CYTOTOXICITY OF INDIRECT IMMUNOTOXIN MEDIATED BY ANTI-GASTRIC CANCER MONOCLONAL ANTIBODIES ON TUMOR CELLS

In the present study, an indirect assay was employed to investigate 5 anti-gastric cancer monoclonal antibodies for their cytotoxic potential as ricin A chain-containing immunotoxins. The tumor cell, were treated with dilutions of tested antibody followed by ricin A chain coupled to goat anti-mouse immunoglobulin. The cytotoxic effect was determined with tetrazolium colorimetric assay. The results showed that among the 5 antibodies chosen, MGb2 and MG7 could be well used for preparation of effective A chain immunotoxins.

Cytotoxic T-lymphocytes response in vitro activated by dendritic cells pulsed with heat shock protein 70 derived from human bladder tumor cell lines of EJ

Objective： To investigate whether human dendritic cells （DC） derived from peripheral blood mononuclear cells （PBMC）, which were pulsed by heat shock protein 70 （HSP70） isolated from human bladder tumor cell lines of E J, were able to induce peptide specific cytotoxic T-lymphocytes （CTL） response in vitro and give the experimental foundation for the future clinical trials of immunotherapy in bladder tumor. Methods： The E J-derived HSP70 co-cultured with DC from the healthy volunteers＇ PBMC, along with the crude lysate （the supematant before HSP70 purification） from EJ cells were used as the experimental groups and DC not pulsed by any tumor cells antigen were the blank control. The autologous T-lymphocytes were added into the above various DC groups, and after incubation, the stimulation indexes （SI） and interferon-y （IFN-γ） were detected to evaluate the immune activities of various DC groups. The killing effects of CTL to target cells, EJ and Hela cells, were determined with 51^Cr releasing test. Results： Both DC/HSP70 and DC/the crude lysate could effectively activate CTL in vitro and kill target cells EJ. The killing effect of DC/HSP70 to EJ was much stronger than DC/the crude lysate （the supernatant before HSP70 purification） （P 〈 0.05）. DC without any tumor cell antigens had a lower killing power to EJ. Meanwhile, DC/ HSP70 had little killing power to Hela non-relevant to bladder tumor histopathologically as compared with EJ cells （P 〈 0.05）. Conclusion： The DC pulsed by HSP70 derived from the autologous tumor cells could induce a peptide complexes specific CTL response to tumor cells, and the CTL response induced by the DC/HSP70 was stronger, which display the basis of the possible clinical application of DC/HSP70 for bladder tumor.

EFFECTS OF PHYTOLACCA ACINOSA POLYSACCHARIDES I ON CYTOTOXICITY OF MACROPHAGES AND ITS PRODUCTION OF TUMOR NECROSIS FACTOR AND INTERLEUKIN 1

The in vivo effects of Phytolacca acinosa poly-saccharides I (PEP-I) on immunologic cytotoxicity of mouse peritoneal macrophages and its production of tumor necrosis factor (TNF) and interleukin 1 (IL-1) were studied. PEP-I 80 or 160 mg kg was given ip twice every 4 day. Both doses were found to have significant enhancing activity on macrophages cytotoxicity against S180 sarcoma cells and malignant transformed fibroblast L929 cells. Peritoneal activated macrophages were incubated with LPS for 2 and 24 hrs to induce TNF and IL-1, respectively. The TNF and IL-1 activities were tested from cytotoxicity against L929 cells in an absorbence assay of enzymatic reaction and proliferation of thymocytes co-stimulated assay separately. The optimal time for TNF production was found on day 8. Significant increases in TNF and IL-1 were observed. In comparison of the effect of PEP-I on TNF with that of known priming agent BCG, there was no difference between them, but PEP-I had a high effect on IL-1. These results suggest that cytotoxicity of macrophages primed by PEP-I is closely related to its TNF and IL-1 production.

Separation and Expansion of Tumor Infiltrating Lymphocytes of Digestive System in Vitro and Their Cytotoxicity

Primary tumor tissues in the digestive system were harvested form 15 patients. By mincing,enzymatic digestion and gradient density separation, sufficient TILs(>5×106) were obtained from 13 of 15 (88.7%) patients in vitro in the presence of 500 μ/ml of recombinant interleukin-2 and 5% fetal calf serum after one month culture. 92.3% (12/13) of TILs proliferated well in vitro (92.3%). TILs expanded from 102-folds to 103-folds after being cultured for one month. CD25+ cell of the most fresh TILs was more than that of peripheral blood lymphocytes. CD25+ cells of TILs during 4th week of the culture was significantly greater (P<0.01) than that of fresh TILs. CD4+/CD8+ ratio was decreased during four culture weeks because of increase of CD8 cells. By using modified colorimetric MTT assay for measuring activity of TILs against various tumor cells the results showed that cytotoxicity of gastro-intestinal TILs autologous tumor cells is greater than on the other tumor cells.

Effect of cytotoxic T-lymphocyte antigen-4,TNF-alpha polymorphisms on osteosarcoma: evidences from a meta-analysis

Objective： Previous studies have investigated the role of cytotoxic T-lymphocyte antigen-4 （CTLA-4） and tumor necrosis factor-alpha （TNF-a） in carcinogenesis of osteosarcoma, but their results were inconsistent. We aimed to clarify the associations between CTLA-4, TNF-a polymorphism and osteosarcoma risk by using meta-analysis. Methods： We searched relevant studies without language restriction in PubMed, EMbase, Cochrane Library, Google Scholar databases, Chinese National Knowledge Infrastructure （CNKI） and conference literature in humans published prior to March 2013. The strengths of the associations between genetic variants and osteosarcoma risk were estimated by odds ratio （OR） with 95% confidence interval （95% CI）. Results： A total of seven studies with 1,198 osteosarcoma patients and 1,493 controls were selected. Four studies were eligible for CTLA-4 （1,003 osteosarcoma and 1,162 controls）, and three studies for TNF-a （195 osteosarcoma and 331 controls）. Pooled results showed that rs231775 polymorphism of CTLA-4 was associated with osteosarcoma risk （GG vs. AA： OR=1.63, 95% CI=1.24-2.13; GG ＋ GA vs. AA： OR=1.56, 95% CI=1.21-2.01; AA ＋ GA vs. GG： OR=0.83, 95% CI=0.71-0.97; G vs. A： OR=1.21, 95% CI=1.08-1.36）. No significant heterogeneity was observed across the studies. No significant associations were found between rs5742909 polymorphism of CTLA-4 or rs1800629 polymorphism of TNF-a and osteosarcoma risk. Conclusions： These results suggest that the rs231775 polymorphism of CTLA-4 may play an important role in carcinogenesis of osteosarcoma.

Cytotoxic synergism of Clostridioides difficile toxin B with proinflammatory cytokines in subjects with inflammatory bowel diseases

Clostridioides difficile(C.difficile)is progressively colonizing humans and animals living with humans.During this process,hypervirulent strains and mutated toxin A and B of C.difficile(TcdA and TcdB)are originating and developing.While in healthy subjects colonization by C.difficile becomes a risk after the use of antibiotics that alter the microbiome,other categories of people are more susceptible to infection and at risk of relapse,such as those with inflammatory bowel disease(IBD).Recent in vitro studies suggest that this increased susceptibility could be due to the strong cytotoxic synergism between TcdB and proinflammatory cytokines the tumor necrosis factor-alpha and interferon-gamma(CKs).Therefore,in subjects with IBD the presence of an inflammatory state in the colon could be the driver that increases the susceptibility to C.difficile infection and its progression and relapses.TcdB is internalized in the cell via three receptors:chondroitin sulphate proteoglycan 4;poliovirus receptor-like 3;and Wnt receptor frizzled family.Chondroitin sulphate proteoglycan 4 and Wnt receptor frizzled family are involved in cell death by apoptosis or necrosis depending on the concentration of TcdB and cell types,while poliovirus receptor-like 3 induces only necrosis.It is possible that cytokines could also induce a greater expression of receptors for TcdB that are more involved in necrosis than in apoptosis.Therefore,in subjects with IBD there are the conditions:(1)For greater susceptibility to C.difficile infection,such as the inflammatory state,and abnormalities of the microbiome and of the immune system;(2)for the enhancement of the cytotoxic activity of TcdB+Cks;and(3)for a greater expression of TcdB receptors stimulated by cytokines that induce cell death by necrosis rather than apoptosis.The only therapeutic approach currently possible in IBD patients is monitoring of C.difficile colonization for interventions aimed at reducing tumor necrosis factor-alpha and interferon-gamma levels when the infection begins.The future perspective is to generate bacteriophages against C.difficile for targeted therapy.

Synthesis and cytotoxic activity of novel curcumin analogues

Five novel curcumin analogues bearing different substituents at 4-position of phenyl group were synthesized. Their structures were confirmed by NMR and HRMS spectrum. Their cytotoxic activities against six tumor cell lines were tested by the standard MTT assay in vitro. The results indicated that four analogues （1A-1C, 1E） with solubilizing moieties showed selective potent cytotoxicity against HepG2, HeLa and CT26 cell lines, and analogue 1A and 1C exhibited more potent cytotoxicity than curcumin against CT26 cell line. It was suggested that introduction of appropriate substituents to 4-position of phenyl group might be a potential option for structural modification of curcumin.

Mycobacterium smegmatis enhances shikonin-induced immunogenic cell death—an efficient in situ tumor vaccine strategy

Tumor vaccines are a promising avenue in cancer immunotherapy.Despite the progress in targeting specific immune epitopes,tumor cells lacking these epitopes can evade the treatment.Here,we aimed to construct an efficient in situ tumor vaccine called Vac-SM,utilizing shikonin(SKN)to induce immunogenic cell death(ICD)and Mycobacterium smegmatis as an immune adjuvant to enhance in situ tumor vaccine efficacy.SKN showed a dose-dependent and time-dependent cytotoxic effect on the tumor cell line and induced ICD in tumor cells as evidenced by the CCK-8 assay and the detection of the expression of relevant indicators,respectively.Compared with the control group,the in situ Vac-SM injection in mouse subcutaneous metastatic tumors significantly inhibited tumor growth and distant tumor metastasis,while also improving survival rates.Mycobacterium smegmatis effectively induced maturation and activation of bone marrow-derived dendritic cells(DCs),and in vivo tumor-draining lymph nodes showed an increased maturation of DCs and a higher proportion of effector memory T-cell subsets with the Vac-SM treatment,based on flow cytometry analysis results.Collectively,the Vac-SM vaccine effectively induces ICD,improves antigen presentation by DCs,activates a specific systemic antitumor T-cell immune response,exhibits a favorable safety profile,and holds the promise for clinical translation for local tumor immunotherapy.

RNA vaccines for anti-tumor therapy

The immune system is able to recognize tumor antigens and this has been the basis for the development of cancer immunotherapies. The immune system can be instructed to recognize and attack tumor cells by means of vaccination strategies. One such strategy involves the delivery of tumor antigen as genetic material. Herewith we describe the use of RNA encoding tumor antigens for vaccination purposes in tumor settings. RNA has features that are interesting for vaccination. Upon transfection, the RNA has no possibility of integration into the genome, and the tumor translated proteins enter the intrinsic antigen processing pathway thus enabling presentation by MHC-I molecules. This can specifically activate cytotoxic CD8 T cells that can attack and kill tumor cells. RNA can be delivered as a naked molecule for vaccination purposes or can be used to transfect dendritic cells. The combination of RNA technology with dendritic cell vaccination provides a powerful tool for cancer immunotherapies.

Cytotoxic T-cells as imaging probes for detecting glioma

Tumor vaccination using tumor-associated antigenprimed dendritic cells(DCs)is in clinical trials.Investigators are using patients’own immune systems to activate T-cells against recurrent or metastatic tumors.Following vaccination of DCs or attenuated tumor cells,clinical as well as radiological improvements have been noted due to migration and accumulation of cytotoxic T-cells(CTLs).CTLs mediated tumor cell killing resulted in extended survival in clinical trails and in preclinical models.Besides administration of primed DCs or attenuated or killed tumors cells to initiate the generation of CTLs,investigators have started making genetically altered T-cells(CTLs)to target specific tumors and showed in vivo migration and accumulation in the implanted or recurrent tumors using different imaging modalities.Our groups have also showed the utilization of both in vivo and in vitro techniques to make CTLs against glioma and used them as imaging probes to determine the sites of tumors.In this short review,the current status of vaccination therapy against glioma and utilization of CTLs as in vivo imaging probes to determine the sites of tumors and differentiate recurrent glioma from radiation necrosis will be discussed.

Magnetic Field Emulations of Small Inhibitor RNA: Effects on Implanted GL261 Tumors in C57BL/6 Immune Competent Mice

EMulate Therapeutics has developed a system for emulating the effects of solvated molecules via their magnetic field recordings. Recordings of magnetic field emissions of select small inhibitor RNAs (siRNAs;murine targeting CTLA-4 and murine targeting PD-1) were tested on C57Bl/6 mice implanted subcutaneously with the GL261 murine tumor cell line. A signal composed of concatenated recordings of siRNA molecules targeting the murine CTLA-4 and PD-1 receptors (labeled A2) was used in immune competent C57Bl/6 mice. The mice were flank implanted with the murine glioblastoma cell line GL261. Mice were exposed to the signal continuously (24 hours a day) until tumor volumes reached the designated volume limit. Tumors were excised and analyzed via PAGE/Western blot for the expression of CTLA-4, PD-1, Ki67, Caspase 3, CD4 and CD8. Terminal blood draws were used for CBCs. We report the down regulation of the checkpoint inhibitors CTLA-4 in the exposed mice. Significant tumor volume reduction was observed in mice exposed to the siRNA signal compared to control mice;no adverse events were recorded. Cell blood counts (CBC) and protein expression patterns were observed to correlate with the expected function of protein expression inhibition of the targets.

Feeder-free differentiation of human iPSCs into natural killer cells with cytotoxic potential against malignant brain rhabdoid tumor cells

Natural killer(NK)cells are cytotoxic immune cells that can eliminate target cells without prior stimulation.Human induced pluripotent stem cells(iPSCs)provide a robust source of NK cells for safe and effective cell-based immunotherapy against aggressive cancers.In this in vitro study,a feeder-free iPSC differentiation was performed to obtain iPSC-NK cells,and distinct maturational stages of iPSC-NK were characterized.Mature cells of CD56^(bright)CD16^(bright)phenotype showed upregulation of CD56,CD16,and NK cell activation markers NKG2D and NKp46 upon IL-15 exposure,while exposure to aggressive atypical teratoid/rhabdoid tumor(ATRT)cell lines enhanced NKG2D and NKp46 expression.Malignant cell exposure also increased CD107a degranulation markers and stimulated IFN-γsecretion in activated NK cells.CD56^(bright)CD16^(bright)iPSC-NK cells showed a ratio-dependent killing of ATRT cells,and the percentage lysis of CHLA-05-ATRT was higher than that of CHLA-02-ATRT.The iPSC-NK cells were also cytotoxic against other brain,kidney,and lung cancer cell lines.Further NK maturation yielded CD56^(-ve) CD16^(bright)cells,which lacked activation markers even after exposure to interleukins or ATRT cells-indicating diminished cytotoxicity.Generation and characterization of different NK phenotypes from iPSCs,coupled with their promising anti-tumor activity against ATRT in vitro,offer valuable insights into potential immunotherapeutic strategies for brain tumors.

Effects of salidroside on glioma formation and growth inhibition together with improvement of tumor microenvironment

Objective：To test the effects of salidroside on formation and growth of glioma together with tumor microenvironment.Methods：Salidroside extracted from Rhodiola rosea was purified and treated on human glioma cells U251 at the concentration of 20 μg/mL.3-（4,5-dimethylthiazol-2-yl）-2,5-dephenyltetrazolium bromide （MTT） assay for cytotoxicity and flow cytometry （FCM） for cell cycle analysis were performed.Then for in vivo study,xenotransplantation tumor model in nude mice was generated and treated with salidroside at the concentration of 50 mg/kg.d for totally 20 d.Body weight and tumor size were detected every 2 d after the treatment.The levels of 8-isoprostane,superoxide dismutase （SOD） and malondialdehyde （MDA）,special markers for oxidative stress,were detected while immunofluoresence staining was performed for astrocyte detection.Results：For in vitro study,salidroside could decrease the viability of human glioma cells U251 and the growth of U251 cells at G0/G1 checkpoint during the cell cycle.For in vivo study,salidroside could also inhibit the growth of human glioma tissue in nude mice.The body weight of these nude mice treated with salidroside did not decrease as quickly as control group.In the tumor xenotransplantation nude mice model,mice were found of inhibition of oxidative stress by detection of biomarkers.Furthermore,overgrowth of astrocytes due to the stimulation of oxidative stress in the cortex of brain was inhibited after the treatment of salidroside.Conclusions：Salidroside could inhibit the formation and growth of glioma both in vivo and in vitro and improve the tumor microenvironment via inhibition of oxidative stress and astrocytes.

ANTITUMOR EFFECTS OF HUMAN IL-15 GENE MODIFIED LUNG CANCER CELL LINE

Human IL15 cDNA fragment, which contains all codons encoding the human IL15 mature protein and signal peptide was transducted into the human lung squmouse cancer cells(PG cells) and murine lung adenocarcinoma cells(LA795 cell lines). Two IL15 highly expressed cell clones PG1 and LA795A were used to inoculate the nude mice and the T739 syngeneic mice respectively. PG1 cell express higher level of class ⅠMHC molecule on their surface than PG cells. It was shown that the modified LA795A tumor cells grew slowly in T739 mice and induced high levels of CTL/NK/LAK activity in vivo as well, compared with the case of inoculation with LA795 or LA795neo. No significant difference in the tumor growth was observed in groups of the nude mice inoculated by PG1, PG and PGneo cells respectively, except the gene modified cells could not show the lung metastasis of tumors. The supernatants derived from the LA795A cell culture could promote CTL/NK/LAK activity from the whole splenocytes and the CD4/CD8deleted splenic cells in vitro. The results indicated that the IL15 gene transfected tumor cells play important roles in the process of antitumor or antitumor metastasis.

Preparation of Adriamycin Magnetic Albumin Microspheres and Their Experimental Antitumor Effects in vitro and in vivo

The adriamycin magnetic microspheres (ADM-MAMs) were prepared by the heat-stabilized protein methods. Their physico-chemical properties were examined; their cytotoxicities against tumor cells in vitro were assayed by a modi-fied MTT method, and their effects were observed on the implanted gastric tumor in Wistar rats given ADM-MAMs via alimentary canal at the presence of the ex-ternal magnetic fields. The results showed that the ADM-MAMs were successful-ly prepared and had cytotoxic effect on tumor cells in vitro similar to the free ADM (P>0. 05). The inhibitory effects of ADM-MAMs on the implanted gastric tumor in vivo were significantly increased as compared with the controls (P<0.01). Our results suggested that ADM-MAMs were a new type of adriamycin (ADM) preparation and its form alteration did not affect its anticancer effects.

Antitumor activities of human autologous cytokineinduced killer(CIK)cells against hepatocellular carcinoma cells in vitro and in vivo

AIM: To characterize the anticancer function of cytokine-induced killer cells (CIK) and develop an adoptive immunotherapy for the patients with primary hepatocellular carcinoma (HCC), we evaluated the proliferation rate, phenotype and the antitumor activity of human CIK cells from healthy donors and HCC patients in vitro and in vivo. METHODS: Peripheral blood mononuclear cells (PBMC) from healthy donors and patients with primary HCC were incubated in vitro and induced into CIK cells in the presence of various cytokines such as interferon-gamma (IFN-gamma), interleukin-1 (IL-1), IL-2 and monoclonal antibody (mAb) against CD3. The phenotype and characterization of CIK cells were identified by flow cytometric analysis. The cytotoxicity of CIK cells was determined by (51)Cr release assay. RESULTS: The CIK cells were shown to be a heterogeneous population with different cellular phenotypes. The percentage of CD3+/CD56+ positive cells, the dominant effector cells, in total CIK cells from healthy donors and HCC patients, significantly increased from 0.1-0.13% at day 0 to 19.0-20.5% at day 21 incubation, which suggested that the CD3+ CD56+ positive cells proliferated faster than other cell populations of CIK cells in the protocol used in this study. After 28 day in vitro incubation, the CIK cells from patients with HCC and healthy donors increased by more than 300-fold and 500-fold in proliferation cell number, respectively. CIK cells originated from HCC patients possessed a higher in vitro antitumor cytotoxic activity on autologous HCC cells than the autologous lymphokine-activated killer (LAK) cells and PBMC cells. In in vivo animal experiment, CIK cells had stronger effects on the inhibition of tumor growth in Balb/c nude mice bearing BEL-7402-producing tumor than LAK cells (mean inhibitory rate, 84.7% vs 52.8%, P【0.05) or PBMC (mean inhibitory rate, 84.7% vs 37.1%, P【0.01). CONCLUSION: Autologous CIK cells are of highly efficient cytotoxic effector cells against primary hepatocellular carcinoma cells and might serve as an alternative adoptive therapeutic strategy for HCC patients.

Antitumorigenic Potential of Diallyl Sulfide in Ehrlich Ascites Tumor Bearing Mice

Objective To study the effects of diallyl sulfide (DAS), an organosulfur compoundpresent in garlic (Allium sativum), on the life span of ehrlich ascites (EA) tumor bearingSwiss albino mice, cytotoxicity and angiogenesis. Methods EA tumor cells weremaintained by serial transplantation in peritoneal cavity of male Swiss albino mice. EAtumor cells were inoculated at concentrations of 1× 106 EA cells, 2.5× 106 EA cells and5× 106 EA cells. DAS was given in 0.2 ml normal saline i. p., daily for seven days followedone hour later by inoculation with EA cells in respective groups. Results The resultsrevealed that administration of DAS increased the life span of EA tumor bearing animals bymore than 25 percent. A significant dose dependant cytotoxic response of DAS was alsoobserved on EA tumor cells. DAS was also found to inhibit the angiogenesis in EA tumorbearing mice in a dose dependent manner. Conclusion It is suggested that DAS may exertits anticarcinogenic effects by more than one mechanism and is a useful chemopreventiveand chemotherapeutic agent.

Immunotherapies for well-differentiated grade 3 gastroenteropancreatic neuroendocrine tumors:A new category in the World Health Organization classification

According to the 2019 World Health Organization(WHO)classification,welldifferentiated grade 3(G3)gastroenteropancreatic(GEP)neuroendocrine tumors(NETs)are a new category of cancer of the digestive system.G3 GEP-NET research and treatment are not as robust as those of lower grade(G1/2)NETs and poorly differentiated neuroendocrine carcinomas(NECs).Previously,the management of high-grade NETs was mainly based on NEC therapies,as highgrade NETs were classified as NECs under the previous WHO classification.Despite this,G3 GEP-NETs are significantly less responsive to platinum-based chemotherapy regimens than NECs,due to their distinct molecular pathogenesis and course of pathological grade transition.Patients with advanced G3 GEPNETs,who have progressed or are intolerant to chemotherapy regimens such as capecitabine plus temozolomide,have limited treatment choices.Immunotherapy has helped patients with a variety of cancers attain long-term survival through the use of immune checkpoint inhibitors.Immunotherapies,either alone or in combination with other therapies,do not have a clear function in the treatment of G3 GEP-NETs.Currently,the majority of immunotherapy studies,both prospective and retrospective,do not reliably differentiate G3 GEP-NETs from NECs.By contrast,a significant number of studies include non-GEP neuroendocrine neoplasms(NENs).Therefore,there is an urgent need to summarize and evaluate these data to provide more effective therapeutic approaches for patients with this rare tumor.The purpose of this mini-review was to screen and summarize information on G3 GEP-NETs from all studies on NENs immunotherapy.

CELLULAR IMMUNITY EFFECT OF LEUKEMIA VACCINE ON TUMOR BURDEN RAT

Objective To evaluate the effect of the active specific immunotherapy with leukemia vaccine in the malignant hematopoietic diseases. Methods We established the animal models by inoculating C 57 BL/6 rats with FBL 3 erythroleukemia cells and prepared three types of tumor vaccine, which were administered on the rats respectively. The MTT colorimetric assay was adopted 2 and 4 weeks later to test the cytotoxicity of macrophage( M Φ ) and that of cytotoxic T lymphocyte(CTL) derived from the rats injected with tumor vaccines, and compared the results with the control group. Results With the growth of erythroleulemia cells in the rats, the cellular immunity was seriously depressed, and the inhibition of specific cellular immunity was later than that of non specific cellular immunity. The tumor vaccine made from inactivated tumor cells, IFA and cytokines (rGM CSF, rIL 2 and rIL 6), promote the cellular immunity of tumor burden rats, especially the specific cellular immunity more efficiently than that of tumor vaccine made from inactivated tumor cells and IFA, but the third vaccine made from inactivated tumor cells alone has no effect. Conclusion The tumor vaccine made from inactivated tumor cells with addition of IFA and cytokines (rGM CSF, rIL 2 and rIL 6) provides a promising future in the active specific immunotherapy against hematopoietic tumor.

Studies on structural features of human tumor necrosis factor

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