CN103800896A - Preparation method and application of autologous tumor vaccine - Google Patents
Preparation method and application of autologous tumor vaccine Download PDFInfo
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- CN103800896A CN103800896A CN201210466990.9A CN201210466990A CN103800896A CN 103800896 A CN103800896 A CN 103800896A CN 201210466990 A CN201210466990 A CN 201210466990A CN 103800896 A CN103800896 A CN 103800896A
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Abstract
The invention relates to a preparation method and application of an autologous tumor vaccine. The method comprises the following specific steps: radiating and/or heating autologous tumor cells to greatly excite the antigenicity of the autologous tumor cells and enhance the presentation property of the antigen by using heat shock proteins; and inactivating the tumor cells and adding an adjuvant to obtain the vaccine. The vaccine prepared by using the method has the special advantages of high presentation property and high tumor immunogenicity, and can be used for greatly exciting the body fluid and cellular immune response of tumor patients to autologous tumors, so that the aims of improving the antigenicity and metastatic tumor effect and prolonging the survival time of tumor patients are fulfilled.
Description
Technical field
The invention belongs to biotechnology and field of immunology, particularly, the present invention relates to a kind of preparation method and application thereof of autologous tumor vaccine.
Background technology
Tumor is one of major causes of death causing at present the mankind.Although be constantly upgraded and improved in the level aspect diagnosis and the treatment of tumor in recent years, the scheme of chemotherapy and radiation is also constantly being improved, and final most patients is still difficult to the misfortune of cheat death.
In the different treatment pattern of malignant tumor, immunization therapy, because of its specific killing tumor cell, has the feature of high efficiency and low toxic and side effects, more and more receives publicity.In recent years, the development that molecular biological progress and the further understanding to function of immune system make and exploitation Biotherapy method have entered the stage of a develop rapidly.The development of tumor vaccine is the topmost direction of current tumor biotherapy.
But escape machine-processed because malignant tumor has panimmunity, mainly comprise that tumor-cell antigen content is low, the destruction of tumor antigen or constantly variation, or it is poor that the processing of tumor antigen is offered, or lack the expression of some immune cofactors, or body's immunity is low inferior, make the clinical therapeutic efficacy of existing tumor tumor vaccine not good.Due to malignant tumor heterogeneity, multiformity, polytropy makes Different Individual in the time suffering from tumor of the same race, and its individual tumors antigen is far from it.Thereby immunotherapy of tumors should be individuation, to induce individual specificity's the active immunity that kills and wounds autologous tumor cell.
At present full cell, as tumor vaccine, can provide those unknown tumor antigens to carry out activating immune system tumor antigen.In mouse tumor model, conventionally use the tumor cell immune mouse of deactivation, to protect mice to avoid the invasion and attack of the tumor of inoculation.But the time retardation using when tumour-cell vaccine is to after inoculated tumour cell one week time, and vaccine has just lost the ability of protecting mice.Cause the clinical treatment reaction of current tumour-cell vaccine poor, be only only applicable to the prevention of recurrence without the tumour patient of specific tumor antigen.Aspect clinical research, seldom obtaining good result for progressive stage patient.
Desirable tumor-special antigen should have immunogenicity, for tumor cell expressed but be not expressed in normal cell.Unfortunately, most of tumor antigens all do not have enough immunogenicities to induce effective immunoreation.
Still lack and have good immunogenicity and specificity autologous tumor vaccine and preparation method thereof at present, this area is in the urgent need to exploitation correlation method and vaccine.
Summary of the invention
Object of the present invention is just to provide a kind of preparation method of autologous tumor vaccine.
Another object of the present invention provides a kind of autologous tumor vaccine and application thereof.
In a first aspect of the present invention, a kind of method of preparing autologous tumor vaccine is provided, comprise step:
(1) obtain the autologous tumor cell separating;
(2) with the autologous tumor cell of radioactive method and/or heating treatment step (1), obtain the tumor cell that antigenicity and angtigen presentation strengthen;
(3) tumor cell step (2) being obtained carries out inactivation treatment, obtains the tumor cell of deactivation;
(4) tumor cell of deactivation step (3) being obtained is prepared as autologous tumor vaccine.
In another preference, described tumor is: solid tumor or non-solid tumor.
In another preference, described solid tumor derives from: brain, lung, incidence, skin, pancreas, gastrointestinal tract, bladder, reproductive tract, spinal cord, spleen, kidney, liver, extremity, skeleton, tongue or larynx.
In another preference, described non-solid tumor derives from blood or bone marrow.
In another preference, described tumor is primary tumor or secondary metastatic tumo(u)r.
In another preference, described tumor derives from non-human mammal tissue or people's tissue.
In another preference, the method for the autologous tumor cell that the described acquisition of step (1) separates is selected from lower group:
Enzyme digestion, mechanical shearing method or manually grind tumor group weave tumor tissues is treated to the autologous tumor cell of educable separation.
In another preference, the described radioactive method of step (2) is selected from lower group: with being selected from α, β, γ, proton or heavy ion lonizing radiation, with optionally from 0.1-50Gy dosage range, optionally from 0.1-10Gy/min close rate, the autologous tumor cell for the treatment of step (1), obtains the tumor cell that antigenicity and angtigen presentation strengthen.
In another preference, lonizing radiation derive from natural or artificial radioactive source.
In another preference, the described heating of step (2) is selected from lower group: heating-up temperature is optionally from 37.5 ℃-50 ℃ (preferably 38 ℃-45 ℃), and heat time heating time is optionally from 1min-2 hour (preferably 30min-1 hour).
In another preference, between step (2) and step (3), also comprise step: the tumor cell that step (2) is obtained to antigenicity and angtigen presentation enhancing is cultivated processing.
In another preference, the cultivation processing time is selected from: 6 hours to 2 weeks.
In another preference, cultivating in processing, use elementary cell culture fluid, and/or add somatomedin or micromolecular compound.
In another preference, the described inactivation treatment of step (3) is selected from lower group: microwave cell deactivation method, electromagnetic wave cell deactivation method, laser cell deactivation method, high temperature cell deactivation method, ultrasonication cell deactivation method, cell freeze thawing repeatedly, homogenate, centrifugal, sedimentation cell deactivation method, zymetology peptic cell deactivation method, hypotonic break method or its combination.
In another preference, in step (4), the tumor cell of the deactivation that step (3) is obtained mixes with adjuvant, obtains autologous tumor vaccine.
In another preference, described adjuvant is Freund's complete adjuvant or Freund's incomplete adjuvant.
In another preference, described adjuvant is selected from lower group: liposome, cytokine (as GM-CSF, G-CSF, CSF, IFN, IL-2 etc.), various vegetable proteins, DNA, deactivation or inactivation of viruses, antibacterial, fungus, microorganism or its combination.
In a second aspect of the present invention, a kind of autologous tumor vaccine is provided, described vaccine is to prepare by the method described in first aspect.
In a third aspect of the present invention, the purposes of autologous tumor vaccine described in second aspect is provided, it is used to the compositions of preparation prevention or treatment tumor.
In another preference, described compositions is pharmaceutical composition or vaccine combination.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can combining mutually between specifically described each technical characterictic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tire out and state no longer one by one at this.
Accompanying drawing explanation
Following accompanying drawing is used for illustrating specific embodiment of the invention scheme, limits and be not used in the scope of the invention being defined by claims.
Fig. 1 shows the measurement result of 3 weeks anti-tumour antibody IgG after self tumor vaccine of injection.
Fig. 2 shows the experiment of antitumor T cell killing.
Fig. 3 shows experiment grouping and operating process.
Fig. 4 shows Graft Versus Tumor fluorescence Real-time and Dynamic mensuration (Live Image) result.
Fig. 5 shows vaccine antigen position cancer (4T1-Luc) effect (test one) result prepared by the method for the embodiment of the present invention 1.
Fig. 6 shows vaccine antigen position cancer (4T1-Luc) effect (test two) result prepared by the method for the embodiment of the present invention 1.
Fig. 7 shows comparison (test three, with the chemotherapeutic Taxol comparison) result of vaccine prepared by the method for the embodiment of the present invention 1 and Taxol anticarcinogenic effect.
Fig. 8 shows that the method for one embodiment of the invention is to the inhibitory action of killing and wounding of experimental lung metastasis cancer.
Fig. 9 shows that one embodiment of the invention prepares the flow process of autologous tumor vaccine.
The specific embodiment
The inventor, through extensive and deep research, is surprised to find that first, and the processing that autologous tumor cell is radiated and/or heated can excite the antigenicity of autologous tumor cell, offering property of heat shock protein enhancement antigen greatly; Carry out again tumor cell deactivation, be aided with adjuvant, make vaccine.Described vaccine has by offering property strong, the special benefits that immunogenicity of tumor is strong, body fluid and the cell immune response of tumor patient to autologous tumor be can strongly excite, anti-constitutional and metastatic tumo(u)r effect improved, the object that extends the tumor patient time-to-live to reach.Complete on this basis the present invention.
Preparation method
The invention provides a kind of method of preparing autologous tumor vaccine, in a preference, comprise step:
(1) obtain the autologous tumor cell separating;
(2) with the autologous tumor cell of radioactive method and/or heating treatment step (1), obtain the tumor cell that antigenicity and angtigen presentation strengthen;
(3) tumor cell step (2) being obtained carries out inactivation treatment, obtains the tumor cell of deactivation;
(4) tumor cell of deactivation step (3) being obtained is prepared as autologous tumor vaccine.
Particularly, comprise the steps (Fig. 9):
Obtain tumor tissues by surgical operation or biopsy;
Gained tumor tissues is prepared to tumor cell as follows: under aseptic condition, get the not downright bad part that tumor is fresh, blood has supplied, put into DMEM or other culture fluid preserves at 4 ℃, rinse with PBS, obtain the tumor cell of purification by enzyme digestion and/or mechanical phonograph recorder separation, moved in culture bottle, 37 ℃, 5%CO
2the constant incubator cultivation of going down to posterity, enters the full Cell vaccine preparation procedure of tumor after reaching required cell number;
The tumor cell of processing in cultivating by the method for radiating and/or heat makes its antigen stimulation, utilizes the offering property of heat shock protein enhancement antigen increasing.；
Further, the tumor cell of processing after cultivating adopts following method to carry out deactivation: microwave cell deactivation method, electromagnetic wave cell deactivation method, laser cell deactivation method, high temperature cell deactivation method, ultrasonication cell deactivation method, cell freeze thawing repeatedly, homogenate, centrifugal, sedimentation cell deactivation method, in zymetology peptic cell deactivation method, the hypotonic method such as break at least one;
After deactivation, obtain tumor whole-cell vaccines.
The present invention is aided with above-mentioned tumor whole-cell vaccines with adjuvant, its adjuvant can be Freund's complete adjuvant or Freund's incomplete adjuvant, through Water-In-Oil adjuvant, liposome, cytokine (as GM-CSF, various vegetable protein DNA), deactivation or inactivation of viruses, antibacterial, fungus, microorganism.Be aided with after adjuvant, can better strengthening response to active immunization, reducing immune negative regulator, and strengthening immunological memory.
The inventive method is that tumor cell is offered after ability through antigenicity stimulation process and enhancement antigen, pass through again inactivation treatment, make it lose oncogenicity, and retain post-stimulatory immunogenicity, using this as individuation knubble tumor vaccine, simultaneously combined immunization adjuvant, sets up the Therapeutic Method of individuation, constantly follow the tracks of individual immunity state and the tumor state of an illness and constantly adjust individuation immunization therapy scheme, to reach best antitumor curative effect.
Immune effect monitoring
Those of ordinary skill in the art can use conventional method to judge vaccine anti tumor immune response.Comprise: the evaluation of antitumor humoral immune reaction, antitumor cell immunoreation evaluation, the evaluation of antitumor clinical response etc.
The evaluation of antitumor humoral immune reaction is to detect take individuation tumor vaccine as antigen coated ELISA method to resisting self tumour antibody titre in individuation tumor vaccine immunity Patients Before And After autoserum, with objective judgement antitumor humoral immune reaction.
Antitumor cell immunoreation is evaluated, and usually, comprises after the prepared novel individuation tumor vaccine of intradermal injection, observes patient self skin mound size (immunoreation of delayed individuation tumor vaccine) in 1-3 days; Or self tumor stimulates specificity lymphocyte transformation experiment: comprise step: get anticoagulation, separate lymphocyte, serum-free culture, adds individuation tumor vaccine or control vector, cultivates, and judge that lymphocyte transformation breeds level (mtt assay); The immunomodulating reaction of individuation tumor vaccine.The immunomodulating reaction of individuation tumor vaccine comprises: detect leukocyte hive off (as CD4/CD8/CD 11b/Gr-1 etc.) and surperficial lethal mark thereof (as FasL/LIGHT/CD25/TNF-α/IFN-γ etc.), can be divided into completely reacted and Low Response two classes according to result, completely reacted antibody titer is high, skin mound is greater than 0.5cm, therefore can maintain former individuation immunization protocol; The antibody titer of Low Response is low, and skin mound is less than 0.5cm, therefore can change individuation tumor vaccine using method and use means of different to strengthen immunoreation.Immunity regulatory cell subgroup comprises: regulatory T cells Treg(CD4+CD25+), the SC MDSC(CD14-CD11b+ in medullary system source), tumor-associated macrophages TAM(M1/M2), Regulatory Dendritic Cells DCreg(CD11b+/Gr-1+), can detect each subgroup with flow cytometry.
Antitumor clinical response: evaluate with tumor imaging size, according to experimental result, patient's immune state, the application of the tumor state of an illness and other antineoplaston scheme, determine when to strengthen antineoplastic immune, adjust individualized treatment scheme, continued for 2,3, the 4 or more courses for the treatment of.Effect monitoring includes but not limited to radiographic index observation, judges without tumor efficiency criterions such as tumor life span, total life spans.
In a word, constantly follow the tracks of individual immunity state and constantly adjust individuation immunization therapy scheme according to the tumor state of an illness, to reach best antitumor curative effect.
As mentioned above, the immunoreation effect of individuation tumor vaccine can react to monitor with cellular immunization, humoral immunization, clinical tumor, monitoring time can be after first immunisation approximately 15 days-60 days, and pass through data evaluation, if when reaction effect is not good, can readjust individuation immunization therapy scheme, adjust immunological adjuvant combination, immunizing dose, immune position, immunity time, immune time as passed through, low dosage radiation stimulates the immune organs such as bone marrow.
Compositions and administering mode
The present invention also provides a kind of compositions, and described compositions can be pharmaceutical composition, can be also vaccine combination.Compositions of the present invention can be curative or preventative.Compositions of the present invention comprises the autologous tumor vaccine of the present invention of effective dose, and at least one pharmaceutically acceptable carrier, diluent or excipient.
Pharmaceutical composition of the present invention can be prepared into various regular dosage forms, comprising (but being not limited to): injection, granule, tablet, pill, suppository, capsule, suspension, spray etc.
(i) pharmaceutical composition
Pharmaceutical composition of the present invention comprises the autologous tumor vaccine of preparing by the inventive method of effective dose.
Term used herein " effective dose " refers to therapeutic agent treatment, alleviates or prevent the amount of target disease or situation, or shows the amount of detectable treatment or preventive effect.This effect can detect by for example antigen levels.Therapeutic effect also comprises the minimizing of physiological symptom.Depend on the nature and extent of the build of this object and health status, disease and select the therapeutic agent that gives and/or the combination of therapeutic agent for the accurate effective dose of a certain object.Therefore it is useless, specifying in advance effective dose accurately.But, for certain given situation, can determine this effective dose with normal experiment.
For the purposes of the present invention, effectively dosage for give individuality approximately 0.2 microgram/kilogram to 2 micrograms/kilogram.
Pharmaceutical composition also can contain pharmaceutically acceptable carrier.Term " pharmaceutically acceptable carrier " refers to be used for the treatment of the carrier of agent (for example protein, VLP or other therapeutic agent) administration.This term refers to some medicament carriers like this: they itself are not induced and produce accepting the harmful antibody of individuality of said composition, and after administration, there is no undue toxicity.Suitable carrier can be large, metabolism macromole slowly, as protein, polysaccharide, polylactic acid (polylactic acid), polyglycolic acid etc.These carriers are well known to those of ordinary skill in the art.In Remington ' s Pharmaceutical Sciences (Mack Pub.Co., N.J.1991), can find discussing fully about pharmaceutically acceptable carrier or excipient.
Combination of Chinese medicine is learned upper acceptable carrier can comprise liquid, as water, saline, glycerol and ethanol.In addition, in these carriers, also may there is complementary material, as wetting agent or emulsifying agent, pH buffer substance etc.Conventionally, compositions can be made to injectable agent, for example liquid solution or suspension; Also can be made into the solid form that is applicable to allocating into solution or suspension, liquid excipient before injection.Liposome is also included within the definition of pharmaceutically acceptable carrier.
(ii) vaccine combination
Vaccine combination of the present invention can be preventative (being prevention infection), can be also curative.Described vaccine combination comprises immunity antigen (autologous tumor vaccine of the present invention), and common and " pharmaceutically acceptable carrier " combination, these carriers comprise itself does not induce any carrier that produces the antibody that the individuality to accepting said composition is harmful.Suitable carrier normally large, metabolism macromole slowly, as protein, polysaccharide, polylactic acid, polyglycolic acid, amino acid polymer, amino acid copolymer, lipid agglutinator (as oil droplet or liposome) etc.These carriers are well known to those of ordinary skill in the art.In addition, these carriers can play immunostimulant (" adjuvant ") effect.In addition, antigen also can and bacterial toxoid (as the toxoid of the pathogen such as diphtheria, tetanus, cholera, helicobacter pylori) coupling.
The preferred adjuvant that strengthens immune composition effect includes but not limited to: (1) aluminum salt (alum), as aluminium hydroxide, aluminum phosphate, aluminum sulfate etc.; (2) oil-in-water emulsion formula, for example, (a) MF59 (referring to WO90/14837), (b) SAF, and (c) Ribi
tMadjuvant system (RAS) (Ribi Immunochem, Hamilton, MT), (3) Saponin adjuvant; (4) Freund Freund's complete adjuvant (CFA) and Freund Freund's incomplete adjuvant (IFA); (5) cytokine, as interleukin (as IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-12 etc.), interferon (as IFN-γ), M-CSF (M-CFS), tumor necrosis factor (TNF) etc.; (6) the detoxification variant of antibacterial ADP-ribosylation toxin (as cholera toxin CT, pertussis toxin, PT PT or E.coli LT LT), referring to for example WO93/13302 and WO92/19265; And (7) carry out other material of enhancing composition effect as immunostimulant.
Vaccine combination (for example, can comprise antigen, pharmaceutically acceptable carrier and adjuvant) including immunogenic composition, contains diluent conventionally, as water, and saline, glycerol, ethanol etc.In addition, complementary material, as wetting agent or emulsifying agent, pH buffer substance etc. can be present in this class carrier.
More specifically, the vaccine including immunogenic composition, the immunogenic polypeptide that comprises immunology effective dose, and above-mentioned other required component." immunology effective dose " refers to that giving individual amount with single dose or a continuous agent part is effective to treatment or prevention.This consumption can be according to the preparation of the ability of treated individual health status and physiological situation, the individual classification for the treatment of (as people), individual immunity system synthesis antibody, required degree of protection, vaccine, treatment doctor the assessment to medical conditions and other correlative factor determine.Estimate that this consumption, by relatively wide scope, can determine by normal experiment.
Conventionally, vaccine combination or immunogenic composition can be made to injectable agent, for example liquid solution or suspension; Also can be made into the solid form that is applicable to allocating into solution or suspension, liquid excipient before injection.Said preparation also can emulsifying or is encapsulated in liposome, to strengthen adjuvant effect.
(iii) route of administration and dosage
Described compositions can directly give object.Object can be people or non-human mammal, is preferably people.When as vaccine, available known method is directly applied to individuality.Conventionally adopt the route of administration identical with conventional vaccine to use these compositionss.
The approach that gives pharmaceutical composition of the present invention or vaccine combination comprises (but being not limited to): the pharmaceutical composition preparing can carry out administration by conventional route, comprising (but being not limited to): as in Intradermal single-point/multi-point injection, subcutaneous single-point/multi-point injection, lymph node or surrounding injection, intramuscular injection, thoracic cavity/lumbar injection, intravenous injection, tumor week/intratumor injection.The visual concrete condition of above-mentioned approach is used separately, use in conjunction if desired.The position of injecting patient self, can be but be not limited to primary tumor, metastasis or its peripheral lymphoid drain district and distal limbs or near-end, chest and back, abdominal part, cervical region, local palp lymph node or lymphatic drainage district.
While making pharmaceutical composition, should consider that using dosage is controlled in the scope of safe and effective amount, concrete dosage also should be considered the factor such as route of administration, patient health situation, and these are all within skilled practitioners skill.
In addition, vaccine of the present invention also can with other drug coupling, comprising (but being not limited to): various cytokines, as IFN, TNF, IL-2 etc.; Various tumor chemotherapeutic drugs, as 5-Fu, methotrexate etc. affect the medicine of Nucleic acid, the alkylating agent such as chlormethine, cyclophosphamide class, amycin, actinomycin D etc. disturb transcription to stop the synthetic medicine of RNA, and vincristine, camptothecin affect the various kinds of drug such as medicine and some hormone of protein synthesis.
Major advantage of the present invention is as follows:
(1) the present invention initiatively excites tumor antigen to express and antigen processing presenting function with irradiating and/or heating, again after deactivation, be aided with adjuvant, and regulate immunization therapy scheme according to individual immunity response situation, reach the object of real individuation knubble immunization therapy;
(2) the present invention can promote to improve in body immunocompetence, particularly for cellular immunization and the humoral immunization of tumor;
(3) technical method for the treatment of or prophylaxis of tumours described in the present invention, be applicable to medical field, particularly prevention or treatment tumor, be also applicable to postoperative residual tumor and have the patient of micrometastasis kitchen range, for this area provides a kind of new selection, have broad application prospects.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition as people such as Sambrook, molecular cloning: laboratory manual (New York:ColdSpring Harbor Laboratory Press, 1989) condition described in, or the condition of advising according to manufacturer.
The preparation of individuation tumor vaccine
Get in the 4T1 of exponential phase cell or Lewis lung cancer cell 1*10
7individual, through gamma-rays (4-10Gy, 1.0Gy/min) treatment with irradiation after 30-60 minute, 37-40 ℃ of heating in water bath 20 minutes; At 37 ℃, 5%CO
2constant incubator 48 hours, then add freund adjuvant after ultrasonication cell, be prepared into emulsifying agent and be tumor whole-cell vaccines.
The subcutaneous breast cancer tumour of individuation tumor vaccine treatment mice
In the present embodiment, confirm through cell, the each index of correlation of zoopery, tumor vaccine prepared by the inventive method has very strong antigen presentation and excites the ability of antibody mediated immunity reaction.Concrete outcome is as follows:
1. promote the generation of anti-tumour antibody
Experimental technique: after the tumor-cell antigen immunity that conventional Balb/c mice is prepared through embodiment 13 weeks, get blood plasma doubling dilution, add the elisa plate coated with tumor cell, show antibody titer (this experiment is as 1:100000) take anti-Mus IgG-HRP and tmb substrate.
Result shows, compared with the tumor vaccine that the tumor antigen of preparing with embodiment 1 is prepared with contrast method, there is stronger short anti-tumour antibody to produce ability (Fig. 1): immune Balb/c mice after 3 weeks, antibody (the t check of the more anti-4T1 breast cancer cell of antigenic stimulus prepared by embodiment 1, p<0.05, n=10), NC: contrast; NS: adjuvant contrast; ORIGINAL: tumor vaccine prepared by contrast method; NEW: tumor vaccine prepared by the present invention.
2. promote antitumor cell immunoreation
Method is the same.The tumor-cell antigen immunity that Balb/c mice is prepared through embodiment 1 is after 3 weeks, the 4T1 tumor cell (4T1-luc) that contains Luciferase of getting lymphocyte (LN) and splenocyte (SP) and build is with 10:1,100:1, the ratio Mixed culture of 1000:1, measures the activity (RLu represents) by the Luciferase of dead 4T1 cell release after 72 hours.
As shown in Figure 2, mice is accepted tumor-cell antigen immunity prepared by embodiment 1 can produce the T cell killing (p<0.05, n=5) stronger compared with adjuvant immunity to result; The upper figure of Fig. 2 is the experiment of adjuvant group antitumor T cell killing, and Fig. 2 figure below is tumor-cell antigen antitumor T cell killing experiment prepared by embodiment 1 method group, and Rlu refers to the activity of Luciferase; NC refers to Normal group; LN refers to lymph-node cell; SP refers to splenocyte.
To the inhibitory action of mouse tumor
According to immunology principle, mice antineoplastic immune is tested in two steps:
1. tumour immunity sensitization: novel tumor antigen after treatment tumor vaccine is first seeded in to mice to be tried subcutaneous, after 14 days, then reinforced immunological once, inoculates homology mouse tumor cell (Fig. 3) after 7 days.
2. immunity anticancer effect: point two classes:
A, inhibitory action to cancer in situ: use BALB/c mouse and 4T1 breast carcinoma cell strain;
B, inhibitory action to metastatic tumor: use C57BL/6 mice and Lewis lung cancer cell strain.Lewis and 4T1 cancerous cell are high malignancy, and growth is fast, are difficult to control, and can form metastatic lung cancer.
The judgement of Graft Versus Tumor:
1. anti-cancer in situ curative effect judgement:
A, vivo tumor fluorescent quantitation: above-mentioned 4T1 cell, with Luciferase gene, therefore 4T1-Luc tumor size can be anaesthetized tumor-bearing mice intraperitoneal perfusion Luciferin substrate by warp-wise, is measured fluorescence intensity after 5 minutes;
B, slide gauge are measured diameter of tumor; These two kinds of methods all can objective reaction tumor size.
2. anti-metastatic lung cancer curative effect: due to experimental Lewis lung cancer fast growth, cancerous node merges in flakes rapidly, cannot calculate tuberosity number, therefore with the full lung result of calculation of weighing.
Mice after the tumor antigen immunity of preparing through embodiment 1, then the intravenous injection of acceptance tumor cell alive or subcutaneous injection formation metastatic carcinoma and cancer in situ, for the research of Graft Versus Tumor.
Experimental result is as follows:
Pair cancer in situ kill and wound inhibitory action
As shown in Figure 4, shown in lotus tumor Balb/c mouse tumor fluorescence living imaging, compared with tumor vaccine (adjuvant+killing tumor cells) group of preparing with matched group (adjuvant immunity) and original method, vaccine group tumor number prepared by embodiment 1 is few, and volume is little.
Tumor growth curve (Fig. 5) shows the more original tumor vaccine preparation method of novel tumor vaccine immune group cancer in situ speed of growth immune group, separately adjuvant group and normal saline group obviously slow (p<0.01), and this experiment repeats all to obtain analog result (Fig. 6, Fig. 7) through three times.It should be noted that the fastest tumor of 4T1-Luc cell enlargement can not inject by Taxol 5mg/kg(every day) suppressed, the vaccine that but can be prepared by the inventive method suppresses.
Pair metastatic lung cancer kill and wound inhibition
Transfer is the lethal main cause of tumor, and for inquiring into the kill and wound inhibitory action of vaccine of the present invention to metastatic tumo(u)r, the experimental lung metastasis using Lewis lung cancer cell on homology C57BL/6 mice is as detection model.
Conventional commercially available C57BL/6 mice (8 week age, female, 5/group) is divided into four groups:
A, normal saline matched group, with normal saline subcutaneous injection simulation immunologic process;
B, adjuvant matched group, only accept adjuvant and negative for tumor cells antigen;
C, new method (novel tumor vaccine) group, adjuvant+tumor antigen after treatment;
D, Taxol group (paclitaxel group): conventional chemotherapy medicine, as positive controls.
Four groups of mices all, accepting after different immune-treateds 21 days, inject 1 × 10 through vein
5individual Lewis lung cancer cell alive.After 23 days, weigh Lung Tumor weight, obtain average and standard deviation.
Result shows (Fig. 8): the lung weight zero difference between three matched groups (without immunity, adjuvant, Taxol), and Taxol 5mg/Kg can not restrain the growth of Lewis lung tumor; But new method (novel tumor vaccine) group makes tumor reduce 400mg, t-test analyzes and shows that these data have significant difference (p=0.0069).
All documents of mentioning in the present invention are all quoted as a reference in this application, are just quoted separately as a reference as each piece of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. a method of preparing autologous tumor vaccine, is characterized in that, comprises step:
(1) obtain the autologous tumor cell separating;
(2) with the autologous tumor cell of radioactive method and/or heating treatment step (1), obtain the tumor cell that antigenicity and angtigen presentation strengthen;
(3) tumor cell step (2) being obtained carries out inactivation treatment, obtains the tumor cell of deactivation;
(4) tumor cell of deactivation step (3) being obtained is prepared as autologous tumor vaccine.
2. the method for claim 1, is characterized in that, described tumor is: solid tumor or non-solid tumor.
3. the method for claim 1, it is characterized in that, the method for the autologous tumor cell that the described acquisition of step (1) separates is selected from lower group: with enzyme digestion, mechanical shearing method or manually grind tumor group weave tumor tissues is treated to the autologous tumor cell of educable separation.
4. the method for claim 1, it is characterized in that, the described radioactive method of step (2) is selected from lower group: with being selected from α, β, γ, proton or heavy ion lonizing radiation, with optionally from 0.1-50Gy dosage range, optionally from 0.1-10Gy/min close rate, the autologous tumor cell for the treatment of step (1), obtains the tumor cell that antigenicity and angtigen presentation strengthen.
5. the method for claim 1, it is characterized in that, the described heating of step (2) is selected from lower group: heating-up temperature is optionally from 37.5 ℃-50 ℃ (preferably 38 ℃-45 ℃), and heat time heating time is optionally from 1min-2 hour (preferably 30min-1 hour).
6. the method for claim 1, is characterized in that, between step (2) and step (3), also comprises step: the tumor cell that step (2) is obtained to antigenicity and angtigen presentation enhancing is cultivated processing.
7. the method for claim 1, it is characterized in that, the described inactivation treatment of step (3) is selected from lower group: microwave cell deactivation method, electromagnetic wave cell deactivation method, laser cell deactivation method, high temperature cell deactivation method, ultrasonication cell deactivation method, cell freeze thawing repeatedly, homogenate, centrifugal, sedimentation cell deactivation method, zymetology peptic cell deactivation method, hypotonic break method or its combination.
8. the method for claim 1, is characterized in that, in step (4), the tumor cell of the deactivation that step (3) is obtained mixes with adjuvant, obtains autologous tumor vaccine.
9. an autologous tumor vaccine, is characterized in that, described vaccine is prepared by method claimed in claim 1.
10. the purposes of autologous tumor vaccine described in claim 9, is characterized in that, it is used to preparation prevention or treats the compositions of tumor.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108114274A (en) * | 2017-12-26 | 2018-06-05 | 中国医学科学院生物医学工程研究所 | A kind of based on tumour cell is tumor vaccine and preparation method thereof of template |
| CN108175853A (en) * | 2018-01-24 | 2018-06-19 | 上海赛群生物科技有限公司 | A kind of tumor cell vaccine and preparation method thereof |
| CN109999187A (en) * | 2019-05-09 | 2019-07-12 | 英诺激光科技股份有限公司 | A method of cancer cell vaccine is prepared using laser |
| CN111603554A (en) * | 2020-07-07 | 2020-09-01 | 华中科技大学同济医学院附属协和医院 | A kind of preparation method and application of antitumor vaccine antigen raw material |
| CN118879633A (en) * | 2024-08-12 | 2024-11-01 | 庞凯 | An in vitro tumor cell processing method, the processed cells and their use in preparing autologous tumor vaccines |
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Cited By (6)
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| CN108114274A (en) * | 2017-12-26 | 2018-06-05 | 中国医学科学院生物医学工程研究所 | A kind of based on tumour cell is tumor vaccine and preparation method thereof of template |
| CN108114274B (en) * | 2017-12-26 | 2019-10-25 | 中国医学科学院生物医学工程研究所 | It is a kind of based on tumour cell be template tumor vaccine and preparation method thereof |
| CN108175853A (en) * | 2018-01-24 | 2018-06-19 | 上海赛群生物科技有限公司 | A kind of tumor cell vaccine and preparation method thereof |
| CN109999187A (en) * | 2019-05-09 | 2019-07-12 | 英诺激光科技股份有限公司 | A method of cancer cell vaccine is prepared using laser |
| CN111603554A (en) * | 2020-07-07 | 2020-09-01 | 华中科技大学同济医学院附属协和医院 | A kind of preparation method and application of antitumor vaccine antigen raw material |
| CN118879633A (en) * | 2024-08-12 | 2024-11-01 | 庞凯 | An in vitro tumor cell processing method, the processed cells and their use in preparing autologous tumor vaccines |
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Application publication date: 20140521 |