Anti-GD3 monoclonal antibody analysis of childhood T-cell acute lymphoblastic leukemia: detection of a target antigen for antibody-mediated cytolysis

We have demonstrated in previous studies significant quantitative differences in the ganglioside content of leukemia cell membranes within immunological subclasses of acute lymphoblastic leukemia (ALL): The disialoganglioside GD3 (disialolactosylceramide) is increased in lymphoblasts with a T-cell immunophenotype compared to non-T-ALL blasts. Utilizing an indirect immunofluorescence assays with a monoclonal antibody to GD3(R24), pretreatment leukemic lymphoblasts from 80 children with ALL were assayed for GD3 expression. GD3 was observed in 75% of leukemic samples in which lymphoblasts exhibited a T-cell phenotype, whereas none of the 33 non-T-ALL samples tested exhibited GD3. Correlation between the expression of GD3 and various antigenic determinants of T-cell differentiation was restricted to CD2; 75% of CD2-negative T-cell ALL blasts failed to express GD3. Anti-GD3 immunoreactivity to T-ALL samples was not restricted to R24 in that two other monoclonal anti-GD3 antibodies were similarly reactive to T-ALL blasts. In vitro incubation of T-cell lymphoblasts with the anti-GD3 antibodies, R24 and C281 and human serum resulted in significant cytotoxicity, and R24 also mediated antibody-dependent cellular cytotoxicity by normal effector cells. Cytotoxicity was specific for those T-ALL blast cell populations which reacted with anti-GD3 as assessed by immunofluorescence microscopy. Since immunoreactivity with monoclonal antibody to GD3 was exclusively observed in a large population of immunophenotypically defined T-cell leukemic lymphoblasts, these studies suggest a possible immunodiagnostic and immunotherapeutic potential for anti-GD3 monoclonal antibodies in T-cell lymphoblastic malignancies.     

Common phenotypic expression of gangliosides GM3 and GD3 in normal human tissues and neoplastic skin lesions.

The expression of gangliosides in non-malignant tissues (epidermis and pigmented nevus) and neoplastic lesions (melanoma, squamous cell carcinoma [SCC] and basal cell carcinoma [BCS]) of the human skin was analyzed immunohistochemically and biochemically to characterize the features associated with malignancy. Immunohistochemical staining with an anti-II3NeuAc-LacCer (GM3) monoclonal antibody (M2590 mAb) and an anti-II3(NeuAc)2-LacCer (GD3) mAb (R24) showed the expression of the gangliosides GM3 and GD3 to vary among the different tissues. M2590 clearly stained epidermal keratinocytes and the tumor cells of BCC and SCC, and strongly stained melanocytes and melanoma cells. In contrast, R24 did not stain epidermal keratinocytes and only faintly stained SCC cells, while it clearly stained BCC cells, and intensely stained melanocytes and melanoma cells. GM3 showed a similar level of staining among the tissue specimens, while the level of GD3 staining was quite variable among the tumor specimens. Biochemical analysis by thin-layer chromatography (TLC) with resorcinol staining and TLC immunostaining with either M2590 or R24 showed both GM3 and GD3 to be commonly expressed by both the normal and malignant skin tissues, including SCC. There was no close correlation between the intensity of immunohistochemical staining and the biochemically detected amounts of these gangliosides. This may have been partly due to the so-called cryptic expression of cell membrane gangliosides. Our results thus suggest that analysis of the tumor-associated expression of gangliosides requires several methods, since the sensitivity of the methods used may have a considerable effect on the diagnostic value of gangliosides as skin cancer markers.     

Expression of GD3 ganglioside in childhood T-cell lymphoblastic malignancies

Lymphoblasts from seven children with T-cell lymphoblastic malignancies and three children with non-T, non-B acute lymphoblastic leukemia (ALL) were analyzed for ganglioside content. Nonmalignant T-cells from thymus served as controls. Both ganglioside and glycoprotein sialic acid were increased approximately 3-3.5-fold in T-cell disease compared to thymic tissue when expressed on a per cell basis, but not on a per milligram protein basis. Thin-layer chromatography of the isolated ganglioside fraction from T-cell lymphoblasts revealed two major resorcinol-positive bands. One ganglioside comigrated with II3-alpha-N-acetylneuraminosyllactosylceramide (GM3), the major ganglioside in normal lymphoid tissue, and the other ganglioside comigrated with authentic II3-alpha-N-acetylneuraminosyl-alpha 2----8-N-acetylneuraminosyllactosylceramide (GD3) in three different solvent systems. Neuraminidase treatment of the latter ganglioside yielded GM3 and lactosyl ceramide, hydrolysis products of GD3. Scanning densitometry revealed that whereas thymus cells contained 97% GM3 and 3% GD3, T-cell lymphoblasts contained from 22 to 86% GD3 and a corresponding decrease in GM3. The shift to increased GD3 was observed in the blasts from all seven T-cell patients, but not in the blasts from the non-T, non-B patients studied. Only trace quantities of GD3 were detected from two continuous T-ALL cell lines, HSB2 and RPMI 8402. The results demonstrate a consistently significant increase in ganglioside GD3 in uncultured, patient-derived T-cell ALL lymphoblasts when compared to non-T-cell ALL and normal lymphoid tissue. Therefore, GD3 may represent a tumor-associated antigen for the T-cell subclass of childhood lymphoblastic malignancy.     

Immunologic and clinicopathologic features of common acute lymphoblastic leukemia antigen-positive childhood T-cell leukemia. A Pediatric Oncology Group Study

The immunologic and clinicopathologic features of common acute lymphoblastic leukemia antigen (CALLA)-positive and CALLA-negative T-acute lymphoblastic leukemia (ALL) and of CALLA-positive non-T, non-B ALL (common ALL) of childhood were compared. Twenty-seven percent of children with T-ALL had blasts that expressed CALLA. This expression was not associated with a significantly different incidence of expression of sheep erythrocyte-rosette receptors, glucocorticoid receptors, peanut agglutinin receptors, or T-cell antigens. CALLA-positive T-cell blasts were more likely to express a p24 leukemia-associated antigen (CD9, 50% versus 8%) and Ia antigens (39% versus 8%) than were CALLA-negative blasts. Patients with CALLA-positive and CALLA-negative T-ALL had similar clinicopathologic features at diagnosis. In contrast, compared to patients with common ALL, patients with CALLA-positive T-ALL were older, had higher leukocyte counts, and an increased incidence of splenomegaly, lymphadenopathy and mediastinal mass, similar to patients with CALLA-negative T-ALL. Patients with CALLA-positive T-ALL were more likely to achieve a complete remission (95% versus 83%, P = 0.055) and tended to have an increased duration of event-free survival (P = 0.07) than did patients with CALLA-negative T-ALL. The expression of T-cell antigens is more important than the expression of CALLA in defining biologically similar subgroups of childhood ALL. Preliminary evidence suggests that within T-ALL the expression of CALLA may be prognostically important.     

Two human monoclonal antibodies reacting with the major gangliosides of human melanomas and comparison with corresponding mouse monoclonal antibodies

The fine specificity analysis of two human monoclonal antibodies (AbFCM1 and AbHJM1) reacting with gangliosides is described and their specificities are compared with analogous mouse monoclonal antibodies (mAbs). These two antibodies were generated from lymphocytes of melanoma patients by Epstein-Barr virus transformation followed by fusion with mouse myeloma NS-1. Using a wide variety of gangliosides, including N-glycolylneuraminic acid (NeuGc)-containing compounds, the precise structures recognized by these two antibodies were elucidated by enzyme-linked immunosorbent assay and immunostaining of thin-layer chromatograms. AbFCM1 reacted with N-acetylneuraminic acid (NeuAc)-type GM3, GD1a, sialylparagloboside, and GT1b in decreasing order of intensity. This antibody also reacted with (NeuAc-NeuGc-)-GD3 and -disialylparagloboside, but did not react with NeuGc-type GM3, GM2, sialylparagloboside, (NeuGc)2-GD3 and -disialylparagloboside. The main epitope structures recognized by AbFCM1 are, therefore, NeuAc alpha 2----3Gal beta 1- and NeuAc alpha 2----8NeuGc alpha 2----Gal beta 1-. These results are similar to the specificity of mouse mAb M2590. AbHJM1 reacted with NeuAc-type GD3 and disialylparagloboside, GD2, GD1b, GM3, and GT1b, in decreasing order of intensity. Among NeuGc-type gangliosides, this antibody reacts with (NeuAc-NeuGc-)-GD3 and -disialylparagloboside, but did not react with gangliosides containing only NeuGc. Consequently the epitope structure recognized by AbHJM1 is probably (R)-(NeuAc alpha 2----8Sialic acid alpha 2----3)Gal beta 1-. Mouse anti-GD3 mAbR24, in contrast, showed strong reactivity only with GD3 and -disialylparagloboside among NeuAc-type gangliosides, but showed a similar pattern to AbHJM1 in its reactivity with NeuGc-containing gangliosides. Although these two human monoclonal antibodies are not highly restricted in their specificities, they reacted best with the major gangliosides, GM3 and GD3, present in the majority of human melanomas.     

Immunogenicity of melanoma-associated gangliosides in cancer patients

The immunogenicity of gangliosides found on human melanoma cells was determined from sera of 26 melanoma patients who were immunized every 1-4 weeks for 4 months with tumor-cell vaccine (TCV) prepared from cultured melanoma cells. Total lipid-bound sialic acid in the gangliosides isolated from TCV was 0.38 mumol/10(8) cells, and was distributed as follows: 44.8% to GM3, 44.2% to GD3, 5.6% to GM2, and 4.6% to GD2. Sera were tested at monthly intervals for antibodies to each ganglioside by ELISA with purified gangliosides as the antigen source. The immunologic specificity of the antibody was confirmed by absorption tests. None of the 26 patients had detectable anti-GM3, anti-GD3, or anti-GD2 antibodies before immunization, although anti-GM2 antibody was detected in 3 patients. After immunization, 2 patients developed IgM anti-GD2, 10 developed IgM anti-GM2, and 2 developed IgG anti-GM2 antibodies. No patient developed detectable anti-GM3 or anti-GD3 antibodies. These results indicate that both GD2 and GM2 expressed on human melanoma cells are immunogenic in humans, although GM2 appears to be more immunogenic. The other two gangliosides, GM3 and GD3, are present in human sera and in human normal tissues, and thus immunologic tolerance may have been established against these gangliosides. Alternatively, circulating GM3 and GD3 may have neutralized anti-GM3 and anti-GD3 antibodies, if any were induced by TCV immunization.     

Immunological subtypes of childhood T-cell acute lymphoblastic leukemia and their prognostic significance

The data on examination and treatment of 39 children with T-cell acute lymphoblastic leukemia (T-ALL) were assessed; all patients received ALL BFM-90-M treatment. The fraction of children with T-ALL among ALL patients in Belarus was 12.2% (pre-T-ALL--15, cortical T-ALL--46 and mature T-ALL--23%). Also, a subtype of T-ALL with atypical expression of markers was identified (13%). Overall 7-year survival in T-ALL patients was 47(20%). The worst prognosis was recorded in the T-ALL subgroup with atypical expression of markers (p < 0.001 as compared with the other subgroups). As for outcome--from best to worst, T-ALL subtypes ranged as follows: cortical T-ALL, mature T-ALL, pre-T-ALL and T-ALL with atypical expression of markers.     

Granulocyte-Colony Stimulating Factor, Granulocyte-Macrophage Colony Stimulating Factor, PIXY-321, Stem Cell Factor, Interleukin-3, and Interleukin-7: Receptor Binding and Effects on Clonogenic Proliferation in Acute Lymphoblastic Leukemia

Cytokines are frequently used after chemotherapy of leukemias and solid tumors to augment recovery of normal hematopoiesis. While the regulation of normal and leukemic myelopoiesis is well investigated, little is known about effects of cytokines on growth and differentiation of lymphoblastic leukemia. In this study, we investigated the expression of receptors for G-CSF, GM-CSF, SCF, IL-3, and IL-7 on acute lymphoblastic leukemia (ALL) blasts and the effects of these growth factors (GF) on ALL blast colony formation. The binding of fluorescence-tagged cytokines to receptors on ALL blasts was studied by flow-cytometry in 27 cases of ALL (24 precursor B-ALL, 3 T-ALL). Receptor-binding for myeloid-associated GF was observed in the majority of precursor B-ALL (G-CSF = 100%, GM-CSF = 65%, IL-3 = 83%, SCF = 74%), but not in T-ALL. Binding of labelled IL-7 was detected in both precursor B- (92%) and T-ALL (100%). The presence of receptors for SCF in ALL was confirmed by polymerase chain reaction for c-kit mRNA in 19/21 cases tested. Expression of receptors for G-CSF, GM-CSF, IL-3, and SCF was not associated with expression of myeloid antigens, or with specific cytogenetic abnormalities. The effects of these GF on clonogenic cells were tested in the ALL blast colony assay and varied between samples, but all cytokines were able to increase clonogenic growth. The GM-CSF/IL-3 fusion molecule PIXY-321 was most effective in promoting colony growth. In some cases inhibition of colony formation was found. We conclude that ALL blast cells have receptors not only for IL-7, but also for G-CSF, GM-CSF, SCF, and IL-3. ALL precursors can respond to these GF with changes in their clonogenic growth indicating the presence of functional receptors. Results may have implications, for therapeutic approaches combining cytokines and chemotherapy.     

Abnormalities of the short arm of chromosome 9 with partial loss of material in hematological disorders

Clinical, hematological, and cytogenetic data of 32 patients with loss of part of the short arm of chromosome 9 (9p-) are reviewed. There were 20 acute lymphoblastic leukemia (ALL), seven non-Hodgkin lymphoma (NHL), three acute myeloid leukemia, one refractory anemia with excess blasts in transformation, and one chronic myeloid leukemia (CML) in blast crisis. The cytogenetic findings were heterogeneous: 13 cases of del(9)(p21), among them four as sole karyotypic change; five cases of del(9)(p12), three of them as sole karyotypic change; four patients with i(9q), three with unbalanced translocations involving 9p12; and seven with unbalanced translocations involving 9p21. In addition, 10 patients showed known specific translocations for determined subgroups of ALL, NHL, and CML. The immunological phenotypes in the 20 ALL patients were common ALL (35%), pre-B-ALL (35%), B-ALL (5%), T-ALL (15%), and null ALL (10%). Three NHL were of T cell origin and the others of B cell origin. No specific association between the karyotypic change, immunophenotype, and clinical presentation could be ascertained for patients with ALL, acute myeloid leukemia, CML in blast crisis, and B-NHL. In T-NHL, three children with deletion of 9p, T immunoblastic lymphoma originating from common thymocyte and presenting with a mediastinal mass and pleural effusion may constitute a definite subgroup with good prognosis. All other cases had a poor outcome. Previously suggested association of 9p- with T-ALL and "lymphomatous features" was not confirmed.     

Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience.

PURPOSE: T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of newly diagnosed cases of childhood acute lymphoblastic leukemia (ALL). Historically, T-ALL patients have had a worse prognosis than other ALL patients. PATIENTS AND METHODS: We reviewed the outcomes of 125 patients with T-ALL treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium trials between 1981 and 1995. Therapy included four- or five-agent remission induction; consolidation therapy with doxorubicin, vincristine, corticosteroid, mercaptopurine, and weekly high-dose asparaginase; and cranial radiation. T-ALL patients were treated the same as high-risk B-progenitor ALL patients. Fifteen patients with T-cell lymphoblastic lymphoma were also treated with the same high-risk regimen between 1981 and 2000. RESULTS: The 5-year event-free survival (EFS) rate for T-ALL patients was 75% +/- 4%. Fourteen of 15 patients with T-cell lymphoblastic lymphoma were long-term survivors. There was no significant difference in EFS comparing patients with T-ALL and B-progenitor ALL (P =.56), although T-ALL patients had significantly higher rates of induction failure (P <.0001), and central nervous system (CNS) relapse (P =.02). The median time to relapse in T-ALL patients was 1.2 years versus 2.5 years in B-progenitor ALL patients (P =.001). There were no pretreatment characteristics associated with worse prognosis in patients with T-ALL. CONCLUSION: T-ALL patients fared as well as B-progenitor patients on DFCI ALL Consortium protocols. Patients with T-ALL remain at increased risk for induction failure, early relapse, and isolated CNS relapse. Future studies should focus on the identification of and treatment for T-ALL patients at high risk for treatment failure.     

Mouse melanoma antigen recognized by Lyt-2- and L3T4- cytotoxic T-lymphocytes

A mouse melanoma (B16) antigen was investigated at a cellular level by three blocking experiments using monoclonal antimelanoma antibodies, soluble melanoma antigen, and enzyme-treated B16 melanoma cells as inhibitors. The activity of antimelanoma cytotoxic T-lymphocytes (CTL) was specifically reduced by addition of the mixture of two monoclonal antimelanoma antibodies, one (M2590) recognizing the cross-species melanoma epitope on GM3(NeuAc) and the other (M562) reactive with the mouse melanoma-specific epitope on protein molecules. The CTL activity was also blocked by GM3 liposome as well as by the soluble antigen. However, 3,000 times more GM3 than the soluble melanoma antigen is required to obtain a similar inhibitory effect. When pronase-treated B16 melanoma cells, which have had protein molecules removed but GM3 left intact on the surface, were used as an inhibitor, their blocking activity was greatly reduced but was still partly observed at a high inhibitor/target ratio. These results indicate that the melanoma antigen is not GM3 itself but is composed of the GM3-protein complex. This finding was also supported by using an interleukin 2-dependent CTL clone whose activity was blocked by both M562 and M2590. Antimelanoma CTL were found to belong to a double-negative T-cell population with Thy-1+, Lyt-2-, L3T4- phenotypes. L3T4+ T-cells were also demonstrated to be necessary for induction of double negative antimelanoma CTL.     

Subpopulations of human T lymphocytes. VI. Analysis of cell markers in acute lymphoblastic leukemia with special reference to Fc receptor expression on E-rosette-forming blasts

A variety of surface markers, terminal deoxynucleotidyl transferase (TdT) activity, morphologic appearance, and cytochemical composition were studied in a group of 16 patients (13 children, 3 adults) with acute lymphoblastic leukemia (ALL). In 9 children, no surface markers were detected on lymphoblasts (null-type ALL). Leukemic blasts of 4 children formed E-rosettes. These E-rosette-forming blasts from 3 adult patients with ALL, were studied for the presence of Fc receptors. Of the leukemic blasts from these 7 patients, 2--76% expressed receptors for IgG Fc. Only 3 of 7 patients showed 9--42% receptors for IgM Fc. In addition, complement receptors were investigated in 6 of those 7 patients with T-cell ALL. Complement receptors were detected on 9--70% of the E rosette forming blasts from all 6 patients. TdT activity was elevated in T-cell ALL and in children with null-type ALL. The heterogeneity of Fc receptor expression on leukemic blasts in these patients demonstrates a malignant proliferation of T cells in different stages of differentiation or maturation. This observation might be helpful in subclassifying T-cell leukemias with regard to prognosis and the response to therapy.     

Aberrant expression of ganglioside and asialoglycosphingolipid antigens in adult T-cell leukemia cells

Gangliosides (GM3, GD3, GM2, gangliotetraose-series gangliosides) and their asialo derivatives of several adult T-cell leukemia (ATL) cell lines (ATL-1K, ATL-3I, ATL-5S, and MT-2 cells) and the lymphocytes from a patient with ATL were quantified by highly sensitive enzyme-immunostaining on silica gel thin layer chromatograms using specific antiglycolipid antibodies. GM2 and GD3 gangliosides and asialo GM1 (GA1) newly appeared in all cultured ATL cells and the lymphocytes from patients with ATL but not in normal human T-lymphocyte-rich fraction. Gangliotetraose-series gangliosides, GM1a, GD1a and GD1b, were also found in cultured ATL cells, but were not detected in normal human lymphocytes or the lymphocytes of a patient with ATL. Quantitative immunostaining analysis of GM2, GD3 gangliosides and GA1 in T-cell lines from non ATL leukemia (Molt-3, CEM and Jurkat) revealed GM2 gangliosides in all the T-cells from non ATL tested and GA1 in Jurkat cells, but no GD3 ganglioside was found in the non ATL leukemia cells tested. The above results indicate that ganglioside GD3 may be a T-cell glycosphingolipid antigen associated with ATL, and ganglioside GM2 and GA1 may be useful as surface markers related with ATL, as well as T-cell lymphoma. The contents of GA1, GM3, GD3, GM2 and gangliotetraose-series gangliosides in ATL cells were all different, even though all the cells used have a common antigen reactive with monoclonal OKT-4 antibody, indicating that there are several subsets of human inducer/helper T-cells, which possess different metabolism and expression of gangliosides.     

Endogenous immune response to gangliosides in patients with confined prostate cancer

Our study investigated whether endogenous IgM antibodies to gangliosides occur in patients with early stages of prostate cancer (CaP) patients, after defining ganglioside profiles of CaP cell lines. Immune and resorcinol staining detected the presence of gangliosides GM3, GM2, GD3, GD2 and GD1a but not GM1a, GD1b or GT1b in the extracts of normal prostatic epithelial cells (PrEC) and neoplastic androgen-insensitive (PC-3, DU145) and -sensitive (LNCaP-FGC and LNCaP-FGC-10) CaP cells. Using a sensitive ELISA, developed and validated in our laboratory, the titers of IgM against 8 gangliosides from sera of patients with benign prostatic hyperplasia (BPH) (n = 11), organ-confined (T1/T2, n = 36) and unconfined (T3/T4, n = 27) CaP and age-matched healthy men (n = 11) were determined double-blinded. Using ANOVA and Fisher's least significant difference (LSD) methods, the log-titers among different groups were compared. CaP patients differed from healthy and BPH patients in increased titers against GD1a and decreased titers against GD3. Titers of antibodies to other gangliosides exhibited no difference between CaP patients and others. The specific augmentation of anti-GD1a IgM in patients with organ-confined CaP (stage T1/T2) but not in patients with unconfined CaP (stage T3/T4) or BPH or in healthy controls is striking. This finding together with identification of GD1a as a major ganglioside in CaP cell lines and with the accruing studies on the immunosuppressive nature of GD1a indicates that augmentation of anti-GD1a IgM in confined CaP may signify an early endogenous immune response to eliminate a "danger signal" from tumor microenvironment and circulation.     

儿童T系急性淋巴细胞白血病与PI3K-Akt-mTOR信号通路抑制剂的相关研究进展

T系急性淋巴细胞白血病(T-ALL)是T系前体细胞发生恶性转化致造血系统恶性病变的一种侵袭性肿瘤.发病率占儿童ALL的15%.研究发现PI3K-Akt-mTOR信号通路与T-ALL发生,白血病细胞增殖、细胞凋亡抑制和细胞耐药相关.通过使用PI3K-Akt-mTOR信号通路抑制剂治疗T-ALL儿童患者,能有针对性地靶向抑制T-ALL细胞,发挥有效的细胞毒作用.通过缩短疾病疗程,提高儿童T-ALL患者的生命质量,减少疾病复发,为传统化疗方案抵抗儿童T-ALL患者提供一种更有效的疾病干预方法.     

An IgG3 monoclonal antibody established after immunization with GM3 lactone: immunochemical specificity and inhibition of melanoma cell growth in vitro and in vivo

In previous studies, an IgM monoclonal antibody (M2590), established after immunization of C57BL/6 mice with syngeneic B16 melanoma cells, was found to react with melanoma cells, but not with various normal cells and tissues (Taniguchi, M., and Wakabayashi, S., Jpn. J. Cancer Res., 75:418-426, 1984). The structure defined by this antibody was identified as GM3 (Hirabayashi, Y., et al., J. Biol. Chem., 260:13328-13333, 1985) organized in membranes at high density, although the real immunogen was suggested to be GM3 lactone (Nores, G. A., et al., J. Immunol., 139:3171-3176, 1987). Since GM3 lactone was found to be highly immunogenic, we subsequently immunized C57BL/6 mice with GM3 lactone coated on Salmonella minnesotae and established hybridoma DH2, secreting an IgG3 antibody showing preferential reactivity with GM3 lactone over GM3 under certain conditions. The reactivity of the DH2 antibody was competitively inhibited by M2590, and it showed a preferential reactivity with melanoma cells and displayed various immunochemical and immunobiological properties similar to those of M2590. However, DH2 antibody inhibited melanoma cell growth in vivo, induced antibody-dependent cytotoxicity in vitro, and showed a preferential accumulation in melanoma growth in vivo. These properties are characteristic of the IgG3 subclass, in striking contrast to IgM antibody M2590, which does not inhibit cell growth in vivo or in vitro and does not induce antibody-dependent cytotoxicity. Thus, immunization with lactone forms of tumor-associated ganglioside antigens might be useful in the production of antibodies and prevention of tumor cell growth in vivo (antitumor vaccines).     

Glucocorticoid receptor in childhood acute lymphoblastic leukemia

Glucocorticoid(GC)hasbeenusedinthetreatmentofchildhoodacutelymphoblasticleukenda(ALL)formanyyears.IthasprovedthattheeffectofGCismediatedthroughaglucocortic0idreceptor(GCR)ofthetargetcell.[1]Therefore,manyexpertshaveconcentratdtheirattentiononGCR,butthereisnoreportonthestudyofGCRinchildho0dALLinChina.InununologicalclassificationofALLmaydifferentiatethecelloriginandclustersofdifferentiation(CD)inleukendacell.Itisoneoftheimportantindicatorstoguidecombinationchemotherapyandt0makeapr0gnos…     

Clinical Experience With Venetoclax Combined With Chemotherapy for Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia

BackgroundPatients with relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) have dismal outcomes. Preclinical studies have suggested that T-ALL cells are sensitive to BCL2 inhibition. The clinical activity of venetoclax, a selective BCL2 inhibitor, in T-ALL is unknown.Patient and MethodsWe retrospectively reviewed the efficacy and safety of venetoclax combined with chemotherapy for patients with R/R T-ALL treated at our institution.ResultsThirteen patients with R/R T-ALL with a median age of 46 years (range, 20-75 years) were treated with venetoclax plus chemotherapy. Five patients (38%) had early T-cell precursor ALL. The patients had received a median of 2 previous lines of therapy (range, 1-11). Venetoclax at a median dose of 200 mg/d for 21 days, generally with a concomitant azole antifungal, was combined with various agents, including hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone), asparaginase, nelarabine, decitabine, or other intensive chemotherapy. Of the 10 patients evaluable for bone marrow response, 6 (60%) achieved a remission with bone marrow blasts < 5%, including 3 with complete hematologic recovery. The median overall survival and relapse-free survival were 7.7 and 4.0 months, respectively. No early death or clinically significant tumor lysis syndrome were reported. The median interval to neutrophil recovery and platelet recovery were 15 days and 44 days, respectively, with prolonged cytopenias observed with venetoclax 400 mg/d or when given for > 14 days per cycle.ConclusionCombination therapy with venetoclax showed promising clinical efficacy in R/R T-ALL. Further studies are warranted to evaluate the clinical benefit of BCL2 inhibitors in T-ALL.     

Gangliosides as targets for immunotherapy for pancreatic adenocarcinoma

BACKGROUND: Pancreatic adenocarcinoma cells express gangliosides and sialyl Lewis (sLe) antigens. It is not known whether these carbohydrate antigens can be targeted by immunotherapy. The authors measured the expression of GM(2) and sLe antigens on the surface of pancreatic carcinoma cells and the serum levels of total gangliosides, GM(2), and antiganglioside antibodies in patients with pancreatic carcinoma. METHODS: Cell surface GM(2) and sLe antigens were measured by cell suspension enzyme linked immunoadsorbent assay (ELISA) in four pancreatic carcinoma cell lines. Sera from 20 pancreatic carcinoma patients and 20 age- and gender-matched healthy volunteers were analyzed for antiganglioside and anti-sLe immunoglobulin (Ig) M titers by ELISA. Serum levels of total gangliosides and GM(2) also were measured. RESULTS: All cell lines expressed GM(2) and sLe antigens. When compared with age- and gender-matched volunteers, patients had significantly higher serum levels of total gangliosides (25.6 +/- 9.0 mg/dL vs. 15.6 +/- 2.7 mg/dL; P < 0.001), GM(2) (0.278 +/- 0.415 mg/dL vs. 0.013 +/- 0.018 mg/dL; P = 0.02), ELISA units of anti-GM(2) IgM antibody (368 +/- 95 vs. 155 +/- 25; P = 0.04) and anti-GD(1b) IgM antibody (351 +/- 91 vs. 138 +/- 26; P = 0.03), but not anti-sLe(x) IgM (1389 +/- 345 vs. 1081 +/- 224; P = 0.46) or anti-sLe(a) IgM antibody (1097 +/- 253 vs. 1200 +/- 315; P = 0.80). Patients with unresectable tumors had higher serum levels of total gangliosides compared with patients with resectable tumors, and a serum level > 25 mg/dL was found to correlate significantly with poor overall survival (P < 0.02). CONCLUSIONS: Increased serum levels of total gangliosides and GM(2) may reflect shedding or release of gangliosides from the surface of tumor cells. Production of IgM antibody against GM(2) and GD(1b) indicates that these gangliosides are immunogenic antigens that may be potential targets for effective active immunotherapy.     

Significance of commonly used prognostic factors differs for children with T cell acute lymphocytic leukemia (ALL), as compared to those with B-precursor ALL. A Pediatric Oncology Group (POG) study.

T cell acute lymphocytic leukemia (T-ALL) and B-precursor ALL differ significantly in the clinical characteristics of the patients at presentation and in laboratory-defined characteristics of the leukemic cells. We assessed for pediatric patients with T-ALL the relative importance of prognostic factors previously demonstrated to predict outcome in B-precursor ALL. Presenting clinical and laboratory features were correlated with outcome for 441 children 12 months to 21 years of age with previously untreated T-ALL, registered on the Pediatric Oncology Group (POG) T3 protocol between 1986 and 1992. These T-ALL prognostic factor analyses were then compared to similar analyses for 1993 patients with B-precursor ALL enrolled during the same time period on the POG ALinC 14 protocol. Quantitative interaction between phenotype and each prognostic factor was studied to determine the relative importance of the prognostic factor for each of the two major immunophenotypes. We also analyzed the importance of maturational stage as a T-ALL prognostic factor, using a modified Ludwig definition of maturational stage. We conclude that several of the clinical and laboratory prognostic factors, which are used reliably for B-precursor ALL, are much less predictive in T-ALL (ie age, WBC, consensus risk group, hyperdiploidy, presence of trans- locations and CALLA expression). There was no significant difference between the phenotypes in the prognostic importance of race or gender. Our data demonstrate a significant difference in outcome among the three maturational stages of T-cell ALL, with the intermediate group faring best. Using traditional risk group criteria to stratify patients with T-ALL for therapy may not be appropriate.