CN106581673A - Ablative immunotherapy - Google Patents
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- CN106581673A CN106581673A CN201710016168.5A CN201710016168A CN106581673A CN 106581673 A CN106581673 A CN 106581673A CN 201710016168 A CN201710016168 A CN 201710016168A CN 106581673 A CN106581673 A CN 106581673A
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- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/26—Universal/off- the- shelf cellular immunotherapy; Allogenic cells or means to avoid rejection
-
- 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
- A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The disclosure herein relates generally to immunotherapy and, more specifically, to the use of immunotherapy for treating tumors and pathogen infected tissues. The immunotherapy relates to first priming patients with allogeneic cells designed to be rejected by a Thl mediated mechanism, then inducing in situ necrosis or apoptosis in a tumor or pathogen infected lesion. Necrosis or apoptosis can be induced by methods such as cryotherapy, irreversible electroporation, chemotherapy, radiation therapy, ultrasound therapy, ethanol chemoablation, microwave thermal ablation, radiofrequency energy or a combination thereof applied against at least a portion of the tumor or pathogen infected tissue. One or more doses of allogeneic cells (e.g., Thl cells) are then delivered within or proximate to the tumor or pathogen-infected tissue in the primed patient. The present invention provides an immunotherapeutic strategy to develop de-novo systemic (adaptive) immunity to a tumor or pathogen.
Description
Technical field
The disclosure relates generally to immunization therapy, and more particularly, to for treating tumor and pathogenic infection tissue
Treatment and composition for.
Background technology
Treat chronic infectious disease using immune strength or cancer be immunization therapy main target.Actively
The method that immunization therapy is intended to activating immune system with specific recognition and destroys tumor or pathogenic infection cell.More than 200
Nian Lai, the method for active immunity treatment is used to prevent a large amount of infectious disease, including variola, rabies, typhoid fever, cholera,
The plague, measles, chickenpox, mumps, poliomyelitis, hepatitis B and tetanus and diphtheria toxin, diphtherotoxin.
The concept of active immunity treatment now be used to develop and be recurred and for controlling with treating existing tumor or prophylaxis of tumours
Treat and the therapeutic cancer vaccine for the purpose of preventing chronic virus infection.Much have been demonstrated successfully to develop in these technologies
Have what specificity killed tumor or pathogenic infection cell ability to carry high-frequency immunocyte in blood circulation.However, to the greatest extent
There is the ability of the immunocyte for producing tumor-resistant antigen activity in pipe, tumor escape mechanism still is able to overwhelm this immunne response,
And cause final tumour progression.
Jing shows that the active immunity treatment of cancer is very effective in a large amount of rodent models.However, in human body
In decades disappointed result has shown that people's vivo immuning system cannot be felt for polytype immunization therapy clinical trial
Know the threat/danger of human cancer cell, and the immune system of the rodent model of same disease.
Chronic viral infection is also identical.Innate immune response can slow down virus replication and can activate triggerable disease-resistant
The cytokine of toxalbumin synthesis.In Secondary cases immune system and virion and destroy infected cell.But, virus is
Develop some coping strategys to avoid immune attack and keep the immune drone.
It is necessary that providing one kind can overcome tumor and viral immune evasion mechanism and train human immune system to feel
Know the active immunity treatment of the threat/danger for causing the human carcinoma cells of immunne response and virus infected cell, the immunity
Response is likely located at the tumor or pathogenic infection cell of any position in can eradicating in vivo.
The content of the invention
The disclosure is related to for induction for tumor or the general of pathogen, the method for secondary immune response and combination
Thing.Methods described is treated and the method for making tumor or pathogenic infection tissue carry out cell distress using homogeneous variant cell
Combine, so as to result in the release of tumor specific antigen or pathogen specific antigen.
On the one hand, the disclosure is a kind of secondary immune response that experimenter's in-vivo tumour or pathogen are directed to for induction
Method.The method includes the steps of：(1) aliquot of homogeneous variant cell is administered to cancer or infectious disease
The experimenter of disease, the homogeneous variant cell be designed in the way of to induce the immunity of anti-Allogeneic T h1 be by subject immune
System is repelled；(2) time of about 7-14 days is allowed to be formed after anti-Allogeneic T h1 immunological memory, to cause in subject extremely
The ablation method of few a part of tumor or infected tissue's death (preferably by necrosis) is (for example, by such as, but not limited to
Such as electroporation, cryoablation, chemotherapy, radiotherapy, ultrasonic therapeutic, ethanol chemical ablation, microwave heating ablation, radio-frequency (RF) energy
Or its combination method) in same subject can and tumor focus or pathogenic infection tissue carry out ablation in situ；So
Afterwards, (3) are (preferred in second aliquot (same cell as being used for pre-sensitization) of the same homogeneous variant cell of intralesional injection
Ground 2-24 hours after ablation steps), set up as antigen uptaking and resist in response to the host of necrosis or apoptosis tissue
The immunne response of secondary ripe adjuvant of the original in delivery cell (that is, dendritic cell).Then from the ripe antigen presentation of focus
Cell migration stimulates systemic anti-neoplastic or antipathogen immunity to lymph node.On the other hand, it is convenient to omit the pre-sensitization
Step.Ablation in situ is carried out to the tissue from tumor or pathogenic infection, then after the ablation, by the allogeneic
The aliquot of cell is injected to set up desired immunne response.
On the other hand, the disclosure comprising it is a kind of for patient for antitumor or the vaccine of pathogen.The vaccine bag
Containing antigenic composition, the antigenic composition includes the antigenicity substance and allogeneic from the tumor or pathogen
The aliquot of cell, wherein establishing rejection and have stimulated tardy for antigen to patient's administration antigenic composition
Type anaphylactic reaction, so as in patient's body as stimulate systemic anti-neoplastic or antipathogen immunity adjuvant.It is described
Vaccine can also include pre-sensitization compositionss, wherein aliquot of the pre-sensitization compositionss comprising homogeneous variant cell.
On the other hand, the disclosure includes a kind of method to patient vaccination's vaccine.Methods described is comprised the steps of：(1)
To the snibject's pre-sensitization compositionss with cancer or infectious disease, the pre-sensitization compositionss comprising be designed to
The decile examination of the homogeneous variant cell that the mode for inducing anti-Allogeneic T h1 immune is repelled by the subject immune system
Sample；(2) time of about 7-14 days is allowed to develop in the subject after anti-Allogeneic T h1 immunological memory, injection is (preferably
In Intradermal mode) originate containing tumor antigen or pathogen antigen (such as attenuated virus, tumor lysate, heat shock protein)
Antigenic composition, preferably containing the autologous lysate from same individual infection or cancerous tissue, the bacteriolyze
Product preferably comprises chaperone, and the lysate (is used to carry out patient by the aliquot of homogeneous variant cell
The same cell of pre-sensitization) prepare, so as to setting up rejection and stimulating to as stimulation systemic anti-neoplastic or antipathogen
The alloantigenic delayed hypersensitivity of the adjuvant of immunity.On the other hand, methods described can be in the feelings without pre-sensitization step
Implement under condition.
On the other hand, comprising being used to treat the therapeutic composition of patient's in-vivo tumour or pathogen, it is wrapped the disclosure
Containing generated in-situ tumor antigen or pathogen antigen and homogeneous variant cell, wherein the homogeneous variant cell and original position life
Into antigen cause immunne response, the thus secondary ripe whole body sexual stimuluses antitumor of the antigen-presenting cell of the patient or anti-
Pathogen immunity.The tumor antigen or pathogen antigen are in-situ preparations at the necrosis organized from institute's tumor or pathogenic infection
's.The therapeutic composition can also include the pre-sensitization compositionss containing homogeneous variant cell.The pre-sensitization compositionss and
1 × 10 is can include about in the antigenic composition8To about 1 × 1010The homogeneous variant cell of individual cell.
On the other hand, this specification includes the vaccine combination for the internal tumor for the treatment of trouble or pathogen, and it is included
Generated in-situ antigen and homogeneous variant cell, the generated in-situ antigen includes tumor antigen or pathogen antigen, wherein
Generate in the original location in the presence of antigen and inject homogeneous variant cell to set up immunne response to patient, thus the antigen of the patient
Secondary ripe whole body sexual stimuluses antitumor in delivery cell or antipathogen immunity.The tumor antigen in the compositionss comes
Come from the original position necrosis of tumor.The pathogen antigen in the compositionss is from the original position of pathogenic infection tissue
Necrosis.The compositionss can also include the pre-sensitization compositionss containing homogeneous variant cell.The pre-sensitization compositionss and institute
State and can include about in vaccine combination 1 × 108About 1 × 1010The homogeneous variant cell of individual cell.
On the other hand, the disclosure includes the method to patient vaccination's vaccine.Methods described is comprised the steps of：(1) to trouble
There are snibject's pre-sensitization compositionss of cancer or infectious disease, the pre-sensitization compositionss include and are designed to induce
The aliquot of the homogeneous variant cell that the mode of anti-Allogeneic T h1 immunity is repelled by the subject immune system；(2)
The time for allowing about 7-14 days develops after anti-Allogeneic T h1 immunological memory, to the tumor or disease in the subject
Pathogen infection tissue carries out ablation in situ with release tumor antigen or pathogen antigen；(3) combination of homogeneous variant cell is administered
Thing (for carrying out the same cell of pre-sensitization to the patient), so as to setting up rejection and stimulating to as stimulation general
The alloantigenic delayed hypersensitivity of antitumor or the adjuvant of antipathogen immunity.On the other hand, methods described can not have
Implement in the case of having pre-sensitization step.
Specific embodiment
The disclosure includes a kind of method for stimulating patient's anti-tumor in vivo or antipathogen immunity.Methods described is included
Carry out " pre-sensitization " to patient first to develop the anti-alloantigens of Th1 by being transfused the aliquot of homogeneous variant cell
Immunological memory.It is desirable that the infusion of homogeneous variant cell stimulates the immune system of patient that the homogeneous variant cell to occur
Reaction.It is able to be allowed through certain hour before forming anti-allogeneic memory in the immune system of patient.In some enforcements
In scheme, patient may need the booster injection (booster) of homogeneous variant cell to develop appropriate Th1 immunological memories.
Patient employed herein not only includes mice, also comprising the mankind.Th1 responses employed herein refer to that generation can
Cytokine spectrum (cytokine profile) of activation T cell and macrophage.Th1 responses are different from Th2 responses, and Th2 should
Answer primary activation to depend on the immunne response of antibody and be opposed with Th1 responses.
In patient evolution after enough anti-Allogeneic T h1 immunological memory, next step is included in tumor bed or disease
Cell injury and/or death in pathogen infection tissue.Tissue injury or death discharge cellular component and raise scavenger cell extremely
Damage location.The release of the cellular component caused by necrosis during tissue injury or tissue die to in-situ preparation tumor or
Pathogen antigen is crucial.Prior art knows to cause many of tissue injury or death in tumor bed or pathogenic infection tissue
The method of kind.It is preferred that by the downright bad and caused death raised scavenger cell to damage location can be caused.It is preferred at some
In embodiment, tissue die or damage are by cryoablation or by irreversible electroporation.Alternatively, tissue is carried out in vitro
Ablation, and the component of release is expelled in patient's body.
Scavenger cell, comprising immature dendritic cell, can pick up (pick up) and discharge from impaired or thanatogenic tissue
Antigen.In order to cause the maturation of the dendritic cell (DC) of the pre-sensitization for antigen Th1 immunity, by homogeneous variant cell
Second aliquot is injected in intralesional mode.Intralesional mode is referred to by injection or other modes directly by the present invention
Compositionss be administered to carcinous region or tumor or pathogenic infection tissue in.In preferred embodiments, it is all to be administered to
The homogeneous variant cell of patient is from identical source.Preferably, it is administered between about 2 to about 24 hours after ablation of tissue of the same race different
Somatic cell.The method is particularly suited for the treatment of entity or metastatic tumo(u)r, specifically be located at prostate, mammary gland, bone,
The patient of the tumor focus of liver, lung or kidney.
For patient it is desirable that being caused due to patient based on the second aliquot for introducing homogeneous variant cell
By introduce the first aliquot and pre-sensitization for homogeneous variant cell Th1 it is immune the fact and repel the allogeneic
Cell, thus develops strong delayed-type hypersensitivity (DTH) reaction.The bystander effect of anti-alloantigen DTH reactions
(by-stander effect) can be produced and collect and process the dendritic cell maturation of antigen and migrate for causing from damaged tissues
To draining lymph node " danger signal ".The induction of tissue injury and the combination of DTH rejectiones can set up initiation and be directed to from damage
The inflammatory environment of the Th1 immunity of tissue institute released antigen.
The general state of the inflammation caused by therapeutic process can be used to cause DC programming (program) T cells to be for receiving
Damage and the whole body secondary immune response for tumor or pathogenic infection cell is caused in tissue and tumor and pathogen are adjusted
The Th1 of the antigen of the immune avoidance mechanism failure of section is immune.Secondary cases immunity referred to and adjusted by B and T cell after antigen is exposed to
Section patient defence, and the defence show specificity, multiformity, Memorability and self/nonego identification.The Secondary cases immunity
It is general in patient's body.Secondary cases immunity it is different from innate immunity, innate immunity be it is nonspecific and
It is exposed to before antigen and there is.
In some embodiments, homogeneous variant cell being administered after ablation can be enough to produce desired response.In other words,
The pre-sensitization carried out to patient with the first aliquot of homogeneous variant cell can be omitted.In these embodiments, will be swollen
Tumor tissue or pathogenic infection tissue are melted, and then inject the aliquot of homogeneous variant cell.
The present invention is also comprising a kind of to the method with cancerous cells or patient vaccination's vaccine of infected tissue.The method can
For utilizing the antigen generated from cancerous cells or infected tissue's situ together with administration homogeneous variant cell to patient vaccination
Vaccine.This method can also be used for hematologic malignancies (for example, chronic lymphocytic leukemia, multiple myeloma and
Non-Hodgkin lymphoma) or disease of viral infection (for example, B or hepatitis C, herpess, HIV) and ablation be difficult assess by shadow
The patient for ringing the other diseases of focus.
Methods described is tried comprising the first decile for carrying out " pre-sensitization " to patient first to pass through infusion homogeneous variant cell
Sample and develop the immunological memory of the anti-alloantigens of Th1.It is desirable that the infusion of homogeneous variant cell stimulates the immunity of patient
System reacts to the homogeneous variant cell.It is able to permit before forming anti-allogeneic memory in the immune system of patient
Perhaps through certain hour.In some embodiments, patient may need the booster injection of homogeneous variant cell appropriate to develop
Th1 immunological memories.
Next step is included and for the immune system of patient to be exposed to thin from the allogeneic except activation as herein described
The antigen of the cancerous cells or pathogenic infection tissue outside born of the same parents.In preferred embodiments, by cancerous cells/tumor
Or pathogenic infection tissue is melted and antigen described in in-situ preparation.The tumor or pathogenic infection tissue are carried out
Original position ablation result in the release of patient's in-vivo tumour antigen or pathogen antigen.Homogeneous variant cell is administered in focus then
Position result in is exempted from by setting up rejection and stimulation in patient's body for the desired of delayed hypersensitivity of antigen
Epidemic disease is reacted.Ablation can pass through cryoablation, electroporation or other cause the Necrotic Death of tumor or pathogenic infection tissue
Method.
In other embodiments, after the pre-sensitization step, methods described can be included：Antigenic composition is administered
To patient's body, the antigenic composition is produced comprising the autologous bacteriolyze containing the antigen from cancerous cells or infected tissue
Thing.The said composition also aliquot comprising homogeneous variant cell, that is, carry out the allogeneic freely used in pre-sensitization step
The homogeneous variant cell of the identical source of cell.Injecting the antigenic composition can set up rejection in patient's body, and
The delayed hypersensitivity for antigen can be stimulated.
Scavenger cell, comprising immature dendritic cell, can pick up and be generated by ablation in situ or by autologous lysate
Antigen.The homogeneous variant cell can cause the maturing dendritic cell of the pre-sensitization for antigen Th1 cellular immunization.For
Patient is it is desirable that due to patient's first aliquot of the pre-sensitization for the homogeneous variant cell in pre-sensitization step
The fact that the Th1 of introduced homogeneous variant cell is immune, introduces homogeneous variant cell and develops in gangrenosum acne lesions position
Strong delayed-type hypersensitivity (DTH) reaction.
The general state of the inflammation caused by therapeutic process can be used to cause DC programming (program) T cells to be for disappearing
Melt and the whole body secondary immune response for tumor or pathogenic infection cell is caused in position and tumor and pathogen are adjusted
The Th1 of the antigen of the immune avoidance mechanism failure of section is immune.
The disclosure additionally provides a kind of immunogenic method for strengthening weak immunogene or non-immunogenicity tumor
Immunne response is set to be offset to protective immune response (for example, from non-protective immunne response (for example, Th2 responses) with one kind
Th1 method).This disease is included, for example, all types of cancers and by the multiple pathogens disease that causes of infection (such as liver
Scorching virus, the fungal infection of such as aspergillosis, HIV, malaria, typhoid fever, cholera, herpesviruss, chlamydia and HPV).
The present invention also includes the therapeutic composition for treating patient's in-vivo tumour or pathogen.The therapeutic combination
Homogeneous variant cell and generated in-situ antigen are preferably comprised, the generated in-situ antigen includes neoplasm necrosises or cause of disease body-sensing
The product of dye tissue necrosiss.The therapeutic composition can also include pre-sensitization compositionss.The pre-sensitization compositionss generally contain
Have and be expelled in patient's body so as to repulsion is produced in the way of causing Allogeneic T h1 immune instead by the immune system of the patient
The homogeneous variant cell answered.
The therapeutic composition is thin comprising the antigenicity substance and allogeneic organized from tumor or pathogenic infection
The aliquot of born of the same parents.In some preferred embodiments, the antigenicity substance is containing from cancerous cells or carrying out self-induction
The in situ antigenicity substance for discharging of antigen institute of dye tissue.The antigenicity substance may originate from tumor or pathogenic infection tissue
Tissue necrosiss are in situ.Preferably, antigenicity substance is derived from the ablation that tumor or pathogenic infection are organized.
The ablation can in vivo, it is in situ or carry out in vitro.In some embodiments, antigenicity substance is comprising based on right
The heat shock protein that tissue in tumor or pathogenic infection tissue is melted and discharged.
The therapeutic composition also includes homogeneous variant cell.In the embodiment with in-situ preparation antigenicity substance
In, the therapeutic combination includes the homogeneous variant cell for being administered directly to the lesions position containing in-situ preparation antigen.By institute
When stating homogeneous variant cell and being expelled in patient's body, rejection can be set up and stimulate delayed hypersensitivity to antigen, from
And as systemic anti-neoplastic in stimulation patient's body or the adjuvant of antiviral immunity.
The therapeutic composition can be comprising as by produced by the pre-sensitization compositionss and the homogeneous variant cell
The other components of the adjuvant of response.The pre-sensitization compositionss and homogeneous variant cell can be included and be typically found in Therapeutic combinations
The other components of thing, for example, preservative.The addition of these components is within the scope of the present invention.
In some embodiments, therapeutic combination can only comprising homogeneous variant cell and generated in-situ antigen, and not
Comprising the pre-sensitization compositionss.Obtaining desired immunne response can not need the pre-sensitization compositionss.
The present invention is also included for patient for tumor or the vaccine combination of pathogen.The vaccine preferably comprises pre-
Sensitization compositionss and antigenic composition.The pre-sensitization compositionss are usually contained and are expelled in patient's body so as to by the patient
Immune system to cause the immunity of Allogeneic T h1 in the way of produce the homogeneous variant cell of rejection.
The antigenic composition is thin comprising the antigenicity substance and allogeneic organized from tumor or pathogenic infection
The aliquot of born of the same parents.In some embodiments, the antigenicity substance is containing from cancerous cells or from infected tissue
Antigen autologous lysate.The antigenicity substance may originate from the tissue necrosiss of tumor or pathogenic infection tissue.It is preferred that
Ground, antigenicity substance is derived from the ablation to tumor or pathogenic infection tissue.The ablation can be carried out in vivo or in vitro.
In some embodiments, the antigenicity material is carried out comprising the tissue in being based on to organizing from tumor or pathogenic infection
The heat shock protein for melting and discharging.The antigenic composition also includes homogeneous variant cell.The antigenicity substance and institute
State homogeneous variant cell to may be combined or individually pack.
The present invention also includes in-situ preparation vaccine combination.Antigenicity substance in the vaccine is generated in the original location, and
And patient is administered to using the homogeneous variant cell as adjuvant, preferably in intralesional mode.Can be by discharging to patient
Tumor or pathogenic infection tissue in the range of the antigenicity substance carries out ablation and realizes generation antigenicity substance in situ.Institute
State the additive method that ablation can pass through cryoablation, electroporation or cause the Necrotic Death of tumor or pathogenic infection tissue.
In some have the embodiment of in-situ preparation antigen, the antigenic composition of patient is administered to comprising of the same race different
Somatic cell, and these cells are administered in the gangrenosum acne lesions position containing the antigen for having discharged.By allogeneic combination
When thing is expelled in patient's body, rejection can be set up and stimulate the delayed hypersensitivity for being directed to antigen, so as to as stimulation
Systemic anti-neoplastic or the adjuvant of antipathogen immunity in patient's body.
The vaccine can be included as the adjuvant that response is produced by the pre-sensitization compositionss and the antigenic composition
Other components.The pre-sensitization compositionss and antigenic composition can include the other components for being typically found in vaccine, example
Such as, preservative.The addition of these components is within the scope of the present invention.
In some embodiments, the vaccine can only include antigenic composition, and not include the pre-sensitization group
Compound.The antigenic composition can be enough to obtain desired immunne response.
The therapeutic vaccine of the present invention can be used to prevent and treat disease, such as be sent out by suppressing or escaping immunne response
Exhibition and/or lasting cancer or chronic viral diseases.
Pre-sensitization step
The purpose of pre-sensitization step is that anti-Allogeneic T h1 immunity is set up in patient's body, and it can be again exposed to together
Remembered when planting antigen.By patient to be exposed to the aliquot of homogeneous variant cell and worked as to patient administration second
Because the immune system by patient caused by immunological memory occurs after repelling to these homogeneous variant cells during aliquot
Pre-sensitization.Preferably, the patient was not immunosuppressant before pre-sensitization, because this can suppress patient to repel being transfused
The ability of homogeneous variant cell, while can also suppress the development of anti-alloantigen Th1 immunity.
In one embodiment of the invention, to be prone to Th1 immune for the immune system of patient.It is preferred that controlling of the same race
It is immune that variant cell does not develop Th2 to develop the Th1 immunity for having response to repulsion homogeneous variant cell.In an embodiment
In, the immune system of the patient can be prone to produce Th1 cytokines (for example, IFN-γ and TNF-α) by administration
Homogeneous variant cell Th1 responses.Th1 cytokines can assist to exempt from the immunne response tendency Th1 types of alloantigen
Epidemic disease.Make patient immune system be prone to Th1 immunity additive method it is also within the scope of the invention.
It is administered (after inducing cell death) or as cause of disease for carrying out pre-sensitization to patient first, being subsequently used for intralesional
Property or the homogeneous variant cell of adjuvant in source of anti-neoplastic be preferably allogeneic activation T cell, more preferably same
Allosome activation CD4+ Th1 cells, more preferably allogeneic CD4+ T cells are planted, it is that effector or memory are thin that its is differentiated
Born of the same parents simultaneously produce high-caliber 1 cytokines (such as IL-2, IL-15, IFN-γ, TNF-α) while also expressing (excellent in cell surface
Selection of land is with high density) as CD40L, TRAIL and FasL effector molecule but do not produce IL-4 or other 2 cytokines.It is congenital
CD40 cytokines IL- of the connection with induced high levels of immunocyte (for example, dendritic cell, macrophage and NK cells)
12 ability.IL-12 makes CD4+ T cells polarize to the immunity of Th1 types, strengthens the propagation of CD8+ T cells, and activates NK cells.
These proinflammatory events can be based on the repulsion of the patients immune system and make to alloantigen on homogeneous variant cell
Th1 immunity stable developments..
In the pre-sensitization step, the allogeneic T cells of activation are administered to into patient, preferably with intravenouss side
Formula, but it is also possible to be administered in Intradermal mode.The homogeneous variant cell is preferably derived from intentional HLA mismatched donors.For vein
The preferred dose of the aliquot of the homogeneous variant cell of interior infusion is at least about 1 × 107Individual cell, more preferably about 1 ×
108To 1 × 1010Between individual cell.The dosage that the homogeneous variant cell outside the scope of immunne response can tentatively be produced also exists
Within the scope of the present invention.
It is desirable that before the impacted tissue of ablation or administration antigenic composition, to the anti-allogeneics of patient Th1
The development of antigen immune is detected.The development of the anti-alloantigen immunity of Th1 may at least need about 7 days.Preferably, make
Patient developed the anti-alloantigen immunity of Th1 at about 7 days to about 14 days.Can test by, for example, ELISPOT, measure
The development of the anti-alloantigen immunity of Th1.The additive method of the development of the anti-alloantigen immunity of detection patient Th1 also exists
Within the scope of the present invention.If the anti-alloantigen immunity of Th1 is weak, the reinforcement of extra homogeneous variant cell can be administered
Pin is injected.Preferably reacted with producing delayed-type hypersensitivity (DTH) in skin with the injection of Intradermal mode booster injection.
The generation of allogeneic T cells
It is desirable that allogeneic T cells can be produced, so as to after activating and being infused in patient's body, the patient
Th1 can be produced immune.It is a kind of for produce have stimulate anti-Allogeneic T h1 immunity institute must property homogeneous variant cell
Method for optimizing include：(1) by leukocyte in the normal screening donor of removal come collecting monocytic cell source material；(2) from institute
State source material and separate CD4+ T cells；(3) at the 0th day, the 3rd day and the 6th day with immobilization AntiCD3 McAb and anti-CD28 monoclonal antis
Body (mAb) is activating CD4+ cells；(4) this was activated again using immobilized AntiCD3 McAb and anti-CD28 monoclonal antibodies at the 9th day
Cell, and it is transfused the cell in 24 hours of activation.
Cell death step
Cells in situ is dead or cell injury causes for DC to raise lesions position, and can provide the antigen absorbed by DC
Source.Preferably, target tissue is destroyed by causing the death process of necrosis.Necrosis refers to individual cells or cell colony
Death causes a large amount of intracellular members to be released in environment.For the purpose of the application, necrosis is included by various methods (bag
Include cryoablation, irreversible electroporation, chemotherapy, radiotherapy, ultrasonic therapeutic, ethanol chemical ablation, microwave heating ablation, penetrate
Frequency energy or its combination) cell death.The cell-stimulating endogenouss distress signal that gangrenosum acne is killed, the distress is responsible for DC and is good for
The stimulus object that health or apoptotic dead cell are not produced is raised and ripe.Additionally, immature DC is exposed to into these thorns
Sharp thing is provided to causing the locally and systemically crucial ripe signal of property Th1 immunity.
In a preferred embodiment, cause death to pass through necrosis, target tissue is preferably freezed in the original location.
Cryosurgery be it is a kind of can apply liquid nitrogen or argon induced tissue necrosis targeting accuracy and in check program.
Jing have studied in vitro and in vivo change biology occurred after cryosurgery neutralization.Frozen cell and by defrosting cell after
The blood vessel for developing silts up and causes tissue injury and necrosis.It is known that, cryosurgery (In-situ condensation) causes can produce pin
To the antigenic stimulus thing of the specific immune response of the self antigen of freezing tissue (can with obtained by Parenteral administration antigen
Compare).
Cryoablation method can make peptides from the pathogenic infection cell through the tumor of cracking or by the antigen of DC process
Discharge, and set up pro-inflammatory cytokine environment.Such as IL-1, IL-2, TNF-α, the IFN- discharged after cryoablation
The cytokine of γ and GM-CSF can activate T, NK cell and the immunity to destroying cancer or pathogenic infection cell should
Answer requisite Langerhans (Langerhans) cell.
In another preferred embodiment, cause death to pass through necrosis, preferably target tissue is carried out not
Reversible electroporation.Irreversible electroporation is to be delivered to the electric pulse of microsecond to millisecond by irreversible cell membrane permeabilization
Organize to produce a kind of tissue ablation techniques of necrocytosiss.In irreversible electroporation, the cell membrane of cell breaks between electrode
Split so as to cause necrocytosiss.Irreversible electroporation can make antigen from the tumor through cracking or the disease of the antigen by DC process
Discharge in pathogen-infected cells, and set up pro-inflammatory cytokine environment.
Another method for optimizing for being used to produce antigen source is that autologous companion's egg is separated from dead infected tissue or tumor
In vain, also referred to as heat shock protein (HSP).Important targets of the HSP in the immunne response to antibacterial, funguses and parasitic pathogen
In.Some of extracellular environment chaperone due to its to partner polypeptide and with the immune interaction of host
Also scalable is congenital and Secondary cases are immune for ability, and in particular professional antigen is in delivery cell.It has been shown that inoculation is from tumor
Heat shock protein can cause antitumor response.Current research shows that HSP immunogenicities are derived from antigenicity associated there
Peptides.
Katsantis describes a kind of for separating chaperone for use as antigen in United States Patent (USP) No.6,875,849
The method for optimizing in source.Srivastava in United States Patent (USP) No.6,797,480, No.6,187,312, No.6,162,436, No.6,
139,841st, additive method is described in No.6,136,315 and No.5,837,251.
Additional step
The purpose of additional step is to cause DC ripe to stimulate for resisting that the focus containing dead target tissue is absorbed
Former Th1 is immune.This can be realized by injecting identical homogeneous variant cell, i.e., as those are used to carry out pre-sensitization to patient
Same origin homogeneous variant cell.The aliquot of the homogeneous variant cell, it is preferable that injected in intralesional mode,
The gangrenosum acne focus being directly entered by caused by the method for cryoablation or other cell deaths.Alternatively, chaperone is worked as
When being used as antigen source, will be used to carry out patient the injection of the identical homogeneous variant cell together with chaperone of pre-sensitization,
It is preferred that in the way of Intradermal.Produce the dosage generally at least about 1 × 10 of the homogeneous variant cell of desired immunne response7It is individual
Cell, more preferably about 1 × 108To 1 × 1010Between individual cell.Can generate outside the scope of desired immunne response
The dosage of homogeneous variant cell is also within the scope of the invention.Preparing for homogeneous variant cell is same as described above.
In order to start immunne response and overcome natural tolerance, immune system is needed from (self) tissue, and gangrenosum acne is thin
Discharged after the born of the same parents' death or antigen related to chaperone must by DC intakes and with the immunity for indicating " danger "
Activation component is presented together." danger " is somebody's turn to do in the little immunne response foundation of memory for homogeneous variant cell.
Resident property DC (referred to as immature DC) of tissue can capture generated in-situ antigen from environment, but be not enough to stimulate
T cell.In the response to pathogenic infection and the inflammatory response for occurring then, DC experience is referred to as ripe atomization,
Thus DC has raised the ability that migrates to draining lymph node and has presented captured antigen to T cell.In order to activate Th1 CD4+
T cell and CTL, DC need to make some maturation/differential stimulus complete (integrate).In the portion that there is pathogen or tumor
Position, is exposed to the of determinant derived from pathogen or tumor, pro-inflammatory cytokine and/or cell debriss induced maturation process
One step.Comprising costimulatory moleculeses and chemokine receptors is raised, thus DC is obtained respectively to T cell and is presented anti-the maturation process
Former ability and migrate to the ability of lymph node.On lymph node, homologous CD4+The presence of T cell is provided for DC's
Extra differential stimulus, so as to adjust survival and the CD4 of activation T cell+The polarization of T cell.
At antigen uptake position, generation DC is ripe, and anamnesis rejection is used as the appropriate inflammatory danger signal of offer
Adjuvant, the signal is ripe to DC, the sequencing of the Th1 immunity of antigen absorbed to the migration of lymph node and for focus is
It is necessary.
Embodiment
Animal
Balb/c mices are hosts, and C57BL/6 (B6) mice is used as the source of Th1 cells.All mices are 6 to 10 all
Age, and raise in hada Sa-specified-pathogens free facility in Hebrew University medical center is stored in, and moved with approved
Thing experimental program is processed.
Prepare Allogeneic T h1 memory cell
Spleen cell is collected from male C57BL/6 mices and cracked with the process of ammonium chloride-potassium (ACK) buffer red thin
Born of the same parents.About 7,000 ten thousand to 1 hundred million cells are isolated in each spleen.Then using on MS posts (Miltenyi Biotec, Germany)
CD4 immunomagnetic beads select (purity by positive>98%) purification is carried out to CD4+ T cells, isolates about 8 to 12,000,000
Cd4 cell, its yield be 50-60%.With paramagnetic beads (the CD3/CD28T cell amplifications that AntiCD3 McAb and anti-CD28 are coated
Pearl, Dynal/Invitrogen) according to initial pearl:Cd4 cell is 3:1 ratio is expanded and produces Th1 memory cells.By Jing
Cross the rm IL-12 of the cd4 cell of purification and the rm IL-7 and 10ng/mL of 20IU/mL recombined small-mouses (rm) IL-2,20ng/ml
(Peprotech, New Jersey) and the anti-Mus IL-4mAb of 10 μ g/mL (Becton Dickenson) be incubated in containing 10%FBS,
Pen .- Strep-glutamine, non essential amino acid (NEAA) (Biological Industries, Israel) and
In the RPMI1640 culture medium of 3.3mM N- acetyl-cysteines (NAC, Sigma) (complete medium).From the 3rd day to the 6th
My god, daily to the complete medium of the CD4 cultures extra factor-containing of the addition with rm IL-2 and rm IL-7, with
Maintain 0.5 to 1 × 106Cell concentration between individual cell/mL.From the 3rd day to the 6th day, extra CD3/ is added daily
CD28 pearls.With the amplification of cell, calculating adds the quantity of pearl to maintain 1:1 pearl:The ratio of cell.In culture 6
After it, cd4 cell expands about 80 to 100 times, and by passing on to harvest cd4 cell and from pearl on physical disruption and magnet
Separate on son.The phenotype of the institute's harvesting for using in an experiment is all higher than 95% CD4+, CD45RO+, CD62Llo、
IFN-α+and IL-4-.
The preparation of CD3/CD28 nanometer pearls
It is diluted in the PBS of Biotinylated mouse AntiCD3 McAb and each comfortable 400 μ L of anti-CD28mAbs (BD Pharmingen)
The final concentration of 25 μ g/ml, then with 1:1 ratio mixing so that final volume is 800 μ L.Wash the Streptavidin of 20 μ l
The nanometer pearl (Miltenyi, Germany) of cladding is simultaneously diluted to the final volume of 200 μ L in PBS.Then by the CD3/ of 800 μ L
The nanometer pearl through dilution of CD28mAb solution and 200 μ L is mixed so that the end of every kind of mAb in the cumulative volume of 1ml
Concentration is 10 μ g/ml.At room temperature, mixture is placed in into rotary blender upper 30 minute.Then the nanometer of mAb will be connected with
Pearl is fully washed by the MS posts (Miltenyi, Germany) on magnet.Then the nano-beads of retention are discharged simultaneously from post
In being resuspended in the PBS of 200 μ L.Nanometer pearl cannot activate Naive T cells.Therefore, nano-beads are to the Th1 memory cells that harvested
Titration (tittered), the Th1 memory cells for being harvested use before 6 days CD3/CD28 T cells expand pearl (Dynal,
Norway) activated in advance.Although being slightly different per batch, usual 20 μ L/107Individual cell be found provide first pass through in advance it is sharp
The optimal activation of Th1 memory cells living.
CD3/CD28 is crosslinked
Need infusion through activation Th1 memory cells experiment in, before infusion by the Th1 cells for being harvested with it is pre-
The nanometer pearl for being connected with CD3/CD28 of first concentration titrations is incubated.In order to reach optimal activation, the cell need with
The nanometer pearl carries out the culture of minimum 4h and most 18h.Optimal activation causes generation and the cell surface of IFN-α
The rise of CD40L and FasL.For these experiments, all infusions of CD3/CD28 crosslinking Th1 memory cells occur in preculture
After 4-8h.The thoroughly cleaning cell before infusion, to eliminate any unrelated nanometer pearl.The crosslinking Th1 for using in these experiments
Memory cell produces 2000ng/ml/10 in cell surface expression FasL and CD40L6The excessive IFN-α of individual cell/6h and little
In per 106The IL-4 of the 20pg/ml of individual cell/6h.Th1 memory cells without CD3/CD28 crosslinkings do not produce cytokine or not
Expression FasL and CD40L.
Cold therapy
Cold therapy is carried out with spherical alumina Asia chilled nitrogen probe (diameter 3mm).The pressure that gas is maintained at into 50 bars is simultaneously
And make the temperature range that Joule-Thomson effect reaches in the tissue -30 to -40 DEG C.An otch is manufactured at the center of tumor,
Cryoprobe is placed with and tumor contact (insertion 1-2mm depths)：Its objective is to affect tumor by freezing, but by halves
Destroy it.The quick freezing (continuing 20 seconds) of three circulations, is then slowly thawed.Ice hockey is produced in lesion center, it reaches
To about 2/3rds total gross tumor volume.
Embodiment 1
In order to detect ability of the Allogeneic T h1 cell in extensive metastatic disease moderate stimulation systemic anti-tumor immunity,
Test below scheme.The tumor cell (including BCL1 leukemia, 4T1 breast carcinoma and 3LL pulmonary carcinoma) of lethal dose is quiet at the 0th day
Arteries and veins is infused in mice body, and intradermal injection tumor cell sets up entity tumor block.At the 7th day, mice 1 × 10 is given5Agent
The Allogeneic T h1 cell of amount.At the 14th day, intra-tumoral injection：(a) normal saline；(b) normal saline+freezing partly ablation
Tumor；(c)103The Allogeneic T h1 cell of individual cell dosage；Or (d) Allogeneic T h1 cell+freezing partly ablation
Any one of tumor is treating mice.At the result of the 90th day surviving animals (n=10) as follows：
Embodiment 2
In order to whether the treatment for studying lotus patients with solid tumor can benefit from the invention in that above-mentioned experimental design is only receiving skin
It is interior to inject tumor to be repeated in the animal body for setting up entity tumor block.The result similar to from metastatic disease that
The result that a little animals are obtained.
The combination of Th1 cells and cold therapy result in high curative rate.Cold therapy kills tumor by necrosis, and it is recognized
For be than by it is apoptotic death (the dead type caused by chemotherapy) more pathologic cell death type.According to recognizing
Make tumor have more immunogenicity for, cold therapy, and therefore the combination of Allogeneic T h1 cell and gangrenosum acne tumor mortality set up
A kind of tumor vaccine type for causing systemic anti-tumor immunity.
Although describing the present invention with reference to preferred embodiment, it would be recognized by those skilled in the art that without departing from this
The change in form and details can be made in bright spirit and scope.
Claims (19)
1. a kind of therapeutic combination for treating patient's in-vivo tumour or pathogen, comprising：
Homogeneous variant cell；With
Antigen comprising neoplasm necrosises or the product of pathogenic infection tissue necrosiss, antigen wherein described in in-situ preparation, thus institute
State homogeneous variant cell and the generated in-situ antigen causes the immunne response of patient, exempted from setting up antitumor or antipathogen
Epidemic disease.
2. a kind of vaccine combination, comprising：
Adjuvant comprising homogeneous variant cell；With
By sick cell or the downright bad and generated in-situ antigen of tissue, the adjuvant that wherein location of necrosis is present is together with original position
The antigen of generation causes the immunne response of patient, to set up the immunity for the disease.
3. compositionss according to claim 1 and 2, further comprising pre-sensitization compositionss, wherein pre-sensitization combination
Thing includes homogeneous variant cell.
4. compositionss according to claim 1 and 2, wherein the antigen is by the tumor or pathogenic infection group
Knit and melted and generated in-situ.
5. compositionss according to claim 4, wherein the ablation passes through cryoablation.
6. compositionss according to claim 4, wherein the ablation passes through electroporation.
7. compositionss according to claim 1 and 2, wherein the antigen includes tumor or pathogen antigen, heat shock protein
White and its combination.
8. compositionss according to claim 1 and 2, wherein the homogeneous variant cell is the T cell of activation.
9. compositionss according to claim 1 and 2, wherein the homogeneous variant cell express high-caliber 1 type cell because
Son.
10. compositionss according to claim 1 and 2, wherein the homogeneous variant cell is high in the cell surface expression
CD40L, TRAIL, FasL of density and its combination.
Include for tumor or the method for the secondary immune response of pathogen, methods described in a kind of 11. induction patient's bodies：
Antigen is generated from the disease or pathogenic infection situ；With
The homogeneous variant cell at the position of in-situ preparation antigen is pointed in administration, so as to set up as from Jing ablation tissue antigen uptakings
Adjuvant immunne response, the thus secondary ripe whole body sexual stimuluses antitumor or disease-resistant original of the antigen-presenting cell of the patient
Body immunity.
12. methods according to claim 11, further include：
To patient's administration pre-sensitization compositionss before in the original location antigen is produced, the pre-sensitization compositionss include to induce allogeneic
The allogeneic T cells that the mode of Th1 immunity is repelled by the immune system of the patient；With
In the original location antigen makes the immune system of the patient form anti-Allogeneic T h1 immunological memory before producing.
13. methods according to claim 11, wherein the antigen is by the tumor or pathogenic infection tissue
Melted and generated in-situ.
14. methods according to claim 13, wherein the ablation passes through cryoablation.
15. methods according to claim 13, wherein the ablation passes through electroporation.
16. methods according to claim 11, wherein the antigen comprising tumor or pathogen antigen, heat shock protein and
Its combination.
17. methods according to claim 11, wherein the homogeneous variant cell is allogeneic T cells.
18. methods according to claim 11, wherein the homogeneous variant cell expresses high-caliber 1 cytokines.
19. methods according to claim 11, wherein the homogeneous variant cell is in the cell surface expression high density
CD40L, TRAIL, FasL and its combination.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13/796,171 | 2013-03-12 | ||
| US13/796,171 US9320794B2 (en) | 2006-11-13 | 2013-03-12 | Ablative immunotherapy |
| CN201480014494.7A CN105102613A (en) | 2013-03-12 | 2014-03-10 | Ablative immunotherapy |
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| CN201480014494.7A Division CN105102613A (en) | 2013-03-12 | 2014-03-10 | Ablative immunotherapy |
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| CN201480014494.7A Pending CN105102613A (en) | 2013-03-12 | 2014-03-10 | Ablative immunotherapy |
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| EP (1) | EP2970910A4 (en) |
| JP (1) | JP6538647B2 (en) |
| KR (1) | KR102265276B1 (en) |
| CN (2) | CN106581673A (en) |
| AU (2) | AU2014249374A1 (en) |
| BR (1) | BR112015022974A8 (en) |
| CA (1) | CA2904853A1 (en) |
| IL (1) | IL241326B (en) |
| PH (1) | PH12015502086A1 (en) |
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| 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 |
| US20080112963A1 (en) * | 2006-11-13 | 2008-05-15 | Immunovative Therapies, Ltd. | Ablative immunotherapy |
| CN101965194A (en) * | 2008-01-31 | 2011-02-02 | 爱吉瑞克斯有限公司 | Vaccine compositions |
| US7972594B2 (en) * | 2006-11-13 | 2011-07-05 | Immunovative Therapies Ltd. | Ablative immunotherapy |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1806849A (en) * | 2005-01-19 | 2006-07-26 | 上海三维生物技术有限公司 | Method of treating tumors |
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2014
- 2014-03-10 KR KR1020157028277A patent/KR102265276B1/en active IP Right Grant
- 2014-03-10 AU AU2014249374A patent/AU2014249374A1/en not_active Abandoned
- 2014-03-10 CN CN201710016168.5A patent/CN106581673A/en active Pending
- 2014-03-10 CA CA2904853A patent/CA2904853A1/en not_active Abandoned
- 2014-03-10 JP JP2016500938A patent/JP6538647B2/en active Active
- 2014-03-10 BR BR112015022974A patent/BR112015022974A8/en not_active Application Discontinuation
- 2014-03-10 WO PCT/US2014/022287 patent/WO2014164396A1/en active Application Filing
- 2014-03-10 EP EP14779681.7A patent/EP2970910A4/en not_active Ceased
- 2014-03-10 CN CN201480014494.7A patent/CN105102613A/en active Pending
- 2014-03-10 SG SG10201707446PA patent/SG10201707446PA/en unknown
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2015
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| 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 |
| US20080112963A1 (en) * | 2006-11-13 | 2008-05-15 | Immunovative Therapies, Ltd. | Ablative immunotherapy |
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Also Published As
| Publication number | Publication date |
|---|---|
| SG10201707446PA (en) | 2017-10-30 |
| BR112015022974A2 (en) | 2017-07-18 |
| CN105102613A (en) | 2015-11-25 |
| EP2970910A4 (en) | 2016-11-16 |
| IL241326A0 (en) | 2015-11-30 |
| PH12015502086A1 (en) | 2016-01-18 |
| KR102265276B1 (en) | 2021-06-16 |
| KR20150138234A (en) | 2015-12-09 |
| BR112015022974A8 (en) | 2019-11-26 |
| AU2014249374A1 (en) | 2015-09-24 |
| CA2904853A1 (en) | 2014-10-09 |
| WO2014164396A1 (en) | 2014-10-09 |
| EP2970910A1 (en) | 2016-01-20 |
| JP2016518319A (en) | 2016-06-23 |
| AU2020201309A1 (en) | 2020-03-12 |
| JP6538647B2 (en) | 2019-07-03 |
| SG11201507350WA (en) | 2015-10-29 |
| IL241326B (en) | 2021-05-31 |
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