IFN-γ promotes graft-versus-leukemia effects without directly interacting with leukemia cells in mice after allogeneic hematopoietic cell transplantation.

The ability of IFN-γ to enhance graft-versus-leukemia (GVL) activity without direct interaction with leukemia cells was examined by comparing GVL effects against IFN-γ receptor-deficient (GRKO) leukemia between wild-type (WT) and IFN-γ-deficient (GKO) allogeneic hematopoietic cell transplantation (allo-HCT). We established a primary IFN-γ-unresponsive T-cell leukemia model using virally-transduced GRKO B6 mouse bone marrow cells overexpressing Notch1. We first assessed GVL effects in lethally-irradiated B6 mice receiving CD4-depleted allo-HCT from WT or GKO BALB/c donors. Administration of CD4(+) cell-depleted allo-HCT from WT, but not GKO, BALB/c donors mediated significant GVL effects against GRKO leukemia. Similar results were obtained in pre-established allogeneic chimeras receiving delayed donor lymphocyte infusion (DLI). Although both WT and GKO DLI achieved significant anti-tumor responses, the former was markedly stronger than the latter. These data indicate that IFN-γ is capable of promoting GVL effects via mechanisms independent of its interaction with leukemia cells.

Paradoxical effects of IFN-gamma in graft-versus-host disease reflect promotion of lymphohematopoietic graft-versus-host reactions and inhibition of epithelial tissue injury.

Interferon-gamma (IFN-gamma) inhibits graft-versus-host disease (GVHD) in lethally irradiated mice receiving allogeneic hematopoietic cell transplantation (allo-HCT) but promotes lethality in unirradiated and sublethally irradiated recipients. We investigated the role of IFN-gamma in GVHD in sublethally irradiated B6D2F1 recipients of B6 allo-HCT. B6D2F1 mice receiving wild-type B6 splenocytes alone died rapidly, whereas those receiving wild-type B6 splenocytes plus marrow survived long-term. Mice in both groups showed rapid elimination of host hematopoietic cells but minimal parenchymal tissue injury. However, mice receiving allo-HCT from IFN-gamma-deficient donors died rapidly regardless of whether donor marrow was given, and they exhibited severe parenchymal injury but prolonged survival of host hematopoietic cells. IFN-gamma plays a similar role in another model involving delayed B6 donor leukocyte infusion (DLI) to established mixed allogeneic (B6-->BALB/c) chimeras. IFN-gamma promotes DLI-mediated conversion from mixed to full donor chimerism while attenuating GVHD. Importantly, IFN-gamma enhances graft-versus-leukemia (GVL) effects in both models. Our data indicate that previously reported IFN-gamma-induced early mortality in allo-HCT recipients is due to augmentation of lymphohematopoietic graft-versus-host reaction (LGVHR) and can be avoided by providing an adequate source of donor hematopoietic stem/progenitor cells. Furthermore, the magnitude of GVL is correlated with the strength of LGVHR, and IFN-gamma reduces the potential of this alloreactivity to cause epithelial tissue GVHD.

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC).

Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for over 85% of all cases. Until recently, chemotherapy - characterized by some benefit but only rare durable responses - was the only treatment option for patients with NSCLC whose tumors lacked targetable mutations. By contrast, immune checkpoint inhibitors have demonstrated distinctly durable responses and represent the advent of a new treatment approach for patients with NSCLC. Three immune checkpoint inhibitors, pembrolizumab, nivolumab and atezolizumab, are now approved for use in first- and/or second-line settings for selected patients with advanced NSCLC, with promising benefit also seen in patients with stage III NSCLC. Additionally, durvalumab following chemoradiation has been approved for use in patients with locally advanced disease. Due to the distinct features of cancer immunotherapy, and rapid progress in the field, clinical guidance is needed on the use of these agents, including appropriate patient selection, sequencing of therapies, response monitoring, adverse event management, and biomarker testing. The Society for Immunotherapy of Cancer (SITC) convened an expert Task Force charged with developing consensus recommendations on these key issues. Following a systematic process as outlined by the National Academy of Medicine, a literature search and panel voting were used to rate the strength of evidence for each recommendation. This consensus statement provides evidence-based recommendations to help clinicians integrate immune checkpoint inhibitors into the treatment plan for patients with NSCLC. This guidance will be updated following relevant advances in the field.

High risk of brain metastases in surgically staged IIIA non-small-cell lung cancer patients treated with surgery, chemotherapy, and radiation.

PURPOSE: Lung cancer is the leading cause of cancer mortality in the United States. We sought to review our experience with surgically staged IIIA (N2) non-small-cell lung cancer (NSCLC), focusing on the patterns of failure in consecutively treated patients from 1988 to 2000. PATIENTS AND METHODS: The records of 177 patients were reviewed. Collected data included stage, histology, use of chemotherapy and radiation, initial and subsequent sites of failure, and survival. One hundred twenty-four patients have died; follow-up time is 35 months among the remaining patients. RESULTS: The median survival from the time of surgery was 21.0 months, with a 3-year overall survival (OS) of 34%. Nodal downstaging to N0 disease correlated with OS and progression-free survival (PFS; P < .001). The most common site of recurrence was the brain. Thirty-four percent of patients recurred in the brain as their first site of failure, and 40% of patients developed brain metastases at some point in their course. In patients with nonsquamous histology and residual nodal involvement after neoadjuvant therapy, the risk of brain metastases was 53% at 3 years. CONCLUSION: Patients treated with neoadjuvant therapy for N2-positive stage IIIA NSCLC enjoy an advantage in both OS and PFS if their lymph node status is downstaged to N(0). Because brain metastases constitute the most common site of failure in these patients, future studies focusing on prophylaxis of brain metastases may improve the outcome in patients with stage IIIA NSCLC.

Autologous stem-cell transplantation can be performed safely without the use of blood-product support.

PURPOSE: Autologous stem-cell transplantation has been shown to be a curative procedure for a variety of leukemias and lymphomas. Most transplants require RBC and platelet support. We report the ability to perform autologous transplantation without blood-product support. SUBJECTS AND METHODS: In this study, we treated 26 patients with religious objection to blood products with autologous stem-cell support without the use of any blood products. Patients received a combination of granulocyte colony-stimulating factor (G-CSF), erythropoietin, and interleukin-11 or G-CSF alone to mobilize stem cells. Post-transplant patients received intravenous iron, erythropoietin, G-CSF, and epsilon aminocaproic acid. RESULTS: There were two major bleeding complications (8%), with two treatment-related deaths (8%). There were three minor bleeding complications (12%). The median fall in hemoglobin level was 4.7 g/dL; the median hemoglobin level 30 days after transplantation was 9.2 g/dL. The median total number of days with platelet count less than 10 x 10(9)/L was 4 days; the median days to platelet recovery greater than 20 x 10(9)/L was 12 days. CONCLUSION: Autologous stem-cell transplantation can be performed safely without the use of any blood products.

Donor bone marrow-derived T cells inhibit GVHD induced by donor lymphocyte infusion in established mixed allogeneic hematopoietic chimeras.

Delayed administration of donor lymphocyte infusion (DLI) to established mixed chimeras has been shown to achieve anti-tumor responses without graft-vs.-host disease (GVHD). Herein we show that de novo donor BM-derived T cells that are tolerant of the recipients are important in preventing GVHD in mixed chimeras receiving delayed DLI. Mixed chimeras lacking donor BM-derived T cells developed significantly more severe GVHD than those with donor BM-derived T cells after DLI, even though both groups had comparable levels of total T cells at the time of DLI. Post-DLI depletion of donor BM-derived T cells in mixed chimeras, as late as 20 days after DLI, also provoked severe GVHD. Although both CD4 and CD8 T cells contributed to the protection, the latter were significantly more effective, suggesting that inhibition of GVHD was not mainly mediated by CD4 regulatory T cells. The lack of donor BM-derived T cells was associated with markedly increased accumulation of DLI-derived alloreactive T cells in parenchymal GVHD target tissues. Thus, donor BM-derived T cells are an important factor in determining the risk of GVHD and therefore, offer a potential therapeutic target for preventing and ameliorating GVHD in the setting of delayed DLI in established mixed chimeras.

Combined treatment with cisplatin and sirolimus to enhance cell death in human mesothelioma.

OBJECTIVE: Although platinum-based chemotherapy is widely used in malignant pleural mesothelioma, its modest therapeutic effect warrants identification of enhancing agents. As with many cancers, the phosphatidylinositol 3-kinase/Akt pathway is often activated in malignant pleural mesothelioma and has been implicated in the tumor's aggressiveness. Sirolimus is a well-established inhibitor of the mammalian target of rapamycin. We sought to determine whether combination treatment with sirolimus and cisplatin would enhance cell death in malignant pleural mesothelioma. METHODS: Human malignant pleural mesothelioma cell lines were incubated with sirolimus or cisplatin alone or in combination and assayed for cell viability. To characterize phosphorylation status after treatment, Akt and downstream proteins of mammalian target of rapamycin pathway, p70 S6 kinase and 4E-BP1, were analyzed by Western blot. Effect of combination treatment was also analyzed with extreme drug resistance assay in 12 human malignant pleural mesothelioma tumors with varying resistance to cisplatin. RESULTS: Individual malignant pleural mesothelioma cell lines exhibited a range of sensitivities to each drug without correlation with subtype. Sirolimus and cisplatin significantly (P = .029) increased cell death versus either drug alone in 4 cell lines. Combined treatment caused dephosphorylation of Akt, 4E-BP1, and p70 S6 kinase. Cell proliferation was significantly decreased in tumors subjected to sirolimus and cisplatin versus cisplatin or sirolimus alone. CONCLUSIONS: Sirolimus appears to enhance the cytotoxicity of cisplatin in malignant pleural mesothelioma cell lines through the mammalian target of rapamycin pathway. These results provide a basis for the clinical evaluation of combined sirolimus and cisplatin chemotherapy in malignant pleural mesothelioma.

Myelogenous leukemia in adult inbred MHC-defined miniature swine: a model for human myeloid leukemias.

This manuscript reports on five cases of spontaneous myelogenous leukemia, similar to human disease, occurring within highly inbred, histocompatible sublines of Massachusetts General Hospital (MGH) MHC-defined miniature swine. In cases where a neoplasm was suspected based on clinical observations, samples were obtained for complete blood count, peripheral blood smear, and flow cytometric analysis. Animals confirmed to have neoplasms were euthanized and underwent necropsy. Histological samples were obtained from abnormal tissues and suspect lesions. The phenotype of the malignancies was assessed by flow cytometric analysis of processed peripheral blood mononuclear cells and affected tissues. Five cases of spontaneous myeloid leukemia were identified in adult animals older than 30 months of age. All animals presented with symptoms of weight loss, lethargy, and marked leukocytosis. At autopsy, all animals had systemic disease involvement and presented with severe hepatosplenomegaly. Three of the five myelogenous leukemias have successfully been expanded in vitro. The clustered incidence of disease in this closed herd suggests that genetic factors may be contributing to disease development. Myelogenous leukemia cell lines established from inbred sublines of MGH MHC-defined miniature swine have the potential to be utilized as a model to evaluate therapies of human leukemia.

Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: a phase II prospective study.

OBJECTIVE: We sought to prospectively determine the feasibility and safety of hyperthermic intraoperative intracavitary cisplatin perfusion immediately after extrapleural pneumonectomy in the treatment of malignant pleural mesothelioma. METHODS: Patients with malignant pleural mesothelioma who were surgical candidates underwent extrapleural pneumonectomy followed by hyperthermic intraoperative intracavitary cisplatin perfusion, consisting of a 1-hour lavage of the chest and abdomen with cisplatin (42 degrees C) at 225 mg/m(2). Pharmacologic cytoprotection consisted of intravenous sodium thiosulfate with or without amifostine. Morbidity and mortality were recorded prospectively. RESULTS: Ninety-six (79%) of 121 enrolled patients underwent extrapleural pneumonectomy, of whom 92 (76%) received hyperthermic intraoperative intracavitary cisplatin perfusion after extrapleural pneumonectomy. Fifty-three (58%) patients had epithelial tumors, and 39 (42%) had nonepithelial histology. Hospital mortality was 4.3%. Morbidity (grade 3 or 4, 49%) included atrial fibrillation in 22 (23.9%) patients, venous thrombosis in 12 (13%) patients, and laryngeal nerve dysfunction in 10 (11%) patients. Nine patients had renal toxicity, which was attributable to cisplatin in 8 of them. Among the 27 patients who also received amifostine (910 mg/m(2)), 1 patient had grade 3 renal toxicity attributable to cisplatin. Recurrence of malignant pleural mesothelioma was documented in 47 (51%) patients, with ipsilateral recurrence in 17.4% of patients. The median survival of the 121 enrolled patients was 12.8 months. CONCLUSIONS: Hyperthermic intraoperative intracavitary cisplatin perfusion following extrapleural pneumonectomy can be performed with acceptable morbidity and mortality. The use of amifostine in addition to sodium thiosulfate might reduce cisplatin-associated renal toxicity. Hyperthermic intraoperative intracavitary cisplatin perfusion following extrapleural pneumonectomy might enhance local control in the chest.