728 results on '"Herberman, RB"'
Search Results
2. Defining the critical hurdles in cancer immunotherapy
- Author
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Fox, BA, Schendel, DJ, Butterfield, LH, Aamdal, S, Allison, JP, Ascierto, PA, Atkins, MB, Bartunkova, J, Bergmann, L, Berinstein, N, Bonorino, CC, Borden, E, Bramson, JL, Britten, CM, Cao, X, Carson, WE, Chang, AE, Characiejus, D, Raja Choudhury, A, Coukos, G, de Gruijl, T, Dillman, RO, Dolstra, H, Dranoff, G, Durrant, LG, Finke, JH, Galon, J, Gollob, JA, Gouttefangeas, C, Grizzi, F, Guida, M, Håkansson, L, Hege, K, Herberman, RB, Stephen Hodi, F, Hoos, A, Huber, C, Hwu, P, Imai, K, Jaffee, EM, Janetzki, S, June, CH, Kalinski, P, Kaufman, HL, Kawakami, K, Kawakami, Y, Keilholtz, U, Khleif, SN, Kiessling, R, Kotlan, B, Kroemer, G, Lapointe, R, Levitsky, HI, Lotze, MT, Maccalli, C, Maio, M, Marschner, JP, Mastrangelo, MJ, Masucci, G, Melero, I, Melief, C, Murphy, WJ, Nelson, B, Nicolini, A, Nishimura, MI, Odunsi, K, Ohashi, PS, O'Donnell-Tormey, J, Old, LJ, Ottensmeier, C, Papamichail, M, Parmiani, G, Pawelec, G, Proietti, E, Qin, S, Rees, R, Ribas, A, Ridolfi, R, Ritter, G, Rivoltini, L, Romero, PJ, Salem, ML, Scheper, RJ, Seliger, B, Sharma, P, Shiku, H, Singh-Jasuja, H, Song, W, Straten, PT, Tahara, H, Tian, Z, van der Burg, SH, von Hoegen, P, Wang, E, Welters, MJP, Winter, H, Withington, T, Wolchok, JD, Xiao, W, Zitvogel, L, Fox, BA, Schendel, DJ, Butterfield, LH, Aamdal, S, Allison, JP, Ascierto, PA, Atkins, MB, Bartunkova, J, Bergmann, L, Berinstein, N, Bonorino, CC, Borden, E, Bramson, JL, Britten, CM, Cao, X, Carson, WE, Chang, AE, Characiejus, D, Raja Choudhury, A, Coukos, G, de Gruijl, T, Dillman, RO, Dolstra, H, Dranoff, G, Durrant, LG, Finke, JH, Galon, J, Gollob, JA, Gouttefangeas, C, Grizzi, F, Guida, M, Håkansson, L, Hege, K, Herberman, RB, Stephen Hodi, F, Hoos, A, Huber, C, Hwu, P, Imai, K, Jaffee, EM, Janetzki, S, June, CH, Kalinski, P, Kaufman, HL, Kawakami, K, Kawakami, Y, Keilholtz, U, Khleif, SN, Kiessling, R, Kotlan, B, Kroemer, G, Lapointe, R, Levitsky, HI, Lotze, MT, Maccalli, C, Maio, M, Marschner, JP, Mastrangelo, MJ, Masucci, G, Melero, I, Melief, C, Murphy, WJ, Nelson, B, Nicolini, A, Nishimura, MI, Odunsi, K, Ohashi, PS, O'Donnell-Tormey, J, Old, LJ, Ottensmeier, C, Papamichail, M, Parmiani, G, Pawelec, G, Proietti, E, Qin, S, Rees, R, Ribas, A, Ridolfi, R, Ritter, G, Rivoltini, L, Romero, PJ, Salem, ML, Scheper, RJ, Seliger, B, Sharma, P, Shiku, H, Singh-Jasuja, H, Song, W, Straten, PT, Tahara, H, Tian, Z, van der Burg, SH, von Hoegen, P, Wang, E, Welters, MJP, Winter, H, Withington, T, Wolchok, JD, Xiao, W, and Zitvogel, L
- Abstract
Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer. © 2011 Fox et al; licensee BioMed Central Ltd.
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- 2011
3. Strategies for enrichment of natural-killer-cell precursors from mouse bone marrow
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Delfino, Domenico Vittorio, Patrene, Kd, Herberman, Rb, and Boggs, Ss
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- 1994
4. Changes of liver-resident NK cells during liver regeneration in rats
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Vujanovic, NL, Polimeno, L, Azzarone, A, Francavilla, A, Chambers, WH, Starzl, TE, Herberman, RB, Whiteside, TL, Vujanovic, NL, Polimeno, L, Azzarone, A, Francavilla, A, Chambers, WH, Starzl, TE, Herberman, RB, and Whiteside, TL
- Abstract
To determine the role of NK cells in regulation of tissue growth, the phenotype and function of liver-resident NK cells were studied after 70% partial hepatectomy in rats. The process of liver regeneration was generally completed by clay 14. In contrast, the number of liver resident NK cells (NKR-P1(bright)) was restored as early as day 3 after partial hepatectomy. However, spontaneous functions of liver resident NK cells, including killing of YAC-1 and P815 targets, Ab-dependent cellular cytotoxicity, and redirected killing via NKR-P1, were continuously suppressed throughout the entire period of liver regeneration (from 3 h to 14 days). Augmentation of NK cytotoxicity against P815 targets and induction of NK cell adherence to plastic following 24 h of IL-2 stimulation showed a similar pattern of suppression. However, IL-2-induced augmentation of YAC-1 killing, proliferation and generation of adherent NK cells, and LAK activity in 5- to 7-day cultures were found to be suppressed only during the first 24 h and increased between days 2 and 7 after hepatectomy. Sorted NK cells (≥95% NKR-P1(bright)) from liver-resident mononuclear leukocytes 24 h after partial hepatectomy showed the same pattern of suppression as unsorted mononuclear leukocytes. In contrast to liver- resident NK cells, no significant changes were detected in peripheral blood or spleen NK cells of rats following partial hepatectomy. Of particular interest, in normal liver, hepatocytes were resistant to NK lysis, while resident NK cells were cytotoxic for various NK-sensitive targets. In contrast, during the early period of liver regeneration, when hepatocytes were sensitive to lysis by liver resident NK cells of normal rats, NK cells obtained from regenerating liver tissues were unable to mediate cytotoxicity. At the final phase of liver regeneration (days 7-14 after hepatectomy), both resistance of hepatocytes to killing by NK cells and cytotoxicity of liver- resident lymphocytes against hepatocytes fro
- Published
- 1995
5. Serial monitoring of immunologic function and phenotype of lymphocytes in the blood of transplanted patients randomized to cyclosporine or FK 506
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Whiteside, TL, Wilson, J, Bryant, J, Zeevi, A, Abu El-Magd, K, Alessiani, M, Fung, J, Herberman, RB, Starzl, TE, Whiteside, TL, Wilson, J, Bryant, J, Zeevi, A, Abu El-Magd, K, Alessiani, M, Fung, J, Herberman, RB, and Starzl, TE
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- 1991
6. Natural killer cell precursors in the CD44neg/dim T-cell receptor population of mouse bone marrow
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Delfino, DV, primary, Patrene, KD, additional, Lu, J, additional, Deleo, A, additional, Deleo, R, additional, Herberman, RB, additional, and Boggs, SS, additional
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- 1996
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7. Induction of protein tyrosine phosphorylation in human natural killer cells by triggering via alpha 4 beta 1 or alpha 5 beta 1 integrins
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Rabinowich, H, primary, Lin, WC, additional, Manciulea, M, additional, Herberman, RB, additional, and Whiteside, TL, additional
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- 1995
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8. Generation of adherent lymphokine activated killer (A-LAK) cells from patients with acute myelogenous leukaemia
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Sedlmayr, P, primary, Rabinowich, H, additional, Winkelstein, A, additional, Herberman, RB, additional, and Whiteside, TL, additional
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- 1992
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9. Generation of natural killer cells from Thy 1.1+ bone marrow precursor cells in the rat
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van den Brink, MR, primary, Herberman, RB, additional, and Hiserodt, JC, additional
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- 1991
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10. Novel method for benchmarking recruitment of African American cancer patients to clinical therapeutic trials.
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Morgenlander KH, Winters SB, Lin CJ, Robertson LB, Heron DE, Herberman RB, Morgenlander, Keith H, Winters, Sharon B, Lin, Chyongchiou J, Robertson, Linda B, Heron, Dwight E, and Herberman, Ronald B
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- 2008
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11. Production by human squamous cell carcinoma of a factor inducing activation and proliferation of immune cells.
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Hirabayashi H, Yasumura S, Lin W, Amoscato A, Johnson JT, Herberman RB, and Whiteside TL
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- 1995
12. KINETICS OF THE RESPONSE OF DIFFERENT CLASSES OF ANTIBODIES TO SKIN ALLOGRAFTS IN MICE
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Herberman Rb and Ting Cc
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Male ,C57BL/6 ,Immunodiffusion ,Pathology ,medicine.medical_specialty ,Immunoglobulins ,Biology ,Antibodies ,Mice ,Transplantation Immunology ,Iodine Isotopes ,medicine ,Animals ,Transplantation, Homologous ,Neoplasm ,Transplantation ,Skin Transplantation ,biology.organism_classification ,medicine.disease ,Coombs Test ,Kinetics ,Immunoglobulin M ,Antibody Formation ,Immunology ,biology.protein ,gamma-Globulins ,Antibody ,Skin allografts - Published
- 1971
13. Re: Mobile phone use and brain tumors in children and adolescents: a multicenter case-control study.
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Morgan LL, Herberman RB, Philips A, Lee Davis D, Morgan, L Lloyd, Herberman, Ronald B, Philips, Alasdair, and Lee Davis, Devra
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- 2012
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14. Characterization of a suppressor T-cell chronic lymphocytic leukemia with ADCC but not NK activity
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Pandolfi, F, Strong, DM, Slease, RB, Smith, ML, Ortaldo, JR, and Herberman, RB
- Abstract
A patient with T-cell chronic lymphocytic leukemia (T-CLL) is reported whose cells demonstrate in vitro suppression of normal lymphocyte mitogen stimulation. The patient, who remains in Rai's clinical stage 0 on no therapy after more than 24 mo of observation, has shown a less aggressive clinical course than is usually attributed to T-CLL. His peripheral blood lymphocytes (PBL) were characterized by functional assays as well as surface markers. Over 90% of the patient's PBL formed rosettes with sheep erythrocytes and were lysed by two T-cell-specific antisera plus complement, while less than 1% bore surface immunoglobulins, and only 3% had complement receptors. In addition, 45% of the PBL demonstrated Ia-like antigens, more than 50% expressed a receptor for the Fc portion of IgG(T gamma), and most of the sheep erythrocyte rosettes were inhibited by theophylline. The patient's cells failed to respond to several mitogens and they caused marked suppression of lymphoproliferative responses to normal PBL to phytohemagglutinin (PHA) and concanavalin A (Con-A). The patient's lymphocytes also exhibited antibody-dependent cytotoxic activity (ADCC) against antibody-coated nucleated target cells, but lacked demonstrable natural killer (NK) activity. This patient's T-CLL cells appear to represent the clonal expansion of a subset of T cells with a previously undescribed pattern of suppressor and cytotoxic activities.
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- 1980
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15. Interleukin-2 induction of lymphokine-activated killer (LAK) activity in the peripheral blood and bone marrow of acute leukemia patients: II. Feasibility of LAK generation in children with active disease and in remission
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Adler, A, Albo, V, Blatt, J, Whiteside, TL, and Herberman, RB
- Abstract
Activation and expansion in culture with rIL-2 of peripheral blood (PB) and/or bone marrow (BM) specimens derived from children with ALL and ANLL, with active disease (AP) and in remission were studied (RP). Baseline NK cytolytic activity from AP was found to be depressed, whereas RP-derived cells had normal NK activity, as assayed against K562 targets. Culture in rIL-2 significantly enhanced the NK activity of both AP- and RP-derived cells and generated LAK activity, as assayed by 4-hour 51Cr release, against NK-resistant Raji cell line and against fresh, allogeneic, and autologous tumor cells. Lytic activity against fresh, cryopreserved leukemia blasts was of lower than that found against cell lines. In three patients higher lytic activity against autologous than against allogeneic blasts was demonstrated. Expansion in culture with rIL-2 varied from twofold to 120-fold. rIL-2 activation and expansion was better in RP than in AP. The predominant phenotype of activated cells, as determined by flow cytometry, was [mean % (SD)]: CD3- = 54 (12), CD8+ = 55 (17), and NKH1+ = 26 (7). The consistently high level of CD8+ cells was accompanied by very low levels of CD4+ cells: mean = 11% (14). Double-marker analysis showed mean of 33% (10) for CD3+/NKH1+ cells and mean = 32 (11) for CD8+/NKH1+ cells, implying that these populations were overlapping. Kinetics of expression of cell surface markers during 2 to 3 weeks in culture showed that CD8+ and NKH1+ enrichment occurred during the first week and lasted for up to 4 weeks, whereas CD4+ expression decreased after the second week. A significant decrease in the expression of IL-2 receptors (CD25) was observed from the second week of culture. This study shows the feasibility of in vitro generation of killer cells from PB and BM of pediatric leukemia patients.
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- 1989
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16. Interleukin 2 induction of lymphokine-activated killer (LAK) activity in the peripheral blood and bone marrow of acute leukemia patients. I. Feasibility of LAK generation in adult patients with active disease and in remission
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Adler, A, Chervenick, PA, Whiteside, TL, Lotzova, E, and Herberman, RB
- Abstract
The feasibility of in vitro interleukin 2 (IL-2) activation and expansion of mononuclear cells (MNCs) derived from adult patients with acute myelogenous leukemia (ANLL) was studied. Patients' natural killer (NK) and lymphokine-activated killer (LAK) cell activity was compared with that of normal donors in terms of: (a) cytolytic activity (four- hour 51Cr release assay) against an NK-sensitive target (K562), NK- resistant targets (Raji/Daudi), and fresh/cryopreserved autologous and allogeneic leukemic blasts; (b) proliferation and expansion in culture with 1,000 U/mL recombinant IL 2 (rIL 2); and (c) the cell surface phenotype of the cultured cells. In 21 of 24 patients with active disease (AP) MNCs derived from the peripheral blood (PBL) or bone marrow (BM) could be cultured and expanded in the presence of rIL 2. These cultures initially contained between 30% and 50% blasts, and during 2 to 4 weeks of culture destruction of blasts and enrichment of up to 60% in cells with the morphology of large granular lymphocytes (LGLs) was observed. Expansion in culture varied between two- and 100- fold. MNCs from all patients in remission (RP) could be activated by rIL 2 and expanded up to 30-fold after 1 to 3 weeks in culture. NK activity of fresh PBLs from AP was significantly lower than in normal controls, whereas NK activity of RP was within the normal range. High levels of postactivation NK and LAK activity on K562/Raji/Daudi and on fresh/cryopreserved leukemic blasts was generated in approximately 50% of cases of AP and in most RP. Cell surface phenotype studies showed that cultured cells derived from ANLL patients were significantly enriched (up to 40%) in NKH-1 (Leu 19) positive cells, with RP LAK cells also expressing a high proportion of CD16 positive cells (up to 40%). This study has shown that it is feasible to activate and significantly expand killer cells derived from active disease and remission ANLL patients during 1 to 3 weeks culture with IL 2 with good maintenance of cytolytic activity. Both initial NK activity and LAK generation was optimal in remission patients. Based on data from this study, a clinical protocol has been developed for treatment of early relapse ANLL patients with LAK cells cultured for 1 to 3 weeks and systemic IL 2.
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- 1988
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17. Chediak-Higashi gene in humans. II. The selectivity of the defect in natural- killer and antibody-dependent cell-mediated cytotoxicity function
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Klein, M, Roder, J, Haliotis, T, Korec, S, JR, Jett, Herberman, RB, Katz, P, and Fauci, AS
- Abstract
Antibody-dependent cell-mediated cytolysis (ADCC) of human tumor cells by FcR(+) nonadherent effector lymphocytes as well as natural killer (NK) activity was markedly impaired in Chediak-Steinbrinck-Higashi Syndrome (C-HS) patients. Compared to a more than 400-fold defect in NK activity in terms of lytic units, the abnormal ADCC response in C-HS donors was 24-fold below normal suggesting a partial but not complete overlap of lymphocytes or lytic mechanisms responsible for ADCC and NK. The ADCC mechanism against erythrocyte targets, however, was normal, thereby suggesting a qualitative difference in these two forms of ADCC. Other effector-cell functions against tumor-cell targets were normal as measured by (a) spontaneous cytolysis mediated by monocytes, (b) spontaneous cytostasis mediated by neutrophils, and (c) lectin-dependent cytolysis mediated by neutrophils. Although one C-HS patient was low in lectin-dependent cytolysis mediated by lymphocytes, the other C-HS patient was normal, thereby suggesting that cytolytic T function was not linked to the NK-ADCC defect. In addition, the proliferative response to T-dependent mitogens was also relatively normal. These results, combined with other studies showing normal cell-mediated and humoral immunity in these same patients, suggest that patients with C-HS have an immunodeficiency which is selective for NK and ADCC activity.
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- 1980
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18. Chediak-Higashi gene in humans. I. Impairment of natural - killer function
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Haliotis, T, Roder, J, Klein, M, Ortaldo, J, Fauci, AS, and Herberman, RB
- Abstract
Natural-killer (NK)-cell function was profoundly depressed in donors homozygous for the Chediak-Steinbrinck-Higashi syndrome (C-HS) gene when compared with age- and sex-matched normals. This apparent defect was not simply a result of a delayed response because little cytolysis was evident in kinetics experiments even after 24 h of incubation. NK cells from C-HS donors failed to lyse adherent (MDA, CEM, and Alab) or nonadherent (K562 and Molt-4) tumor cell lines or nontransformed human fetal fibroblasts. Therefore, the apparent C-HS defect was not a result of a shift in target selectivities. In addition, the depressed reactivity did not appear to be a result of suppressor cells or factors because: (a) enriched NK populations (nonadherent lymphocytes bearing receptors for the Fc portion of IgG) from C-HS donors were low in NK-cell function, (b) C-HS mononuclear cells did not inhibit the cytotoxicity of normal cells in coculture experiments, and (c) cells from the C-HS donors remained poorly reactive even after culture for up to 7 d. The nature of the defective NK activity in C-HS patients is not clear but may lie within the lytic mechanism rather than at the level of the recognition structure or population size because the frequency of target-binding cells was normal. In vitro NK activity could be partially restored by interferon treatment. Combined with the results presented in the following paper (4), these observations suggest that the C-HS gene causes a selective immunodeficiency disorder, mainly involving NK cells. This finding, in conjunction with the high incidence of spontaneous possibly malignant, lymphoproliferative disorders in these patients, may have important implications regarding the theory of immune surveillance mediated by NK cells.
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- 1980
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19. Characteristics of human large granular lymphocytes and relationship to natural killer and K cells
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Timonen, T, JR, Ortaldo, and Herberman, RB
- Abstract
Recent evidence, has demonstrated an association between a subpopulation of peripheral blood mononuclear cells, morphologically identified as large granular lymphocytes (LGL), and natural killer (NK) activity. We have now evaluated more directly the role of LGL in both NK activity and antibody- dependent cellular cytotoxicity (ADCC), by using highly enriched populations of LGL, obtained by centrifugation of peripheral blood mononuclear cells on Percoll discontinuous density gradients. Both spontaneous and interferon- augmented NK and ADCC activities were exclusively associated with the LGL- enriched, low density fractions. The majority of LGL formed conjugates with NK-susceptible and antibody-coated target cells. Approximately 20 percent of small conventional lymphocytes also formed conjugates with the target cells for NK, but this was not associated with cytotoxic activity. Virtually all LGL were found to have receptors for the Fc portion of IgG (FcγR). The frequency of LGL among blood leukocytes was 2-6 percent. LGL could be enriched to an average purity of 95 percent by combining discontinuous density gradient centrifugation with subsequent adsorptions of the low density fractions on monolayers of immobilized immune complexes. About 50 percent of LGL were found to be FcγR-bearing T cells (T(G)), forming low affinity rosettes with sheep erythrocytes at 4 degrees C. Only 10-20 percent of LGL formed high affinity rosettes with sheep erythrocytes at 29 degrees C. LGL could be enriched to a purity of more than 90 percent by depleting high affinity rosette-forming cells from low density Percoll fractions. LGL were only a subpopulation of T(G) cells, because some lymphocytes with conventional morphology also adhered to the immobilized immune complex monolayers and formed high affinity rosettes with sheep erythrocytes. Separation of these cells from LGL by discontinuous density gradient centrifugation indicated that they are not cytotoxic, suggesting a morphological and functional subdivision of T(G) cells. The verification in this study that virtually all human NK and K cells have a characteristic morphology adds a useful parameter to the monitoring of human lymphocytes, and the ability to purify these cells by simple physical procedures should be invaluable in their further characterization.
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- 1981
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20. Characteristics of human large granular lymphocytes and relationship to natural killer and K cells
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Herberman Rb, Ortaldo, and Tuomo Timonen
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Cytotoxicity, Immunologic ,Male ,Rosette Formation ,Time Factors ,Immunology ,chemical and pharmacologic phenomena ,Antigen-Antibody Complex ,Cell Separation ,Receptors, Fc ,Biology ,Cytoplasmic Granules ,Peripheral blood mononuclear cell ,Immune system ,Centrifugation, Density Gradient ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,Lymphocytes ,Antibody-dependent cell-mediated cytotoxicity ,Differential centrifugation ,Antibody-Dependent Cell Cytotoxicity ,Articles ,Molecular biology ,Immune complex ,Killer Cells, Natural ,biology.protein ,Female ,Adsorption ,Interferons ,Antibody ,Percoll - Abstract
Recent evidence, has demonstrated an association between a subpopulation of peripheral blood mononuclear cells, morphologically identified as large granular lymphocytes (LGL), and natural killer (NK) activity. We have now evaluated more directly the role of LGL in both NK activity and antibody- dependent cellular cytotoxicity (ADCC), by using highly enriched populations of LGL, obtained by centrifugation of peripheral blood mononuclear cells on Percoll discontinuous density gradients. Both spontaneous and interferon- augmented NK and ADCC activities were exclusively associated with the LGL- enriched, low density fractions. The majority of LGL formed conjugates with NK-susceptible and antibody-coated target cells. Approximately 20 percent of small conventional lymphocytes also formed conjugates with the target cells for NK, but this was not associated with cytotoxic activity. Virtually all LGL were found to have receptors for the Fc portion of IgG (FcγR). The frequency of LGL among blood leukocytes was 2-6 percent. LGL could be enriched to an average purity of 95 percent by combining discontinuous density gradient centrifugation with subsequent adsorptions of the low density fractions on monolayers of immobilized immune complexes. About 50 percent of LGL were found to be FcγR-bearing T cells (T(G)), forming low affinity rosettes with sheep erythrocytes at 4 degrees C. Only 10-20 percent of LGL formed high affinity rosettes with sheep erythrocytes at 29 degrees C. LGL could be enriched to a purity of more than 90 percent by depleting high affinity rosette-forming cells from low density Percoll fractions. LGL were only a subpopulation of T(G) cells, because some lymphocytes with conventional morphology also adhered to the immobilized immune complex monolayers and formed high affinity rosettes with sheep erythrocytes. Separation of these cells from LGL by discontinuous density gradient centrifugation indicated that they are not cytotoxic, suggesting a morphological and functional subdivision of T(G) cells. The verification in this study that virtually all human NK and K cells have a characteristic morphology adds a useful parameter to the monitoring of human lymphocytes, and the ability to purify these cells by simple physical procedures should be invaluable in their further characterization.
- Published
- 1981
21. Natural killer cells and tumor immunity
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J C Hiserodt and Herberman Rb
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Allergy ,Lymphokine-activated killer cell ,Immunology ,Immunity ,Antibodies, Monoclonal ,Tumor immunity ,Biology ,medicine.disease ,Natural killer T cell ,Rats ,Killer Cells, Natural ,Mice ,Immune system ,Neoplasms ,Antigens, Surface ,medicine ,Interleukin 12 ,Animals ,Humans ,Interleukin-2 ,Interferons ,Neoplasm Metastasis - Published
- 1983
22. Cellular immunity to murine sarcoma virus-induced tumors as measured by macrophage migration inhibition assay
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Landolfo, Santo Giuseppe, Herberman, Rb, and Holden, H. T.
- Published
- 1977
23. RECEPTORS FOR INTERLEUKIN-2 ON HUMAN SQUAMOUS-CELL CARCINOMA CELL-LINES AND TUMOR INSITU
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Weidmann, E., Sacchi, M., Plaisance, S., Heo, Ds, Yasumura, S., Lin, Wc, Johnson, Jt, Herberman, Rb, Bruno Azzarone, and Whiteside, Tl
24. Nippon Jibiinkoka Gakkai Kaiho
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JR, JP McCoy, primary, Herberman, RB, additional, and Carey, TE, additional
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- 1989
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25. The FDA guidance on therapeutic cancer vaccines: the need for revision to include preventive cancer vaccines or for a new guidance dedicated to them.
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Finn OJ, Khleif SN, and Herberman RB
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- Disease Progression, Humans, Immune System, Medical Oncology standards, Neoplasm Metastasis, Practice Guidelines as Topic, United States, United States Food and Drug Administration, Cancer Vaccines standards, Cancer Vaccines therapeutic use, Neoplasms prevention & control
- Abstract
Cancer vaccines based on antigens derived from self molecules rather than pathogens have been under basic and clinical investigations for many years. Up until very recently, they had been tested primarily in the setting of metastatic disease with the goal to engage the immune system in slowing down disease progression. Many therapeutic vaccine trials, either investigator initiated or led by pharmaceutical companies, have been completed and many are currently ongoing, following the FDA Guidance on therapeutic cancer vaccines published in 2011. In recent years, the target of cancer vaccines is being shifted to early cancer and even premalignant disease with the goal of preventing cancer. Although some issues addressed in the FDA Guidance on therapeutic vaccines apply to preventive vaccines, many do not. Here, we discuss a set of recommendations for revising the current Guidance to also cover preventive vaccines, or to include in a new Guidance dedicated specifically to vaccines for cancer prevention., (©2015 American Association for Cancer Research.)
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- 2015
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26. Therapeutic in situ autovaccination against solid cancers with intratumoral poly-ICLC: case report, hypothesis, and clinical trial.
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Salazar AM, Erlich RB, Mark A, Bhardwaj N, and Herberman RB
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- Adolescent, Brain Neoplasms immunology, Carboxymethylcellulose Sodium therapeutic use, Drug Administration Routes, Facial Neoplasms immunology, Humans, Male, Polylysine therapeutic use, RNA, Double-Stranded, Rhabdomyosarcoma, Embryonal immunology, Vaccination methods, Brain Neoplasms therapy, Cancer Vaccines therapeutic use, Carboxymethylcellulose Sodium analogs & derivatives, Facial Neoplasms therapy, Immunologic Factors therapeutic use, Poly I-C therapeutic use, Polylysine analogs & derivatives, Rhabdomyosarcoma, Embryonal therapy
- Abstract
Pathogen-associated molecular patterns (PAMP) are stand-alone innate and adaptive immunomodulators and critical vaccine components. We present a strategy of sequential intratumoral (i.t.) and intramuscular (i.m.) injections of the stabilized dsRNA viral mimic and PAMP, polyinosinic-polycytidylic acid-polylysine-carboxymethylcellulose (poly-ICLC, Hiltonol; Oncovir). We report the first treated patient, a young man with an exceptionally advanced facial embryonal rhabdomyosarcoma with extension to the brain. After treatment, the patient showed tumor inflammation consistent with immunotherapy, followed by gradual, marked tumor regression, with extended survival. Sequential i.t. and i.m. poly-ICLC injections mimicking a viral infection can induce an effective, in situ, personalized systemic therapeutic "autovaccination" against tumor antigens of a patient. We postulate a three-step immunomodulatory process: (i) innate-immune local tumor killing induced by i.t. poly-ICLC; (ii) activation of dendritic cells with Th1 cell- and CTL-weighted priming against the released tumor antigens; and (iii) i.m. poly-ICLC maintenance of the systemic antitumor immune response via chemokine induction, facilitation of CTL killing through the induction of costimulators such as OX40, inflammasome activation, and increase in the T-effector/Treg ratio. These results support the use of certain simple and inexpensive i.t. PAMPs to favorably stimulate effective immunity against solid cancers. A phase II clinical trial testing the hypothesis presented has begun accrual (clinicaltrials.gov, NCT01984892)., (©2014 American Association for Cancer Research.)
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- 2014
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27. Immunotherapy of cancer via mediation of cytotoxic T lymphocytes by methionine enkephalin (MENK).
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Li W, Chen W, Herberman RB, Plotnikoff NP, Youkilis G, Griffin N, Wang E, Lu C, and Shan F
- Subjects
- Animals, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, Calcium metabolism, Cell Nucleus immunology, Cell Nucleus metabolism, Enkephalin, Methionine immunology, Lymphocyte Activation drug effects, Male, Mice, Mice, Inbred C57BL, Random Allocation, Receptors, Opioid, delta biosynthesis, Receptors, Opioid, delta immunology, Receptors, Opioid, mu biosynthesis, Receptors, Opioid, mu immunology, Sarcoma 180 drug therapy, Enkephalin, Methionine pharmacology, Immunotherapy, Adoptive methods, Sarcoma 180 immunology, Sarcoma 180 therapy, T-Lymphocytes, Cytotoxic drug effects, T-Lymphocytes, Cytotoxic immunology
- Abstract
The aim of this study was to investigate the immunological mechanisms by which synthetic methionine enkephalin (MENK) exerts therapeutic effects on tumor growth. Our findings in vivo or in vitro show that MENK treatment either in vivo or in vitro could up-regulate the percentages of CD8+T cells, induce markers of activated T cells, increased cytotoxic activity against mouse S180 tumor cells and increase secretion of IFNγ. In addition, the adoptively transferred CD8+T cells, after either in vitro or in vivo treatment with MENK, result in significantly increased survival of S180 tumor-bearing mice and significant shrinkage in tumor growth. Opioid receptors are detected on normal CD8+T cells and exposure to MENK leads to increased expression of opioid receptors. Interaction between MENK and the opioid receptors on CD8+T cells appears to be essential for the activation of CTL, since the addition of naltrexone (NTX), an opioid receptor antagonist, significantly inhibits all of the effects of MENK. The evidence obtained indicates that the MENK-induced T cell signaling is associated with a significant up-regulation of Ca2+ influx into the cytoplasm and the translocation of NFAT2 into nucleus, and these signaling effects are also inhibited by naltrexone., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2014
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28. Exposure limits: the underestimation of absorbed cell phone radiation, especially in children.
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Gandhi OP, Morgan LL, de Salles AA, Han YY, Herberman RB, and Davis DL
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- Animals, Certification, Child, Computer Simulation, Humans, Radiation Injuries epidemiology, Cell Phone standards, Environmental Exposure standards, Radiation Dosage
- Abstract
The existing cell phone certification process uses a plastic model of the head called the Specific Anthropomorphic Mannequin (SAM), representing the top 10% of U.S. military recruits in 1989 and greatly underestimating the Specific Absorption Rate (SAR) for typical mobile phone users, especially children. A superior computer simulation certification process has been approved by the Federal Communications Commission (FCC) but is not employed to certify cell phones. In the United States, the FCC determines maximum allowed exposures. Many countries, especially European Union members, use the "guidelines" of International Commission on Non-Ionizing Radiation Protection (ICNIRP), a non governmental agency. Radiofrequency (RF) exposure to a head smaller than SAM will absorb a relatively higher SAR. Also, SAM uses a fluid having the average electrical properties of the head that cannot indicate differential absorption of specific brain tissue, nor absorption in children or smaller adults. The SAR for a 10-year old is up to 153% higher than the SAR for the SAM model. When electrical properties are considered, a child's head's absorption can be over two times greater, and absorption of the skull's bone marrow can be ten times greater than adults. Therefore, a new certification process is needed that incorporates different modes of use, head sizes, and tissue properties. Anatomically based models should be employed in revising safety standards for these ubiquitous modern devices and standards should be set by accountable, independent groups.
- Published
- 2012
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29. Defining the critical hurdles in cancer immunotherapy.
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Fox BA, Schendel DJ, Butterfield LH, Aamdal S, Allison JP, Ascierto PA, Atkins MB, Bartunkova J, Bergmann L, Berinstein N, Bonorino CC, Borden E, Bramson JL, Britten CM, Cao X, Carson WE, Chang AE, Characiejus D, Choudhury AR, Coukos G, de Gruijl T, Dillman RO, Dolstra H, Dranoff G, Durrant LG, Finke JH, Galon J, Gollob JA, Gouttefangeas C, Grizzi F, Guida M, Håkansson L, Hege K, Herberman RB, Hodi FS, Hoos A, Huber C, Hwu P, Imai K, Jaffee EM, Janetzki S, June CH, Kalinski P, Kaufman HL, Kawakami K, Kawakami Y, Keilholtz U, Khleif SN, Kiessling R, Kotlan B, Kroemer G, Lapointe R, Levitsky HI, Lotze MT, Maccalli C, Maio M, Marschner JP, Mastrangelo MJ, Masucci G, Melero I, Melief C, Murphy WJ, Nelson B, Nicolini A, Nishimura MI, Odunsi K, Ohashi PS, O'Donnell-Tormey J, Old LJ, Ottensmeier C, Papamichail M, Parmiani G, Pawelec G, Proietti E, Qin S, Rees R, Ribas A, Ridolfi R, Ritter G, Rivoltini L, Romero PJ, Salem ML, Scheper RJ, Seliger B, Sharma P, Shiku H, Singh-Jasuja H, Song W, Straten PT, Tahara H, Tian Z, van Der Burg SH, von Hoegen P, Wang E, Welters MJ, Winter H, Withington T, Wolchok JD, Xiao W, Zitvogel L, Zwierzina H, Marincola FM, Gajewski TF, Wigginton JM, and Disis ML
- Subjects
- Humans, International Cooperation, Translational Research, Biomedical, Immunotherapy, Neoplasms therapy
- Abstract
Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer.
- Published
- 2011
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30. Regulatory approval of cancer risk-reducing (chemopreventive) drugs: moving what we have learned into the clinic.
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Meyskens FL Jr, Curt GA, Brenner DE, Gordon G, Herberman RB, Finn O, Kelloff GJ, Khleif SN, Sigman CC, and Szabo E
- Subjects
- Biomarkers, Tumor metabolism, Breast Neoplasms metabolism, Clinical Trials as Topic, Drug Industry methods, Early Detection of Cancer, Female, Humans, Male, Medical Oncology methods, Neoplasms prevention & control, Patient Compliance, Risk, Anticarcinogenic Agents pharmacology, Chemoprevention methods, Drug Approval
- Abstract
This article endeavors to clarify the current requirements and status of regulatory approval for chemoprevention (risk reduction) drugs and discusses possible improvements to the regulatory pathway for chemoprevention. Covering a wide range of topics in as much depth as space allows, this report is written in a style to facilitate the understanding of nonscientists and to serve as a framework for informing the directions of experts engaged more deeply with this issue. Key topics we cover here are as follows: a history of definitive cancer chemoprevention trials and their influence on the evolution of regulatory assessments; a brief review of the long-standing success of pharmacologic risk reduction of cardiovascular diseases and its relevance to approval for cancer risk reduction drugs; the use and limitations of biomarkers for developing and the approval of cancer risk reduction drugs; the identification of individuals at a high(er) risk for cancer and who are appropriate candidates for risk reduction drugs; business models that should incentivize pharmaceutical industry investment in cancer risk reduction; a summary of scientific and institutional barriers to development of cancer risk reduction drugs; and a summary of major recommendations that should help facilitate the pathway to regulatory approval for pharmacologic cancer risk reduction drugs.
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- 2011
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31. Sheddase activity of tumor necrosis factor-alpha converting enzyme is increased and prognostically valuable in head and neck cancer.
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Ge L, Baskic D, Basse P, Vujanovic L, Unlu S, Yoneyama T, Vujanovic A, Han J, Bankovic D, Szczepanski MJ, Hunt JL, Herberman RB, Gollin SM, Ferris RL, Whiteside TL, Myers EN, and Vujanovic NL
- Subjects
- ADAM Proteins antagonists & inhibitors, ADAM Proteins genetics, ADAM17 Protein, Adult, Aged, Aged, 80 and over, Amphiregulin, Blotting, Western, Cells, Cultured, EGF Family of Proteins, Enzyme-Linked Immunosorbent Assay, Female, Glycoproteins metabolism, Head and Neck Neoplasms pathology, Humans, Immunoenzyme Techniques, Intercellular Signaling Peptides and Proteins metabolism, Keratinocytes metabolism, Male, Middle Aged, Mouth Mucosa metabolism, Neoplasm Recurrence, Local pathology, Neoplasm Staging, Prognosis, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Small Interfering pharmacology, Receptors, Tumor Necrosis Factor metabolism, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Transforming Growth Factor alpha metabolism, ADAM Proteins metabolism, Head and Neck Neoplasms enzymology, Neoplasm Recurrence, Local enzymology, Tumor Necrosis Factor-alpha metabolism
- Abstract
Tumor necrosis factor alpha converting enzyme (TACE) is a sheddase overexpressed in cancers that generates cancer cell growth and survival factors, and is implicated in carcinogenesis and tumor growth. This indicates that TACE could be a potentially important cancer biomarker. Unexpectedly, TACE expression in cancer tissues does not correlate with cancer stage or invasiveness. Although TACE sheddase activity is a more direct and potentially better indicator of TACE biology and might be a better cancer biomarker than TACE expression, it has not been studied in cancer tissues. In the present study, we developed a reliable specific assay for quantification of TACE sheddase activity, investigated TACE activity and TACE protein expression in head and neck cancer (HNC) tissues, and examined the correlation of the results with HNC clinical stages and likelihood to recur. We found that HNC cell lines and tissues contained remarkably higher quantities of TACE activity and TACE protein than normal keratinocytes or oral mucosa. siRNA silencing of TACE resulted in the inhibition of release of the tumorogenic factors amphiregulin and transforming growth factor alpha, and tumor protective factors tumor necrosis factor receptors from HNC cells. Importantly, TACE activity, but not TACE protein expression, was significantly higher in large, T3/T4, primary tumors relative to small, T1/T2, primary tumors, and especially in primary tumors likely to recur relative to those unlikely to recur. These data show that increased TACE activity in cancer is biologically and clinically relevant, and indicate that TACE activity could be a significant biomarker of cancer prognosis.
- Published
- 2009
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32. Biological significance of prolactin in gynecologic cancers.
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Levina VV, Nolen B, Su Y, Godwin AK, Fishman D, Liu J, Mor G, Maxwell LG, Herberman RB, Szczepanski MJ, Szajnik ME, Gorelik E, and Lokshin AE
- Subjects
- Animals, Base Sequence, Cell Line, Tumor, Cell Proliferation, DNA Primers, Female, Flow Cytometry, Genital Neoplasms, Female metabolism, Genital Neoplasms, Female pathology, Humans, Immunohistochemistry, Mice, Mice, Nude, Prolactin blood, Prolactin genetics, RNA, Messenger genetics, Signal Transduction, Genital Neoplasms, Female physiopathology, Prolactin physiology
- Abstract
There is increasing evidence that prolactin (PRL), a hormone/cytokine, plays a role in breast, prostate, and colorectal cancers via local production or accumulation. Elevated levels of serum PRL in ovarian and endometrial cancers have been reported, indicating a potential role for PRL in endometrial and ovarian carcinogenesis. In this study, we show that serum PRL levels are significantly elevated in women with a strong family history of ovarian cancer. We show dramatically increased expression of PRL receptor in ovarian and endometrial tumors as well as in endometrial hyperplasia, signifying the importance of PRL signaling in malignant and premalignant conditions. PRL mRNA was expressed in ovarian and endometrial tumors, indicating the presence of an autocrine loop. PRL potently induced proliferation in several ovarian and endometrial cancer cell lines. Binding of PRL to its receptor was followed by rapid phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, mitogen-activated protein kinase/ERK kinase 1, signal transducer and activator of transcription 3, CREB, ATF-2, and p53 and activation of 37 transcription factors in ovarian and endometrial carcinoma cells. PRL also activated Ras oncogene in these cells. When human immortalized normal ovarian epithelial cells were chronically exposed to PRL, a malignant transformation occurred manifested by the acquired ability of transformed cells to form clones, grow in soft agar, and form tumors in severe combined immunodeficient-beige mice. Transformation efficiency was diminished by a Ras inhibitor, providing proof that PRL-induced transformation uses the Ras pathway. In summary, we present findings that indicate an important role for PRL in ovarian and endometrial tumorigenesis. PRL may represent a risk factor for ovarian and endometrial cancers.
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- 2009
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33. Interleukin-2 administration alters the CD4+FOXP3+ T-cell pool and tumor trafficking in patients with ovarian carcinoma.
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Wei S, Kryczek I, Edwards RP, Zou L, Szeliga W, Banerjee M, Cost M, Cheng P, Chang A, Redman B, Herberman RB, and Zou W
- Subjects
- Antigen-Presenting Cells, Cell Movement drug effects, Cell Proliferation drug effects, Cell Separation, Female, Humans, Immunotherapy, Lymphocyte Activation drug effects, Middle Aged, Ovarian Neoplasms drug therapy, Ovarian Neoplasms pathology, T-Lymphocytes, Regulatory immunology, CD4-Positive T-Lymphocytes immunology, Forkhead Transcription Factors metabolism, Interleukin-2 administration & dosage, Ovarian Neoplasms immunology, T-Lymphocytes immunology
- Abstract
Interleukin (IL)-2 is used in the immunotherapy of patients with certain cancer and HIV infection. IL-2 treatment reliably results in 16% to 20% objective clinical response rate in cancer patients, with significant durability of responses in selected patients. However, the mechanisms of therapeutic activity in responding versus nonresponding patients remain poorly understood. CD4(+)CD25(+)FOXP3(+) regulatory T (Treg) cells contribute to immunosuppressive networks in human tumors. We treated 31 ovarian cancer patients with IL-2. We show that administration of IL-2 induces the proliferation of existent Treg cells in patients with ovarian cancer. The potency of Treg cell proliferation is negatively determined by the initial prevalence of Treg cells, suggesting that Treg cells are a factor for self-controlling Treg cell proliferation. After IL-2 cessation, the number of Treg cells more efficiently dropped in clinical responders than nonresponders. Furthermore, IL-2 treatment stimulates chemokine receptor CXCR4 expression on Treg cells, enables Treg cell migration toward chemokine CXCL12 in the tumor microenvironment, and may enforce Treg cell tumor accumulation. Our findings support the concept that administration of IL-2 numerically and functionally affects the Treg cell compartment. These data provide an important insight in evaluating the clinical benefit and therapeutic prediction of IL-2 treatment in patients with cancer.
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- 2007
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34. A novel cross-disciplinary multi-institute approach to translational cancer research: lessons learned from Pennsylvania Cancer Alliance Bioinformatics Consortium (PCABC).
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Patel AA, Gilbertson JR, Showe LC, London JW, Ross E, Ochs MF, Carver J, Lazarus A, Parwani AV, Dhir R, Beck JR, Liebman M, Garcia FU, Prichard J, Wilkerson M, Herberman RB, and Becich MJ
- Abstract
Background: The Pennsylvania Cancer Alliance Bioinformatics Consortium (PCABC, http://www.pcabc.upmc.edu) is one of the first major project-based initiatives stemming from the Pennsylvania Cancer Alliance that was funded for four years by the Department of Health of the Commonwealth of Pennsylvania. The objective of this was to initiate a prototype biorepository and bioinformatics infrastructure with a robust data warehouse by developing a statewide data model (1) for bioinformatics and a repository of serum and tissue samples; (2) a data model for biomarker data storage; and (3) a public access website for disseminating research results and bioinformatics tools. The members of the Consortium cooperate closely, exploring the opportunity for sharing clinical, genomic and other bioinformatics data on patient samples in oncology, for the purpose of developing collaborative research programs across cancer research institutions in Pennsylvania. The Consortium's intention was to establish a virtual repository of many clinical specimens residing in various centers across the state, in order to make them available for research. One of our primary goals was to facilitate the identification of cancer-specific biomarkers and encourage collaborative research efforts among the participating centers., Methods: The PCABC has developed unique partnerships so that every region of the state can effectively contribute and participate. It includes over 80 individuals from 14 organizations, and plans to expand to partners outside the State. This has created a network of researchers, clinicians, bioinformaticians, cancer registrars, program directors, and executives from academic and community health systems, as well as external corporate partners - all working together to accomplish a common mission. The various sub-committees have developed a common IRB protocol template, common data elements for standardizing data collections for three organ sites, intellectual property/tech transfer agreements, and material transfer agreements that have been approved by each of the member institutions. This was the foundational work that has led to the development of a centralized data warehouse that has met each of the institutions' IRB/HIPAA standards., Results: Currently, this "virtual biorepository" has over 58,000 annotated samples from 11,467 cancer patients available for research purposes. The clinical annotation of tissue samples is either done manually over the internet or semi-automated batch modes through mapping of local data elements with PCABC common data elements. The database currently holds information on 7188 cases (associated with 9278 specimens and 46,666 annotated blocks and blood samples) of prostate cancer, 2736 cases (associated with 3796 specimens and 9336 annotated blocks and blood samples) of breast cancer and 1543 cases (including 1334 specimens and 2671 annotated blocks and blood samples) of melanoma. These numbers continue to grow, and plans to integrate new tumor sites are in progress. Furthermore, the group has also developed a central web-based tool that allows investigators to share their translational (genomics/proteomics) experiment data on research evaluating potential biomarkers via a central location on the Consortium's web site., Conclusions: The technological achievements and the statewide informatics infrastructure that have been established by the Consortium will enable robust and efficient studies of biomarkers and their relevance to the clinical course of cancer. Studies resulting from the creation of the Consortium may allow for better classification of cancer types, more accurate assessment of disease prognosis, a better ability to identify the most appropriate individuals for clinical trial participation, and better surrogate markers of disease progression and/or response to therapy.
- Published
- 2007
35. Cancer chemoprevention and cancer preventive vaccines--a call to action: leaders of diverse stakeholder groups present strategies for overcoming multiple barriers to meet an urgent need.
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Herberman RB, Pearce HL, Lippman SM, Pyenson BS, and Alberts DS
- Subjects
- Anticarcinogenic Agents, Chemoprevention, Clinical Trials as Topic, Humans, Research Design, Cancer Vaccines therapeutic use, Neoplasms immunology, Neoplasms prevention & control
- Abstract
The emerging field of cancer prevention through chemoprevention agents and cancer vaccines offers significant promise for reducing suffering and death from cancer. However, that promise may not be kept unless major barriers to progress are lowered or eliminated. Among the most significant barriers are the relatively small investment from government and industry in research and development of cancer preventive agents; a predominant emphasis of translational cancer research on therapeutic interventions for metastatic or advanced cancer; complexities of prevention trial design; a relatively uncharted Food and Drug Administration (FDA) approval process for preventive agents; insufficient public and patient understanding of the importance and potential for cancer preventive measures, with consequent unpredictable public and patient willingness to take preventive agents; an uncertain reimbursement from payors; and limitations in patent law, liability protection, and data package exclusivity that undermine the opportunity for recouping investment. Viewed individually or collectively, each of these barriers serves as a substantial deterrent to intellectual and financial investment by all sectors of the cancer community. In an effort to ultimately overcome these barriers, a Cancer Prevention Research Summit was assembled June 12-13, 2006 in Bethesda, Maryland, organized by C-Change with support from the AACR. The Summit brought together some 120 leaders from private, public, and not-for-profit entities, including cancer researchers and clinicians; federal health officials; regulatory agency representatives; pharmaceutical, biotech, and food industry leaders; patent attorneys; economists; public and private provider group executives; and advocates. Participants engaged in a detailed process to more carefully define the major barriers, identify potential solutions, and formulate initial priorities and recommendations for action. At the conclusion of this dialogue among experts, the following recommended actions were outlined: define policy solutions to patent, intellectual property, and liability law barriers; create an advisory document about the approval process for cancer chemopreventive agents and vaccines for the FDA; develop new design models for cancer chemopreventive clinical trials; outline the business case for chemopreventive agents and vaccines for federal research agencies, payors and investors; and implement a communications strategy to increase public awareness about the importance of chemoprevention and cancer preventive vaccines.
- Published
- 2006
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36. NK cells in cancer immunotherapy: three decades of discovery.
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Boyiadzis M, Foon KA, and Herberman RB
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- Animals, Humans, Killer Cells, Natural metabolism, Models, Biological, Immunotherapy, Adoptive methods, Killer Cells, Natural immunology, Killer Cells, Natural physiology, Neoplasms therapy
- Abstract
Natural killer cells were first described in the early 1970s on a functional basis according to their ability to lyse tumor cells in the absence of prior stimulation. Since their discovery, NK cells have been shown to have other important functions that led to the use of NK cells as a form of adoptive immunotherapy. Over the next 5-10 years, with the advances in the field of NK cells we will undoubtedly see the use of allogeneic and autologous NK cells at the forefront of cancer immunotherapy.
- Published
- 2006
37. Spontaneous CD4+ T cell responses against TRAG-3 in patients with melanoma and breast cancers.
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Janjic B, Andrade P, Wang XF, Fourcade J, Almunia C, Kudela P, Brufsky A, Jacobs S, Friedland D, Stoller R, Gillet D, Herberman RB, Kirkwood JM, Maillere B, and Zarour HM
- Subjects
- Animals, Antigen Presentation, Breast Neoplasms metabolism, CD4-Positive T-Lymphocytes metabolism, Cell Line, Clone Cells, Drug Resistance, Neoplasm immunology, Epitopes, T-Lymphocyte immunology, Female, Humans, Immunodominant Epitopes immunology, Interferon-gamma biosynthesis, Lung Neoplasms immunology, Lung Neoplasms metabolism, Melanoma metabolism, Melanoma, Experimental immunology, Melanoma, Experimental metabolism, Mice, Neoplasm Proteins immunology, Neoplasm Proteins metabolism, Peptide Fragments immunology, Peptide Fragments metabolism, Breast Neoplasms immunology, CD4-Positive T-Lymphocytes immunology, Melanoma immunology, Neoplasm Proteins biosynthesis
- Abstract
The taxol resistance gene TRAG-3 was initially isolated from cancer cell lines that became resistant to taxol in vitro. TRAG-3 is a cancer germline Ag expressed by tumors of different histological types including the majority of melanoma, breast, and lung cancers. In the present study, we report that patients with stage IV melanoma and breast cancers developed spontaneous IFN-gamma-producing CD4+ T cell responses against a single immunodominant and promiscuous peptide epitope from TRAG-3 presented in the context of multiple HLA-DR molecules. The TRAG-3-specific CD4+ T cells and clones were expanded in vitro and recognized not only peptide pulsed APCs but also autologous dendritic cells (DCs) loaded with the TRAG-3 protein. All stage IV melanoma patients with TRAG-3-expressing tumors developed spontaneous CD4+ T cell responses against TRAG-3, demonstrating its strong immunogenicity. None of these patients had detectable IgG Ab responses against TRAG-3. TCRbeta gene usage studies of TRAG-3-specific CD4+ T cell clones from a melanoma patient and a normal donor suggested a restricted TCR repertoire in patients with TRAG-3-expressing tumors. Altogether, our data define a novel profile of spontaneous immune responses to cancer germline Ag-expressing tumors, showing that spontaneous TRAG-3-specific CD4+ T cells are directed against a single immunodominant epitope and exist independently of Ab responses. Because of its immunodominance, peptide TRAG-3(34-48) is of particular interest for the monitoring of spontaneous immune responses in patients with TRAG-3-expressing tumors and for the development of cancer vaccines.
- Published
- 2006
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38. IL-18-induced CD83+CCR7+ NK helper cells.
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Mailliard RB, Alber SM, Shen H, Watkins SC, Kirkwood JM, Herberman RB, and Kalinski P
- Subjects
- Cell Line, Chemotaxis immunology, Cytokines immunology, Dendritic Cells immunology, Dendritic Cells metabolism, Flow Cytometry, Humans, Interferon-gamma metabolism, Interleukins metabolism, Killer Cells, Natural immunology, Lymph Nodes immunology, Lymph Nodes metabolism, Receptors, CCR7, T-Lymphocytes, Helper-Inducer immunology, CD83 Antigen, Antigens, CD immunology, Cell Differentiation immunology, Cell Movement immunology, Immunoglobulins immunology, Killer Cells, Natural cytology, Membrane Glycoproteins immunology, Receptors, Chemokine immunology, T-Lymphocytes, Helper-Inducer cytology
- Abstract
In addition to their cytotoxic activities, natural killer (NK) cells can have immunoregulatory functions. We describe a distinct "helper" differentiation pathway of human CD56+CD3- NK cells into CD56+/CD83+/CCR7+/CD25+ cells that display high migratory responsiveness to lymph node (LN)-associated chemokines, high ability to produce interferon-gamma upon exposure to dendritic cell (DC)- or T helper (Th) cell-related signals, and pronounced abilities to promote interleukin (IL)-12p70 production in DCs and the development of Th1 responses. This helper pathway of NK cell differentiation, which is not associated with any enhancement of cytolytic activity, is induced by IL-18, but not other NK cell-activating factors. It is blocked by prostaglandin (PG)E2, a factor that induces a similar CD83+/CCR7+/CD25+ LN-homing phenotype in maturing DCs. The current data demonstrate independent regulation of the "helper" versus "effector" pathways of NK cell differentiation and novel mechanisms of immunoregulation by IL-18 and PGE2.
- Published
- 2005
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39. Natural killer-dendritic cell cross-talk in cancer immunotherapy.
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Kalinski P, Mailliard RB, Giermasz A, Zeh HJ, Basse P, Bartlett DL, Kirkwood JM, Lotze MT, and Herberman RB
- Subjects
- Animals, Dendritic Cells cytology, Dendritic Cells metabolism, Humans, Killer Cells, Natural cytology, Killer Cells, Natural metabolism, Receptor Cross-Talk physiology, Receptors, Immunologic physiology, Cell Communication immunology, Dendritic Cells immunology, Immunotherapy, Adoptive methods, Killer Cells, Natural immunology, Neoplasms immunology, Neoplasms therapy
- Abstract
Natural killer (NK) cells and dendritic cells (DCs), two important components of the immune system, can exchange bidirectional activating signals in a positive feedback. Myeloid DCs, the cell type specialised in the presentation of antigen and initiation of antigen-specific immune responses, have recently been documented to be involved in supporting innate immunity, promoting the production of cytokines and cytotoxicity of NK cells, and enhancing their tumouricidal activity. Natural interferon-producing cells/plasmacytoid DCs (IPCs/PDCs) play an additional role in NK cell activation. Reciprocally, NK cells, traditionally considered to be major innate effector cells, have also recently been shown to play immunoregulatory 'helper' functions, being able to activate DCs and to enhance their ability to produce pro-inflammatory cytokines, and to stimulate T helper (Th) 1 and cytotoxic T lymphocyte (CTL) responses of tumour-specific CD4+ and CD8+ T cells. Activated NK cells induce the maturation of myeloid DCs into stable type-1 polarised DCs (DC1), characterised by up to a 100-fold enhanced ability to produce IL-12p70 in response to subsequent interaction with Th cells. In addition, the ability of NK cells to kill tumour cells may facilitate the generation of tumour-related antigenic material, further accelerating the induction of tumour-specific immunity. DC1, induced by NK cells or by NK cell-related soluble factors, are stable, resistant to tumour-related suppressive factors, and demonstrate a strongly enhanced ability to induce Th1 and CTL responses in human in vitro and mouse in vivo models. Compared with the standard mature DCs that are used in clinical trials at present, human NK cell-induced DC1s act as superior inducers of anticancer CTL responses during in vitro sensitisation. This provides a strong rationale for the combined use of NK cells and DCs in the immunotherapy of patients with cancer and patients with chronic infections that are resistant to standard forms of treatment. Stage I/II clinical trials that are being implemented at present should allow evaluation of the immunological and clinical efficacy of combined NK-DC therapy of melanoma and other cancers.
- Published
- 2005
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40. Multiplexed immunobead-based cytokine profiling for early detection of ovarian cancer.
- Author
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Gorelik E, Landsittel DP, Marrangoni AM, Modugno F, Velikokhatnaya L, Winans MT, Bigbee WL, Herberman RB, and Lokshin AE
- Subjects
- Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Humans, Middle Aged, Ovarian Neoplasms blood, Ovarian Neoplasms pathology, Predictive Value of Tests, ROC Curve, Biomarkers, Tumor blood, CA-125 Antigen blood, Cytokines blood, Ovarian Neoplasms diagnosis
- Abstract
Early detection of ovarian cancer might improve clinical outcome. Some studies have shown the role of cytokines as a new group of tumor markers for ovarian cancer. We hypothesized that a panel comprised of multiple cytokines, which individually may not show strong correlation with the disease, might provide higher diagnostic power. To evaluate the diagnostic utility of cytokine panel, we used a novel multianalyte LabMAP profiling technology that allows simultaneous measurement of multiple markers. Concentrations of 24 cytokines (cytokines/chemokines, growth, and angiogenic factors) in combination with cancer antigen-125 (CA-125), were measured in sera of 44 patients with early-stage ovarian cancer, 45 healthy women, and 37 patients with benign pelvic tumors. Six markers, i.e., interleukin (IL)-6, IL-8, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), and CA-125, showed significant differences in serum concentrations between ovarian cancer and control groups. Out of this group, IL-6, IL-8, VEGF, EGF, and CA-125, were used in a classification tree analysis that resulted in 84% sensitivity at 95% specificity. The receiver operator characteristic curve created using the combination of markers produced sensitivities between 90% and 100% in the area of 80% to 90% specificity, whereas the receiver operator characteristic curve for CA-125 alone resulted in sensitivities of 70% to 80%. The classification tree analysis for discrimination of benign condition from ovarian cancer used CA-125, granulocyte colony-stimulating factor (G-CSF), IL-6, EGF, and VEGF resulting in 86.5% sensitivity and 93.0% specificity. The presented data show that simultaneous testing of a panel of serum cytokines and CA-125 using LabMAP technology may present a promising approach for ovarian cancer detection.
- Published
- 2005
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41. A novel epitope of N-CAM defines precursors of human adherent NK cells.
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Li S, Xu J, Makarenkova VP, Tjandrawan T, Vakkila J, Reichert T, Gooding W, Lagenaur CF, Achim CL, Chambers WH, Herberman RB, Whiteside TL, and Vujanovic NL
- Subjects
- Antibodies, Monoclonal immunology, Antigens, Surface immunology, Antigens, Surface metabolism, CD56 Antigen metabolism, Cell Adhesion drug effects, Cell Adhesion immunology, Cell Count, Cell Differentiation drug effects, Cell Differentiation immunology, Cell Lineage drug effects, Cell Lineage immunology, Cell Membrane immunology, Cell Membrane metabolism, Cell Proliferation drug effects, Cells, Cultured, Chemotaxis, Leukocyte drug effects, Chemotaxis, Leukocyte immunology, Cytotoxicity, Immunologic immunology, Humans, Immunophenotyping, Integrins immunology, Integrins metabolism, Interleukin-2 immunology, Interleukin-2 pharmacology, Killer Cells, Natural drug effects, Killer Cells, Natural immunology, Lectins, C-Type immunology, Lectins, C-Type metabolism, Lymphoid Tissue immunology, Lymphoid Tissue metabolism, Membrane Glycoproteins immunology, Membrane Glycoproteins metabolism, NK Cell Lectin-Like Receptor Subfamily B, Receptors, IgG immunology, Receptors, IgG metabolism, Stem Cells drug effects, Stem Cells immunology, CD56 Antigen immunology, Epitopes immunology, Killer Cells, Natural metabolism, Stem Cells metabolism
- Abstract
Activated, adherent natural killer (A-NK) cells represent a distinct subpopulation of interleukin (IL)-2-stimulated NK cells, which are selectively endowed with the increased expression of integrins and ability to adhere to solid surfaces, migrate into, infiltrate, and destroy cancerous tissues. The present study defines the phenotype and functions of precursors of A-NK (pre-A-NK) cells in humans. Peripheral blood pre-A-NK cells, in contrast to the rest of NK cells, express a novel epitope of CD56 neuronal cell adhesion molecule, termed ANK-1, and increased cell-surface levels of integrins. Pre-A-NK cells also express low levels of CD56 and CD161, and some express CD162 receptor, do not express CD25 or activation markers, and are effective mediators of NK cytotoxicity. Thus, pre-A-NK cells are generally similar to CD56(dim) NK cells. However, pre-A-NK cells differ from the main NK cell subpopulation by having a lower expression level of CD16 and a lower ability to mediate redirected antibody-dependent, cell-mediated cytotoxicity. More importantly, pre-A-NK cells are preferentially endowed with the ability to rapidly respond to IL-2 by integrin-mediated adherence to endothelial cells, extracellular matrix, and plastic. This early, specific response of pre-A-NK cells to IL-2 is followed by their activation, vigorous proliferation, and differentiation into phenotypically and functionally similar A-NK cells. Pre-A-NK cells represent only approximately 26% of peripheral blood NK cells but encompass the majority of NK cells in normal and cancerous, solid tissues. We conclude that pre-A-NK cells represent a distinct subset of resting, mature NK cells with the characteristics indicative of their ability to migrate and reside in solid tissues.
- Published
- 2004
- Full Text
- View/download PDF
42. Translation of scientific insights to benefit patients with cancer.
- Author
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Herberman RB
- Subjects
- Forecasting, History, 20th Century, History, 21st Century, Humans, Killer Cells, Natural metabolism, Neoplasms immunology, Neoplasms metabolism, Quality of Life, Antineoplastic Agents therapeutic use, Killer Cells, Natural immunology, Neoplasms therapy, Research trends
- Published
- 2004
- Full Text
- View/download PDF
43. Immunologic aspects of chronic fatigue syndrome. Report on a Research Symposium convened by The CFIDS Association of America and co-sponsored by the US Centers for Disease Control and Prevention and the National Institutes of Health.
- Author
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Gerrity TR, Papanicolaou DA, Amsterdam JD, Bingham S, Grossman A, Hedrick T, Herberman RB, Krueger G, Levine S, Mohagheghpour N, Moore RC, Oleske J, and Snell CR
- Subjects
- Autonomic Nervous System immunology, Autonomic Nervous System physiopathology, Fatigue Syndrome, Chronic virology, Humans, Hypothalamo-Hypophyseal System immunology, Hypothalamo-Hypophyseal System physiopathology, Immune System Diseases physiopathology, Immune System Diseases virology, Interdisciplinary Communication, Neurosecretory Systems physiopathology, Societies, Medical organization & administration, Societies, Medical trends, Fatigue Syndrome, Chronic immunology, Immune System Diseases immunology, Neuroimmunomodulation immunology, Neurosecretory Systems immunology
- Abstract
Chronic fatigue syndrome (CFS) is a serious health concern affecting over 800,000 Americans of all ages, races, socioeconomic groups and genders. The etiology and pathophysiology of CFS are unknown, yet studies have suggested an involvement of the immune system. A symposium was organized in October 2001 to explore the possibility of an association between immune dysfunction and CFS, with special emphasis on the interactions between immune dysfunction and other abnormalities noted in the neuroendocrine and autonomic nervous systems of individuals with CFS. This paper represents the consensus of the panel of experts who participated in this meeting. Data suggest that persons with CFS manifest changes in immune responses that fall outside normative ranges, but current research does not provide definitive evidence on whether these immune abnormalities are a cause or result of the illness. It has become clear that CFS cannot be understood based on single measurements of immune, endocrine, cardiovascular, or autonomic nervous system dysfunction. This panel encourages a new emphasis on multidisciplinary research into CFS.
- Published
- 2004
- Full Text
- View/download PDF
44. Tumor-localization by adoptively transferred, interleukin-2-activated NK cells leads to destruction of well-established lung metastases.
- Author
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Yang Q, Hokland ME, Bryant JL, Zhang Y, Nannmark U, Watkins SC, Goldfarb RH, Herberman RB, and Basse PH
- Subjects
- Animals, Carcinoma, Lewis Lung pathology, Carcinoma, Lewis Lung secondary, Carcinoma, Lewis Lung therapy, Female, Injections, Intravenous, Interleukin-2 pharmacology, Lung Neoplasms pathology, Melanoma, Experimental pathology, Mice, Mice, Inbred C57BL, Neoplasm Metastasis, Tumor Cells, Cultured, Adoptive Transfer methods, Interleukin-2 therapeutic use, Killer Cells, Natural immunology, Lung Neoplasms secondary, Lung Neoplasms therapy, Lymphocytes, Tumor-Infiltrating immunology
- Abstract
We have shown previously that i.v. injection of interleukin-2-(IL-2) activated natural killer (A-NK) cells together with IL-2 leads to a substantial localization of the A-NK cells into most, but not all, well-established B16 lung metastases in C57BL/6 mice within 12-24 hr. We demonstrate that the morphology of the lung metastases, (loose or more compact in appearance), and their location in the lungs (on the surface or deep in the lung parenchyma) are closely tied to the infiltration-permissiveness of the metastases as well as their sensitivity to treatment with A-NK cells. Although more than 1100 A-NK cells/mm(2) were found in deep metastases with a "loose" morphology (D-L), only 534, 90 and 89 cells/mm(2) were found in surface-loose (S-L), surface-compact (S-C) and deep-compact (D-C) metastases, respectively. The best infiltrated metastases responded best to the A-NK cell therapy. Thus, metastases of the D-L phenotype became reduced by 65-90% after treatment with 2 x 10(6) A-NK cells and IL-2 (120000 IU Peg-IL-2 every 12 hr for 3 days) compared to similar lesions in animals treated with PEG-IL-2 alone. In contrast, poorly infiltrated metastases, that is lesions of the compact phenotype (D-C and S-C) as well as loose metastases on the lung surface (S-L), did not react significantly to this treatment. We conclude that adoptively transferred A-NK cells are able to eliminate even well-established metastases. The existence of metastases that are resistant to infiltration by the transferred effector cells at time of treatment might reduce the efficacy of cell-based immuno-therapeutic ventures., (Copyright 2003 Wiley-Liss, Inc.)
- Published
- 2003
- Full Text
- View/download PDF
45. Local administration of IL-12-transfected dendritic cells induces antitumor immune responses to colon adenocarcinoma in the liver in mice.
- Author
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Satoh Y, Esche C, Gambotto A, Shurin GV, Yurkovetsky ZR, Robbins PD, Watkins SC, Todo S, Herberman RB, Lotze MT, and Shurin MR
- Subjects
- Adenocarcinoma immunology, Adenocarcinoma secondary, Adenoviridae genetics, Animals, Antigens, CD immunology, Antigens, CD metabolism, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Cell Division physiology, Colonic Neoplasms immunology, Colonic Neoplasms pathology, Colonic Neoplasms therapy, Dendritic Cells transplantation, Humans, Immunity, Cellular, Interleukin-12 metabolism, Liver Neoplasms, Experimental immunology, Liver Neoplasms, Experimental secondary, Liver Neoplasms, Experimental therapy, Lymph Nodes immunology, Lymph Nodes metabolism, Lymphocyte Activation immunology, Lymphocytes, Tumor-Infiltrating immunology, Male, Mice, Mice, Inbred C57BL, Spleen cytology, Spleen immunology, T-Lymphocytes, Cytotoxic immunology, Transduction, Genetic, Tumor Cells, Cultured immunology, Tumor Cells, Cultured metabolism, Tumor Cells, Cultured transplantation, Adenocarcinoma therapy, Dendritic Cells immunology, Immunotherapy, Adoptive, Interleukin-12 genetics, Transfection
- Abstract
Colorectal cancer is one of the most common fatal malignancies in the United States, with an incidence second only to lung cancer. The liver is the most common site of colorectal metastases and frequently the only affected organ once the primary tumor has been surgically removed. The only potentially curative treatment for metastatic colorectal cancer in the liver is surgery, although most patients are not eligible for resection. We have therefore, evaluated the therapeutic efficacy of dendritic cells (DCs) engineered to express IL-12 in a liver metastasis model. Direct administration of DCs into the portal vein significantly inhibited the growth of established MC38 colon carcinoma in the liver in C57BL/6 mice. This effect was accompanied by an intratumoral accumulation of CD4+, CD8+, and NLDC-145+ immune effector cells, and also resulted in a systemic immune response as determined by enhanced production of IFN-gamma by T lymphocytes isolated from both spleen and draining lymph nodes. Evaluation of homing of Cy3-labeled DCs following the portal vein injection confirmed their distribution in the liver and lymphoid tissue. Thus, a local delivery of DCs transduced with the IL-12 gene can not only inhibit colorectal tumor growth in vivo but also mount systemic antitumor immune responses. This approach is likely to improve the outcome of immunotherapy for metastatic colorectal cancer since high numbers of tumor-associated DCs positively correlate with a more favorable prognosis. Simultaneous local gene therapy with IL-12 will further improve clinical efficacy without placing the patient at risk for systemic toxicity.
- Published
- 2002
- Full Text
- View/download PDF
46. Cancer immunotherapy with interleukin-2-activated natural killer cells.
- Author
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Basse PH, Whiteside TL, and Herberman RB
- Subjects
- Adoptive Transfer, Animals, Cells, Cultured, Female, Humans, Leukocytes, Mononuclear metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Neoplasm Metastasis, Neoplasm Transplantation, Tumor Cells, Cultured, Immunotherapy methods, Interleukin-2 metabolism, Killer Cells, Natural metabolism, Neoplasms therapy
- Abstract
Natural killer (NK) cells are a subset of lymphocytes with a distinct morphologic appearance (large granular lymphocytes [LGL]) and the ability to kill virally infected and tumor targets but to spare most normal cells. NK cells respond to a variety of biologic agents, such as interleukin-2 (IL-2), or interferons, by upregulation of cytolytic, secretory, and proliferative functions. In cancer-bearing hosts, NK cells have been considered to be the major component of antitumor immunity responsible for rapid elimination of malignant cells from the blood. More recently, however, studies have demonstrated the ability of adoptively transferred, IL-2-activated NK cells to selectively localize into solid tumors tissue and to eliminate established tumors. While these findings indicate a role for NK cells in cancer immunotherapy, additional studies are needed in both animal models and in humans to optimize clinical protocols of cancer therapy based on these cells.
- Published
- 2002
- Full Text
- View/download PDF
47. Cancer immunotherapy with natural killer cells.
- Author
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Herberman RB
- Subjects
- Adjuvants, Immunologic pharmacology, Animals, Histamine pharmacology, Humans, Killer Cells, Natural drug effects, Major Histocompatibility Complex, Neoplasms therapy, Reactive Oxygen Species, Antineoplastic Agents pharmacology, Cytotoxicity, Immunologic, Immunologic Factors pharmacology, Immunotherapy, Active, Immunotherapy, Adoptive, Interferons pharmacology, Interleukin-2 pharmacology, Killer Cells, Natural physiology, Neoplasms immunology, T-Lymphocyte Subsets physiology
- Abstract
Natural killer (NK) cells were first identified for their ability to kill tumor cells of different origins. They were subsequently found to be able to kill some normal cells, especially those infected by certain viruses. Natural killer cells are a distinct lymphocytic population, with the morphology of large granular lymphocytes, and they lack surface Ig or T-cell markers. Natural killer cytotoxicity is enhanced in vitro in the presence of cytokines such as interleukin-2 and interferon-alpha. However, when used in immunotherapy, these cytokines have not consistently augmented NK activity or shown antitumor effects. One explanation for this divergence is that NK cell activity is suppressed in tumor tissues by various factors, including reactive oxygen species produced by infiltrating monocytes and macrophages. Agents that inhibit the generation of reactive oxygen species, such as histamine, may abrogate the suppression exerted on NK cells by monocytes/macrophages, therefore offering potential therapeutic benefit as immunoadjuvants., (Copyright 2002, Elsevier Science (USA). All rights reserved.)
- Published
- 2002
- Full Text
- View/download PDF
48. Allelic polymorphisms in the FcgammaRIIC gene can influence its function on normal human natural killer cells.
- Author
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Ernst LK, Metes D, Herberman RB, and Morel PA
- Subjects
- Adult, Alleles, Amino Acid Sequence, Antigens, CD immunology, Base Sequence, Cell Culture Techniques, Female, Gene Expression Regulation, Humans, Killer Cells, Natural physiology, Male, Middle Aged, Molecular Sequence Data, Protein Isoforms biosynthesis, Protein Isoforms chemistry, Protein Isoforms metabolism, Receptors, IgG biosynthesis, Receptors, IgG immunology, Antigens, CD genetics, Killer Cells, Natural immunology, Polymorphism, Genetic, Receptors, IgG genetics
- Abstract
Natural killer (NK) cells are important in host defense against viruses and tumors and can induce death of virally infected cells following engagement of cell surface receptors. Human NK cells express receptors for the Fc portion of IgG which stimulate antibody-dependent cell-mediated cytotoxicity and induce cytokine production. We have shown that NK cells from certain individuals can express, in addition to CD16 (FcgammaRIIIa), isoforms of CD32 (FcgammaRIIc1-4). Expression of CD32 on NK cells is dependent on an allelic polymorphism of the FcgammaRIIC gene. We analyzed the expression and function of CD32 on NK cells from 31 normal donors. Fourteen of the 31 (45%) donors expressed CD32 on their NK cells. Molecular characterization of FcgammaRIIc isoforms expressed by the CD32+ donors revealed that the majority of donors expressed the FcgammaRIIc1 isoform. Interestingly, 3 of the 14 positive donors did not express FcgammaRIIc1, and we identified a novel isoform, FcgammaRIIc5, expressed by these individuals. The expression of this isoform was correlated to a second allelic polymorphism that controls exon splicing. One of the three was found to express FcgammaRIIb on the NK cells. Biochemical analysis revealed that CD32+ donors of both types expressed a 40-kDa protein, specifically immunoprecipitated by anti-CD32 monoclonal antibodies. Functionally, only individuals expressing the FcgammaRIIc1 isoform were able to trigger reverse antibody-dependent cell-mediated cytotoxicity via CD32 whereas a CD32+ individual expressing the FcgammaRIIb isoform was unable to trigger this function. These results demonstrate that the presence of multiple allelic polymorphisms in the FcgammaRIIC gene determine the expression and function of CD32 on NK cells.
- Published
- 2002
- Full Text
- View/download PDF
49. Measurement of NK activity by the microcytotoxicity assay (MCA): a new application for an old assay.
- Author
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Wahlberg BJ, Burholt DR, Kornblith P, Richards TJ, Bruffsky A, Herberman RB, and Vujanovic NL
- Subjects
- Apoptosis, Breast Neoplasms immunology, Chromium Radioisotopes, Female, Humans, Kinetics, Leukocytes, Mononuclear immunology, Necrosis, Reproducibility of Results, Sensitivity and Specificity, Tumor Cells, Cultured, Cytotoxicity Tests, Immunologic methods, Killer Cells, Natural immunology
- Abstract
Natural killer (NK) cells are spontaneously cytotoxic immune effector cells with the ability to selectively destroy tumor cells without harming normal cells. To perform this function, NK cells utilize two main cytotoxicity pathways, the well known perforin/granzyme-mediated secretory/necrotic killing and the recently defined TNF family ligand-mediated non-secretory/apoptotic killing. The former mechanism is manifested mainly against a few cultured leukemia cell targets, while the latter mediates killing against a large variety of tumor cell targets. Therefore, the biological role and significance of these mechanisms might be different. The NK cell-mediated necrotic killing has been reliably and selectively measured in humans by the standard 4-h 51Cr release assay (CRA) against K562 myeloid leukemia cell targets. However, no standardized high throughput assay is available for testing the NK cell-mediated apoptotic killing. Here, we introduce the modified MCA as a convenient method for measuring perforin/granzyme-independent NK cell-mediated apoptotic killing. The assay is performed in microwells of Terasaki tissue culture microtest plates, using adherent tumor cell targets, which are selectively susceptible to non-secretory/apoptotic killing and resistant to secretory/necrotic killing mediated by NK cells. Target cells are plated in microwells and incubated overnight to adhere to the plastic surface and to regenerate cell surface-bound TNF family receptors. Following this adherence, target cells are co-incubated with freshly isolated human peripheral blood mononuclear leukocytes (PBMNL) or purified subpopulations of immune cells for 24 h in various effector/target (E/T) ratios. During this incubation, dead target cells become non-adherent and are removed by washing the wells. Remaining adherent (viable) target cells are fixed, stained and optically counted. A notable dose-dependent (peak at 200:1 E/T ratio), time-dependent (peak at 24 h of incubation) and donor-dependent killing of tumor cells was consistently and reproducibly induced by PBMNL of normal donors. Using purified subpopulations of immune cells, it was demonstrated that among PBMNL, CD3(-)CD56(+)CD16(+) mature NK cells are the only mediators of tumor cell killing in MCA, as well as in CRA. Comparative studies of NK activity detected by MCA and CRA, performed with PBMNL from normal individuals and breast cancer patients, showed no significant correlation between the cytotoxicities measured in the two assays. In addition, while NK activity measured in CRA was normal in most breast cancer patients, NK activity assessed in MCA was decreased in a large majority of the patients. Thus, MCA is a sensitive NK assay, which is biologically different from CRA, and may be clinically relevant. MCA has also a higher throughput, and is more practical and economical than CRA.
- Published
- 2001
- Full Text
- View/download PDF
50. Ig-binding receptors on human NK cells as effector and regulatory surface molecules.
- Author
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Sulica A, Morel P, Metes D, and Herberman RB
- Subjects
- Animals, Antigens, CD chemistry, Antigens, CD genetics, Antigens, CD immunology, Humans, Immunoglobulin G immunology, Immunoglobulin M immunology, Receptors, IgG chemistry, Receptors, IgG genetics, Receptors, IgG immunology, Structure-Activity Relationship, Immunoglobulins immunology, Killer Cells, Natural immunology, Receptors, Fc immunology
- Abstract
The receptors on human natural killer 9NK cells which can specifically bind the Fc portion of immunoglobulin molecules (Fc receptors) have been extensively studied. The best known and studied Fc receptor on human NK cells is FcgammaRIIIa. Interactions of NK cells with IgG antibodies via this receptor are well known to induce a signal transduction cascade and lead to antibody-dependent cell-mediated cytotoxicity (ADCC) as well as release of various cytokines. In addition, interactions with monomeric IgG and FcgammaRIIIa have been demonstrated, which result in negative regulation of NK activity and other immunomodulatory effects. Over the past several years, it has also become increasingly appreciated that human NK cells express a variety of other Fc receptors, including FcmuR, which also can mediate effector and immunoregulatory functions. Also, a novel form of FcgammaR has been demonstrated on human NK cells, termed FcgammaRIIc. Recent molecular studies have shown considerable polymorphism in the genes for FcgammaIIc and the functional consequences are being dissected. This appears to include cross-talk between FcgammaRIIIa and at least some forms of FcgammaRIIc, which may have important functional consequences.
- Published
- 2001
- Full Text
- View/download PDF
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