167 results on '"John W. Hadden"'
Search Results
2. The Prospects for Immunorestoration in the Treatment of Immuno-Deficiency Arising from Aging or Stress
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John W. Hadden
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business.industry ,Immunology ,Immuno-Deficiency ,Medicine ,business - Published
- 2020
3. Increased lymphocyte infiltration in patients with head and neck cancer treated with the IRX-2 immunotherapy regimen
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Wolf Herve Fridman, Harvey Brandwein, Neil L. Berinstein, J. Michael White, Cécile Badoual, James E. Egan, Lorraine Baltzer, Lynn C. Goldstein, Adel K. El-Naggar, Theresa L. Whiteside, John W. Hadden, Paul H. Naylor, and Gregory T. Wolf
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Adult ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,H&E stain ,Article ,Lymphocytes, Tumor-Infiltrating ,Immune system ,medicine ,Humans ,Immunology and Allergy ,Aged ,CD20 ,biology ,business.industry ,CD68 ,Immunotherapy ,Middle Aged ,medicine.disease ,Survival Analysis ,Primary tumor ,Oncology ,Head and Neck Neoplasms ,biology.protein ,Cytokines ,Regression Analysis ,Immunohistochemistry ,Female ,business ,CD8 - Abstract
Twenty-seven subjects with squamous cell cancer of the head and neck received the neoadjuvant IRX-2 immunotherapy regimen prior to surgery in a Phase 2 trial. Pretreatment tumor biopsies were compared with the primary tumor surgical specimens for lymphocyte infiltration, necrosis and fibrosis, using hematoxylin and eosin stain and immunohistochemistry in 25 subjects. Sections were examined by three pathologists. Relative to pretreatment biopsies, increases in lymphocyte infiltration (LI) were seen using H and E or immunohistochemistry. CD3+ CD4+ T cells and CD20+ B cells were primarily found in the peritumoral stroma and CD3+ CD8+ T cells and CD68+ macrophages were mainly intratumoral. LI in the surgical specimens were associated with reductions in the primary tumor size. Improved survival at 5 years was correlated with high overall LI in the tumor specimens. Neoadjuvant IRX-2 immunotherapy regimen may restore immune responsiveness presumably by mobilizing tumor infiltrating effector lymphocytes and macrophages into the tumor.
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- 2011
4. A Phase 1 Safety Study of an IRX-2 Regimen in Patients With Squamous Cell Carcinoma of the Head and Neck
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Jose Luis Barrera Franco, Lorraine Baltzer, Zygmund Roth, Daniel E. Kenady, Scott M. Freeman, Harvey Brandwein, and John W. Hadden
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Adult ,Male ,Oncology ,Cancer Research ,Cellular immunity ,medicine.medical_specialty ,medicine.medical_treatment ,Indomethacin ,Population ,Gluconates ,Drug Administration Schedule ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Adverse effect ,education ,Cyclophosphamide ,Aged ,education.field_of_study ,business.industry ,Middle Aged ,medicine.disease ,Head and neck squamous-cell carcinoma ,Intention to Treat Analysis ,Clinical trial ,Radiation therapy ,Regimen ,Head and Neck Neoplasms ,Carcinoma, Squamous Cell ,Cytokines ,Female ,Immunotherapy ,Safety ,business ,Progressive disease - Abstract
Objectives Head and neck squamous cell carcinoma (HNSCC) is associated with profound defects in cellular immunity. IRX-2, a primary cell-derived biologic containing multiple cytokines, has enhanced immune responses and induced tumor rejection in preclinical studies. This phase 1 open label study aimed to determine the clinical and laboratory safety of an IRX-2 regimen in patients with HNSCC. Methods Patients with HNSCC who had failed surgery and/or radiation therapy were enrolled. IRX-2 was injected subcutaneously at 115 units per dose, 2 doses/d over 10 days, starting on day 4. Patients received low-dose cyclophosphamide infusion on day 1 and took oral indomethacin and zinc daily from day 1 through day 21. Safety and laboratory assessments were undertaken throughout the treatment and 4 weeks after completion of the regimen. Results A total of 13 patients with advanced disease were enrolled in the safety/intent-to-treat population; all experienced treatment-emergent adverse events (AEs). The most frequent AEs were blood and lymphatic disorders, followed by gastrointestinal disorders. Most AEs were mild to moderate in severity. Three patients discontinued the study due to an AE, including 2 deaths. Two patients died after the study period due to tumor progression. No death or discontinuation was considered related to the study drugs. Antitumor responses were noted by radiographic assessment. In the 8 patients who had antitumor data at day 21, 1 patient had complete response, 5 had stable disease, and 2 had progressive disease. Conclusions The IRX-2 regimen was tolerated in patients with advanced HNSCC who failed surgery and/or radiation therapy. The safety and antitumor activity observed warrants further studies.
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- 2011
5. Preclinical studies with IRX-2 and thymosin α1 in combination therapy
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Paul H. Naylor and John W. Hadden
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Combination therapy ,General Neuroscience ,medicine.medical_treatment ,Thymosin ,Biological activity ,Dendritic cell ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Immune system ,History and Philosophy of Science ,Immunology ,medicine ,Cancer research ,Animal studies ,Thymalfasin ,Adjuvant - Abstract
Thymosin alpha1 (Talpha1) is a 28 amino acid biologically active protein with pleiotropic immune enhancing activity. IRX-2 is a primary cell-derived biologic containing multiple cytokines that enhance dendritic cell maturation, promote T-cell growth and differentiation, and inhibit tumor-mediated apoptosis of T cells. IRX-2 is being developed as an immunotherapeutic agent as a novel T-cell adjuvant platform for vaccines as well. Based on their biological activities, thymosin alpha1 and IRX-2 were predicted to exhibit synergistic effects when evaluated in animal and human studies. In animal studies, the combination of IRX-2 and Talpha1 (IRX-3) increased T-cell numbers compared to either alone during recovery from hydrocortisone mediated reduction. IRX-3 further enhanced reduction in tumor burden following chemotherapy compared to IRX-2. Based on these studies, IRX-3 is predicted to be especially important in a setting where reversal of immune suppression due to the presence of tumor, irradiation, and/or chemotherapy is likely to be an important factor in cytokine activity.
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- 2010
6. Immunopharmacology of Thymosin 1 and Cytokine Synergy
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Guido Rasi, Enrico Garaci, Paul H. Naylor, John W. Hadden, and Karen Quadrini
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Cellular immunity ,business.industry ,General Neuroscience ,medicine.medical_treatment ,T cell ,Thymosin ,Lewis lung carcinoma ,Biological activity ,General Biochemistry, Genetics and Molecular Biology ,Immunopharmacology ,Immune system ,Cytokine ,medicine.anatomical_structure ,History and Philosophy of Science ,Immunology ,Cancer research ,Medicine ,business - Abstract
Thymosin alpha1 (Talpha1) is a 28 amino acid biologically active protein cleaved from positions 2-29 of a precursor protein, prothymosin alpha. Since its discovery, Talpha1 has been administered to animals and humans in a wide variety of settings and its pharmacologic effects are to enhance cellular immunity. Talpha1 administration is highly effective in settings where irradiation, chemotherapy, tumor burden, or immune senescence have caused a reduction of T cell number and/or function. Recent in vitro studies, including the one reported here, suggest that Talpha1 may act via pathways commonly used by various cytokines. This raises the possibility that Talpha1 and cytokines may have synergistic activity through potentiation of cytokine activity by Talpha1. Improved control of tumor growth when tumor-bearing mice were treated with Talpha1 and high doses of IL-2 has been previously reported. We extended those studies with the Lewis lung carcinoma mouse model using IRX-2, a natural well-defined biologic containing multiple cytokines, in combination with Talpha1 (IRX-3). Although IRX-2 was effective alone (using doses that contain significantly less IL-2 than in most typical studies), adding Talpha1 led to significant improvement in survival of the tumor-bearing mice. Based on these observations, the immunopharmacology of Talpha1 predicts an important clinical role for Talpha1 in the restoration of cellular immune activity when used in combination with cytokines. Patients who experience immune suppression due to the presence of tumor, irradiation, and/or chemotherapy or aging of the host would most benefit from this treatment combination.
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- 2007
7. Long-term immune dysfunction after radiotherapy to the head and neck area
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John W. Hadden, Adela C Poitevin, Jose L Barrera-Franco, Rocio B Morales, and Emma Verastegui
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Pathology ,Time Factors ,medicine.medical_treatment ,Lymphocyte ,Immunology ,Uterine Cervical Neoplasms ,Central Nervous System Neoplasms ,Immune system ,Antigen ,T-Lymphocyte Subsets ,Lymphopenia ,Internal medicine ,Immunopathology ,medicine ,Humans ,Immunology and Allergy ,Lymphocyte Count ,Neoplasms, Squamous Cell ,Prospective Studies ,Prospective cohort study ,Pharmacology ,Radiotherapy ,business.industry ,Head and neck cancer ,Middle Aged ,medicine.disease ,Radiation therapy ,medicine.anatomical_structure ,Head and Neck Neoplasms ,Female ,business ,Immunologic Memory ,CD8 ,Follow-Up Studies - Abstract
Background : Hematological side effects are not generally expected due to radiotherapy involving limited radiation fields; however, patients with squamous cell carcinoma of the head and neck (SCCH&N) receiving radiation therapy frequently have chronic intraoral infections. Xerostomia has been implicated as a cause of it, but local or systemic immune alterations are not usually considered. Methods : With the purpose of evaluating the impact of radiotherapy treatment to different anatomic sites on immune function, 70 patients were evaluated during and after radiotherapy: 50 cases with SCCH&N, 10 with squamous cell carcinoma of the uterine cervix (SCCUC) and 10 patients with central nervous system tumors (CNS). We analyzed lymphocyte counts and T-cell subsets, and over time, their association with the presence of intracellular infections and disease-free survival. Results : Severe lymphopenia was observed in patients with SCCUC and SCCH&N by the fifth week of treatment. Patients with CNS tumors developed mild lymphopenia. In patients with SCCH&N and UC, lower counts were seen in B cells and total T lymphocyte counts including both CD4 + and CD8 + cell subsets. The patients with SCCUC recovered lymphocyte counts by the 24th month but T-cell subsets lagged behind. None of the SCCH&N patients had fully recovered by 60 months of follow-up. Recurrence correlates with low lymphocyte counts. Discussion : This work highlights the vulnerability of the head and neck area to the impact of radiotherapy as a reservoir of lymphoid cells. The possibility of recovery as a consequence of thymopoiesis and/or peripheral clonal expansion may limit the antigen-specific recognition of relevant tumor or microbial antigens and cause significant and prolonged immune alterations that may impact long-term survival.
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- 2003
8. A trial of IRX-2 in patients with squamous cell carcinomas of the head and neck
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Jose Luis Barrera, Emma Verastegui, J de la Garza, Elba M. Hadden, Abelardo Meneses, Juan Zinser, John W. Hadden, and M Kurman
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Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Lymphocyte ,Indomethacin ,Immunology ,Gastroenterology ,Disease-Free Survival ,Immunopathology ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Immunology and Allergy ,Neoplasms, Squamous Cell ,Cyclophosphamide ,Lymph node ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Pharmacology ,business.industry ,Cancer ,Immunotherapy ,Middle Aged ,medicine.disease ,Surgery ,Radiation therapy ,Zinc ,medicine.anatomical_structure ,Head and Neck Neoplasms ,Cytokines ,Female ,Lymphocytopenia ,Multivitamin ,business - Abstract
A Phase II trial in 42 patients with squamous cell cancer of the head and neck (H and NSCC) was performed using a combination immunotherapy with 10-20 days of perilymphatic injections of a natural cytokine mixture (NCM: IRX-2; 200 units IL-2 equivalence) preceded by low dose cyclophosphamide (CY; 300 mg/m(2)) and followed by daily oral indomethacin (25 mg t.i.d.) and zinc (65 mg in a multivitamin preparation). Thirty-nine patients underwent subsequent surgical resection and 22 stage IV patients received additional radiotherapy. Forty-two percent were adjudged to have complete and partial clinical responses (>50% tumor reduction); an additional five patients had minor responses for a total of 58%. Comparison of post-treatment biopsies or surgical specimens showed 90% of patients had reduction in tumor area from 79% to 48% (over half of which was fragmented) and increased area of leukocyte infiltration from 9% to 32% (79% of which was lymphoid). The treatment with IRX-2 was not associated with significant side effects and 24 of patients showed improvement in eating, breathing or phonation or reduced pain and bleeding. Fifteen patients with lymphocytopenia (lymphocyte counts [LC] less than or equal to 1500 mm(3)) showed significant increases in LC, CD3+, CD4+ and CD8+ T lymphocytes of 401, 147, 95 and 100/mm(3), respectively. Analysis of outcome of 32 on protocol patients after 36 months versus 32 concurrent institutional H and NSCC controls showed delayed recurrences and significant increases in mean survival time (MST) and survival (p's
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- 2003
9. Immunodeficiency and cancer: prospects for correction
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John W. Hadden
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Pharmacology ,Immunity, Cellular ,Thymic involution ,Cellular immunity ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Immunologic Deficiency Syndromes ,Cancer ,Immunotherapy ,Biology ,medicine.disease ,Cytokine ,Immune system ,Adjuvants, Immunologic ,Antigen ,Neoplasms ,medicine ,Animals ,Humans ,Immunology and Allergy ,Immunodeficiency - Abstract
Cellular immunodeficiency is associated with human cancer. Extensive reviews on cancer of the head and neck, lung, esophagus and breast convince the author that for these diseases the immunodeficiency is reasonably well established yet the mechanisms are poorly understood. Evidence indicates that other tumors are similarly associated with cellular immune deficiency. The advent of recombinant cytokines and of antitumor monoclonal antibodies has served to focus attention toward direct tumoricidal mechanisms. As tumor antigens relating to cellular and humoral immune mechanisms are being defined and vaccine strategies are increasingly being attempted, it is critical to confront issues of the mechanism of anergy and effective immunorestoration in order to maximize the potential of cellular immune response to address these tumor antigens. Intrinsic to this approach is the introduction of contrasuppressive therapy to alleviate the tumor-associated immune suppression. Encouraging attempts have been made with plasmapheresis, indomethacin, low-dose cyclophosphamide, anti CTLA-4, anti FAS ligand and, perhaps in the future, more judiciously applied chemotherapy. In contrast to the popular notion that thymic involution cannot be reversed in the adult, studies from the author's laboratory indicate that in aged hydrocortisone stressed mice, a natural Type 1-cytokine mixture (IRX-2) hastens the reversal of thymic involution and promotes T-cell responses to cytokines and mitogens. Recombinant IL-1 and IL-2 by themselves, and in combination, were inactive. Similar positive effects were observed with oral zinc, zinc-thymulin and thymosin alpha(1). The combination of a natural cytokine mixture (IRX-2) with thymosin alpha1 had a very large effect and increased the absolute number of peripheral T lymphocytes as measured in the spleen. In studies of combination immunotherapy in lymphocytopenic squamous cell head and neck cancer patients using IRX-2 (18 patients) and IRX-2 plus thymosin alpha(1) (IRX-3) in IRX-2-refractory patients (7 patients), marked increases in CD(45)RA(+) 'naive' T cells (>250/mm(3)) were observed. These are among the first insights into how to generate T lymphocyte replacement in the adult. These and many other experimental efforts point to ways to achieve more effective immunotherapy of human cancer in the future, particularly if tumor-induced immune deficiency can be effectively addressed.
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- 2003
10. T cell immunostimulation by methyl inosine 5′-monophosphate: application to infectious diseases
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John W. Hadden and Kathy L. Signorelli
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Pharmacology ,Aging ,Cellular immunity ,Influenza vaccine ,T-Lymphocytes ,Viral Vaccine ,Immunology ,Immunosenescence ,Biology ,Communicable Diseases ,Virology ,Vaccination ,Immune system ,Adjuvants, Immunologic ,Inosine Monophosphate ,Infectious disease (medical specialty) ,medicine ,Animals ,Humans ,Immunology and Allergy ,Immunization ,Inosine ,medicine.drug - Abstract
Methyl inosine 5'-monophosphate (MIMP) was designed and synthesized in an endeavor to generate compounds with immunostimulatory activity based on the precedent of purines, particularly inosine playing a central role in the development and function of the immune system. This review will summarize the immune-enhancing effects of MIMP on a variety of immunological responses both in vitro and in vivo. Among these studies, MIMP displays protective effects in several in vivo models of infectious disease following administration by one of several routes including oral. Furthermore, MIMP enhanced responses to Hepatitis B and influenza vaccines. Vaccination represents an extremely powerful tool for combating a variety of diseases, perhaps even cancer. However, to date, vaccines have been limited by their inability to produce cell-mediated responses and by the low immunogenicity of soluble/subunit antigens. In addition, there are difficulties in eliciting sufficient responses in immunocompromised individuals, which includes the elderly, due to the natural immunosenescence that occurs with aging. The data described here suggest that MIMP could be used to overcome some of these limitations. The application of MIMP as an adjuvant to the influenza vaccine, focusing on the elderly, at-risk populations will be discussed in more detail; however, several other bacterial and viral vaccine and/or disease targets merit further consideration.
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- 2003
11. Lymph node histology in head and neck cancer: impact of immunotherapy with IRX-2
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Jaime de la Garza, John W. Hadden, Jose Luis Barrera, Emma Verastegui, and Abelardo Meneses
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Adult ,Male ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,T cell ,Indomethacin ,Immunology ,Antineoplastic Combined Chemotherapy Protocols ,Biopsy ,medicine ,Humans ,Immunology and Allergy ,Neoplasms, Squamous Cell ,Cyclophosphamide ,Lymph node ,B cell ,Aged ,Aged, 80 and over ,Pharmacology ,medicine.diagnostic_test ,business.industry ,Immunotherapy ,Middle Aged ,Tumor antigen ,Zinc ,medicine.anatomical_structure ,Epidermoid carcinoma ,Chemotherapy, Adjuvant ,Head and Neck Neoplasms ,Cytokines ,Female ,Lymph Nodes ,Lymph ,business - Abstract
To determine if lymph nodes (LN) of patients receiving IRX-2 immunotherapy reflect changes in histology.National Cancer Institute, Mexico City, Mexico.Thirty patients with advanced squamous cell carcinoma of the head and neck (H and N SCC) and 10 non-cancer controls.A 21-day cycle of preoperative immunotherapy, including a single intravenous infusion of low-dose cyclophosphamide (300 mg/M(2)), 10 or 20 daily perilymphatic injections of a natural cytokine mixture (IRX-2) (approximately 200 U interleukin-2 equivalence by enzyme-linked immunosorbent assay), daily oral indomethacin, and daily oral zinc with multivitamins, followed by surgery (20 patients); surgery only (10 patients); LN biopsy controls (10).Pretreatment biopsies were performed to confirm the diagnosis. Clinical responses were assessed at surgery, and the specimen and a sample of lymph node were analyzed with respect to changes in morphology and lymphoid and inflammatory infiltration (T and B lymphocytes, plasma cells, macrophages, granulocytes, and giant cells). The postsurgical characteristics were ascribed percentages based on a representative section and compared.All 20 H and N SCC patients treated with IRX-2 showed the changes of immune regression of their tumors, previously characterized [Arch. Pathol. Lab. Med. 122 (1998) 447]. The 10 H and N SCC controls showed no such changes. Lymph node histology of the 10 H and N SCC controls showed, compared to non-cancer controls, reduced size, decreased T cell area and density and increased sinus histiocytosis. The lymph nodes of IRX-2-treated H and N SCC patients showed increased size (over both control groups), increased T cell area and density and decreased follicles and sinus histiocytosis. The T cell and/or B cell areas of LN of IRX-2-treated patients showed a high correlation with T and/or B cell infiltration into these tumors (p0.001).The lymph nodes of patients with H and N SCC are distinguished by T cell depletion and sinus histiocytosis (SH). Immunotherapy reverses these changes and induces nodal expansion and lymphoid infiltration into the tumor that correlates with LN changes. The correlation of nodal expansion with tumor lymphoid infiltration and regression implies an effective immunization to host tumor antigens occurring at the level of the regional lymph node. The reversal of sinus histiocytosis, by IRX-2 treatment, in association with nodal expansion suggests that tumor antigen processing via dendritic cells is defective in cancer-bearing patients and that it is corrected by the treatment.
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- 2003
12. A pilot study of perilymphatic leukocyte cytokine mixture (IRX-2) as neoadjuvant treatment for early stage cervical carcinoma: preliminary report
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Emma Verastegui, Alfonso Dueñas-González, Aida Mota, John W. Hadden, A. Chavez-Blanco, Aurora González, J. L. Barrera-Franco, José Chanona, Abelardo Meneses, J de la Garza, and Carlos Lopez-Graniel
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Pharmacology ,Cervical cancer ,Chemotherapy ,Pathology ,medicine.medical_specialty ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Immunotherapy ,medicine.disease ,Cytokine ,medicine ,Carcinoma ,Immunology and Allergy ,Adenocarcinoma ,business ,Neoadjuvant therapy ,medicine.drug - Abstract
Clinical and experimental data demonstrate that local cytokines are able to induce tumor regression and in some cases antitumor systemic immune response. IRX-2 is a cell-free mixture of cytokines obtained from unrelated donor lymphocytes with demonstrated ability to induce immune mediated regression of squamous cell carcinomas of head and neck. The objective of this study was to evaluate the antitumor activity and toxicity of IRX-2 in untreated early stage cervical cancer patients. Ten consecutive patients clinically staged IB1, IB2 and IIA were treated with a neoadjuvant immunotherapy regimen that consisted in a single IV dose of cyclophosphamide at 300 mg/m2 on day 1, oral indomethacin or ibuprofen and zinc sulfate were administered from days I to 21 and 10 regional perilymphatic injections of IRX-2 on days 3 to 14. All patients were scheduled for radical hysterectomy on day 21. The clinical and pathological responses, toxicity and survival were evaluated. Clinical response was seen in 50% of patients (three partial responses, two minor responses). Seven patients underwent surgery and pathological tumor reduction associated with tumor fragmentation was found in five cases. Histological studies demonstrated a rather heterogeneous cell type infiltrating pattern in the tumor which included lymphocytes, plasma cells, neutrophils, macrophages and eosinophils. Immunohistochemical analysis of the surgical specimens demonstrated an increase of tumor infiltrating CD8+ cells. The treatment was well tolerated except for mild pain and minor bleeding during injections and gastric intolerance to indomethacin. At 31 months of maximum follow-up (median 29), eight patients are disease-free. Our results suggest that the immunotherapy approach used induces tumor responses in cervical cancer patients. Further studies are needed to confirm these results as well as to elucidate the mechanisms underlying these effects.
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- 2002
13. Protection by methyl inosine monophosphate (MIMP) against aerosol influenza virus infection in mice
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John W. Hadden and K. Noel Masihi
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Aerosols ,Pharmacology ,Immunology ,Orthomyxoviridae ,Biology ,biology.organism_classification ,Virology ,Virus ,Survival Rate ,Mice ,Titer ,Route of administration ,Immune system ,Orthomyxoviridae Infections ,Influenza A virus ,Inosine Monophosphate ,biology.protein ,Animals ,Immunology and Allergy ,Female ,Nasal administration ,Antibody ,Viral load - Abstract
Methyl inosine monophosphate (MIMP) is a novel thymomimetic purine immunomodulator capable of enhancing a wide variety of immune responses. Intravenous (i.v.) administration of MIMP 1 day prior to influenza virus infection could confer partial protection and significantly increase the mean survival of treated mice. Intranasal (i.n.) administration of MIMP improved survival rates and incorporation of MIMP in squalane-saline emulsion 1 day prior to or 1 h after influenza infection conferred complete protection. Mice administered MIMP had reduced levels of lung virus and lower titers of circulating serum hemagglutination-inhibition (HI) antibodies. Complete survival and reduction of viral load after influenza challenge infection suggests effective stimulation by MIMP of protective responses against influenza virus.
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- 2002
14. Immunomodulatory properties of Mycoplasma pulmonis
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S. Estrada-Parra, Jorge Reyes-Esparza, John W. Hadden, and A. Romero-Rojas
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Pharmacology ,medicine.medical_treatment ,Lymphocyte ,Immunology ,Mycoplasma hominis ,Biology ,biology.organism_classification ,Microbiology ,Membrane ,Cytokine ,medicine.anatomical_structure ,Immune system ,medicine ,Mycoplasma pulmonis ,Immunology and Allergy ,Interferon gamma ,Interleukin 4 ,medicine.drug - Abstract
Experiments are presented that were performed in order to understand the mechanisms causing these effects on the immune system. Mitogenic effects of Mycoplasma membranes on mouse spleen cells were shown using M. capricolum . The observed mitogenic activity is proportional to the amount of membranes used, as measured by protein content. Separation of T and B cells was performed by two techniques, the anti-Thy1.2 plus complement method and the Dynabead technique. Using the former technique, it was shown that removal of T cells markedly reduced effects of stimulation by mycoplasma membranes, but did not abolish it. The separated cells were still stimulated by PHA, indicating that the preparation still contained T cells. Furthermore, removal of T cells preferentially reduced the PHA response over that of mycoplasma membranes, indicating that mycoplasma membranes stimulate both B and T lymphocytes. The Dynabead system was found to be the more efficient separation technique, and by using it we were able to make the following observations. Inactivated Mp, membranes and culture supernatant stimulated B cells, whereas T cells were only slightly stimulated by inactivated Mp and membranes. There was an increase in proliferation when T cells were incubated with adherent cells from peripheral blood. Finally, we showed that spleen cells from infected animals produce more IL-4 and less IFN-γ than cells from non-infected animals when stimulated with membranes, inactivated Mp, culture supernatant or phytohemagglutinin. Altogether, these results show that lymphocytes from Mycoplasma -infected animals are directly affected and this effect is probably due to superantigen-like molecules from M. pulmonis .
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- 2001
15. Immunomodulatory properties of Mycoplasma pulmonis
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John W. Hadden, C. Ponce-Hernández, S. Estrada-Parra, A. Ciprián, and A. Romero-Rojas
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Pharmacology ,biology ,Lymphocyte ,Immunology ,Antibody titer ,Spleen ,Mycoplasma hominis ,Mycoplasma ,biology.organism_classification ,medicine.disease_cause ,Microbiology ,medicine.anatomical_structure ,Immune system ,Antigen ,medicine ,Mycoplasma pulmonis ,Immunology and Allergy - Abstract
For many years, it has been recognized that Mycoplasma infection affects the host's immune system in different ways. In this work, experiments were performed to characterize the influence of Mycoplasma pulmonis infection on various immunological parameters and to follow the kinetics of their variations. A Balb/c mouse model was used to assess hematological evaluations, changes in spleen weight, antibody responses against sheep erythrocytes, neutrophil phagocytosis, colloidal carbon clearance, and anti-Mycoplasma antibody responses. At the hematological level, infected animals were found to have significantly increased total lymphocyte and polymorphonuclear leukocyte counts and an augmentation in spleen weight. Seven days after Mycoplasma infection, antibody responses against sheep erythrocytes were considerably diminished, and at days 7 and 14 after infection, phagocytic activity was also reduced. After 1 week of infection, the colloidal carbon clearance pattern was decreased, and during the whole infectious process, anti-Mycoplasma antibody titers were found to be low. Results from this part of research show a persistent infection that does not resolve in a short period, which is associated with a general dysfunction in the immune system and poor immune responses against several different antigens.
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- 2001
16. Immunomodulatory properties of Mycoplasma pulmonis
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C. Ponce-Hernández, S E Mendoza, J A Reyes-Esparza, John W. Hadden, A. Romero-Rojas, and S. Estrada-Parra
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Pharmacology ,biology ,Immunology ,Mycoplasmataceae ,Mycoplasma hominis ,Mycoplasma ,biology.organism_classification ,medicine.disease_cause ,Microbiology ,Immune system ,Delayed hypersensitivity ,Humoral immunity ,Mycoplasma pulmonis ,medicine ,Immunology and Allergy ,CD8 - Abstract
Mycoplasma infection affects the host's immune system in different ways. In this work, a kinetic approach was used to try to determine the mechanisms by which Mycoplasma cause these effects. Experiments were performed using Balb/c mice infected with Mycoplasma pulmonis and several immunological parameters were determined. It was found that at days 10 and 15 post-infection, there were significant changes in the percentages of CD4+ and CD8 + cells, in both peripheral blood and the thymus. Significant sequential increases in concentrations of both IFN-gamma and IL-4 were detected in sera, such that at day 15, there was a peak in IFN-gamma, concentration and at day 38, IL-4 concentration also peaked. By day 46, both IFN-gamma and IL-4 fell to control levels despite continued infection. Delayed hypersensitivity (DTH) was reduced in infected animals compared to non-infected controls. A small recovery in DTH was observed at day 30, which was reduced again by day 40. Altogether, the results show features of a transitional shift from Th1 to Th2 in animals that are ultimately immunologically incompetent (in both cellular and humoral immunity). It appears to be this state of incompetence that allows the microorganism to survive and thus provides an explanation for the chronic state of the disease, which is a characteristic of Mycoplasma infection.
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- 2001
17. Aspects of the immunopharmacology of thymosin α1
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John W. Hadden
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business.industry ,medicine.medical_treatment ,Immunology ,T lymphocytopenia ,Cancer ,medicine.disease ,Microbiology ,Immunopharmacology ,Infectious Diseases ,Immune system ,Cytokine ,Immunology and Allergy ,Medicine ,business ,Immunodeficiency ,Thymosin α1 - Abstract
In this report some of the salient features of thymosin-α 1 's immunopharmacology are summarized. Our studies have shown that therapy using IRX-3 (a combination of thymosin-α 1 with IRX-2—natural cytokine mixture) produced more dramatic effects than either alone in reversing immunodeficiency in aged mice. If these effects translate into the human, we would anticipate that we would observe correction of T lymphocytopenia and to do so at least in part by promoting development and exodus from the thymus of recent thymic emigrees. We expect that IRX-3 will find use in a variety of conditions associated with cellular immune deficiency including infections and cancer.
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- 2001
18. Clinical and pathological bio-responses induced with a cytokine mixture (IRX-2) in patients with oral cavity squamous cell carcinoma
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Abelardo Meneses, Jose Luis Barrera, John W. Hadden, Emma Verastegui, J de la Garza, and Juan Zinser
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Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Lymphocyte ,Immunology ,Immunotherapy ,medicine.disease ,Microbiology ,Infectious Diseases ,Immune system ,Cytokine ,medicine.anatomical_structure ,Toxicity ,Biopsy ,medicine ,Immunology and Allergy ,Oral Cavity Squamous Cell Carcinoma ,business ,Infiltration (medical) - Abstract
Twenty three adults with recently diagnosed, biopsy confirmed oral cavity squamous cell carcinoma (OCSCC), were treated with a sterile, endotoxin-free, serum-free mixture of natural cytokines (IRX-2) in a 21 day cycle prior to surgery. Tumor dimension, toxicity and disease free survival were monitored. Tumor histology including tumor reduction, fragmentation and lymphoid infiltration were also assessed in the original biopsy and following surgery. The number of blood vessels were in the initial biopsies and in the surgical specimen were counted. All 23 patients responded clinically with a decrease in the size of tumor and reduction in pain. Twenty responded with the healing of ulcerated lesions. Histological responses included lymphocyte infiltration and tumor fragmentation and a decrease in the number of vessels (in 14 of 17 patients evaluated). The latter observation correlated with decreased bleeding. Improvement of immunologic parameters with increased CD3, CD4 and CD8 T lymphocyte counts occurred. The IRX-2 immunotherapy induced lymphocyte mobilization and infiltration in OCSCC associated with clinical and histological tumor responses indicative of immune regression. Minimal toxicity was observed. A Phase III trial seems warranted.
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- 2001
19. Review Article The immunology and immunotherapy of breast cancer: an update
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John W. Hadden
- Subjects
Pharmacology ,Tumor-infiltrating lymphocytes ,business.industry ,medicine.medical_treatment ,Immunology ,Cancer ,Immunotherapy ,medicine.disease ,Breast cancer ,Immune system ,Antigen ,medicine ,Adenocarcinoma ,business ,Adjuvant - Abstract
Adenocarcinomas of the breast behave clinically and epidemiologically in ways that show host resistance factors are important for outcome in addition to grade and stage of malignancy. Immune reactivity to autologous tumors is indicated by the general presence of lymphoid infiltration (LI) and regional lymph node changes; however, these changes predict favorable outcome only in non-metastatic disease. LI is characterized by CD4+ and CD8+ tumor infiltrating lymphocytes reflecting latent cell-mediated immunity (CMI). CMI and humoral immune reactivity have been demonstrated to autologous tumor and a variety of tumor-associated antigens (TAA) have been implicated including CEA, HER-2/neu, MAGE-1, p53, T/Tn and MUC-1. Immune incompetence involving CMI is progressive with the stage of breast cancer and is prognostically significant. Immunotherapy of several types has been designed to address this immunodeficiency and the TAAs involved. Animal models have employed drug therapy, cytokine transfection, vaccines with autologous tumor, cytokines like interferon alpha (IFN-alpha) and interleukin-2 (IL-2), TAA tumor vaccines, and immunotoxins with evidence of tumor regression by immunologic means. Immunotherapy of human breast cancer is a rapidly growing experimental area. Positive results have been obtained with natural IFN and interleukins, particularly in combination strategies (but not with high dose recombinant IFN or IL-2), with autologous tumor vaccine (but not yet with transfected autologous tumor); with a mucin carbohydrate vaccine (Theratope) in a combination strategy (but not with mucin core antigen) and with several immunotoxins. Combination strategies involving immunorestoration, contrasuppression, adjuvant, and immunotoxins are suggested for the future.
- Published
- 1999
20. The immunopharmacology of head and neck cancer: an UPDATE
- Author
-
John W. Hadden
- Subjects
Cellular immunity ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Antineoplastic Agents ,Immune system ,Adjuvants, Immunologic ,Antigen ,Antigens, Neoplasm ,Immune Tolerance ,medicine ,Humans ,Pharmacology ,biology ,business.industry ,Immunotherapy ,Immunopharmacology ,Epidermoid carcinoma ,Head and Neck Neoplasms ,Humoral immunity ,Carcinoma, Squamous Cell ,biology.protein ,Lymph Nodes ,Antibody ,business ,Immunocompetence - Abstract
Patients with head and neck squamous cell cancer have cell-mediated immune defects and anergy, which progress with disease. T-lymphocytopenia and dysfunction, monocyte dysfunction, prostaglandins, antigen–antibody complexes, serum and cell suppressive factors, radiation therapy and poor nutrition with zinc deficiency all contribute. Nevertheless, cell-mediated immunoreactivity to tumor is manifest in the majority of the patient’s blood and regional nodes, and in the tumor itself by tumor-infiltrating lymphocytes. Lymphocytes from these sources cloned in the presence of interleukin-2± tumor extracts show relatively specific cytotoxicity against squamous cell cancer. Humoral immunity is intact, and increased IgA and IgE levels and antibodies reactive to tumor antigens are common. Tumor-associated antigens detected in serum and tumor include carcinoembryonic antigen, tumor polypeptide antigen, squamous cell cancer antigens, tumor antigen-4 and various mucin antigens. The mucin antigens, in particular, can elicit T-cell responses. Humoral reactivity to such antigens is manifest in circulating immune complexes and immunoglobulin coating of tumor surfaces. Immunotherapeutic efforts in head and neck squamous cell cancer should logically employ T-cell adjuvants, contrasuppression and immunorestoration. Non-specific stimulation with bacille Calmette–Guerin (BCG), levamisole and other agents has not been successful. Encouraging results have been observed in limited trials with indomethacin and plasmapheresis. Early trials with local administration of low dosages of interferon- α , natural interleukin-2 and a natural interleukin mixture have produced partial and complete regressions with no toxicity and with intense leukocyte infiltration indicating cellular immunity. Efforts are needed to define the mechanisms and the antigens involved in these reactions. On the contrary, treatments with high dosages of recombinant interferon- α and interleukin-2 have yielded few responses and considerable toxicity. Combination strategies are discussed which may improve upon these initial immunotherapeutic effects of these low dose trials.
- Published
- 1998
21. The Immunology of Breast Cancer
- Author
-
John W. Hadden
- Subjects
biology ,medicine.medical_treatment ,Cancer ,Immunotherapy ,medicine.disease ,Breast cancer ,Immune system ,Antigen ,Immunity ,Immunology ,medicine ,biology.protein ,Immunology and Allergy ,Adenocarcinoma ,Pharmacology (medical) ,Antibody - Abstract
Adenocarcinoma of the breast is a major cancer of women. Evidence indicates that breast cancers may be latent for long periods, perhaps as a result of host response. Based upon an extensive review of the available literature, it appears that breast cancers are immunogenic and that host reactions to the antigens involved determine prognosis. Breast cancers generally show lymphocyte infiltration. These tumour-associated lymphocytes correlate with prognosis when histological grade and clinical stage are controlled for as variables. The interpretation of secondary changes in regional lymph nodes is controversial. The data indicate prognostically significant reactions reflecting immunity. Tumour-associated lymphocytes from tumour and regional nodes are T lymphocytes that are suppressed in their function, presumably by factors derived from both the patients’ tumour and tumour-immune cell interaction. However, when they are grown in interleukin-2 they can show a high degree of antitumour reactivity. Studies of patients’ immune competence show progressive cellular immune deficiency which correlates with prognosis. A variety of human studies in vitro and in vivo show both cellular and humoral immune reactions to tumour-associated antigens. Tumour markers and antigens include HER-2/neu, P53, mucin carbohydrates and peptides, mouse mammary tumour virus-related peptides and other less well characterised antigens. Murine models for breast cancer show a similar immunological picture and provide a proving ground for testing immunotherapeutics. Early immunotherapy of breast cancer in humans was not successful; however, recent efforts using combinations involving tumour vaccines, adjuvants, contrasuppression, thymic hormones and natural interleukins are encouraging.
- Published
- 1995
22. The treatment of zinc deficiency is an immunotherapy
- Author
-
John W. Hadden
- Subjects
Pharmacology ,Thymic Factor, Circulating ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,chemistry.chemical_element ,Immunotherapy ,Zinc ,Biology ,medicine.disease ,chemistry ,Zinc deficiency ,medicine ,Animals ,Humans ,Deficiency Diseases - Published
- 1995
23. Methyl inosine monophosphate (MIMP) augments T-lymphocyte mitogen responses and reverses various immunosuppressants
- Author
-
Ronald G. Coffey, Alfredo Giner-Sorolla, Marina Sosa, John W. Hadden, Yulai Wang, and Elba M. Hadden
- Subjects
medicine.medical_specialty ,Lipopolysaccharide ,medicine.drug_class ,T-Lymphocytes ,Lymphocyte ,Immunology ,Prostaglandin ,HIV Infections ,Pharmacology ,Biology ,Antiviral Agents ,Immunostimulant ,Dinoprostone ,Mice ,chemistry.chemical_compound ,Inosine Monophosphate ,In vivo ,Internal medicine ,medicine ,Animals ,Humans ,Cells, Cultured ,Dose-Response Relationship, Drug ,Interferon-alpha ,T lymphocyte ,In vitro ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Mitogens ,Immunosuppressive Agents ,Spleen ,CD8 - Abstract
Methyl inosine monophosphate (MIMP) augments preferentially the in vitro responses of human and murine lymphocytes to a T-cell mitogen such as phytohemagglutinin (PHA) and inconsistently to a B-cell mitogen such as pokeweed or lipopolysaccharide (LPS). In a normal interleukin-2-dependent cell line (CTLL), MIMP showed little or no effect on IL-2 action; however, in a murine CTLL line exhibiting impaired responses to IL-2, MIMP stimulated thymidine incorporation and restored the response to IL-2. MIMP augments the PHA responses of both CD4+ and CD8+ human peripheral blood T-cells. The effect of MIMP to augment the PHA response of human lymphocytes is paralleled by the parent molecule, IMP. MIMP, but not IMP, is resistant to hydrolysis by 5'nucleotidase; thus, MIMP appears to be a protected analogue of IMP which is capable of in vivo action. MIMP (100 micrograms/ml) augments the PHA responses of 15 to 24 elderly humans. MIMP also augments the PHA responses of eight HIV-infected pre-AIDS patients but not of eight AIDS patients. When PHA responses of human lymphocytes are suppressed in vitro by an HIV-derived immunosuppressive peptide, interferon alpha, or prostaglandin PGE2, MIMP (0.1-100 micrograms/ml) progressively restores the depressed response; however, when the suppression is severe (greater than 50%), MIMP cannot restore the response. These data indicate that MIMP potentiates normal T-lymphocyte mitogen responses and restores those impaired by a variety of inflammatory and immunosuppressive influences.
- Published
- 1995
24. Immunology of Head and Neck Cancer
- Author
-
John W. Hadden
- Subjects
Monocyte ,Mucin ,Biology ,Immune system ,Carcinoembryonic antigen ,medicine.anatomical_structure ,Antigen ,Immunology ,Humoral immunity ,biology.protein ,medicine ,Immunology and Allergy ,Pharmacology (medical) ,Antibody ,Cytotoxicity - Abstract
Patients with squamous cell cancer of the head and neck region frequently have cell-mediated immune defects and anergy, which progress with disease. T lymphocytopenia and dysfunction, monocyte dysfunction, prostaglandins, antigen-antibody complexes, serum and cell suppressive factors, radiation therapy and poor nutrition with zinc deficiency all play a role. However, cell-mediated immunoreactivity to tumour is manifest in the majority of patients in blood and regional nodes, and in the tumour itself by tumour-infiltrating lymphocytes. Lymphocytes from these sources cloned in the presence of interleukin-2 ± tumour extracts show relatively specific cytotoxicity against squamous cell cancer. Humoral immunity is intact, and increased IgA levels and antibodies reactive to tumour antigens are common. Tumour-associated antigens detected in tumour and serum include carcinoembryonic antigen, tumour polypeptide antigen, squamous cell cancer antigen, tumour antigen-4 and various mucin antigens. The mucin antigens, in particular, elicit T cell cytotoxicity.
- Published
- 1995
25. Cell-Free Thymic Extract from Hypertensive Rats Induces Hypertension in Normotensive Rats
- Author
-
Marie D. Sauro and John W. Hadden
- Subjects
Male ,medicine.medical_specialty ,Immunology ,Endogeny ,Thymus Gland ,Cell free ,In Vitro Techniques ,Toxicology ,Immune Dysfunction ,Rats, Inbred WKY ,Thymus Extracts ,Rats, Sprague-Dawley ,Spontaneously hypertensive rat ,In vivo ,Rats, Inbred SHR ,Internal medicine ,medicine.artery ,medicine ,Animals ,Immunology and Allergy ,Aorta ,Pharmacology ,business.industry ,General Medicine ,Rats ,Blood pressure ,Endocrinology ,Vasoconstriction ,Hypertension ,medicine.symptom ,business - Abstract
This study examined the role of the thymus in hypertension. Seven to eight week old, normotensive Wistar-Kyoto rats (WKYs) (systolic blood pressure 138 +/- 7 mm Hg) received a bolus injection of (1) WKY thymic extract (control), (2) spontaneously hypertensive rat (SHR) thymic extract, (3) SHR liver extract or (4) normotensive Sprague-Dawley rat (SD) thymic extract. Blood pressures of WKYs receiving SHR thymic rose significantly (p < 0.01) over an eight week period (168 +/- 6 mm Hg), while WKYs injected with WKY thymic extract (143 +/- 10), SHR liver extract (144 +/- 5) or SD thymic extract (138 +/- 4) showed no change in blood pressure. Thymuses from WKYs injected with SHR extract were significantly (p < 0.01) smaller than thymuses from WKYs injected with WKY extract. Aorta from WKYs administered SHR extract were significantly (p < 0.01) hyperresponsive to contractile agents, suggesting that immune dysfunction may lead to vascular damage as seen in several hypertensive models. The results suggest that hypertension can be transferred via an endogenous thymic factor, possibly a viral pathogen.
- Published
- 1995
26. T-cell adjuvants
- Author
-
John W. Hadden
- Subjects
Cellular immunity ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,Immunology ,Epitope ,chemistry.chemical_compound ,Adjuvants, Immunologic ,Animals ,Humans ,Medicine ,Hypersensitivity, Delayed ,AIDS Vaccines ,Pharmacology ,biology ,business.industry ,Interleukins ,Immunotherapy ,Thymus Hormones ,Cytokine ,medicine.anatomical_structure ,chemistry ,biology.protein ,Vaccinia ,Antibody ,business ,Adjuvant - Abstract
T-cell adjuvancy involves the use of agents to stimulate preferentially delayed type hypersensitivity (DTH). Traditional adjuvants like Alum, Freunds, muramyl peptides, and endotoxins are not selective. Natural infection (e.g. vaccinia) may yield selective DTH. Low dose cyclophosphamide (CY) with mycobacteria was the first experimental T-cell adjuvant. New adjuvant formulations (ISCOMS, MAPS, etc.) with synthetic T-cell epitopes offer improved formulations. Upregulation of TH-1 helper cells and their actions with interleukins like IL-2, IL-12, and gamma IFN or antibodies to IL-4 and IL-10 may augment potently pathogen and tumor resistance. Similarly, transfection of tumor target cells with genes for IL-2, IL-12, gamma IFN, etc., offers novel vaccine treatment approaches. Finally, "thymomimetic" peptides like thymosin alpha 1 or drugs like levamisole or isoprinosine alone or in conjunction with interleukins may augment TH-1 and DTH responses. These approaches are seeing increasing emphasis in new treatment strategies for cancer and infections like HIV.
- Published
- 1994
27. A short course of neoadjuvant IRX-2 induces changes in peripheral blood lymphocyte subsets of patients with head and neck squamous cell carcinoma
- Author
-
Neil L. Berinstein, Paul H. Naylor, Lorraine Baltzer, Gregory T. Wolf, John W. Hadden, Lisa H. Butterfield, Theresa L. Whiteside, and James E. Egan
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,Lymphocyte ,medicine.medical_treatment ,Immunology ,Phases of clinical research ,Article ,Immune system ,Lymphocytes, Tumor-Infiltrating ,T-Lymphocyte Subsets ,Internal medicine ,medicine ,Carcinoma ,Immunology and Allergy ,Humans ,Neoadjuvant therapy ,business.industry ,Cancer ,medicine.disease ,Head and neck squamous-cell carcinoma ,Neoadjuvant Therapy ,medicine.anatomical_structure ,Head and Neck Neoplasms ,Peripheral blood lymphocyte ,Carcinoma, Squamous Cell ,Cytokines ,business - Abstract
IRX-2, a primary cell-derived biologic with pleotropic immune activity, was shown to induce increased lymphocyte infiltrations into the tumor of patients with head and neck squamous cell cancer (HNSCC) after 10 days of neoadjuvant therapy (Berinstein et al. 2011). In the same patients enrolled in the Phase II study, peripheral blood lymphocyte subsets were monitored pre- and post-IRX-2 therapy to evaluate changes induced by IRX-2.Absolute lymphocyte numbers were determined in whole blood using the TetraONE System. Lymphocytes were further separated on Ficoll-Hypaque gradients and evaluated by multiparameter flow cytometry. Lymphocyte numbers, including regulatory T cells (Treg) and naïve, memory and effector T cells, were compared in pre- and post-therapy specimens.Total lymphocyte numbers remained unchanged after IRX-2 therapy. Significant changes occurred in numbers of circulating B cells and NKT cells, which decreased following IRX-2 therapy. The frequency of circulating Treg (CD4(+)CD25(high)) remained unaltered (e.g., 6.7 ± 0.6% vs. 7.5 ± 0.8%; means ± SEM) as was the CD8(+)/Treg ratio (6.6 before and 6.7 after IRX-2 therapy). The mean absolute number of CD3(+)CD45RA(+)CCR7(+) (naïve) T cells was decreased after IRX-2 therapy but numbers of total memory (i.e., central and peripheral) and terminally differentiated T cells were unchanged.IRX-2-mediated reductions in B and NKT cell numbers in the blood suggest a redistribution of these cells to tissues. A decrease in naïve T cells implies their up-regulated differentiation to memory T cells. Unchanged Treg numbers after IRX-2 therapy indicate that IRX-2 does not expand this compartment, potentially benefiting anti-tumor immune responses.
- Published
- 2011
28. Immunopharmacologic Properties of Inosine 5'-Methyl Monophosphate (MIMP)
- Author
-
John W. Hadden, Alfredo Giner-Sorolla, Marina Sosa, Elba M. Hadden, and Anutosh R. Saha
- Subjects
Immunity, Cellular ,Chemistry ,T-Lymphocytes ,General Neuroscience ,Immunity ,Lymphocyte Activation ,Antiviral Agents ,General Biochemistry, Genetics and Molecular Biology ,History and Philosophy of Science ,Biochemistry ,Inosine Monophosphate ,Antibody Formation ,medicine ,Animals ,Humans ,Inosine ,medicine.drug - Published
- 1993
29. Novel neoadjuvant immunotherapy regimen safety and survival in head and neck squamous cell cancer
- Author
-
Michael J. Kaplan, John W. Hadden, Gregory T. Wolf, William R. Carroll, Paul M. Spring, Robert W. Dolan, Lorraine Baltzer, Terry D. Kirkley, Scott M. Freeman, Harvey Brandwein, M. Boyd Gillespie, Jeffrey S. Moyer, James Y. Suen, Jason G. Newman, Daniel E. Kenady, and Willard E. Fee
- Subjects
Oncology ,Adult ,Male ,Cellular immunity ,medicine.medical_specialty ,Pathology ,Cyclophosphamide ,medicine.medical_treatment ,Injections, Subcutaneous ,Indomethacin ,Interleukin-1beta ,Antineoplastic Agents ,Gluconates ,Disease-Free Survival ,Drug Administration Schedule ,Article ,Interferon-gamma ,Internal medicine ,Carcinoma ,medicine ,Humans ,Survival rate ,Neoadjuvant therapy ,Aged ,business.industry ,Tumor Necrosis Factor-alpha ,Immunotherapy ,Middle Aged ,medicine.disease ,Head and neck squamous-cell carcinoma ,Neoadjuvant Therapy ,Survival Rate ,Regimen ,Otorhinolaryngology ,Head and Neck Neoplasms ,Carcinoma, Squamous Cell ,Cytokines ,Interleukin-2 ,Female ,business ,medicine.drug - Abstract
Cellular immune suppression is observed in head and neck squamous cell cancer (HNSCC) and contributes to poor prognosis. Restoration of immune homeostasis may require primary cell-derived cytokines at physiologic doses. An immunotherapy regimen containing a biologic, with multiple-active cytokine components, and administered with cytoxan, zinc, and indomethacin was developed to modulate cellular immunity.Study methods were designed to determine the safety and efficacy of a 21-day neoadjuvant immunotherapy regimen in a phase 2 trial that enrolled 27 therapy-naïve patients with stage II to IVa HNSCC. Methods included safety, clinical and radiologic tumor response, disease-free survival (DFS), overall survival (OS), and tumor lymphocytic infiltrate (LI) data collection.Acute toxicity was minimal. Patients completed neoadjuvant treatment without surgical delay. By independent radiographic review, 83% had stable disease during treatment. OS was 92%, 73%, and 69% at 12, 24, and 36 months, respectively. Histologic analysis suggested correlation between survival and tumor LI.Immunotherapy regimen was tolerated. Survival results are encouraging.
- Published
- 2010
30. Mechanisms of T-cell protection from death by IRX-2: a new immunotherapeutic
- Author
-
Harvey Brandwein, John W. Hadden, Miroslaw J. Szczepanski, Marta Szajnik, Malgorzata Czystowska, Karen Quadrini, and Theresa L. Whiteside
- Subjects
Cancer Research ,Programmed cell death ,T cell ,medicine.medical_treatment ,T-Lymphocytes ,Immunology ,Blotting, Western ,Apoptosis ,Enzyme-Linked Immunosorbent Assay ,Cell Separation ,Biology ,Exosome ,Jurkat cells ,Article ,Cell Line ,Jurkat Cells ,Cell Line, Tumor ,medicine ,Immunology and Allergy ,Humans ,T lymphocyte ,Immunotherapy ,Flow Cytometry ,Microvesicles ,medicine.anatomical_structure ,Oncology ,Cytokines ,Signal Transduction - Abstract
IRX-2 is a novel immunotherapeutic containing physiologic quantities of several cytokines which protects human T lymphocytes from tumor-induced or drug-induced apoptosis. Here, we investigate the mechanisms responsible for IRX-2-mediated protection of T lymphocytes exposed to tumor-derived microvesicles (TMV).Jurkat cells or primary human T cells ± IRX-2 were co-incubated with TMV and then examined by flow cytometry or Western blots for expression of molecules regulating cell survival (FLIP, Bcl-2, Bcl-xL, Mcl-1) or death (Fas, caspase 8, caspase 9, Bax, Bid). ANX V binding, caspase activation or cytochrome c release were also measured ± cycloheximide (CHX) or ± the Akt-specific inhibitor. Jurkat cells transfected with the cFLIP gene were used to evaluate the role of cFLIP in IRX-2-mediated protection. Effects of CHX on IRX-2-mediated protection and activation of NF-κB upon the TMV/IRX-2 treatment were also measured.IRX-2 protected T cells from apoptosis by preventing Fas overexpression induced by TMV and blocking caspase 8 activation by up-regulating cFLIP. Jurkat cells overexpressing cFLIP were more resistant to TMV-induced apoptosis than the mock-transfected cells (p0.02). Signaling via the PI3K/Akt pathway, IRX-2 corrected the imbalance of pro- versus anti-apoptotic proteins induced by TMV and promoted NF-κB translocation to the nucleus. CHX abolished IRX-2-mediated protection in T cells, suggesting that IRX-2 induces de novo synthesis of one or more proteins that are required for protection.This biologic may be therapeutically useful for protection of activated T cells from tumor-induced immune suppression and death.
- Published
- 2010
31. Preclinical studies with IRX-2 and thymosin alpha1 in combination therapy
- Author
-
Paul H, Naylor and John W, Hadden
- Subjects
Thymosin ,Mice ,Adjuvants, Immunologic ,Thymalfasin ,Neoplasms ,T-Lymphocytes ,Animals ,Cytokines ,Humans ,Apoptosis ,Cell Differentiation ,Dendritic Cells - Abstract
Thymosin alpha1 (Talpha1) is a 28 amino acid biologically active protein with pleiotropic immune enhancing activity. IRX-2 is a primary cell-derived biologic containing multiple cytokines that enhance dendritic cell maturation, promote T-cell growth and differentiation, and inhibit tumor-mediated apoptosis of T cells. IRX-2 is being developed as an immunotherapeutic agent as a novel T-cell adjuvant platform for vaccines as well. Based on their biological activities, thymosin alpha1 and IRX-2 were predicted to exhibit synergistic effects when evaluated in animal and human studies. In animal studies, the combination of IRX-2 and Talpha1 (IRX-3) increased T-cell numbers compared to either alone during recovery from hydrocortisone mediated reduction. IRX-3 further enhanced reduction in tumor burden following chemotherapy compared to IRX-2. Based on these studies, IRX-3 is predicted to be especially important in a setting where reversal of immune suppression due to the presence of tumor, irradiation, and/or chemotherapy is likely to be an important factor in cytokine activity.
- Published
- 2010
32. IRX-2 increases the T cell-specific immune response to protein/peptide vaccines
- Author
-
April E. Nixon, Karla E. Hernandez, Paul H. Naylor, John W. Hadden, Ching Y. Wang, Harvey Brandwein, and Gabriel P. Haas
- Subjects
medicine.medical_treatment ,T cell ,T-Lymphocytes ,Biology ,Cancer Vaccines ,Interferon-gamma ,Mice ,Immune system ,Antigen ,Adjuvants, Immunologic ,medicine ,Animals ,Humans ,B cell ,Mice, Inbred BALB C ,General Veterinary ,General Immunology and Microbiology ,ELISPOT ,Public Health, Environmental and Occupational Health ,3T3 Cells ,Prostate-Specific Antigen ,Acquired immune system ,Infectious Diseases ,medicine.anatomical_structure ,Immunology ,Vaccines, Subunit ,Molecular Medicine ,Cytokines ,Female ,Cancer vaccine ,Adjuvant - Abstract
Therapeutic cancer vaccines are attractive due to the prospect of specificity and their lack of toxicity; however, their clinical development has been hampered by several biologic and clinical challenges. One of the most important biologic challenges is the relative lack of effective cellular immune adjuvants. Effective physiologic immune responses are characterized by the local generation of a complex cytokine environment that activates and regulates multiple immune cell types. IRX-2 is a primary cell-derived biologic with physiological levels of multiple active cytokine components, produced under pharmaceutical standards. The hypothesis that IRX-2 amplifies the T cell response to defined antigens was assessed in mice by measuring the T cell-specific peptide response to a dominant mouse peptide (NFT) derived from human prostate-specific membrane antigen (PSMA). IRX-2 enhances the T cell response to NFT when antigens were delivered either via irradiated cells expressing human PSMA, NFT peptide in Incomplete Freund's adjuvant (IFA) or NFT peptide conjugated to KLH. The T cell-specific activity was measured in spleen or lymph nodes cells by IFN-γ ELISpot and/or IFN-γ secretion over 6 days or in vivo by peptide-specific delayed-type hypersensitivity reaction (DTH). Further more, a single administration of IRX-2 with the antigen was not active as compared to 4 or 9 additional administrations which were sufficient to enhance the T cell response to antigens. The influence of IRX-2 on the B cell response to ovalbumin when it was used as a carrier protein was measured by ELISA. IRX-2 was compared to a commercially available combination adjuvant (MPL+TDM in squalene/Tween 80) which based on the literature is a potent adjuvant in murine systems. In the T cell assay IRX-2 was superior to the commercially available combination adjuvant and while IRX-2 also increased antibody titer, it was not as potent as the combination adjuvant. Mice immunized with IRX-2 and antigen also exhibited delayed tumor progression following challenge with PSMA-expressing tumor cells. These studies demonstrate that IRX-2 is an immunomodulator with adjuvant activity which preferentially enhances the T cell-specific responses to tumor associated antigens. Based on these studies, IRX-2 is a candidate for evaluation as a T cell adjuvant in a variety of preclinical vaccine delivery systems as well as in human clinical trials with cancer vaccine candidates.
- Published
- 2010
33. Gamma-interferon corrects aberrant protein kinase C levels and immunosuppression in the spontaneously hypertensive rat
- Author
-
Marie D. Sauro and John W. Hadden
- Subjects
Male ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Spleen ,Lymphocyte Activation ,Rats, Inbred WKY ,Interferon-gamma ,Spontaneously hypertensive rat ,In vivo ,Rats, Inbred SHR ,Internal medicine ,Immune Tolerance ,medicine ,Splenocyte ,Animals ,Interferon gamma ,cardiovascular diseases ,Protein Kinase C ,Protein kinase C ,Pharmacology ,business.industry ,Kinase ,Rats ,Enzyme Activation ,Cytokine ,medicine.anatomical_structure ,Endocrinology ,Hypertension ,business ,medicine.drug - Abstract
The effects of gamma-interferon (gamma-IFN) on protein kinase C (PKC) levels and immunosuppression in the spontaneously hypertensive rat (SHR) were examined. First, an abnormal PKC distribution was found in spleen, thymus and aorta from SHRs relative to normotensive controls. Biweekly injections of rat recombinant gamma-IFN (1000 U/kg) restored basal or resting PKC levels to those found in normotensive Wistar-Kyoto (WKY) rats. We also examined the effects of in vivo gamma-IFN treatment on nuclear PKC (nPKC) activation in purified, isolated splenocyte nuclei. It was found that basal nPKC levels were higher in untreated SHRs than gamma-IFN SHRs or WKYs. Also, while nuclei from untreated SHRs were relatively unresponsive to various immunoreactive substances and PKC activators, gamma-IFN treatment significantly restored activity. Last, the proliferative response to mitogen challenge of isolated splenocytes from untreated SHRs, gamma-IFN-treated SHRs and WKYs was studied. Although gamma-IFN treatment did not restore the proliferative response to that of WKYs, the mitogen response was significantly enhanced by treatment with gamma-IFN. The data show that gamma-IFN acts to restore normal immune function and corrects aberrant PKC levels and adds to the growing body of knowledge suggesting a role for immune dysfunction in the etiology of hypertension.
- Published
- 1992
34. Potentiation of immune responses in mice by a new inosine derivative—Methyl inosine monophosphate (MIMP)
- Author
-
Anutosh R. Saha, John W. Hadden, Elba M. Hadden, Marina Sosa, Yulai Wang, Alfredo Giner-Sorolla, and Jorge Coto
- Subjects
medicine.drug_class ,T-Lymphocytes ,Immunology ,chemical and pharmacologic phenomena ,Immunopotentiator ,Pharmacology ,Lymphocyte Activation ,Median lethal dose ,Immunostimulant ,Lethal Dose 50 ,Mice ,Adjuvants, Immunologic ,Inosine Monophosphate ,Oral administration ,medicine ,Animals ,Hypersensitivity, Delayed ,Antibody-Producing Cells ,Inosine ,Mice, Inbred BALB C ,biology ,Lethal dose ,Concanavalin A ,Antibody Formation ,Toxicity ,biology.protein ,Female ,medicine.drug - Abstract
Inosine 5′ - methyl monophosphate (MIMP) is a new immunomodulator designed to improve upon the activity of other thymomimetic purines. In Balb/c mice, MIMP was assessed for toxicity and activity on immune responses. The lethal dose for half the mice ( LD 50 ) exceeded 500 mg/kg of body weight by both the parenteral and oral routes. At doses of 1 – 100 mg/kg, the mice showed no visible untoward effects. The antibody response of splenocytes to sheep erythrocytes (SRBC) was measured by IgM plaque-forming cells (PFC) in soft agar under optimal conditions of immunization and challenge. MIMP (1 – 100 mg/kg) was given by both the intraperitoneal and oral routes (gavage) at the time of SRBC injection and 4 days thereafter. The PFC response was found to be significantly augmented. The maximum effect (approximately 2 ×) was observed at 50 and 100 mg/kg, via intraperitoneal (i.p.) and oral routes, respectively. Increases (maximally 1.5 ×) in the responses of splenic lymphocytes to mitogen stimulation with phytohemagglutinin (PHA) and concanavalin A (Con A) were observed under similar conditions of MIMP treatment. SRBC-induced delayed-hypersensitivity (DTH) was also measured under optimal conditions. By both i.p. and oral routes, enhancement of DTH response was produced by the lower doses of MIMP (0.01–1 mg/kg). Again, a second peak of optimum stimulation of DTH response was produced by 50 mg/kg of MIMP when administered by both routes. The effect was observed mainly on the sensitization rather than on the expression phase. MIMP qualifies as an effective immunopotentiator in normal mice.
- Published
- 1992
35. Methyl inosine monophosphate: A potential immunotherapeutic for early human immunodeficiency virus (HIV) infection
- Author
-
Robert M. Nelson, Alfredo Giner-Sorolla, Elba M. Hadden, Craig Monell, Steven Specter, John W. Hadden, Joseph Ongradi, Mette Strand, and Marina Sosa
- Subjects
Adult ,medicine.drug_class ,Ratón ,medicine.medical_treatment ,Lymphocyte ,Indomethacin ,Immunology ,HIV Infections ,In Vitro Techniques ,Biology ,Immunostimulant ,Mice ,Adjuvants, Immunologic ,Inosine Monophosphate ,In vivo ,Immunopathology ,medicine ,Animals ,Humans ,Lymphocytes ,Phytohemagglutinins ,Inosine ,Pharmacology ,Mice, Inbred BALB C ,Chemotherapy ,Leukemia, Experimental ,Immunosuppression ,Middle Aged ,Friend murine leukemia virus ,medicine.anatomical_structure ,Interleukin-2 ,Female ,medicine.drug - Abstract
MIMP is a new thymomimetic purine under development for immunorestorative therapy. Lymphocytes were obtained from eight patients with acquired immunodeficiency disease (AIDS), eight with symptomatic pre-AIDS (ARC), and 22 normal controls and were stimulated in vitro with phytohemagglutinin (PHA). AIDS patients (mean CD4 counts of 40) showed PHA responses less than 10% of control while ARC patients (mean CD4 counts of 544) showed responses approximately 50% of the control responses. MIMP (0.1, 1, 10 and 100 micrograms/ml) progressively augmented the PHA responses in all these groups. The augmentation of the responses of the leukocytes of AIDS patients while statistically significant was minimal. The augmentation of the responses of ARC patients was significant and their maximal responses approached control levels. The effect of 1 micrograms/ml MIMP was comparable with that observed with indomethacin (10(-6) M) and interleukin-2 (IL2 - 4 units/ml) and was additive with each of these stimulants. In a parallel manner, MIMP restored the suppression of control lymphocytes induced by the immunosuppressive 17 amino acid fragment of the P41 peptide of HIV. In vivo experiments showed that MIMP significantly delayed death in a murine FLV AIDS model at a dose of 1 mg/kg by the oral or parenteral route. MIMP is under preclinical development for early HIV disease to forestall progression to AIDS by attenuating virus-induced immunosuppression.
- Published
- 1992
36. Methyl inosine monophosphate (MIMP), a new purine immunomodulator for HIV infection
- Author
-
John W. Hadden, Elba M. Hadden, and Alfredo Giner-Sorolla
- Subjects
Purine ,T-Lymphocytes ,Lymphocyte ,Immunology ,HIV Infections ,Pharmacology ,Biology ,Lymphocyte Activation ,Mice ,chemistry.chemical_compound ,Adjuvants, Immunologic ,Inosine Monophosphate ,In vivo ,Nucleotidase ,Splenocyte ,medicine ,Animals ,Humans ,Inosine ,Mice, Inbred BALB C ,Biological activity ,In vitro ,medicine.anatomical_structure ,chemistry ,Biochemistry ,medicine.drug - Abstract
Prior work has documented the thymomimetic and immunotherapeutic activity of purine molecules related in structure to inosine. Synthesis of a series of new structures has yielded a stable methylated form of IMP resistant to hydrolysis by 5′ nucleotidase. With both human peripheral blood lymphocytes and murines splenocytes, Methyl Inosine Monophosphate (MIMP) augments proliferative responses to T-cell mitogens like phytohemagglutinin (PHA), but less so, or not at all, to B-cell mitogens like pokeweed or endotoxin (LPS). MIMP does not directly stimulate lymphocytes alone in the absence of mitogen. The optimal effects of MIMP parallel the optimal effects of PHA. The magnitude of the effect is greater and more consistent than with other purine immunomodulators. MIMP is non-toxic in vitro and in vivo and is orally active in mice. Significant effects are observed as low as 0.1 and 1 μg/ml in vitro and 0.1 or 1 mg/kg in vivo . MIMP is a candidate third generation purine under development for immunotherapeutic purposes.
- Published
- 1991
37. Sequence-Specific Binding of DNA by Non-Histone Proteins and Their Migration from Cytoplasm to Nucleus During Gene Activation
- Author
-
Vincent G. Allfrey, Akira Inoue, Robert A. Good, Jonathan Karn, Edward M. Johnson, and John W. Hadden
- Subjects
Regulation of gene expression ,biology ,Chromatin ,Cell biology ,chemistry.chemical_compound ,medicine.anatomical_structure ,Histone ,chemistry ,Cytoplasm ,medicine ,biology.protein ,Phosphorylation ,Nucleus ,DNA ,Sequence (medicine) - Published
- 2008
38. Effects of cytokines on human thymic epithelial cells in culture
- Author
-
A. Kameda, Thomas S. Kupper, John W. Hadden, Charles A. Dinarello, and A. Galy
- Subjects
musculoskeletal diseases ,medicine.medical_specialty ,education.field_of_study ,TEC ,medicine.medical_treatment ,T cell ,education ,Immunology ,Population ,Interleukin ,hemic and immune systems ,Biology ,Cell biology ,Paracrine signalling ,Thymocyte ,Cytokine ,medicine.anatomical_structure ,Endocrinology ,Epidermal growth factor ,Internal medicine ,medicine ,tissues - Abstract
Our earlier study reported the ability of interleukin 1 (IL1) to promote proliferation and to induce morphological changes of human thymic epithelial cells (TEC) in culture. The present study was undertaken to examine the effects of IL1 on the secretory function of TEC. Both human recombinant IL1 α and IL1 β induced TEC to produce molecules in the culture supernatant fluids (TES) which displayed marked thymocyte proliferative capacities. This activity was specifically induced by IL1 since other TEC growth factors such as epidermal growth factor and a bovine pituitary extract had no effect on promoting secretion of T cell-activating molecules by TEC. Using specific radioimmunoassays for both forms of IL1, we found that unstimulated TEC produced negligible amounts of IL1 α and IL1 β in TES, which were not increased by IL1 stimulation, and we concluded that the IL1-induced TES molecules were not IL1. IL1 induced TEC to produce IL6, as detected by the hybridoma growth factor biological activity. Neutralizing anti-IL6 antibodies completely blocked the thymocyte activating capacities of the IL1-induced TES thus implying a major role for IL6 in TEC-derived T cell activation. IL1 also induced TEC to produce GM-CSF as measured by bioassay and confirmed by an immunoenzymetric assay. Our results confirm that TEC are a source of cytokines and show that TEC respond to IL1 by producing cytokines with consequences on the thymic lymphoid population. This further emphasizes the importance and complexity of paracrine molecular interactions involved in intrathymic development.
- Published
- 1990
39. IRX-2, a novel in vivo immunotherapeutic, induces maturation and activation of human dendritic cells in vitro
- Author
-
Frances Santiago-Schwarz, Karen Quadrini, James E. Egan, Kathy L. Signorelli, John W. Hadden, and Harvey Brandwein
- Subjects
Cancer Research ,Receptors, CCR7 ,medicine.medical_treatment ,T cell ,T-Lymphocytes ,Immunology ,Lymphocyte Activation ,Monocytes ,Antigens, CD ,medicine ,Immunology and Allergy ,Humans ,Antigen-presenting cell ,Cell Shape ,Pharmacology ,CD86 ,CD40 ,biology ,business.industry ,Cell Differentiation ,Immunotherapy ,Dendritic cell ,Dendritic Cells ,medicine.disease ,Head and neck squamous-cell carcinoma ,Interleukin-12 ,Endocytosis ,Cytokine ,medicine.anatomical_structure ,biology.protein ,Cancer research ,Cytokines ,Receptors, Chemokine ,Lymphocyte Culture Test, Mixed ,business - Abstract
IRX-2 is a uniform, well-defined set of natural cytokines currently in Phase II clinical trials for squamous cell carcinoma of the head and neck (HNSCC). In preliminary clinical studies of HNSCC patients, IRX-2 therapy has shown promising results, increasing overall survival of patients from 32% to 61% at 48 months. Although it is known that specific cytokines in IRX-2 enhance T cell activity [e.g., interleukin-2 (IL-2), interferon-gamma, IL-1beta], we chose to investigate the influence of IRX-2 on monocyte-derived dendritic cells (Mo-DCs) isolated from human peripheral blood in an effort to further understand the clinical findings. We show here that IRX-2 treatment of human monocyte-derived DC resulted in morphologic, phenotypic, and functional changes consistent with the development of mature activated DC. Specifically, IRX-2-treated DC increased expression of CD83 and CCR7, markers for DC maturation and migration, respectively, and increased the expression of HLA-DR, CD54, and the costimulatory molecules CD86 and CD40, which are critical mediators of T cell activation. Functional changes in DC induced by IRX-2 included a reduced endocytic capacity, increased ability to stimulate T cells and increased IL-12 cytokine production. These results provide a plausible mechanistic explanation for the in vivo clinical activity of IRX-2 and an additional rationale for the use of IRX-2-based immunotherapy in patients.
- Published
- 2007
40. IRX-2 and thymosin alpha1 (Zadaxin) increase T lymphocytes in T lymphocytopenic mice and humans
- Author
-
Emma Verastegui, Elba M. Hadden, and John W. Hadden
- Subjects
CD4-Positive T-Lymphocytes ,medicine.medical_specialty ,Thymalfasin ,Lymphocyte ,medicine.medical_treatment ,T-Lymphocytes ,CD8-Positive T-Lymphocytes ,General Biochemistry, Genetics and Molecular Biology ,Mice ,History and Philosophy of Science ,Internal medicine ,Lymphopenia ,Medicine ,Animals ,Humans ,business.industry ,General Neuroscience ,Thymosin ,T lymphocyte ,medicine.disease ,medicine.anatomical_structure ,Endocrinology ,Cytokine ,Toxicity ,Immunology ,Cytokines ,Lymphocytopenia ,business ,CD8 - Abstract
Mouse studies showed a synergy of thymosin alpha1 (Talpha1) and a natural cytokine mixture (IRX-2) in increasing T lymphocyte number and responses. Clinical studies with IRX-2 showed increases of T lymphocytes in lymphocytopenic cancer patients but relatively little effect on irradiated, lymphocytopenic patients. The present phase 1 and 2 study shows that Talpha1 enhances the effect of IRX-2 in these lymphocytopenic patients. Patients (seven) were treated with subcutaneously injected IRX-2 (200 units IL-2 equivalence), Talpha1 (1.6 mg/day) (four patients), or the combination of IRX-2 and Talpha1 (seven patients) daily for 10 days. Peripheral blood lymphocytes (T, B, NK) and subsets (CD4, CD8) were measured at the start of treatment and on day 11. IRX-2 and Talpha1 had little or no significant effect. The combination markedly increased various lymphocyte populations (>350 cells/microL). Four patients followed for 6 weeks displayed sustained increases involving both naive and memory T cells. Responses to persistent infections were observed in three of the four patients and no significant toxicity was observed. Talpha1 and IRX-2 synergize to increase safely T cells in lymphocytopenic patients.
- Published
- 2007
41. Immunopharmacology of thymosin alpha1 and cytokine synergy
- Author
-
Paul H, Naylor, Karen, Quadrini, Enrico, Garaci, Guido, Rasi, and John W, Hadden
- Subjects
Thymosin ,Immunity, Cellular ,Mice ,Lung Neoplasms ,Thymalfasin ,Animals ,Cytokines ,Humans ,Drug Synergism ,Neoplasms, Experimental ,Protein Kinase C - Abstract
Thymosin alpha1 (Talpha1) is a 28 amino acid biologically active protein cleaved from positions 2-29 of a precursor protein, prothymosin alpha. Since its discovery, Talpha1 has been administered to animals and humans in a wide variety of settings and its pharmacologic effects are to enhance cellular immunity. Talpha1 administration is highly effective in settings where irradiation, chemotherapy, tumor burden, or immune senescence have caused a reduction of T cell number and/or function. Recent in vitro studies, including the one reported here, suggest that Talpha1 may act via pathways commonly used by various cytokines. This raises the possibility that Talpha1 and cytokines may have synergistic activity through potentiation of cytokine activity by Talpha1. Improved control of tumor growth when tumor-bearing mice were treated with Talpha1 and high doses of IL-2 has been previously reported. We extended those studies with the Lewis lung carcinoma mouse model using IRX-2, a natural well-defined biologic containing multiple cytokines, in combination with Talpha1 (IRX-3). Although IRX-2 was effective alone (using doses that contain significantly less IL-2 than in most typical studies), adding Talpha1 led to significant improvement in survival of the tumor-bearing mice. Based on these observations, the immunopharmacology of Talpha1 predicts an important clinical role for Talpha1 in the restoration of cellular immune activity when used in combination with cytokines. Patients who experience immune suppression due to the presence of tumor, irradiation, and/or chemotherapy or aging of the host would most benefit from this treatment combination.
- Published
- 2007
42. T cell targeted immune enhancement yields effective T cell adjuvants
- Author
-
John W. Hadden and Paul H. Naylor
- Subjects
animal diseases ,medicine.medical_treatment ,T cell ,T-Lymphocytes ,Immunology ,chemical and pharmacologic phenomena ,Biology ,Immune system ,Antigen ,Adjuvants, Immunologic ,Immunity ,medicine ,Immunology and Allergy ,Animals ,Humans ,Antigens ,Pharmacology ,Immunity, Cellular ,Innate immune system ,Lymphokine ,biochemical phenomena, metabolism, and nutrition ,Acquired immune system ,medicine.anatomical_structure ,bacteria ,Cytokines ,Adjuvant ,T-Lymphocytes, Cytotoxic - Abstract
Given the critical role of cell-mediated immunity (CMI) in defense against attack from pathogens that establish chronic infections, it has become abundantly clear that current vaccine methodology will not be sufficient to develop the appropriate immune response for protection and/or clearance of infection. By extension, this logic also applies to cancer vaccines where T cell immune-mediated destruction is a critical mechanism for control of the disease. This review describes our current thoughts on the events associated with immune activation and evaluates the various approaches to achieve successful immune activation with defined or targeted antigens as opposed to using inactivated or attenuated organisms. The advantages and disadvantages of the current adjuvants for antigens that focus on mimicking the infection events via the innate immune system or antigen uptake are described in the context of generation of T cell specific responses. A central theme of the discussions is the importance of cytokines in modulating the immune response towards T cell immunity, either by adjuvant modulation or use of natural cytokine mixtures targeted towards the site of immune activation. Also discussed is the possibility that thymomimetic agents such as thymosin alpha1, levamisole and methyl inosine monophosphate (MIMP) may be useful in enhancing the T cell mediated arm of the immune response.
- Published
- 2003
43. Combination immunotherapy of squamous cell carcinoma of the head and neck: a phase 2 trial
- Author
-
Jose Luis Barrera, Emma Verastegui, Juan Zinser, Abelardo Meneses, Jaime de la Garza, and John W. Hadden
- Subjects
Adult ,Male ,medicine.medical_specialty ,Cyclophosphamide ,medicine.medical_treatment ,Indomethacin ,Lymphocyte Activation ,Gastroenterology ,Disease-Free Survival ,Internal medicine ,Biopsy ,medicine ,Carcinoma ,Humans ,Neoadjuvant therapy ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,General Medicine ,Immunotherapy ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Neoadjuvant Therapy ,Surgery ,Radiation therapy ,Drug Combinations ,Zinc ,Otorhinolaryngology ,Epidermoid carcinoma ,Head and Neck Neoplasms ,Lymphatic Metastasis ,Carcinoma, Squamous Cell ,Cytokines ,Female ,business ,medicine.drug - Abstract
Objectives To test the efficacy of a natural cytokine mixture (IRX-2), cyclophosphamide, indomethacin, and zinc to induce immune regression of squamous cell carcinoma (SCC) of the head and neck (H&N) prior to conventional therapy and to characterize the responses. Patients and Design A phase 2 trial was performed in 15 adults with recently diagnosed, biopsy-confirmed H&N SCC (3 with stage II disease, 6 with stage III disease, and 6 with stage IV disease). The patients were treated with 20 days of perilymphatic injections of IRX-2 (administered subcutaneously at the base of the skull) in combination with contrasuppression consisting of a low-dose infusion of cyclophosphamide (300 mg/m2), and daily oral indomethacin and zinc (StressTabs) in a 21-day cycle before surgery and/or radiotherapy. Tumor dimensions, toxic effects, and disease-free survival were monitored. The tumor sections were histologically examined after surgery, and tumor reduction, fragmentation, and lymphoid infiltration were assessed. Results All 15 patients responded clinically to the 21-day IRX-2 protocol: 1 with a complete response, 7 with a partial response, and 7 with a minor response. All 15 patients responded pathologically with tumor reduction (mean, 42%) and fragmentation (mean, 50%) in the histological section and increased lymphoid infiltration. The adverse effects of the IRX-2 protocol were negligible except for an allergic skin rash (n = 1) and parotiditis (n = 1). Indomethacin caused gastritis in 1 patient. Reduction of pain and ulceration and bleeding were observed in 8 and 4 patients, respectively. Four of 5 patients with lymphopenia showed increased CD3, CD4, and CD8 cell counts. After surgery (n = 13) and/or radiotherapy (n = 10) and with a mean follow-up of 17 months, 3 patients have had recurrences, 1 patient has died of disease, 1 patient has been re-treated with immunotherapy and has no evidence of disease, and 1 patient is alive with disease. Two patients died of other causes with no evidence of disease. Conclusions The IRX-2 immunotherapy induced lymphocyte mobilization and infiltration in H&N SCC associated with clinical and histological tumor responses indicative of immune regression in all 15 patients. Minimal toxic effects were observed, and overall survival may have been improved. A phase 3 trial seems warranted.
- Published
- 2000
44. A natural cytokine mixture (IRX-2) and interference with immune suppression induce immune mobilization and regression of head and neck cancer
- Author
-
Jaime de la Garza, John W. Hadden, Jose Luis Barrera, Juan Zinser, Roxana Del Rio, Emma Verastegui, and Abelardo Meneses
- Subjects
Interleukin 2 ,medicine.medical_specialty ,Cyclophosphamide ,medicine.medical_treatment ,T-Lymphocytes ,Immunology ,Population ,Indomethacin ,Gastroenterology ,Immune system ,T-Lymphocyte Subsets ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Lymphocyte Count ,education ,Pharmacology ,education.field_of_study ,Chemotherapy ,business.industry ,Immunotherapy ,Cytokine ,Epidermoid carcinoma ,Chemotherapy, Adjuvant ,Head and Neck Neoplasms ,Carcinoma, Squamous Cell ,Cytokines ,Immunization ,business ,medicine.drug - Abstract
Prior studies indicate that combination immunotherapy of squamous cell cancer (SCC) of head and neck (H&N) with cytokines is feasible (Hadden et al., 1994). To induce immune regression of H&N SCC 20 stage II-IV patients received 3 weeks prior to surgery low dose cyclophosphamide (300 mg/M2), then 10 daily perilymphatic injections of a natural cytokine mixture (IRX-2)(150 units of IL-2 equivalence) and daily oral indomethacin and zinc. Tumor responses, T-lymphocyte and subset counts, and toxicity were monitored. Six patients had major clinical responses (both complete [CR] and partial [PR]) without major toxicity. Five of 20 patients were lymphocytopenic (1242 +/- 88 mm3) prior to treatment and the immunotherapy induced marked significant increases in total lymphocyte counts, CD3+ T-cells, and both CD4+ and CD8+ T-cells as well as a population of CD3+, CD4-, and CD8- lymphocytes. The post treatment specimen of 18/20 patients showed histologically tumor fragmentation, overall reduction and diffuse infiltration with lymphocytes and plasma cells. Histologic tumor reductions in these patients averaged 44% and the lymphoid infiltration increased 4.7 fold from 9-42%. The immune infiltration of the tumor reflects varying degrees of both T- and B-cells and indicates immunization to the tumor. The immunization achieved may improve clinical control of H&N SCC by improving the possibility that surgical resection of advanced loco-regional disease will leave no viable tumor.
- Published
- 1998
45. Immunomodulators
- Author
-
John W. Hadden
- Published
- 1996
46. The Immunotherapy of HIV Infection with Drugs
- Author
-
John W. Hadden
- Subjects
Drug ,medicine.medical_specialty ,Mechanism (biology) ,business.industry ,Clinical events ,medicine.medical_treatment ,media_common.quotation_subject ,Human immunodeficiency virus (HIV) ,Immunotherapy ,medicine.disease_cause ,medicine.disease ,Cancer immunotherapy ,Acquired immunodeficiency syndrome (AIDS) ,medicine ,Clinical endpoint ,Intensive care medicine ,business ,media_common - Abstract
The history of the effort to treat HIV infection with immunotherapeutic drugs has been a frustrating one. Soon after the onset of this epidemic in 1981, there were extensive efforts to use a long list of drugs being employed in cancer immunotherapy to treat AIDS. As predicted (Hadden, 1985), these attempts failed (Hadden, 1991; Specter and Hadden, 1992). The problem, quite simply, related to the predicted inability of any drug to increase T-cell number by any mechanism other than the inhibition of HIV replication. In approaching this discussion, I recognize that this topic is not in vogue. In fact, in some recent reviews, the subject of immunotherapeutic drugs is not even mentioned (Laurence, 1995; Lederman, 1995). I take a different view (Hadden, 1991). I would contend that the efforts using some of the drugs have taught that not only are they safe but also that they can reduce the development of AIDS-defining clinical events and can often delay the predicted decline in CD4 T lymphocytes. Nevertheless, the efforts have not demonstrated a convincing mechanism of action. The problem remains to be properly phrased: What can immunotherapeutic drugs be expected to do for HIV infection? and How do we measure the effect by other than clinical endpoints?, i. e., how can we prove the mechanism of action? It will be the purpose of this chapter to review the progress of efforts to employ such drugs in HIV infection prior to the development of AIDS and to delineate prospects for better defining and improving such treatment.
- Published
- 1996
47. Drugs for the Treatment of Inflammatory and Autoimmune Disease
- Author
-
Ronald G. Coffey and John W. Hadden
- Subjects
musculoskeletal diseases ,Autoimmune disease ,business.industry ,Arthritis ,Inflammation ,medicine.disease ,Gout ,Psoriatic arthritis ,Immune system ,Rheumatoid arthritis ,Immunology ,medicine ,Reactive arthritis ,medicine.symptom ,business - Abstract
Drugs that are used to treat acute and chronic inflammatory disorders suppress natural processes that contribute to the signs and symptoms of inflammation. Drugs that are used to treat simple forms of arthritis such as gout and osteoarthritis relieve pain and swelling and improve mobility. These agents are often referred to as nonsteroidal antiinflammatory drugs (NSAIDs). In the absence of known infection, chronic inflammation with strong immune components is termed autoimmune. Drugs that are used to treat autoimmune arthritides such as rheumatoid arthritis and the reactive arthritides (psoriatic arthritis and Reiter’s syndrome) act not only to suppress inflammation but also to modify the disease process by impairing the expression of the immune components of the inflammation. These latter drugs are often referred to as disease-modifying antirheumatic drugs (DMARDs). DMARDs can act as immunomodulators or as immunosuppressive agents. Autoimmune disorders without attendant inflammation are generally treated with immunosuppressive drugs alone. Antiinflammatory and immunosuppressive drugs are listed in Table I.
- Published
- 1996
48. Thymic Endocrinology and Prospects for Treating Thymic Involution
- Author
-
John W. Hadden
- Subjects
Cellular immunity ,medicine.medical_specialty ,Thymic involution ,Paracrine signalling ,Immune system ,Endocrinology ,Internal medicine ,medicine ,Endocrine system ,Involution (medicine) ,Biology ,Autocrine signalling ,Receptor - Abstract
In the early 1960s, the central role of the thymus in cellular immunity was simultaneously and independently discovered by R. A. Good and co-workers and J. F. A. R Miller and co-workers (Good, 1991; Miller, 1991). The thymus has only recently been analyzed in a manner that allows an understanding, on the one hand, of the complicated and stepwise manner by which T cells mature and acquire the many surface receptors necessary for identifying antigen and the molecular and cellular world around them and, on the other hand, of the autocrine, paracrine, and endocrine influences that regulate their differentiation, proliferation, secretion, and cytotoxicity. It is the purpose of this review to focus on the endocrine thymus and to elaborate on those factors and mechanisms that contribute to thymic development and involution. The possibilities for therapeutic intervention to reverse thymic involution and induce new T-cell development for the treatment of secondary cellular immune deficiencies associated with diseases such as cancer, infection, and autoimmunity will be discussed.
- Published
- 1996
49. Immunotherapy with natural interleukins and/or thymosin alpha 1 potently augments T-lymphocyte responses of hydrocortisone-treated aged mice
- Author
-
Anutosh R. Saha, Elba M. Hadden, John W. Hadden, and Marina Sosa
- Subjects
Hydrocortisone ,Thymalfasin ,medicine.medical_treatment ,T-Lymphocytes ,Immunology ,Spleen ,Thymus Gland ,Recombinant Interleukin ,Immunocompromised Host ,Leukocyte Count ,Mice ,In vivo ,medicine ,Splenocyte ,Animals ,Humans ,Pharmacology ,Mice, Inbred BALB C ,business.industry ,Thymosin ,Age Factors ,Organ Size ,Recombinant Proteins ,Thymocyte ,Cytokine ,medicine.anatomical_structure ,Interleukin-2 ,Female ,business ,CD8 ,Cell Division ,Interleukin-1 - Abstract
Cytokines and thymic hormones are thought to play critical roles in the regulation of T-lymphocyte development and function. In an effort to determine the effectiveness of such agents in an immunotherapeutic strategy, we employed aged mice in a hydrocortisone treatment model to generate an immunodeficient state and to study its reconstitution. Mice were given five daily injections of a natural cytokine mixture (NCM), recombinant interleukins (rIL-1, rIL-2) or their combination, thymosin alpha 1 or fraction 5 (T alpha 1, TF5), or the combinations of NCM plus T alpha 1 and of NCM plus TF5. Spleen and thymus weights were obtained and the cellular responses to stimulation in vitro with NCM, IL-1, IL-2 and mitogens (PHA and Con A) were assayed. Both NCM and T alpha 1 in vivo treatment augmented thymocyte and splenocyte in vitro responses to both interleukins and mitogens. Neither treatments with equivalent doses of rIL-1, rIL-2 nor their combination, nor TF5 achieved similar results. Of all the treatments, only NCM plus T alpha 1 augmented spleen weight; none augmented thymus weight. Surface marker analyses of T-lymphocytes and subsets indicate that treatment of mice with NCM plus T alpha 1 increased spleen T-cell numbers of both CD4 and CD8 positive cells significantly. These data indicate that NCM and T alpha 1 alone and in combination may be therapeutically useful to restore T-lymphocyte number or function in secondary immunodeficiency.
- Published
- 1995
50. Zinc induces thymulin secretion from human thymic epithelial cells in vitro and augments splenocyte and thymocyte responses in vivo
- Author
-
Anutosh R. Saha, John W. Hadden, and Elba M. Hadden
- Subjects
medicine.medical_specialty ,Cellular immunity ,Aging ,Thymic Factor, Circulating ,medicine.medical_treatment ,Immunology ,Administration, Oral ,Thymus Gland ,Thymulin ,chemistry.chemical_compound ,In vivo ,Internal medicine ,medicine ,Splenocyte ,Humans ,Cells, Cultured ,Pharmacology ,Thymic involution ,biology ,Epithelial Cells ,Receptors, Interleukin-2 ,Thymocyte ,Zinc ,Cytokine ,Endocrinology ,chemistry ,Concanavalin A ,biology.protein ,Immunotherapy ,Spleen - Abstract
Zinc is incorporated into zinc-thymulin by the thymus and in this form is a critical hormonal regulator of cellular immunity. In the absence of serum, zinc induces human thymic epithelial cells (TEC) to secrete a factor which promotes the expansion of interleukin-2 (IL-2) receptor positive human peripheral blood lymphocytes in response to a low dose of phytohemagglutinin (PHA). This factor is removed by antithymulin antisera plus filtration and is thus presumed to be zinc-thymulin. Intraperitoneal treatment of hydrocortisone treated aged mice with zinc-thymulin (100 ng/day x 5) resulted in mild augmentation of splenocyte but not thymocyte responses in vitro to IL-1, IL-2, and natural cytokine mixture (NCM) and to PHA and concanavalin A (Con A) (average increase 40%). Like zinc-thymulin treatment, oral ingestion of zinc (72 micrograms/day x 5) resulted in augmentation of splenocyte IL responses; in contrast, it augmented thymocyte responses to all stimuli (average increase 100%). These preliminary experiments indicate that treatment with zinc may have immunotherapeutic relevance, particularly in the aged and stressed organism.
- Published
- 1995
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