body to which the immune system must respond. So, for example, a bacterial infection is best destroyed by activated macrophages in conjunction with specific antibodies, and a viral infection is best attacked by cytotoxic T cells, which effectively destroy cells infected with the virus. Cancer cells are usually killed by a combination of cytotoxic T cells, natural killer cells, and antibodies.
Known maturation protocols are carried out under in vivo conditions in which DCs are likely to interact with antigens during or after antigen treatment.
...
Immature dendritic cells can be subjected to continuous maturation for a period of time that is less than the period of time that elapses before the immature dendritic cells are fully mature. If dendritic cells undergo full in vitro maturation , then these cells will lose their ability to absorb and process antigen after being administered to a patient. The methods described herein demonstrate that dendritic cells must be matured for a period of time sufficient for activation such that significant levels of IL-6, IL-8, IL-12 and / or TNFa described herein are produced prior to the release of partially mature dendritic cells, in order to obtain a preparation for administration to a patient or individual in need of immunostimulation.
Surprisingly, it has been found that activated dendritic cells that produce some or a threshold amount of IL-6, IL-8, IL-12 and / or TNFa have a level of immunotherapeutic activity that correlates with a favorable treatment outcome, as determined from such properties such as an increase in life expectancy and / or an increase in the period of time until cancer recurrence. Thus, activated dendritic cells that produce levels in excess of the threshold amounts of IL-6, IL-8, IL-12 and / or TNFa provide compositions with improved properties that can be used for administration to an individual, and these compositions are more effective in achieving a favorable treatment outcome.
Detailed description of the invention
The present invention relates to a method for determining the immunotherapeutic activity of an activated dendritic cell composition, said method comprising the steps of: (i) obtaining activated dendritic cells; (ii) determining the relative amounts of IL-6, IL-8, IL-12 and / or TNFa; (iii) comparing a determined amount of IL-6, IL-8, IL-12 and / or TNFa with a threshold amount; and (iv) confirming that the activated dendritic cell composition has low immunotherapeutic activity if one or any combination and / or all of IL-6, IL-8, IL-12 and / or TNFa is below the threshold; or confirmation that the activated dendritic cell composition has high immunotherapeutic activity if one or any combination and / or all of IL-6, IL-8, IL-12, and TNFa are above a threshold level.
The present invention also relates to a method for increasing the immunotherapeutic activity of a population of activated DCs, said method comprising the steps of: (i) obtaining a population of activated dendritic cells; (ii) determining the relative amounts of IL-6, IL-8, IL-12 and / or TNFa; (iii) comparing a determined amount of IL-6, IL-8, IL-12 and / or TNFa with a threshold amount; (iv) confirmation that any one or any combination and / or all of IL-6, IL-8, IL-12 and / or TNFa are below the threshold; and (v) adding a sufficient amount of an agent that can induce the production of one or any combination and / or all of IL-6, IL-8, IL-12 and / or TNFa by activated DCs as long as the amount of IL-6, IL- 8, IL-12 and / or TNFa will not exceed the threshold amount, resulting in a population of activated DCs,
In addition, the present invention relates to a method for selecting a patient responsive to the administration of activated dendritic cells by determining the immunotherapeutic activity of an activated dendritic cell composition taken from a patient, said method comprising the steps of: (i) obtaining activated dendritic cells; (ii) determining the relative amounts of IL-6, IL-8, IL-12 and / or TNFa; (iii) comparing a determined amount of IL-6, IL-8, IL-12 and / or TNFa with a threshold amount; and (iv) confirming that the activated dendritic cell composition has low immunotherapeutic activity if one or any combination and / or all of IL-6, IL-8, IL-12 and / or TNFa is below the threshold; or confirmation that the activated dendritic cell composition has high immunotherapeutic activity,
In addition, the present invention relates to a method for selecting a patient unresponsive to the administration of activated dendritic cells by determining the immunotherapeutic activity of a composition of activated dendritic cells taken from a patient, said method comprising the steps of: (i) obtaining activated dendritic cells; (ii) determining the relative amounts of IL-6, IL-8, IL-12 and / or TNFa; (iii) comparing a determined amount of IL-6, IL-8, IL-12 and / or TNFa with a threshold amount; and (iv) confirming that the activated dendritic cell composition has low immunotherapeutic activity if one or any combination and / or all of IL-6, IL-8, IL-12 and / or TNFa is below the threshold; or confirmation that the activated dendritic cell composition has high immunotherapeutic activity,
The present invention also relates to a method for selecting dendritic cell maturation agents for the production of activated dendritic cells with increased immunotherapeutic activity, said method comprising the steps of: (i) obtaining activated dendritic cells by contacting immature dendritic cells with a dendritic cell maturation test agent; (ii) determining the relative amounts of IL-6, IL-8, IL-12 and / or TNFa; (iii) comparing a determined amount of IL-6, IL-8, IL-12 and / or TNFa with a threshold amount; and (iv) confirming that the activated dendritic cell composition has low immunotherapeutic activity if one or any combination and / or all of IL-6, IL-8, IL-12 and / or TNFa is below the threshold; or confirmation that that the composition of activated dendritic cells has a high immunotherapeutic activity if one or any combination and / or all of IL-6, IL-8, IL-12 and / or TNFa have a level above the threshold, and selection of an agent for maturation of dendritic cells that induces the production activated dendritic cells at a level above the threshold. Once the dendritic cell maturation agent has been identified, it can be used to induce the production of partially mature and activated dendritic cells as described herein.
AI
