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B. Robinson
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MS09 - Immune Therapies for Lung Cancer (ID 26)
- Event: WCLC 2013
- Type: Mini Symposia
- Track: Medical Oncology
- Presentations: 4
- Moderators:D.P. Carbone, B. Robinson
- Coordinates: 10/29/2013, 14:00 - 15:30, Bayside Auditorium A, Level 1
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MS09.1 - Biology of the B7 Family Members (CTLA4, PD1, PDL1) (ID 496)
14:05 - 14:25 | Author(s): S. Antonia
- Abstract
- Presentation
Abstract not provided
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MS09.2 - Treatment Targeting PD1/PDL1 and Toxicity (ID 497)
14:25 - 14:45 | Author(s): J. Brahmer
- Abstract
- Presentation
Abstract
Tumors evade immune system attack through various different mechanisms. One such mechanism is through coopting inhibitory immune checkpoints.(1) These inhibitory checkpoints cause compromised T cell activation and effector function. The two immune checkpoints best known are CTLA-4 and PD-1.(2) CTLA-4 is the receptor that is expressed earlier on in T cell activation and whose ligands are B7.1 and B7.2. Tumor cells have not been known to express the CTLA-4 ligands which are only known to be expressed on antigen presenting cells (APC). CTLA-4 deficient mice die early on of massive lymphoproliferative disorders.(3) Alternatively, the PD-1 receptor is expressed later on in T cell activation in the periphery and binds to two ligands, PD-L1(B7-H1) and PD-L2 (B7-DC). Both ligands are known to be expressed in peripheral tissues on APCs as well as tumor cells. Both ligands are upregulated by type 1 and 2 interferons, particularly gamma interferon.(4) PD-1 deficient mice develop strain specific autoimmune diseases later on in life.(5) Antibodies developed to block the binding between co-inhibitory receptor and its ligands cause T cell activation. While CTLA-4 blockade via the antibody, ipilimumab, has yielded an improvement in survival in patients with melanoma, PD-1 blockade is earlier on its development.(6,7) Several antibodies are in various stages of development. Of the antibodies designed to bind to the PD-1 receptor, Nivolumab (BMS-936558) is furthest along in development. In the first in human, single dose study of nivolumab, no maximum tolerated dose was found.(8) The pharmacokinetics of the antibody revealed a 14 day half-life, but the antibody was found to occupy T cell receptors for up to 3 months after treatment leading to prolonged pharmacodynamic effects. The toxicities were relatively mild and consistent with the immune mechanism of action. Early signs of clinical activity were seen in patients with melanoma, colon cancer, non-small cell lung cancer (NSCLC), and renal cell cancer (RCC).(9) Two patients remain in a complete response even up to almost 5 years after their last treatment. One patient’s response was maintained up to 18 months after stopping treatment and when the cancer progressed, the patient was retreated with nivolumab resulting again in a response. More recently, a multidose phase I study of Nivolumab was performed.(10) Again, no maximum tolerated dose was found up to 10 mg/kg every two weeks. Toxicities again tended to be manageable and consistent with the immune mechanism of action. Because of initial signs of significant clinical activity, expansion cohorts in NSCCLC, RCC, and melanoma were enrolled. Exciting responses in NSCLC (17%) were seen. These responses were durable with a median duration of response of 17 months. Based on these results, two phase III trials have been initiated in the second line treatment setting comparing nivolumab to docetaxel in both squamous cell and non-squamous cell carcinomas. Another anti-PD-1 antibody, MK-3475, recently reported similar toxicities consistent with the immune mechanism of action as well as initial clinical activity in melanoma (47% response rate).(11) Further expansion cohorts were enrolled in NSCLC and information is forthcoming. Antibodies blocking the ligand, PD-L1, have also been developed. Theoretically there may be differences in activity and toxicities between the two groups of antibodies. By blocking the PD-L1, the interaction between PD-1 and PD-L2 remains intact. It remains to be seen if this is meaningful, clinically. The first in human study of once every two week dosing of BMS-936559 reported initial tumor activity in several tumor types including NSCLC (10%) as well as a tolerable safety profile.(12) Another PD-L1 antibody, MPDL3280A, initial phase I trial was reported at ASCO in 2013. Toxicities were mild, no MTD was reached, and initial clinical activity was seen in multiple tumor type including NSCLC (22%).(13) These trials demonstrate that the PD-1 pathway is important in tumor immune evasion, and by blocking this pathway, immune activation occurs which in turn can cause durable tumor control. References 1. Zou W: Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5:263-74, 2005 2. Chen L: Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol 4:336-47, 2004 3. Waterhouse P, Penninger JM, Timms E, et al: Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985-8, 1995 4. Keir ME, Butte MJ, Freeman GJ, et al: PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677-704, 2008 5. Nishimura H, Nose M, Hiai H, et al: Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141-51, 1999 6. Hodi FS, O'Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-23, 2010 7. Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517-26, 2011 8. Brahmer JR, Drake CG, Wollner I, et al: Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28:3167-75, 2010 9. Lipson EJ, Sharfman WH, Drake CG, et al: Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res 19:462-8, 2013 10. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-54, 2012 11. Iannone R, Gergick K, Cong C, et al: Efficacy and safety of MK-3475 in patients with advanced melanoma, 9th International Congress of the Society for Melanoma Research. Los Angeles. California, 2012 12. Brahmer JR, Tykodi SS, Chow LQ, et al: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455-65, 2012 13. Herbst R, Gordon M, Fine J, et al: A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors, ASCO Annual Meeting 2013. Chicago, I.L., 2013Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MS09.3 - Treatment Targeting CTLA4 Efficacy and Toxicity (ID 498)
14:45 - 15:05 | Author(s): T. Lynch
- Abstract
- Presentation
Abstract not provided
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MS09.4 - Lung Cancer Vaccines (ID 499)
15:05 - 15:25 | Author(s): J.F. Vansteenkiste
- Abstract
- Presentation
Abstract
Surgical resection is the standard therapy for early stage NSCLC, but about half of the patients still develop a relapse and die of their cancer. In case of unresectable locally advanced disease, the combination of chemo- and radiotherapy may cure some patients, but the majority will relapse. Targeted agents have brought progress for patients with advanced NSCLC selected based on molecular factors such as EGFR or ALK mutation, but other novel approaches are needed. One is therapeutic cancer vaccination (TCV), which may become an important part in our future treatment armamentarium, especially for patients with local or locally advanced NSCLC. Cancer immunotherapy in a broad sense is any interaction with the immune system to treat cancer. A first approach is non-antigen-specific modulation of the immune system. Historical experience (BCG, C. parvum, interferon, interleukins, thymosin, etc.) was disappointing. Promising response rates in heavily pre-treated NSCLC patients were reported in recent phase I trials with agents acting on the interaction between antigen presenting cells, T-lymphocytes and tumor cells. Examples are antibodies against Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) or against Programmed Death 1 receptor or its ligands. Antigen-specific immunotherapy aims at specific priming of immune system to recognize the tumor as foreign, thereby generating specific antibodies and/or cytotoxic T cells. This is “therapeutic cancer vaccination”. Conditions for optimal TCV are: 1/ specificity (well-defined target antigen in the tumor, not in other tissues); 2/ selectivity (use in the population expressing the target); 3/ immunogenicity (interaction with antigen leads to effective humoral and/or cellular response); 4/ tumor sensitive to immune kill in order to obtain improvement in patients’ outcome. Although the historical results of TCV for NSCLC were disappointing, knowledge from the last decades about the molecular pathology of tumors, of the immune system in general, and of tumor immunity in particular, has led to the introduction of several modern and more sophisticated TCVs. These vaccine formulations have shown encouraging data in phase II randomized clinical trials, and are now being studies in large phase III studies. Important examples are the MAGE-A3 vaccine in resected early stage NSCLC, the BLP-25 vaccine in locally advanced NSCLC after chemoradiotherapy, and e.g. belagenpumatucel-L and the TG4010 vaccine in advanced stage NSCLC. The MAGE-A3 protein is totally tumor-specific and present in about 35% of early stage NSCLC. In the hypothesis generating double-blind, randomized, placebo-controlled phase II study, 182 patients with completely resected MAGE-A3-positive stage IB-II NSCLC received recombinant MAGE-A3 protein combined with an immunostimulant (13 doses over 27 months) or placebo [1]. No significant toxicity was observed. There was a 24% - non-significant - improvement in disease-free survival (HR 0.76; 95% CI 0.48 to 1.21). Moreover, a predictive gene signature, initially described in advanced melanoma patients could be confirmed in early stage NSCLC [2].A large phase III study (n=2270) with MAGE-A3 vaccine is recruited and awaiting results (MAGRIT, NCT00480025). Mucins like the MUC1 protein are present in many epithelia, but MUC1 expression is altered (mainly by aberrant glycosylation) in many cancer types, including NSCLC. The tandem repeat MUC1-peptide liposomal vaccine BLP-25 has been studied in patients with stage IIIB-IV NSCLC [3]. Patients in disease control after conventional treatment with chemo(-radio)therapy were randomly assigned to BLP25 (8 weekly s.c. immunizations, followed by administration at 6-week intervals) plus BSC or BSC alone. While overall survival (OS) was not significantly different in the total group, a challenging effect was observed in stage IIIB patients (HR 0.524; 95%CI 0.261-1.052). No significant toxicity was observed. At the 2013 ASCO meeting, the double-blind, randomized, placebo-controlled phase III study was presented (START, NCT00409188) [4]. Patients not progressing after primary chemoradiotherapy for unresectable stage III NSCLC were randomized to BLP25 or placebo. In the primary analysis population (n=1239), OS was better with the vaccine (HR 0.88, 95%CI 0.75-1.03). In the predefined subgroup analysis in patients after concurrent chemoradiotherapy (n=806) there was a median OS difference of 10.2 months (HR 0.78, 95%CI 0.64-0.95). While the most obvious role for TCV is for patients with small residual disease after treatment, several compound are in phase III testing in advanced NSCLC as well. Belagenpumatucel-L is a vaccine based on a mixture of allogeneic tumor cells with TGF-β2 antisense blockade as adjuvant. In a phase II open trial, survival was related to the dose administered [5]. A phase III trial in patients with stage III-IV NSCLC in disease control after first-line therapy is now fully recruited (STOP, NCT00676507). TG4010 is a vaccine based on a recombinant viral vector (attenuated strain of vaccinia virus) expressing both the tumor-associated antigen MUC1 and interleukin-2. In a phase II randomized study, 148 patients with advanced NSCLC expressing MUC1 by immunohistochemistry received either up to 6 cycles of cisplatin-gemcitabine plus TG4010, or the same chemotherapy alone [6]. The primary endpoint, a 6-month progression-free survival more than 40% in the experimental arm was met. A confirmatory phase IIB-III trial is ongoing (TIME, NCT01383148). 1. Vansteenkiste J, Zielinski M, Linder A, et al. Adjuvant MAGE-A3 immunotherapy in resected non-small cell lung cancer: Phase II randomized study results. J Clin Oncol 2013; 31: 2396-2403. 2. Ulloa-Montoya F, Louahed J, Dizier B, et al. Predictive gene signature in MAGEA3 antigen-specific cancer immunotherapy. J Clin Oncol 2013; 31: 2388-2395. 3. Butts C, Murray N, Maksymiuk A, et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small cell lung cancer. J Clin Oncol 2005; 23: 6674-6681. 4. Butts CA, Socinski MA, Mitchell P et al. START: A phase III study of L-BLP25 cancer immunotherapy for unresectable stage III non-small cell lung cancer. J Clin Oncol 31 Suppl, abstract 7500. 2013. 5. Nemunaitis J, Dillman RO, Schwarzenberger PO, et al. Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small cell lung cancer. J Clin Oncol 2006; 24: 4721-4730. 6. Quoix E, Ramlau R, Westeel V, et al. Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small cell lung cancer: a controlled phase 2B trial. Lancet Oncol 2011; 12: 1125-1133.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MS24 - Mesothelioma Biology and Biomarkers (ID 41)
- Event: WCLC 2013
- Type: Mini Symposia
- Track: Mesothelioma
- Presentations: 4
- Moderators:B. Robinson, H. Pass
- Coordinates: 10/30/2013, 14:00 - 15:30, Bayside 104, Level 1
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MS24.1 - A Tractable Animal Model of Mesothelioma (ID 574)
14:04 - 14:24 | Author(s): R. Lake
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Abstract
We have developed a novel transgenic mouse (MexTAg) where cellular transformation is driven by the SV40 (simian virus 40) large T antigen (TAg). In these mice, TAg is specifically targeted to the mesothelial compartment because it is expressed under the control of a tissue specific promoter. MexTAg mice uniformly develop mesothelioma after exposure to asbestos, with no spontaneous formation of other tumours. The key differences between MexTAg and wild type animals are the higher incidence and the shorter latency of the disease. Survival after diagnosis is not different suggesting that TAg does not drive a more aggressive disease. The model is comparable to human mesothelioma because of the eliciting carcinogen and because the location, pathology, molecular lesions and tumour response to therapy are similar (Robinson et al., 2006; Robinson et al., 2011). It is thought that asbestos fibres drive cellular transformation via the production of reactive oxygen species and the induction of chronic local inflammation. Accordingly, we have begun to test antioxidants and anti-inflammatory drugs as potential cancer prevention agents. We have reported that dietary supplementation with the antioxidants, vitamins A, E and selenium does not affect overall survival nor the time to progression of asbestos-induced mesothelioma in MexTAg mice (Robinson et al., 2012). We have extended our analysis to vitamin D and compared survival of asbestos-exposed MexTAg mice provided with diets supplemented (4500 IU/kg feed) or deficient in vitamin D (cholecalciferol). Survival of supplemented mice was significantly shorter than mice given standard diet (median survival, 29 and 32.5 weeks respectively). Mice deficient in vitamin D developed mesothelioma at the same rate as control mice. We conclude that vitamin D is unlikely to moderate the incidence of disease in asbestos exposed populations or to ameliorate the pathology in patients with established mesothelioma. Mesotheliomas in MexTAg mice respond to cytotoxic chemotherapy. Gemcitabine treatment from week 16 prolonged survival of asbestos-exposed MexTAg mice increasing the median survival from 33 weeks to 48 weeks. Interestingly, latency was not significantly prolonged, but animals survived for longer after the first signs of disease were noted. To understand the importance of the immune system in the pathogenesis of mesothelioma, we crossed MexTAg mice with immune deficient RAG KO mice. Perhaps surprisingly, MexTAg mice with no acquired immunity lived longer with a more indolent disease than their immunocompetent sibs. We compared cell lines derived from mesotheliomas from MexTAg mice and cell lines from wild type mice with human mesothelioma cell lines by expression array. TAg expressing mouse tumours were 90% identical to wild type mouse tumours. The key pathway that was different was cell cycle-associated. Human mesotheliomas commonly have a deletion of the cdkN2 locus, encoding the tumour suppressor genes p16 and p15. While wild type mouse tumours carried a homologous p16 deletion, TAg tumours did not. We hypothesize that TAg expressing mice develop tumours in an accelerated way following asbestos exposure because they are not dependent on deletion of p16 for tumourigenesis. Robinson, C., I. van Bruggen, A. Segal, M. Dunham, A. Sherwood, F. Koentgen, B.W. Robinson, and R.A. Lake. 2006. A novel SV40 TAg transgenic model of asbestos-induced mesothelioma: malignant transformation is dose dependent. Cancer Res 66:10786-10794. Robinson, C., A. Walsh, I. Larma, S. O'Halloran, A.K. Nowak, and R.A. Lake. 2011. MexTAg mice exposed to asbestos develop cancer that faithfully replicates key features of the pathogenesis of human mesothelioma. Eur J Cancer 47:151-161. Robinson, C., S. Woo, A. Walsh, A.K. Nowak, and R.A. Lake. 2012. The antioxidants vitamins A and E and selenium do not reduce the incidence of asbestos-induced disease in a mouse model of mesothelioma. Nutrition and cancer 64:315-322.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MS24.2 - In Vitro Models in Mesothelioma (ID 575)
14:24 - 14:47 | Author(s): V.C. Broaddus, D. Barbone
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Abstract
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MS24.3 - Apoptosis and Chemoresistance (ID 576)
14:47 - 15:07 | Author(s): S. Busacca
- Abstract
- Presentation
Abstract not provided
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MS24.4 - New Biomarker Research in Mesothelioma (ID 577)
15:07 - 15:30 | Author(s): J. Creaney
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Abstract
Malignant mesothelioma (MM) represents a significant clinical challenge. Not only can this tumour be difficult to diagnose but treatment options are limited. There is a desperate clinical need for biomarkers that can aid the diagnosis of MM, and/or predict survival and measure disease response to treatment. MM diagnosis is challenging as phenotypic differentiation of malignant mesothelial cells from benign reactive ones is notoriously difficult. No immunohistochemical marker(s) can uniformly define the cancer either. Invasive pleural tissue sampling for MM is more frequently negative than in any other cancer type [1]. A reliable diagnostic marker will present a major aid to clinicians. The median survival for the MM population is less than 12 months, however about 5% of patients live for several years and unusually long survivals of over 10 years have also been seen. But no reliable prognostic algorithm exists to predict survival in individual cases – a question of utmost concern for patients and their families. There is no cure for MM. Chemotherapy may improve survival, but only 30 to 40% of patients respond [2]. Thus finding a biomarker that may reflect disease burden and response to therapy, and hence prognosis, will be a significant advance. It has been nearly a decade since mesothelin [3] and MPF [4,5]were reported as candidate biomarkers for MM, both providing similar diagnostic accuracy [6]. A recent meta-analysis of serum mesothelin in the diagnosis of MM determined that having a sensitivity of 32% at a 95% specificity was too low for diagnostic use and highlighted the need for ongoing research for better biomarker(s) [7]. However, studies world-wide on a range of soluble markers including osteopontin, hyaluronic acid, CA125, CA15-3 and others have failed to improve upon diagnostic accuracy. More potential biomarkers such as fibulin-3 and the SOMamer panel have recently been identified [8,9]and the search to discover novel biomarker(s) for this disease using a variety of genomic, proteomic and immunologic approaches continues. For these candidate MM biomarkers to attain their professed clinical potential, independent externally validated studies with large, representative patient cohorts will be required. The next stage will then need studies to determine how to integrate promising markers into clinical diagnostic and/or management algorithms, a process essential to improve outcomes for MM patients. 1 Davies, H. E. et al. Outcome of patients with nonspecific pleuritis/fibrosis on thoracoscopic pleural biopsies. Eur J Cardiothorac Surg 38, 472-477, (2010). 2 Nowak, A. & Bydder, S. Management of malignant pleural mesothelioma: a review. Asia Pacific J clin Oncol (2007). 3 Robinson, B. W. et al. Mesothelin-family proteins and diagnosis of mesothelioma. Lancet 362, 4 Onda, M. et al. Megakaryocyte potentiation factor cleaved from mesothelin precursor is a useful tumor marker in the serum of patients with mesothelioma. Clin Cancer Res 12, 4225-4231 (2006). 5 Shiomi, K. et al. Novel ELISA system for detection of N-ERC/mesothelin in the sera of mesothelioma patients. Cancer Sci 97, 928-932 (2006). 6 Hollevoet, K. et al. Diagnostic performance of soluble mesothelin and megakaryocyte potentiating factor in mesothelioma. Am J Respir Crit Care Med 181, 620-625, (2010). 7 Hollevoet, K. et al. Serum mesothelin for diagnosing malignant pleural mesothelioma: an individual patient data meta-analysis. J Clin Oncol 30, 1541-1549, (2012). 8 Ostroff, R. M. et al. Early detection of malignant pleural mesothelioma in asbestos-exposed individuals with a noninvasive proteomics-based surveillance tool. PLoS One 7, e46091, (2012). 9 Pass, H. I. et al. Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma. N Engl J Med 367, 1417-1427, (2012).Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
