James Talmadge - Academia.edu (original) (raw)

Papers by James Talmadge

Bone Marrow Transplantation

Journal of Turgut Ozal Medical Center, 1996

Phytohemagglutinin (PHA) is principally a T lymphocyte mitogen, producing a greater stimulatory e... more Phytohemagglutinin (PHA) is principally a T lymphocyte mitogen, producing a greater stimulatory effect on CD4 helper/inducer T lymphocytes than on CD8 suppressor/cytotoxic T cells. In this study, we investigated if there are differences in the mitogenic response to PHA between autologous bone marrow (BM) and granulocyte-monocyte colony stimulating factor (GM-CSF)-mobilized peripheral stem cell (PSC) products as well as to normal peripheral blood leukocytes (PBL). BM and PSC products from 24 patients with non-Hodgkin’s lymphoma (NHL) were collected and assays of cell proliferation in response to PHA were performed both before and following 5 days co-incubation with IL-2. The proliferative response to PHA by cells from both PSC and BM products were significantly lower than normal PBL (p<0.001). The PHA response of PSC was significantly higher than that observed with BM (p<0.01). The response to PHA of PSC was higher than BM (p<0.05). When compared before culture with IL-2, th...

Advances in Experimental Medicine and Biology, 2020

Patients with cancer frequently overexpress inflammatory cytokines with an associated neutrophili... more Patients with cancer frequently overexpress inflammatory cytokines with an associated neutrophilia both of which may be downregulated by diets with high omega-3 polyunsaturated fatty acids (ω-3 PUFA). The anti-inflammatory activity of dietary ω-3 PUFA has been suggested to have anticancer properties and to improve survival of cancer patients. Currently, the majority of dietary research efforts do not differentiate between obesity and dietary fatty acid consumption as mediators of inflammatory cell expansion and tumor microenvironmental infiltration, initiation, and progression. In this chapter, we discuss the relationships between dietary lipids, inflammation, neoplasia and strategies to regulate these relationships. We posit that dietary composition, notably the ratio of ω-3 vs. ω-6 PUFA, regulates tumor initiation and progression and the frequency and sites of metastasis that, together, impact overall survival (OS). We focus on three broad topics: first, the role of dietary lipids in chronic inflammation and tumor initiation, progression, and regression; second, lipid mediators linking inflammation and cancer; and third, dietary lipid regulation of murine and human tumor initiation, progression, and metastasis.

Infection Prevention in Practice, 2019

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Advances in experimental medicine and biology, 2017

The approvals of Provenge (Sipuleucel-T), Ipilimumab (Yervoy/anti-CTLA-4) and blockers of the PD-... more The approvals of Provenge (Sipuleucel-T), Ipilimumab (Yervoy/anti-CTLA-4) and blockers of the PD-1 - PD-L1/PD-L2 pathway, such as nivolumab (Opdivo), pembrolizumab (Keytruda), or atezolizumab (Tecentriq), have established immunotherapy as a key component of comprehensive cancer care. Further, murine mechanistic studies and studies in immunocompromised patients have documented the critical role of immunity in effectiveness of radio- and chemotherapy. However, in addition to the ability of the immune system to control cancer progression, it can also promote tumor growth, via regulatory T cells (Tregs), myeloid-derived dendritic cells (MDSCs) and tumor associated macrophages (TAM), which can enhance survival of cancer cells directly or via the regulation of the tumor stroma.An increasing body of evidence supports a central role for the tumor microenvironment (TME) and the interactions between tumor stroma, infiltrating immune cells and cancer cells during the induction and effector pha...

Advances in experimental medicine and biology, 2017

Rodent and clinical studies have documented that myeloid cell infiltration of tumors is associate... more Rodent and clinical studies have documented that myeloid cell infiltration of tumors is associated with neutrophilia, lymphocytopenia and poor patient outcomes. This contrasts with lymphocyte infiltration of tumors, which is associated with improved outcomes. Lifestyle parameters such as high fat diet s and omega (ω)-6 polyunsaturated fatty acids (PUFA) intake may influence these inflammatory parameters including extramedullary myelopoiesis that can contribute to a metastatic "niche". While, tumor secretion of growth factors (GFs) and chemokines regulate tumor-immune-cell crosstalk, in this chapter, we also emphasize how lifestyle choices, including, obesity, high-fat and high ω-6 PUFA dietary content, contribute to inflammation and myeloid cell infiltration of tumors. A relationship between obesity and high-fat diets (notably the saturated fats in Western diets) and tumor incidence, metastasis, and poor outcomes is generally accepted. However, the mechanisms of dietary pr...

International Immunopharmacology, 2016

Head and Neck Management of the Cancer Patient, 1986

There have been remarkable and continuing advances in the techniques for the diagnosis and treatm... more There have been remarkable and continuing advances in the techniques for the diagnosis and treatment of primary neoplasms; however, the growth of tumor cells in organs distant to the primary tumor remains responsible for most deaths from cancer. Conventional therapy may be effective when primary neoplasms are detected before metastasis has occurred, but there is increasing evidence that metastasis occurs in most patients prior to the time of diagnosis.

Pathology and Immunopathology Research, 1987

Polyinosinic-polycytidylic acid [poly(I,C)] is a double-stranded RNA that is a potent interferon ... more Polyinosinic-polycytidylic acid [poly(I,C)] is a double-stranded RNA that is a potent interferon (IFN) inducer in rodents and, when suitably complexed with poly-L-lysine and carboxymethylcellulose [poly(I,C)-LC], also in primates and humans. In addition, poly(I,C)-LC has shown significant therapeutic activity in a number of preclinical tumor models and significant toxicity in both the preclinical and clinical settings. To better understand the toxicity of this agent, particularly in light of the previously reported bell-shaped dose response curve for immunomodulation and therapeutic activity, we undertook a pharmacological/toxicological study of poly(I,C)-LC. These experiments revealed that the injection of toxic doses of poly(I,C)-LC significantly reduced the body weight of animals and induced serological and histological abnormalities. We found that poly(I,C) is the toxic moiety of poly(I,C)-LC and that both agents induced pulmonary thrombosis as well as hepatic necrosis. The hepatic necrosis was reflected in serum enzyme levels, with significant increases in ornithine carbonyl transferase, serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase levels. In addition, reduced platelet counts indicated a significant increase in platelet consumption in agreement with the thrombosis. There were, however, only minor changes in prothrombin and activated prothrombin times. It was of interest that coincubating poly(I,C)-LC and peritoneal macrophages in vitro resulted in the production of tumor necrosis factor, which has a similar pattern of toxicity; this finding suggests that poly(I,C)-LC&#39;s pattern of toxicity may be associated with the induction of TNF and/or IFN.

Vaccine, 1999

Eleven HIV-1 seronegative subjects previously injected with an HIV-1 p17 synthetic peptide vaccin... more Eleven HIV-1 seronegative subjects previously injected with an HIV-1 p17 synthetic peptide vaccine (HGP-30) were given two booster immunizations to evaluate memory cell responses and the ability to boost cellular and humoral immune responses. Five of 11 subjects showed a signi®cant increase in their antibody titres to HGP-30 or p17 and 6/11 had T-cell proliferation responses to either HGP-30 or p17. HIV-1 virus challenge studies in SCID mice demonstrated that 39 of 50 mice (78%) receiving PBMC from 5 of the HGP-30 immunized subjects were protected from infection with a dierent strain of HIV-1 compared to 4 of 30 mice (13%) that received PBMC from 3 non-immunized subjects (p < 0.001). These studies show that booster immunizations with HGP-30 vaccine are safe and non-toxic and induce protective cell mediated immune responses.

Cancer Research, 2014

Fatty diets can induce low-grade inflammation that we report is increased by chronic alcohol cons... more Fatty diets can induce low-grade inflammation that we report is increased by chronic alcohol consumption (CAC). CAC as 16.6% of total calories when administered in combination with the Lieber-DeCarli high-fat diet increases inflammation included hepatic and splenic extramedullary hematopoiesis (EMH) as assessed by flow cytometry, immunohistochemistry and a colony forming unit-granulocyte macrophage (CFU-GM) assay. Further, an increased number of hepatic myeloid derived suppressor cells (MDSCs) CD11b+Gr1+ cells that were predominantly Ly6cbr are observed. The increase in MDSCs is associated with an increased number of hepatic non-parenchymal cells including adipocytes (Oil Red O). Consistent with the increased number of hepatic MDSCs and EMH is a decrease in bone marrow cellularity and progenitor cells measured by flow cytometry (Lin-CD11b-Gr1-Sca-1+) and CFU-GM/femur. Unexpectedly, we observed demineralization and osteolytic lesions by micro computed tomography (micro CT) in all bon...

Immunopharmacology, 1984

The coculture of spleen cells with specific antigens in the presence of thymosin fraction five (F... more The coculture of spleen cells with specific antigens in the presence of thymosin fraction five (F5) results in the stimulation of the lymphocyte response. To observe the stimulation, a suboptimal responder-to-stimulator ratio must be utilized. Suboptimal assay conditions also are needed in immunization challenge studies in which thymosin F5 acts as an effective immunoadjuvant. The data reported here suggest that to study the efficiency of a biological response modifier, suboptimal assay conditions are best for observation of immunomodulation. We also report that thymosin F5, in addition to exhibiting adjuvantlike activity for T cells, is stimulatory in assays of mixed lymphocyte response and in the in vitro stimulation of cytotoxic T effector cells, following a mixed lymphocyte-tumor culture.

Medical Oncology, 1994

Two clinical results of peripheral blood stem cell support are commonly considered: (1) the effec... more Two clinical results of peripheral blood stem cell support are commonly considered: (1) the effect on hematopoietic recovery and (2) the effect on the underlying malignancy. The dynamics of hematopoietic recovery after autoiogous bone marrow transplantation and after autologous peripheral blood stem cell transplantation in a clinical setting are similar if no exogenous cytokines are administered and the peripheral stem ceils are collected while their numbers are not deliberately increased (mobilised). If mobilized peripheral stem cells are transplanted, hematopoietic recovery is accelerated. In some circumstances, patients who receive peripheral stem cell transplantation may experience an improved progression-free survival after high-dose therapy when compared with similar patients who receive autologous bone marrow transplantation. Explanations for such a survival advantage might include (1) a lower likelihood of occult tumor cells capable of restoring disease in peripheral stem cell autograft products than in bone marrow harvests, (2) a greater number of cytotoxic effector cells capable of destroying occult tumor ceils in the peripheral stem cell collections than in bone marrow harvests, and (3) a different and advantageous pattern of immunologic recovery following autologous peripheral stem cell transplant compared to autologous bone marrow transplant.

Clinical & Experimental Metastasis, 2015

Lenalidomide (LEN) and metronomic cyclophosphamide (CTX) regulate angiogenesis and immunosuppress... more Lenalidomide (LEN) and metronomic cyclophosphamide (CTX) regulate angiogenesis and immunosuppressive cells linked to the progression of metastatic castration-resistant prostate cancer (mCRPC). A phase-I/II, dose-escalation trial of LEN plus oral CTX was conducted in patients with previously treated mCRPC. In the phase-I study, CTX was given at 50 mg (day 1-28) and LEN at 10-25 mg (day 1-21) on a 28-day cycle using a ''3?3'' study design. In phase II, patients received LEN at 25 mg (day 1-21) with CTX at 50 mg PO QD (day 1-28) on a 28-day cycle. Nineteen patients in phase I were evaluable for toxicity. The maximum tolerated dose (MTD) was not observed at any of the dose levels (DLs) tested. Six patients received treatment in phase II before the trial was closed. A C 50 % reduction in PSA was observed in 31.7 % evaluable patients. Radiographically, one patient had a partial response. Stable disease was documented in 68 % of evaluable patients after two therapy cycles. Circulating tumor cells (CTCs) decreased in 22.7 % and remained stable in 31.8 % of patients. Baseline numbers of peripheral MDSCs (MDSC; Lin-DR-CD11b ?) were significantly increased in patients versus normal donors, and were decreased by chemotherapy. At baseline, MDSCs correlated directly with CTCs, and inversely with T-and B cell frequency supporting their immunosuppressive activity. The combination of LEN and metronomic CTX can be safely administered, reversing cellular immunosuppression in this group of elderly patients with mCRPC. Further research is required to identify responsive subgroup(s) and validate the biomarkers. Keywords Metronomic chemotherapy Á Metastatic castration-resistant prostate cancer Á Lenalidomide Á Myeloid-derived suppressor cell Á FoxP3 ? T-regulatory (T-reg) cell Á Circulating tumor cells

Journal of Hematotherapy & Stem Cell Research, 2000

The hematopoietic sequelae of intramuscular administration of flt-3 ligand (FL) and granulocytema... more The hematopoietic sequelae of intramuscular administration of flt-3 ligand (FL) and granulocytemacrophage colony-stimulating factor (GM-CSF) alone, or in combination, were compared in BALB/c mice. Changes in hematopoiesis were measured in the marrow, spleen and blood using an in vitro colony-forming unit (CFU) assay and flow cytometrically (expression of CD34 and stem cell antigen (Sca)-1). FL administration was associated with a significant increase in the absolute number of CFU and CD34 1 cells in the marrow and CFU, CD34 1 , Sca-1 1 , and CD34 1 Sca-1 1 cells in the spleen and blood. These data demonstrate that FL expands and mobilizes a range of hematopoietic progenitors. By comparison, GM-CSF administration was associated with a significant increase in the number of CFU in the spleen and a significant reduction in marrow CD34 1 , Sca-1 1 , and CD34 1 Sca-1 1 cells. These data suggest that GM-CSF-driven expansion of CFU may be at the expense of more primitive cells. The pattern of progenitor cell expansion associated with FL 1 GM-CSF administration was similar to that of FL alone with the following exceptions. The numbers of spleen and blood CFU were significantly greater and the number of marrow CD34 1 Sca-1 1 cells were significantly less, than with FL alone. These data suggest that co-administration of these cytokines may combine the expansion of the more primitive cell populations (associated with FL) with the expansion of the more mature CFU population (associated with GM-CSF) to yield a greater overall CFU expansion and elevation of CFU in the blood. However, increasing the expansion and mobilization of the relatively mature, rather than the more primitive, hematopoietic progenitors, may be of limited value as a mobilization strategy, if the goal is the expansion and isolation of increased numbers of "high-quality," primitive cells for transplantation.

JNCI Journal of the National Cancer Institute, 1988

We describe a gene, NM23, that is associated with the tumor metastatic process. NM23 RNA levels w... more We describe a gene, NM23, that is associated with the tumor metastatic process. NM23 RNA levels were highest in cells and tumors of relatively low metastatic potential in two experimental systems: (1) murine K-1735 melanoma cell lines, in which the gene was identified, and (2) N-nitroso-N-methylurea-induced rat mammary carcinomas. NM23 RNA levels did not correlate with cell sensitivity to host immunological responses and may, therefore, be associated with intrinsic aggressiveness. The predicted carboxy-terminal protein sequence encoded by the pNM23 cDNA clone is novel compared with Genebank animal, bacterial, and viral sequences.

Journal of Interferon & Cytokine Research, 1999

Previous reports showed the abnorm al activation of im m une cells in growth factor-mobilized per... more Previous reports showed the abnorm al activation of im m une cells in growth factor-mobilized peripheral blood stem cell (PBSC) produ cts, which m ight be responsible for depressed T cell responsiveness to mitogens compared with norm al peripheral blood m ononuclear cells (PBM C). In the present study, the m RNA expression levels of interleukin (IL)-2, IL-4, IL-10, and interferon-g (IFN-g) were significantly higher in C D4 1 and C D8 1 T cells from mobilized PB SC products compared with C D4 1 and C D8 1 cells from norm al peripheral blood (PB). The m RNA expression levels of IL-4 and IL-10 were significantly higher in C D8 1 compared with C D4 1 cells from PBSC products. However, the expression of IL-2 and IFN-g m RNA transcripts was sim ilar in the C D4 1 and C D 8 1 T cells from PBSC products. The levels of IL-10, IL-8, and tum or necrosis factor (TNF)-a m RNA were also significantly higher in m onocytes isolated from PB SC products com pared with monocytes isolated from normal PB. Expression of IL-10-specific m RNA in monocytes also was significantly higher than the levels observed in C D8 1 cells from PBSC products. W e suggest that both C D4 1 and C D8 1 cells in the PBS C products are highly activated. However, their response to phytohem agglutinin (PH A) m itogenesis is depressed in part because of IL-10 expression by C D 8 1 cells and m onocytes in addition to the higher levels of m onocyte-dependen t T cell inhibitory activity. These data dem onstrate that aberrant IL-10 expression in the C D8 1 T cells and m onocytes present in PB SC products may represent a possible mechanism of im mune dysfunction in patients after high-dose chem otherapy (H DT) and peripheral blood stem cell transplantation (PBSC T).

Journal of Immunotherapy, 1998

The expansion of T and natural killer (NK) cells in growth factormobilized peripheral blood stem ... more The expansion of T and natural killer (NK) cells in growth factormobilized peripheral blood stem cell (PSC) products with interleukin-2 (IL-2) requires a reduction in monocyte frequency. Monocytes are enriched with stem cells during apheresis and, in this series of growth factor-mobilized PSC products from breast cancer patients, represented 36 f 6% of the cells in the product. Immunophenotyping studies revealed that monocytes inhibited the proliferation of NK cells (CD56' and CD3-CD8' CD56' cells) and T cells (CD3', CD4' , and CD8' cells) during IL-2 co-culture for 7, 14, or 21 days. A reduction in monocytes resulted in 61-fold expansion of CD3-CD8' CD56' cells compared with a 3.7-fold increase of CD3' cells by day 21. In addition, following IL-2 co-culture, cells from PSC products with a reduced frequency of monocytes had a significantly increased T cell mitogenic response and NK cell activity in PSC products compared with intact products. We suggest that monocytes inhibit the IL-2-dependent proliferation and augmented function of NK and T cells from growth factor-mobilized PSC products.

Journal of Immunotherapy, 1993

We examined the effect of a maximum tolerated, split-dose chemotherapy protocol of cyclophosphami... more We examined the effect of a maximum tolerated, split-dose chemotherapy protocol of cyclophosphamide, cisplatin, and 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) on neutrophil and lymphocyte subpopulations in the peripheral blood leukocytes (PBLs), thymus, bone marrow, and spleen. It was found that this protocol of polychemotherapy, modeled after the induction protocol used with autologous bone marrow transplantation (AuBMT) for breast cancer, suppressed both B- and T-cell populations and T-cell function at times when the absolute neutrophil count had returned to normal or supernormal numbers. We observed an organ- and phenotype-specific T- and B-cell recovery to normal levels following chemotherapy. However, despite normalization of cellularity and phenotype frequency, splenic lymphocytes remained unable to respond to normally concanavalin A (ConA). This polychemotherapy protocol in mice with an extensive experimental metastasis mammary tumor burden, was a dose lethal to 20% of the test group, which could be overcome with treatment by BMT and rHu interleukin (IL)-7. Furthermore, therapy with the T-cell augmenting agent rHu IL-7 had additive therapeutic activity and significantly prolonged survival beyond that of chemotherapy and BMT although it did not cure any mice with a heavy tumor burden. In summary, these studies demonstrate an organ-specific and selective polymorphonuclear neutrophil and T- and B-cell reconstitution following multidrug, split-dose chemotherapy on tissue and PBL populations, and a chronic depression in T-cell function, which when modified can result in significant therapeutic activity.

Bone Marrow Transplantation

Journal of Turgut Ozal Medical Center, 1996

Phytohemagglutinin (PHA) is principally a T lymphocyte mitogen, producing a greater stimulatory e... more Phytohemagglutinin (PHA) is principally a T lymphocyte mitogen, producing a greater stimulatory effect on CD4 helper/inducer T lymphocytes than on CD8 suppressor/cytotoxic T cells. In this study, we investigated if there are differences in the mitogenic response to PHA between autologous bone marrow (BM) and granulocyte-monocyte colony stimulating factor (GM-CSF)-mobilized peripheral stem cell (PSC) products as well as to normal peripheral blood leukocytes (PBL). BM and PSC products from 24 patients with non-Hodgkin’s lymphoma (NHL) were collected and assays of cell proliferation in response to PHA were performed both before and following 5 days co-incubation with IL-2. The proliferative response to PHA by cells from both PSC and BM products were significantly lower than normal PBL (p<0.001). The PHA response of PSC was significantly higher than that observed with BM (p<0.01). The response to PHA of PSC was higher than BM (p<0.05). When compared before culture with IL-2, th...

Advances in Experimental Medicine and Biology, 2020

Patients with cancer frequently overexpress inflammatory cytokines with an associated neutrophili... more Patients with cancer frequently overexpress inflammatory cytokines with an associated neutrophilia both of which may be downregulated by diets with high omega-3 polyunsaturated fatty acids (ω-3 PUFA). The anti-inflammatory activity of dietary ω-3 PUFA has been suggested to have anticancer properties and to improve survival of cancer patients. Currently, the majority of dietary research efforts do not differentiate between obesity and dietary fatty acid consumption as mediators of inflammatory cell expansion and tumor microenvironmental infiltration, initiation, and progression. In this chapter, we discuss the relationships between dietary lipids, inflammation, neoplasia and strategies to regulate these relationships. We posit that dietary composition, notably the ratio of ω-3 vs. ω-6 PUFA, regulates tumor initiation and progression and the frequency and sites of metastasis that, together, impact overall survival (OS). We focus on three broad topics: first, the role of dietary lipids in chronic inflammation and tumor initiation, progression, and regression; second, lipid mediators linking inflammation and cancer; and third, dietary lipid regulation of murine and human tumor initiation, progression, and metastasis.

Infection Prevention in Practice, 2019

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Advances in experimental medicine and biology, 2017

The approvals of Provenge (Sipuleucel-T), Ipilimumab (Yervoy/anti-CTLA-4) and blockers of the PD-... more The approvals of Provenge (Sipuleucel-T), Ipilimumab (Yervoy/anti-CTLA-4) and blockers of the PD-1 - PD-L1/PD-L2 pathway, such as nivolumab (Opdivo), pembrolizumab (Keytruda), or atezolizumab (Tecentriq), have established immunotherapy as a key component of comprehensive cancer care. Further, murine mechanistic studies and studies in immunocompromised patients have documented the critical role of immunity in effectiveness of radio- and chemotherapy. However, in addition to the ability of the immune system to control cancer progression, it can also promote tumor growth, via regulatory T cells (Tregs), myeloid-derived dendritic cells (MDSCs) and tumor associated macrophages (TAM), which can enhance survival of cancer cells directly or via the regulation of the tumor stroma.An increasing body of evidence supports a central role for the tumor microenvironment (TME) and the interactions between tumor stroma, infiltrating immune cells and cancer cells during the induction and effector pha...

Advances in experimental medicine and biology, 2017

Rodent and clinical studies have documented that myeloid cell infiltration of tumors is associate... more Rodent and clinical studies have documented that myeloid cell infiltration of tumors is associated with neutrophilia, lymphocytopenia and poor patient outcomes. This contrasts with lymphocyte infiltration of tumors, which is associated with improved outcomes. Lifestyle parameters such as high fat diet s and omega (ω)-6 polyunsaturated fatty acids (PUFA) intake may influence these inflammatory parameters including extramedullary myelopoiesis that can contribute to a metastatic "niche". While, tumor secretion of growth factors (GFs) and chemokines regulate tumor-immune-cell crosstalk, in this chapter, we also emphasize how lifestyle choices, including, obesity, high-fat and high ω-6 PUFA dietary content, contribute to inflammation and myeloid cell infiltration of tumors. A relationship between obesity and high-fat diets (notably the saturated fats in Western diets) and tumor incidence, metastasis, and poor outcomes is generally accepted. However, the mechanisms of dietary pr...

International Immunopharmacology, 2016

Head and Neck Management of the Cancer Patient, 1986

There have been remarkable and continuing advances in the techniques for the diagnosis and treatm... more There have been remarkable and continuing advances in the techniques for the diagnosis and treatment of primary neoplasms; however, the growth of tumor cells in organs distant to the primary tumor remains responsible for most deaths from cancer. Conventional therapy may be effective when primary neoplasms are detected before metastasis has occurred, but there is increasing evidence that metastasis occurs in most patients prior to the time of diagnosis.

Pathology and Immunopathology Research, 1987

Polyinosinic-polycytidylic acid [poly(I,C)] is a double-stranded RNA that is a potent interferon ... more Polyinosinic-polycytidylic acid [poly(I,C)] is a double-stranded RNA that is a potent interferon (IFN) inducer in rodents and, when suitably complexed with poly-L-lysine and carboxymethylcellulose [poly(I,C)-LC], also in primates and humans. In addition, poly(I,C)-LC has shown significant therapeutic activity in a number of preclinical tumor models and significant toxicity in both the preclinical and clinical settings. To better understand the toxicity of this agent, particularly in light of the previously reported bell-shaped dose response curve for immunomodulation and therapeutic activity, we undertook a pharmacological/toxicological study of poly(I,C)-LC. These experiments revealed that the injection of toxic doses of poly(I,C)-LC significantly reduced the body weight of animals and induced serological and histological abnormalities. We found that poly(I,C) is the toxic moiety of poly(I,C)-LC and that both agents induced pulmonary thrombosis as well as hepatic necrosis. The hepatic necrosis was reflected in serum enzyme levels, with significant increases in ornithine carbonyl transferase, serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase levels. In addition, reduced platelet counts indicated a significant increase in platelet consumption in agreement with the thrombosis. There were, however, only minor changes in prothrombin and activated prothrombin times. It was of interest that coincubating poly(I,C)-LC and peritoneal macrophages in vitro resulted in the production of tumor necrosis factor, which has a similar pattern of toxicity; this finding suggests that poly(I,C)-LC&#39;s pattern of toxicity may be associated with the induction of TNF and/or IFN.

Vaccine, 1999

Eleven HIV-1 seronegative subjects previously injected with an HIV-1 p17 synthetic peptide vaccin... more Eleven HIV-1 seronegative subjects previously injected with an HIV-1 p17 synthetic peptide vaccine (HGP-30) were given two booster immunizations to evaluate memory cell responses and the ability to boost cellular and humoral immune responses. Five of 11 subjects showed a signi®cant increase in their antibody titres to HGP-30 or p17 and 6/11 had T-cell proliferation responses to either HGP-30 or p17. HIV-1 virus challenge studies in SCID mice demonstrated that 39 of 50 mice (78%) receiving PBMC from 5 of the HGP-30 immunized subjects were protected from infection with a dierent strain of HIV-1 compared to 4 of 30 mice (13%) that received PBMC from 3 non-immunized subjects (p < 0.001). These studies show that booster immunizations with HGP-30 vaccine are safe and non-toxic and induce protective cell mediated immune responses.

Cancer Research, 2014

Fatty diets can induce low-grade inflammation that we report is increased by chronic alcohol cons... more Fatty diets can induce low-grade inflammation that we report is increased by chronic alcohol consumption (CAC). CAC as 16.6% of total calories when administered in combination with the Lieber-DeCarli high-fat diet increases inflammation included hepatic and splenic extramedullary hematopoiesis (EMH) as assessed by flow cytometry, immunohistochemistry and a colony forming unit-granulocyte macrophage (CFU-GM) assay. Further, an increased number of hepatic myeloid derived suppressor cells (MDSCs) CD11b+Gr1+ cells that were predominantly Ly6cbr are observed. The increase in MDSCs is associated with an increased number of hepatic non-parenchymal cells including adipocytes (Oil Red O). Consistent with the increased number of hepatic MDSCs and EMH is a decrease in bone marrow cellularity and progenitor cells measured by flow cytometry (Lin-CD11b-Gr1-Sca-1+) and CFU-GM/femur. Unexpectedly, we observed demineralization and osteolytic lesions by micro computed tomography (micro CT) in all bon...

Immunopharmacology, 1984

The coculture of spleen cells with specific antigens in the presence of thymosin fraction five (F... more The coculture of spleen cells with specific antigens in the presence of thymosin fraction five (F5) results in the stimulation of the lymphocyte response. To observe the stimulation, a suboptimal responder-to-stimulator ratio must be utilized. Suboptimal assay conditions also are needed in immunization challenge studies in which thymosin F5 acts as an effective immunoadjuvant. The data reported here suggest that to study the efficiency of a biological response modifier, suboptimal assay conditions are best for observation of immunomodulation. We also report that thymosin F5, in addition to exhibiting adjuvantlike activity for T cells, is stimulatory in assays of mixed lymphocyte response and in the in vitro stimulation of cytotoxic T effector cells, following a mixed lymphocyte-tumor culture.

Medical Oncology, 1994

Two clinical results of peripheral blood stem cell support are commonly considered: (1) the effec... more Two clinical results of peripheral blood stem cell support are commonly considered: (1) the effect on hematopoietic recovery and (2) the effect on the underlying malignancy. The dynamics of hematopoietic recovery after autoiogous bone marrow transplantation and after autologous peripheral blood stem cell transplantation in a clinical setting are similar if no exogenous cytokines are administered and the peripheral stem ceils are collected while their numbers are not deliberately increased (mobilised). If mobilized peripheral stem cells are transplanted, hematopoietic recovery is accelerated. In some circumstances, patients who receive peripheral stem cell transplantation may experience an improved progression-free survival after high-dose therapy when compared with similar patients who receive autologous bone marrow transplantation. Explanations for such a survival advantage might include (1) a lower likelihood of occult tumor cells capable of restoring disease in peripheral stem cell autograft products than in bone marrow harvests, (2) a greater number of cytotoxic effector cells capable of destroying occult tumor ceils in the peripheral stem cell collections than in bone marrow harvests, and (3) a different and advantageous pattern of immunologic recovery following autologous peripheral stem cell transplant compared to autologous bone marrow transplant.

Clinical & Experimental Metastasis, 2015

Lenalidomide (LEN) and metronomic cyclophosphamide (CTX) regulate angiogenesis and immunosuppress... more Lenalidomide (LEN) and metronomic cyclophosphamide (CTX) regulate angiogenesis and immunosuppressive cells linked to the progression of metastatic castration-resistant prostate cancer (mCRPC). A phase-I/II, dose-escalation trial of LEN plus oral CTX was conducted in patients with previously treated mCRPC. In the phase-I study, CTX was given at 50 mg (day 1-28) and LEN at 10-25 mg (day 1-21) on a 28-day cycle using a ''3?3'' study design. In phase II, patients received LEN at 25 mg (day 1-21) with CTX at 50 mg PO QD (day 1-28) on a 28-day cycle. Nineteen patients in phase I were evaluable for toxicity. The maximum tolerated dose (MTD) was not observed at any of the dose levels (DLs) tested. Six patients received treatment in phase II before the trial was closed. A C 50 % reduction in PSA was observed in 31.7 % evaluable patients. Radiographically, one patient had a partial response. Stable disease was documented in 68 % of evaluable patients after two therapy cycles. Circulating tumor cells (CTCs) decreased in 22.7 % and remained stable in 31.8 % of patients. Baseline numbers of peripheral MDSCs (MDSC; Lin-DR-CD11b ?) were significantly increased in patients versus normal donors, and were decreased by chemotherapy. At baseline, MDSCs correlated directly with CTCs, and inversely with T-and B cell frequency supporting their immunosuppressive activity. The combination of LEN and metronomic CTX can be safely administered, reversing cellular immunosuppression in this group of elderly patients with mCRPC. Further research is required to identify responsive subgroup(s) and validate the biomarkers. Keywords Metronomic chemotherapy Á Metastatic castration-resistant prostate cancer Á Lenalidomide Á Myeloid-derived suppressor cell Á FoxP3 ? T-regulatory (T-reg) cell Á Circulating tumor cells

Journal of Hematotherapy & Stem Cell Research, 2000

The hematopoietic sequelae of intramuscular administration of flt-3 ligand (FL) and granulocytema... more The hematopoietic sequelae of intramuscular administration of flt-3 ligand (FL) and granulocytemacrophage colony-stimulating factor (GM-CSF) alone, or in combination, were compared in BALB/c mice. Changes in hematopoiesis were measured in the marrow, spleen and blood using an in vitro colony-forming unit (CFU) assay and flow cytometrically (expression of CD34 and stem cell antigen (Sca)-1). FL administration was associated with a significant increase in the absolute number of CFU and CD34 1 cells in the marrow and CFU, CD34 1 , Sca-1 1 , and CD34 1 Sca-1 1 cells in the spleen and blood. These data demonstrate that FL expands and mobilizes a range of hematopoietic progenitors. By comparison, GM-CSF administration was associated with a significant increase in the number of CFU in the spleen and a significant reduction in marrow CD34 1 , Sca-1 1 , and CD34 1 Sca-1 1 cells. These data suggest that GM-CSF-driven expansion of CFU may be at the expense of more primitive cells. The pattern of progenitor cell expansion associated with FL 1 GM-CSF administration was similar to that of FL alone with the following exceptions. The numbers of spleen and blood CFU were significantly greater and the number of marrow CD34 1 Sca-1 1 cells were significantly less, than with FL alone. These data suggest that co-administration of these cytokines may combine the expansion of the more primitive cell populations (associated with FL) with the expansion of the more mature CFU population (associated with GM-CSF) to yield a greater overall CFU expansion and elevation of CFU in the blood. However, increasing the expansion and mobilization of the relatively mature, rather than the more primitive, hematopoietic progenitors, may be of limited value as a mobilization strategy, if the goal is the expansion and isolation of increased numbers of "high-quality," primitive cells for transplantation.

JNCI Journal of the National Cancer Institute, 1988

We describe a gene, NM23, that is associated with the tumor metastatic process. NM23 RNA levels w... more We describe a gene, NM23, that is associated with the tumor metastatic process. NM23 RNA levels were highest in cells and tumors of relatively low metastatic potential in two experimental systems: (1) murine K-1735 melanoma cell lines, in which the gene was identified, and (2) N-nitroso-N-methylurea-induced rat mammary carcinomas. NM23 RNA levels did not correlate with cell sensitivity to host immunological responses and may, therefore, be associated with intrinsic aggressiveness. The predicted carboxy-terminal protein sequence encoded by the pNM23 cDNA clone is novel compared with Genebank animal, bacterial, and viral sequences.

Journal of Interferon & Cytokine Research, 1999

Previous reports showed the abnorm al activation of im m une cells in growth factor-mobilized per... more Previous reports showed the abnorm al activation of im m une cells in growth factor-mobilized peripheral blood stem cell (PBSC) produ cts, which m ight be responsible for depressed T cell responsiveness to mitogens compared with norm al peripheral blood m ononuclear cells (PBM C). In the present study, the m RNA expression levels of interleukin (IL)-2, IL-4, IL-10, and interferon-g (IFN-g) were significantly higher in C D4 1 and C D8 1 T cells from mobilized PB SC products compared with C D4 1 and C D8 1 cells from norm al peripheral blood (PB). The m RNA expression levels of IL-4 and IL-10 were significantly higher in C D8 1 compared with C D4 1 cells from PBSC products. However, the expression of IL-2 and IFN-g m RNA transcripts was sim ilar in the C D4 1 and C D 8 1 T cells from PBSC products. The levels of IL-10, IL-8, and tum or necrosis factor (TNF)-a m RNA were also significantly higher in m onocytes isolated from PB SC products com pared with monocytes isolated from normal PB. Expression of IL-10-specific m RNA in monocytes also was significantly higher than the levels observed in C D8 1 cells from PBSC products. W e suggest that both C D4 1 and C D8 1 cells in the PBS C products are highly activated. However, their response to phytohem agglutinin (PH A) m itogenesis is depressed in part because of IL-10 expression by C D 8 1 cells and m onocytes in addition to the higher levels of m onocyte-dependen t T cell inhibitory activity. These data dem onstrate that aberrant IL-10 expression in the C D8 1 T cells and m onocytes present in PB SC products may represent a possible mechanism of im mune dysfunction in patients after high-dose chem otherapy (H DT) and peripheral blood stem cell transplantation (PBSC T).

Journal of Immunotherapy, 1998

The expansion of T and natural killer (NK) cells in growth factormobilized peripheral blood stem ... more The expansion of T and natural killer (NK) cells in growth factormobilized peripheral blood stem cell (PSC) products with interleukin-2 (IL-2) requires a reduction in monocyte frequency. Monocytes are enriched with stem cells during apheresis and, in this series of growth factor-mobilized PSC products from breast cancer patients, represented 36 f 6% of the cells in the product. Immunophenotyping studies revealed that monocytes inhibited the proliferation of NK cells (CD56' and CD3-CD8' CD56' cells) and T cells (CD3', CD4' , and CD8' cells) during IL-2 co-culture for 7, 14, or 21 days. A reduction in monocytes resulted in 61-fold expansion of CD3-CD8' CD56' cells compared with a 3.7-fold increase of CD3' cells by day 21. In addition, following IL-2 co-culture, cells from PSC products with a reduced frequency of monocytes had a significantly increased T cell mitogenic response and NK cell activity in PSC products compared with intact products. We suggest that monocytes inhibit the IL-2-dependent proliferation and augmented function of NK and T cells from growth factor-mobilized PSC products.

Journal of Immunotherapy, 1993

We examined the effect of a maximum tolerated, split-dose chemotherapy protocol of cyclophosphami... more We examined the effect of a maximum tolerated, split-dose chemotherapy protocol of cyclophosphamide, cisplatin, and 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) on neutrophil and lymphocyte subpopulations in the peripheral blood leukocytes (PBLs), thymus, bone marrow, and spleen. It was found that this protocol of polychemotherapy, modeled after the induction protocol used with autologous bone marrow transplantation (AuBMT) for breast cancer, suppressed both B- and T-cell populations and T-cell function at times when the absolute neutrophil count had returned to normal or supernormal numbers. We observed an organ- and phenotype-specific T- and B-cell recovery to normal levels following chemotherapy. However, despite normalization of cellularity and phenotype frequency, splenic lymphocytes remained unable to respond to normally concanavalin A (ConA). This polychemotherapy protocol in mice with an extensive experimental metastasis mammary tumor burden, was a dose lethal to 20% of the test group, which could be overcome with treatment by BMT and rHu interleukin (IL)-7. Furthermore, therapy with the T-cell augmenting agent rHu IL-7 had additive therapeutic activity and significantly prolonged survival beyond that of chemotherapy and BMT although it did not cure any mice with a heavy tumor burden. In summary, these studies demonstrate an organ-specific and selective polymorphonuclear neutrophil and T- and B-cell reconstitution following multidrug, split-dose chemotherapy on tissue and PBL populations, and a chronic depression in T-cell function, which when modified can result in significant therapeutic activity.