Virtual Library
Start Your Search
C. Mascaux
Moderator of
-
+
O08 - Preclinical Therapeutic Models I (ID 92)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Biology
- Presentations: 7
- Moderators:C. Mascaux, R. Natale
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside Auditorium A, Level 1
-
+
O08.01 - A novel autophagosome non-small cell lung cancer vaccine (DRibbles) contains short-lived proteins, defective ribosomal products, at least nine NCI-prioritized antigens, and agonists for TLR 2, 3, 4, 7, and 9. (ID 2612)
16:15 - 16:25 | Author(s): H.J. Ross, T. Hilton, S. Puri, B. Joshi, J. Han, B. Bhattacharya, T. Moudgil, C. Dubay, R.E. Sanborn, H. Hu, R. Van De Ven, W. Urba, S. Aung, R. Puri, B.A. Fox
- Abstract
- Presentation
Background
Tumor-derived autophagosomes, referred to as DRibbles, are novel cancer vaccines that have been shown to be effective against 5 preclinical models of established tumors. We hypothesize that DRibbles’ efficacy stems from their ability to present stabilized tumor-derived short-lived proteins (SLiPs) and defective ribosomal products (DRiPs) that are, due to their short-lived nature, normally not processed and presented by professional antigen presenting cells. These SLiPs and DRiPs represent a potential pool of tumor antigens against which the host is not tolerant. A pilot clinical trial of an autologous DRibble vaccine demonstrated feasibility and suggested immune effects in 4 patients with advanced NSCLC (WCLC 2013, submitted). In order to expand the DRibble strategy to patients without an autologous tumor source, we have produced an allogeneic DRibble vaccine (DPV-001) from two NSCLC cell lines and developed a panel of 13 NSCLC cell lines expressing relevant antigenic targets that will be used to monitor induction of tumor-specific immunity.Methods
The two NSCLC cell lines used to produce the DPV-001 vaccine (UbiLT3 and 6) were cultured with bortezomib and ammonium chloride to block the proteasome and prevent lysosomal degradation of SLiPs and DRiPs. Gene expression profiles were performed for each lot produced (Human Gene 1.0 ST arrays). Stability of indicator tumor antigens was assessed by Western blots. Toll-like receptor (TLR) agonist activity was assessed using HEK blue cells transfected with specific TLRs. After informed consent, a panel of NSCLC cell lines was established from 13 patients (tumor tissue or pleural fluid). These cell lines were HLA-typed for use in immunologic monitoring studies. cDNA was synthesized in triplicate from total RNA extracted from each cell line in log phase growth. Samples were then analyzed using human microarrays containing approximately 17,000 oligonucleotides (CBER array). Data files were uploaded into the mAdb database and analyzed by software provided by the Center for Information Technology (CIT), NIH. Group t-test was used to compare gene expression differences between NSCLC and normal lung tissues and between cell lines.Results
Analyses confirm reproducible gene expression profiles from both cell lines during DPV-001 manufacture, and stability studies demonstrate that the vaccine remains stable for 23 months. The vaccine contains at least nine NCI-prioritized cancer antigens and agonists for 5 TLRs. Gene expression profiles of the 13 NSCLC cell lines identified 46 commonly overexpressed genes, all of which are expressed in the DPV-001 vaccine.Conclusion
The DPV-001 vaccine provides a source of broad-spectrum relevant NSCLC antigens. We are conducting a multicenter, randomized, phase II trial of adjuvant DPV-001 vaccine in patients with definitively treated stage IIIA/B NSCLC. T-cell immune responses will be monitored using HLA matched cell lines from the indicator panel of 13 NSCLC cell lines. NIH grants R21 CA123864 (WJU) and R43/44 CA121612 (SA, TH), Kuni Foundation (WJU), Murdoch Trust, Robert Franz, Wes and Nancy Lematta, Lyn and Jack Loacker, and the Chiles Foundation. Clinicaltrials.gov study identifier pendingOnly 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.
-
+
O08.02 - Critical Role of CD28 Costimulation in Tumor-Targeted T-cell Therapy Clinical Trial for Pleural Malignancies (ID 2995)
16:25 - 16:35 | Author(s): J. Villena-Vargas, L. Cherkassky, C. Colovos, E. Servais, L.A. Rodriguez, V.W. Rusch, M. Sadelain, P.S. Adusumilli
- Abstract
- Presentation
Background
Successful translation of adoptive T-cell therapy for solid cancers is predicated on the ability to generate a potent antitumor immune response and establish T-cell persistence. Thoracic malignancies typically lack expression of costimulatory ligands but do express negative regulators of T- cell function—factors that may impede T-cell therapy. We hypothesized that cancer antigen–targeted T cells engineered with activating CD28 costimulatory signaling would eradicate tumor and establish long-term functional persistence.Methods
Mesothelin-specific chimeric antigen receptors (CARs) were engineered without (Mz) or with (M28z) a CD28 costimulatory domain. CAR-transduced human T cells were evaluated in vitro for cytotoxicity ([51]Cr-release assay), cytokine release (Luminex cytokine-release assay), and proliferation (cell-counting assay). In vivo assessment included monitoring of tumor progression by bioluminescence imaging (BLI), flow cytometric analysis of splenic/peripheral blood T-cell phenotypes, and Kaplan-Meier analysis of median survival, in NOD-scid IL-2Rγ-null mice bearing orthotopically implanted mesothelin-expressing mesothelioma cells (MSTO-211H: CD80/86-, TGF-β+, PD-L1+) and treated with human T cells transduced to express either Mz, M28z, or a control vector.Results
In vitro, M28z CAR–transduced T cells exhibited equivalent cytotoxicity but enhanced Th1 cytokine secretion and antigen-specific proliferation, compared with Mz transduced T cells. In vivo, mice treated with a single low dose of M28z CAR–transduced T cells achieved tumor eradication and prolonged survival (median survival not reached; p=0.01), compared with mice treated with an equal dose of Mz-transduced (median survival, 63 days; tumor eradication in 20% of mice) or control CAR–transduced (median survival, 36 days) T cells (Figure 1A, 1B). Furthermore, CD28 costimulation enhanced CD62L[-]CD45RA[-] effector memory T-cell persistence (Figure 1C), leading to a robust T-cell proliferative response and superior control of tumor burden on tumor rechallenge 87 days after T-cell administration (Figure 1D, 1E). Figure 1Conclusion
CD28 costimulation plays an important role in achieving long-term antitumor efficacy and functional persistence in mesothelin-targeted T-cell therapy. These data provide the scientific rationale for our upcoming clinical trial for pleural malignancies.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.
-
+
O08.03 - T-cell Imaging to Noninvasively Monitor Adoptive T-cell Therapy for Thoracic Malignancies (ID 2994)
16:35 - 16:45 | Author(s): J. Villena-Vargas, L.A. Rodriguez, M. Moroz, L. Cherkassky, V.W. Rusch, M. Sadelain, V. Ponomarev, P.S. Adusumilli
- Abstract
- Presentation
Background
Noninvasive T-cell imaging technology allows monitoring of adoptive T-cell responses without the need for invasive biopsies. Herein, we report dynamic imaging of tumor-targeted T cells in preclinical models by use of luminescent-enhanced firefly luciferase vector, and we further demonstrate the successful use of a clinical-grade herpes simplex virus type 1 thymidine kinase (HSV1-tk)–incorporated vector for monitoring of T-cell trafficking, antigen-specific proliferation, and biodistribution.Methods
T cells transduced with mesothelin-targeted chimeric antigen receptors (M28z) were either cotransduced with an enhanced firefly luciferase vector (effLuc-M28z) or singly transduced with HSV1-tk-M28z (TK-M28z). To simultaneously visualize tumor during T-cell PET imaging, cancer-cell imaging was performed using MSTO-GFP/ffLuc+ (MSTO-211H cells transduced to express mesothelin and the green fluorescent protein/firefly luciferase fusion protein). In vitro, uptake of [18]F-FEAU radiotracer by T cells was measured by [3]H channel counting. In vivo studies used either SCID-beige or NSG mice bearing pleural or flank tumors. Bioluminescence imaging (BLI) quantification was determined by the mean number of photons per second in the region of interest. PET imaging with [18]F-FEAU was performed in a 3-dimensional microPET scanner. T-cell imaging results were validated by flow cytometric and immunohistochemical analysis of harvested tissue.Results
Quantification studies showed a linear relationship between photon emission and T-cell number both in vitro and in vivo. In vivo, evaluation of T-cell biodistribution kinetics, by intravenous administration of effLuc-M28z T cells into mice bearing flank tumors, demonstrated initial accumulation of T cells in the lungs, liver, and spleen and progressive accumulation in the tumor (Figure 1A). Pleurally administered effLuc-M28z+ T cells displayed an increasing BLI signal (5-fold; p<0.01) in response to antigen 72 hours after administration, compared with pleurally administered effLuc+ T cells alone (control) (Figure 1B). T-cell accumulation in pleural tumor and extrathoracic sites (spleen) was confirmed by flow cytometric analysis of tissues harvested at serial time points (Figure 1C). These results were reproduced with clinical-grade vector TK-M28z+ T cells administered intrapleurally in mice bearing pleural tumor. Serial [18]F-FEAU PET imaging showed antigen-specific T-cell accumulation with decreasing tumor burden, as seen by corresponding tumor BLI (Figure 1D). Figure 1Conclusion
We provide an optimized method for monitoring of T-cell trafficking, localization and proliferation in thoracic malignancies. Our findings—derived using a clinical-grade imaging construct and substrate—provide convincing evidence for the use of noninvasive T-cell monitoring in our upcoming adoptive T-cell therapy clinical trial.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.
-
+
O08.04 - DISCUSSANT (ID 3905)
16:45 - 17:00 | Author(s): D.P. Carbone
- Abstract
- Presentation
Abstract not provided
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.
-
+
O08.06 - Combining the HSP90 inhibitor, AT13387, with crizotinib improves response in an ALK-positive model of NSCLC. (ID 2163)
17:00 - 17:10 | Author(s): T. Smyth, J. Munck, A. Rodriguez-Lopez, R. McMenamin, N. Thompson, M. Azab, J. Lyons, N.G. Wallis
- Abstract
- Presentation
Background
Activation of anaplastic lymphoma kinase (ALK) via the EML4 translocation occurs in a proportion of non-small cell lung cancers (NSCLC). Whilst inhibitors of ALK such as crizotinib have been successful in the clinic, most patients ultimately relapse due to resistance via a number of different mechanisms. EML4-ALK and many critical components of signalling pathways involved in resistance are clients for the chaperone HSP90. This offers an alternative approach for targeting both ALK inhibitor-sensitive and -resistant disease through inhibition of HSP90 alone or in combination with an ALK inhibitor. AT13387 is a potent second-generation HSP90 inhibitor currently being clinically tested in a number of indications, including ALK-positive NSCLC as single-agent and in combination with the ALK inhibitor, crizotinib. Here we describe its activity in preclinical models of ALK-positive NSCLC and investigate its potential in combination with crizotinib.Methods
The activity of AT13387 was investigated in vitro in the EML4-ALK translocated H2228 cell line. Protein levels were determined by western blotting. In vivo, AT13387 was evaluated in an H2228 tumor xenograft and an EML4-ALK translocated patient-derived xenograft model by measuring inhibition of tumor growth.Results
AT13387 potently inhibited the proliferation of the crizotinib-sensitive EML4-ALK NSCLC cell line, H2228, in vitro with an IC~50~ value of 69 nM. The HSP90 client proteins, EML4-ALK and AKT, along with their phospho-forms, were depleted on treatment of these cells with AT13387. A simultaneous reduction in levels of phospho-ERK, phospho-AKT and phospho-S6 indicated that ALK signalling was inhibited, whilst induction of HSP70 confirmed HSP90 inhibition. In vivo, AT13387 demonstrated activity in ALK-dependent xenograft models, including an ALK-dependent patient-derived xenograft model. When mice bearing H2228 tumor xenografts were treated with AT13387 (70 mg/kg or 55 mg/kg ip once weekly), significant inhibition of tumor growth was observed. As expected, treatment with crizotinib (50 mg/kg po daily) caused partial tumor regression in this model (75% regression after 8 weeks of treatment). However, when AT13387 (55mg/kg weekly) was combined with the crizotinib treatment, a further enhancement of the inhibition of tumor growth over either of the monotherapies (88 % regression after 8 weeks) was observed, with 5 out of 7 tumors achieving complete regression, suggesting that the upfront addition of AT13387 to crizotinib treatment could lead to an improved response and potentially delay the emergence of resistance. In addition, this combination was well-tolerated.Conclusion
AT13387 was shown to be effective in models of ALK-positive NSCLC as monotherapy or in combination with crizotinib, supporting the ongoing Phase II trial of AT13387 in ALK-positive NSCLC as single agent and in combination with crizotinib. These data suggest that treatment with an HSP90 inhibitor such as AT13387, alone or in combination with crizotinib, has therapeutic potential in ALK-positive NSCLC and that, furthermore, upfront combination of the two agents could extend the duration of response.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.
-
+
O08.07 - Patient-derived primary non-small cell lung carcinoma (NSCLC) xenograft models for mechanistic studies of resistance to EGFR tyrosine kinase inhibitor therapy (ID 2380)
17:10 - 17:20 | Author(s): C. Mascaux, P. Martin, E. Stewart, D. Panchal, L. Kim, S. Sakashita, D. Wang, M. Li, N. Pham, N. Leighl, G. Liu, F.A. Shepherd, M. Tsao
- Abstract
- Presentation
Background
Non-small cell lung cancer (NSCLC) patients with tumors bearing “driver” mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain have very high response rates to small molecule EGFR TK inhibitors (TKIs). However, all patients eventually develop resistance to the TKIs, and more recent reports have shown that patients who have stopped TKI therapy may be sensitive again upon re-treatment. While several genetic mechanisms of resistance have been documented, including the gate keeper T790M mutation and Met amplification, cell line studies in vitro have also implicated alternate epigenetic mechanisms that may explain the clinical progression observed in patients with EGFR mutations treated by TKIs. Studies in vivo using patient-derived primary lung tumor xenograft models have not been reported.Methods
Patient-derived primary tumor xenografts were established from surgically resected early stage NSCLC implanted subcutaneously in non-obese diabetic severe combined immune deficient (NOD-SCID) mice. Tumors were passaged after reaching the humane endpoint 1.5 cm maximum diameter. EGFR TKI therapy was initiated when tumors reached ~6 mm diameter. Treatment included daily oral gavage for erlotinib (50 mg/Kg) and dacomitinib (3 mg/Kg). Cetuximab was administered weekly intraperitoneally (50 mg/Kg).Results
Among 33 tumors with EGFR mutations engrafted into the mice, only 6 (18.2 %) formed tumors that could be propagated beyond first passage. Three models have been studied for their responses to EGFR TKIs. Model 148 with L858R mutation showed intrinsic pan-resistance to erlotinib and dacomitinib, as well as to cetuximab. This model was derived from a patient who received pre-operative erlotinib in a window of opportunity trial and did not respond. The patient relapsed after surgery and did not receive additional TKI therapy. Model 137 with exon19 E746-A750 deletion mutation demonstrated complete response to both erlotinib and dacomitinib. However, microscopic examination of tissue from the implantation site revealed viable tumor cells, consistent with the inability of TKI to completely eradicate tumor cells even when complete response is observed clinically. The patient subsequently developed disease recurrence and responded to third line gefitinib treatment. Model 164 has double exon19 L747-T751 deletion/T790M mutations. As anticipated, the xenograft failed to respond to erlotinib but responded dramatically to cetuximab alone. Importantly, model 164 xenograft showed transient stabilization of the tumor growth when treated by dacomitinib, but eventually developed progressive growth after 2 weeks of treatment. Resistance was reversible each time the dacomitinib-resistant tumor was propagated, without drug in new mice. The reversibility of resistance observed upon re-initiation of dacomitinib treatment suggests an epigenetic mechanism for TKI resistance. This patient developed recurrence after surgery and failed to respond to second line erlotinib treatment.Conclusion
Patient-derived primary lung cancer xenografts may provide important patient-like models to study mechanisms of resistance to targeted therapies, and to test novel treatment strategies that may improve further treatment efficacy.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.
-
+
O08.08 - DISCUSSANT (ID 3906)
17:20 - 17:35 | Author(s): G. Giaccone
- Abstract
- Presentation
Abstract not provided
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.
Author of
-
+
E09 - Chemoprevention (ID 9)
- Event: WCLC 2013
- Type: Educational Session
- Track: Prevention & Epidemiology
- Presentations: 1
- Moderators:U. Pastorino, P. Yang
- Coordinates: 10/29/2013, 14:00 - 15:30, Bayside 104, Level 1
-
+
E09.4 - New Biomarkers for Chemoprevention Studies (ID 416)
15:05 - 15:25 | Author(s): C. Mascaux
- Abstract
- Presentation
Abstract
Smoking exposes the respiratory mucosa to carcinogens in a “field cancerization” process. Smokers develop bronchial lesions, at the pre-invasive stages, preceding the development of invasive lung cancer. Because of the field of cancerization, these lesions are multiple and occur throughout the bronchial airways, which make complete resection of bronchial premalignant lesions impractical. Chemoprevention aims to prevent the development of lung cancer. The administration of chemopreventive agents may be effective, alone or in association with local treatment, in reducing the risk of developing lung cancer. So far no phase III trial testing chemopreventive agents for lung cancer has shown a consistent and reproducible benefit. Therefore no agent can be recommended currently for the chemoprevention of lung cancer (Szabo et al, Chest, 143 (5), Supplement, 2013, e40S-e60S). Future chemoprevention trials should be conducted based on the knowledge of lung carcinogenesis drivers and pathways (Keith et al, Nature Reviews, 10, 2013, 334-343). This would allow the choice of drugs with a better chance of benefit and the customization of the chemoprevention agents. Personalized approaches based on prediction of response to therapy by biomarkers are integrated in lung cancer treatment, with much higher success rate and reduced useless toxicity. In the context of chemoprevention, no or minimal sides effect must be obtained in the high risk population receiving the drug because of the absence of active disease, the fact that the treatment might have to be taken for many years by a large population at high-risk and consequently, the potential huge impact on public health. Therefore biomarkers could play crucial roles as surrogate intermediate endpoint and as predictors of response to targeted treatment. Lung cancers express lower levels of prostacyclin than normal lung tissues. Prostacyclin prevents lung cancer in a variety of mouse models. A randomized phase II trial comparing oral iloprost (a prostacyclin analogue) to placebo in high-risk subjects demonstrated improvement in bronchial histology but only in former smokers (Keith et al, Cancer Prev Res, 4 (6), 2011, 793-802). This placebo-controlled study offered the opportunity for investigation of other potential intermediate endpoints and predictive biomarkers to incorporate into chemoprevention trials. Matched biopsies (baseline-BL and the same site at follow-up-FU after 6 months of Iloprost or placebo) were obtained in 125 high-risk individuals who completed the trial: 40/35 and 25/25 current/former smokers in the Iloprost and placebo arm, respectively. We analyzed 496 biopsies including 4 matched biopsy pairs per patient: the best and the worst histology at BL and the 2 biopsies from same site at FU. Total RNA was extracted from formalin fixed paraffin embedded sections adjacent to the diagnostic section and 14 selected miRNA previously identified in high-grade bronchial preneoplasia were analyzed by qRT-PCR (Mascaux et al, Eur Respir J, 33, 2009, 352-359). The expression of seven miRNAs was significantly correlated with histology at BL. The expression of miR-34c was inversely correlated with histology at BL (p<0.0001) and with change in histology at FU (p=0.0003), independent of treatment or smoking status. Several miRNAs were also found to be differentially expressed in current smokers as compared with former smokers. In current smokers, miR-375 was up-regulated at BL (p<0.0001) and down-regulated after treatment with iloprost (p=0.0023). No miRNA at baseline reliably predicted a response to iloprost. Thus, miR-34c was inversely correlated with BL histology and with histology changes. Mir-34c changes at FU could be used as a quantitative biomarker to assess histological response in formalin-fixed bronchial biopsies in future lung cancer chemoprevention studies (Mascaux et al, Canc Prev Res, 6 (2), 2013, 100-108). This utility of miR-34c to assess the histological response to chemoprevention needs to be further demonstrated prospectively in other chemoprevention trials. The high-throughput gene expression profiling of bronchial epithelium (Gustafson et al, Sci Transl Med, 2 (26), 2010, 26ra25) and in lung preneoplasia (Mascaux et al, J Thor Oncol, 4 (suppl to 9), 2009, abstract PRS.2, page S282) could allow the discovery of new targets for chemoprevention and the possibility of customized lung cancer chemoprevention, by selecting the agents based on the different molecular profile of the individuals at high risk. Thus future chemoprevention trials should be undertaken based on the biological drivers and pathways of lung carcinogenesis. The chemoprevention trials should include the collection of biological samples to allow testing biomarker for their role as surrogate intermediate endpoint, for the selection of the patients who are at higher risk and for the personalization of the chemoprevention approach, with the purpose of optimizing the benefit and avoiding useless toxicity in high-risk but cancer-free individuals.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.
-
+
O08 - Preclinical Therapeutic Models I (ID 92)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Biology
- Presentations: 1
- Moderators:C. Mascaux, R. Natale
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside Auditorium A, Level 1
-
+
O08.07 - Patient-derived primary non-small cell lung carcinoma (NSCLC) xenograft models for mechanistic studies of resistance to EGFR tyrosine kinase inhibitor therapy (ID 2380)
17:10 - 17:20 | Author(s): C. Mascaux
- Abstract
- Presentation
Background
Non-small cell lung cancer (NSCLC) patients with tumors bearing “driver” mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain have very high response rates to small molecule EGFR TK inhibitors (TKIs). However, all patients eventually develop resistance to the TKIs, and more recent reports have shown that patients who have stopped TKI therapy may be sensitive again upon re-treatment. While several genetic mechanisms of resistance have been documented, including the gate keeper T790M mutation and Met amplification, cell line studies in vitro have also implicated alternate epigenetic mechanisms that may explain the clinical progression observed in patients with EGFR mutations treated by TKIs. Studies in vivo using patient-derived primary lung tumor xenograft models have not been reported.Methods
Patient-derived primary tumor xenografts were established from surgically resected early stage NSCLC implanted subcutaneously in non-obese diabetic severe combined immune deficient (NOD-SCID) mice. Tumors were passaged after reaching the humane endpoint 1.5 cm maximum diameter. EGFR TKI therapy was initiated when tumors reached ~6 mm diameter. Treatment included daily oral gavage for erlotinib (50 mg/Kg) and dacomitinib (3 mg/Kg). Cetuximab was administered weekly intraperitoneally (50 mg/Kg).Results
Among 33 tumors with EGFR mutations engrafted into the mice, only 6 (18.2 %) formed tumors that could be propagated beyond first passage. Three models have been studied for their responses to EGFR TKIs. Model 148 with L858R mutation showed intrinsic pan-resistance to erlotinib and dacomitinib, as well as to cetuximab. This model was derived from a patient who received pre-operative erlotinib in a window of opportunity trial and did not respond. The patient relapsed after surgery and did not receive additional TKI therapy. Model 137 with exon19 E746-A750 deletion mutation demonstrated complete response to both erlotinib and dacomitinib. However, microscopic examination of tissue from the implantation site revealed viable tumor cells, consistent with the inability of TKI to completely eradicate tumor cells even when complete response is observed clinically. The patient subsequently developed disease recurrence and responded to third line gefitinib treatment. Model 164 has double exon19 L747-T751 deletion/T790M mutations. As anticipated, the xenograft failed to respond to erlotinib but responded dramatically to cetuximab alone. Importantly, model 164 xenograft showed transient stabilization of the tumor growth when treated by dacomitinib, but eventually developed progressive growth after 2 weeks of treatment. Resistance was reversible each time the dacomitinib-resistant tumor was propagated, without drug in new mice. The reversibility of resistance observed upon re-initiation of dacomitinib treatment suggests an epigenetic mechanism for TKI resistance. This patient developed recurrence after surgery and failed to respond to second line erlotinib treatment.Conclusion
Patient-derived primary lung cancer xenografts may provide important patient-like models to study mechanisms of resistance to targeted therapies, and to test novel treatment strategies that may improve further treatment efficacy.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.
