Activation by anti-CD3 of tumor-draining lymph node cells for specific adoptive immunotherapy

Lymph nodes draining progressive tumors contain tumor-sensitized but not functional preeffector T lymphocytes. These cells can acquire antitumor reactivity after stimulation with tumor cells and interleukin-2 (IL-2). We demonstrated here that, in the absence of tumor cells, preeffector cells could be stimulated and expanded by sequential culture with anti-CD3 monoclonal antibody and IL-2. The adoptive transfer of such activated cells mediated immunologically specific reductions of established pulmonary metastases. The therapeutic effects could be enhanced by the administration of IL-2. This activation represents a secondary immune response because effector cells could be generated only from tumor-draining but not from normal or adjuvant-stimulated lymph nodes. Furthermore, treatment of advanced metastases with these cells resulted in prolongation of survival and cure of the disease. Thus, anti-CD3 may serve as a universal reagent for activating tumor-sensitized T lymphocytes for cancer therapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29366/1/0000436.pd

Anti-cytokine autoantibodies are ubiquitous in healthy individuals

AbstractAnti-cytokine autoantibodies in healthy individuals have been widely reported but the occurrence is variable and inconstant. We hypothesized that cytokine-binding in vivo may explain their variable and infrequent detection. Therefore, we focused on the detection of the cytokine-autoantibody complexes and found that anti-cytokine autoantibody to IL-2, IL-8, tumor necrosis factor-α, vascular endothelial growth factor and granulocyte-colony stimulating factor were present in all 15 individuals evaluated, while those to IL-3, osteopontin and macrophage-colony stimulating factor were not detected in anyone. Autoantibodies against IL-4, IL-6, IL-10, and interferon-gamma were variously detected. Thus, we discovered that anti-cytokine autoantibodies to multiple cytokines are ubiquitous in healthy individuals

Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: a retrospective analysis

<p>Abstract</p> <p>Background</p> <p>Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Few treatment options are available for NSCLC patients who have responded to gefitinib treatment and demonstrated tumor progression. The present study was conducted to evaluate the efficacy and toxicity of the 2^ndEGFR-TKI administration.</p> <p>Methods</p> <p>We retrospectively analyzed 11 patients who had obtained a partial response (PR) or stable disease (SD) with gefitinib treatment and were re-treated with EGFR-TKI after failure of the initial gefitinib treatment.</p> <p>Results</p> <p>Three patients (27%) were treated with gefitinib as the 2^ndEGFR-TKI, and 8 patients (73%) received erlotinib. Only one patient (9%) showed PR, 7 (64%) achieved SD, and 3 (27%) had progressive disease. The disease control rate was 73% (95% CI, 43% - 91%) and the median progression-free survival was 3.4 months (95% CI, 2 - 5.2). The median overall survival from the beginning of the 2^ndEGFR-TKI and from diagnosis were 7.3 months (95% CI, 2.7 - 13) and 36.7 months (95% CI, 23.6 - 43.9), respectively. No statistical differences in PFS or OS were observed between gefitinib and erlotinib as the 2^ndEGFR-TKI (PFS, P = 0.23 and OS, P = 0.052). The toxicities associated with the 2^ndEGFR-TKI were generally acceptable and comparable to those observed for the initial gefitinib therapy.</p> <p>Conclusions</p> <p>Our results indicate that a 2^ndEGFR-TKI treatment can be an effective treatment option for gefitinib responders.</p

Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: a retrospective analysis

<p>Abstract</p> <p>Background</p> <p>Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Few treatment options are available for NSCLC patients who have responded to gefitinib treatment and demonstrated tumor progression. The present study was conducted to evaluate the efficacy and toxicity of the 2^ndEGFR-TKI administration.</p> <p>Methods</p> <p>We retrospectively analyzed 11 patients who had obtained a partial response (PR) or stable disease (SD) with gefitinib treatment and were re-treated with EGFR-TKI after failure of the initial gefitinib treatment.</p> <p>Results</p> <p>Three patients (27%) were treated with gefitinib as the 2^ndEGFR-TKI, and 8 patients (73%) received erlotinib. Only one patient (9%) showed PR, 7 (64%) achieved SD, and 3 (27%) had progressive disease. The disease control rate was 73% (95% CI, 43% - 91%) and the median progression-free survival was 3.4 months (95% CI, 2 - 5.2). The median overall survival from the beginning of the 2^ndEGFR-TKI and from diagnosis were 7.3 months (95% CI, 2.7 - 13) and 36.7 months (95% CI, 23.6 - 43.9), respectively. No statistical differences in PFS or OS were observed between gefitinib and erlotinib as the 2^ndEGFR-TKI (PFS, P = 0.23 and OS, P = 0.052). The toxicities associated with the 2^ndEGFR-TKI were generally acceptable and comparable to those observed for the initial gefitinib therapy.</p> <p>Conclusions</p> <p>Our results indicate that a 2^ndEGFR-TKI treatment can be an effective treatment option for gefitinib responders.</p

Improvement of Asthma Management in Actual Practice Consistent with Prevalence of Anti-inflammatory Agents—Based on Questionnaire Surveys in Niigata Prefecture, Japan from 1998 to 2002—

Background: Because bronchial inflammation was recognized as a basic component of bronchial asthma, the strategy for asthma management has changed in the last two decades. In Japan there are few clinico-epidemiological reports of changes in the management of bronchial asthma in actual practice. In this study, we analyzed practical asthma management in Japan, and examined changes in the prevalence of asthma medication and relation between these changes and the level of asthma control and management. Methods: From 1998 to 2002, questionnaires on asthma control, asthma related emergent episodes and satisfaction in daily life. Questionnaires were distributed to adult asthmatic patients. Questionnaires about the patients’ profiles and medication were also given to the patients’ doctors. Results: The total number of patient responders was approximately 2500—3300 per year. The rate of peak flow meter (PEFM) use was under approximately only 40% and plateaued from 2000 to 2002. The percentage of inhaled corticosteroid use and leukotriene receptor antagonist use increased, from 62.0%, 27.2% to 77.4%, 40.6% respectively. Indicators for asthma control, including presence of attacks and sleep disturbance, were significantly improved. Limited to PEFM users, there was an improvement hospitalization, ambulance use or ED visits and in satisfaction in daily life based on a Quality of Life (QOL) indicator. Conclusions: These results indicate that the prevalence of anti-inflammatory agents, including inhaled corticosteroids and leukotriene receptor antagonist, was associated with an adequate improvement in asthma control in clinical practice. In asthma management in clinical practice, prevalence of PEFM may play an important role in the improvement of asthma related emergent episodes or QOL

Eradication of Established Murine Skin Tumors by Cyclic Chemoimmunotherapy with Cyclophosphamide and Effector T Cells

Background: Nonmyeloablative chemotherapy followed by adoptiveimmunotherapy is an attractive strategy for depleting regulatory T cells in the host. However, its efficacy is transient. Here, we aim to investigate whether cyclic chemoimmunotherapy has therapeutic efficacy against cancer. Methods:We examined the efficacy of cyclic chemoimmunotherapy with cyclophosphamide and adoptively transferred effector T cells against 5-day, established MCA205 murine skin sarcomas. Results: Cyclophosphamide administration followed by adoptive immunotherapy augmented the trafficking of effector T cells into established tumors. Further, multiple cyclophosphamide administrations helped effector T cells to persist at the sites.Chemoimmunotherapy achieved complete tumor regression even with the transfer of a limited number of effector T cells (5×106).Conclusion: Cyclic chemoimmunotherapy, which maintains adoptively transferred T cells by impairing regulatory T cells, is a potentially suitable treatment for established tumors