Immunological Treatment in MPM
D.H. Sterman, J. Stevenson, A.R. Haas, S.M. Albelda
Malignant Mesothelioma has been a target of immunotherapy for decades. Early studies used systemic and/or intrapleural cytokines delivery to initiate immune response. In the early 1990s, Boutin and colleagues showed significant clinical responses in early-stage mesothelioma to intrapleural administration of interferon-gamma. Subcutaneous interferon-alpha (a Type 1 interferon) demonstrated anti-tumor activity in clinical trials. Immunotherapy trials using IL-2 have also been conducted, either as single agent intrapleural, or in combination with multi-modality therapy. Vaccines have also been studied in clinical trials. Approaches include autologous tumor cells (with and without adjuvants such as GM-CSF) and a vaccine containing peptides from the Wilms tumor-1 (WT-1) gene product with cellular and humoral immune responses induced, and notation of anecdotal clinical responses. More recently, a trial conducted in the Netherlands by Hegmans et al. using tumor antigen-loaded dendritic cells has shown promise.
Based on strong preclinical data, a clinical using an agonistic CD40 antibody to stimulate immune responses in combination with Gemcitabine chemotherapy was recently initiated at the Sir Charles Gairdiner Hospital in Perth, Australia. The protein mesothelin, which is highly upregulated on mesothelioma, has been indentified as a potentially good tumor antigen and thus a target for immunotherapy. Clinical trials initiated at the NCI using a high affinity antibody alone (MORAB-009) or a fusion protein between an anti-mesothelin antibody and pseudomonas exotoxin (SS1P) are being conducted. Two Phase I studies showed SSP1 was relatively well tolerated and resulted in some interesting clinical effects, including partial responses and stable disease. A Phase II trial combining SS1P with standard chemotherapy is ongoing at the NCI in the U.S. A trial using a modified listeria bacterial vector encoding mesothelin was also conducted, however preliminary results did not demonstrate generation of impressive cellular immune responses.
Our group at the University of Pennsylvania conducted a series of Phase 1 clinical trials of a replication-incompetent adenoviral vector encoding HSVtk (Ad.HSVtk) delivered intrapleurally (followed by Ganciclovir) into 34 patients with pleural mesothelioma. Dose limiting toxicity was not reached, side effects were minimal and gene transfer was confirmed in a dose-related fashion with clearly detectable gene transfer (evidenced by immunostaining) at tumor surfaces and up to 30-50 cell layers deep. Anti-tumor antibodies and strong anti-adenoviral immune responses, including high titers of neutralizing antibody and proliferative T-cell responses were generated, however, with no obvious adverse side effects. Interestingly, a number of clinical responses were seen at the higher dose levels, including two patients that remained alive (one without disease) for more than 10 years after vector instillation.
Based on a series of preclinical experiments, our group has completed a series of Phase 1 dose escalation studies evaluating the safety and feasibility of intrapleural interferon-beta gene transfer using an adenoviral vector (Ad.IFNb) in patients with malignant pleural mesothelioma (MM) and metastatic pleural effusions (MPE). Ad.IFNb was administered through an indwelling pleural catheter in doses ranging from 9 x 1011 to 3 x 1012 viral particles (vp). A total of 27 patients in 3 trials have been dosed since 2005 and include 17 with malignant mesotheliomas, 5 with advanced lung cancer, 3 with metastatic ovarian cancer, and 2 with metastatic breast cancer. In the first trial, we used one dose of vector; later trials used two doses spaced at 14 or 7 days apart. Subjects were evaluated for toxicity, gene transfer, humoral, cellular, and cytokine-mediated immune responses, and tumor responses via 18-fluorodeoxyglucose (18FDG) positron-emission tomography (PET) scans and chest CT scans. Intrapleural Ad.INF-b was generally well tolerated with transient lymphopenia the most common side effect. The presence of the vector did not elicit a marked cellular infiltrate in the pleural space.
Good gene transfer seen after first dose with high IFN beta levels measured in the pleural fluid after vector installation. However, only very low gene transfer seen after a second dose- with either 14 day and 7 day spacing. We attribute this to rapid upregulation of neutralizing antibodies against adenovirus. Anti-tumor humoral immune responses were seen almost all patients with reactions seen against known Meso tumor antigens (SV40 large T antigen and mesothelin) and against unknown proteins in cell lysates. Given the caveats of Phase 1 trials (small numbers, different doses, heavily pretreated patients), we still saw clinical responses (defined as prolonged stable disease, prolonged survival, partial or complete responses by modified RESIST criteria, decreased metabolic tumor activity by PET scanning, or mixed responses) in about 1/3 of the patients. We are currently administering two doses of a similar Type I interferon transgene - Intrapleural Ad.INF-alpha-2b - spaced only three days apart. This appears to be well tolerated. Based on strong preclinical data supporting the combination of gene therapy and chemotherapy, we have started a trial using Ad. INF instillation into the first treatment cycle of first line (Cisplatin/Pemetrexed) or second line chemotherapy (Gemcitabine). We are also utilizing concomitant COX-2 inhibition with Celecoxib to modulate intratumoral immunosuppression, and to decrease suppressor cell activity, as has been demonstrated by Hegmans, et al.
Our groups is also generating designer chimeric T cells in which a single chain antibody fragment is linked to the transmembrane and cytoplasmic regions of the T-cell receptor. This artificial T-cell receptor is then transduced into T-cells that are then reinfused. The T-cells are then activated by cells expressing mesothelin. Preclinical data show striking activity against mesothelin-expressing tumors in mice. Mesotheliomas make large amounts of the immunoinhibitory cytokine, transforming growth factor-beta (TGF-b). Preclinical studies using TGF-b blockers have shown activity in mouse models of mesothelioma and a clinical trial using an anti- TGF-b antibody is ongoing at the University of Pennsylvania and the University of Chicago.
In summary, immunotherapies are being actively studied in mesothelioma and have shown some promising results. Future trials are focusing on combining these approaches with chemotherapy and surgery. Given the relatively mild and non-overlapping toxicities, we believe these, or other immunologic approaches will soon become part of the standard therapeutic armamentarium.
Based on strong preclinical data, a clinical using an agonistic CD40 antibody to stimulate immune responses in combination with Gemcitabine chemotherapy was recently initiated at the Sir Charles Gairdiner Hospital in Perth, Australia. The protein mesothelin, which is highly upregulated on mesothelioma, has been indentified as a potentially good tumor antigen and thus a target for immunotherapy. Clinical trials initiated at the NCI using a high affinity antibody alone (MORAB-009) or a fusion protein between an anti-mesothelin antibody and pseudomonas exotoxin (SS1P) are being conducted. Two Phase I studies showed SSP1 was relatively well tolerated and resulted in some interesting clinical effects, including partial responses and stable disease. A Phase II trial combining SS1P with standard chemotherapy is ongoing at the NCI in the U.S. A trial using a modified listeria bacterial vector encoding mesothelin was also conducted, however preliminary results did not demonstrate generation of impressive cellular immune responses.
Our group at the University of Pennsylvania conducted a series of Phase 1 clinical trials of a replication-incompetent adenoviral vector encoding HSVtk (Ad.HSVtk) delivered intrapleurally (followed by Ganciclovir) into 34 patients with pleural mesothelioma. Dose limiting toxicity was not reached, side effects were minimal and gene transfer was confirmed in a dose-related fashion with clearly detectable gene transfer (evidenced by immunostaining) at tumor surfaces and up to 30-50 cell layers deep. Anti-tumor antibodies and strong anti-adenoviral immune responses, including high titers of neutralizing antibody and proliferative T-cell responses were generated, however, with no obvious adverse side effects. Interestingly, a number of clinical responses were seen at the higher dose levels, including two patients that remained alive (one without disease) for more than 10 years after vector instillation.
Based on a series of preclinical experiments, our group has completed a series of Phase 1 dose escalation studies evaluating the safety and feasibility of intrapleural interferon-beta gene transfer using an adenoviral vector (Ad.IFNb) in patients with malignant pleural mesothelioma (MM) and metastatic pleural effusions (MPE). Ad.IFNb was administered through an indwelling pleural catheter in doses ranging from 9 x 1011 to 3 x 1012 viral particles (vp). A total of 27 patients in 3 trials have been dosed since 2005 and include 17 with malignant mesotheliomas, 5 with advanced lung cancer, 3 with metastatic ovarian cancer, and 2 with metastatic breast cancer. In the first trial, we used one dose of vector; later trials used two doses spaced at 14 or 7 days apart. Subjects were evaluated for toxicity, gene transfer, humoral, cellular, and cytokine-mediated immune responses, and tumor responses via 18-fluorodeoxyglucose (18FDG) positron-emission tomography (PET) scans and chest CT scans. Intrapleural Ad.INF-b was generally well tolerated with transient lymphopenia the most common side effect. The presence of the vector did not elicit a marked cellular infiltrate in the pleural space.
Good gene transfer seen after first dose with high IFN beta levels measured in the pleural fluid after vector installation. However, only very low gene transfer seen after a second dose- with either 14 day and 7 day spacing. We attribute this to rapid upregulation of neutralizing antibodies against adenovirus. Anti-tumor humoral immune responses were seen almost all patients with reactions seen against known Meso tumor antigens (SV40 large T antigen and mesothelin) and against unknown proteins in cell lysates. Given the caveats of Phase 1 trials (small numbers, different doses, heavily pretreated patients), we still saw clinical responses (defined as prolonged stable disease, prolonged survival, partial or complete responses by modified RESIST criteria, decreased metabolic tumor activity by PET scanning, or mixed responses) in about 1/3 of the patients. We are currently administering two doses of a similar Type I interferon transgene - Intrapleural Ad.INF-alpha-2b - spaced only three days apart. This appears to be well tolerated. Based on strong preclinical data supporting the combination of gene therapy and chemotherapy, we have started a trial using Ad. INF instillation into the first treatment cycle of first line (Cisplatin/Pemetrexed) or second line chemotherapy (Gemcitabine). We are also utilizing concomitant COX-2 inhibition with Celecoxib to modulate intratumoral immunosuppression, and to decrease suppressor cell activity, as has been demonstrated by Hegmans, et al.
Our groups is also generating designer chimeric T cells in which a single chain antibody fragment is linked to the transmembrane and cytoplasmic regions of the T-cell receptor. This artificial T-cell receptor is then transduced into T-cells that are then reinfused. The T-cells are then activated by cells expressing mesothelin. Preclinical data show striking activity against mesothelin-expressing tumors in mice. Mesotheliomas make large amounts of the immunoinhibitory cytokine, transforming growth factor-beta (TGF-b). Preclinical studies using TGF-b blockers have shown activity in mouse models of mesothelioma and a clinical trial using an anti- TGF-b antibody is ongoing at the University of Pennsylvania and the University of Chicago.
In summary, immunotherapies are being actively studied in mesothelioma and have shown some promising results. Future trials are focusing on combining these approaches with chemotherapy and surgery. Given the relatively mild and non-overlapping toxicities, we believe these, or other immunologic approaches will soon become part of the standard therapeutic armamentarium.
Source: klikpdpi.com
