scholarly journals Combining radiomics and mathematical modeling to elucidate mechanisms of resistance to immune checkpoint blockade in non-small cell lung cancer

2017 ◽  
Author(s):  
Daryoush Saeed-Vafa ◽  
Rafael Bravo ◽  
Jamie A. Dean ◽  
Asmaa El-Kenawi ◽  
Nathaniel Mon Père ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Checkpoint Inhibitor ◽  
Cancer Recurrence ◽  
Initial Response ◽  
Resistance Mechanisms ◽  
Ct Images ◽  
Immune Checkpoint Blockade ◽  
Imaging Features ◽  
Mechanisms Of Resistance ◽  
Number Of Patients

AbstractImmune therapies have shown promise in a number of cancers, and clinical trials using the anti-PD-L1/PD-1 checkpoint inhibitor in lung cancer have been successful for a number of patients. However, some patients either do not respond to the treatment or have cancer recurrence after an initial response. It is not clear which patients might fall into these categories or what mechanisms are responsible for treatment failure. To explore the different underlying biological mechanisms of resistance, we created a spatially explicit mathematical model with a modular framework. This construction enables different potential mechanisms to be turned on and off in order to adjust specific tumor and tissue interactions to match a specific patient's disease. In parallel, we developed a software suite to identify significant computed tomography (CT) imaging features correlated with outcome using data from an anti-PDL-1 checkpoint inhibitor clinical trial for lung cancer and a tool that extracts these features from both patient CT images and “virtual CT” images created from the cellular density profile of the model. The combination of our two toolkits provides a framework that feeds patient data through an iterative pipeline to identify predictive imaging features associated with outcome, whilst at the same time proposing hypotheses about the underlying resistance mechanisms.

Integration of proteomic and clinical data for the prediction of response to immune checkpoint inhibitor therapy in non-small cell lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21110-e21110
Author(s):  
Yuval Shaked ◽  
Michal Harel ◽  
Coren Lahav ◽  
Eyal Jacob ◽  
Itamar Sela ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
Host Response ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Resistance Mechanisms ◽  
Small Cell ◽  
Plasma Samples ◽  
Small Cell Lung ◽  
Nsclc Patients

e21110 Background: Immune checkpoint inhibitor (ICI) therapy represents one of the most promising cancer treatments to date. However, despite unprecedented rates of durable response, only a small proportion of patients benefits from this approach. Major efforts are therefore required to characterize treatment resistance mechanisms, as well as to identify reliable biomarkers for response. We have previously shown that in response to various types of cancer therapy, including ICIs, the host may induce pro-tumorigenic processes that can promote therapy resistance. Here we examined systemic host-response proteomic profiles in non-small cell lung cancer (NSCLC) patients, aiming to discover biomarkers for response to ICI therapy and to unravel underlying resistance mechanisms. Methods: As part of our ongoing PROPHETIC clinical trial (NCT04056247), plasma samples were obtained at baseline (T0) and early-on treatment (T1; following the first treatment) from 120 NSCLC patients receiving ICI therapy. Proteomic profiling of the plasma samples was performed using proximity-extension assay (PEA) technology; validation was carried out for a fraction of the samples using ELISA-based arrays. To identify a proteomic signature that predicts clinical outcome, machine learning algorithms were applied following a random separation of the cohort into a discovery set and a validation set. Results: A proteomic signature predictive of response to treatment was identified and validated. Bioinformatic analysis identified potential mechanisms of resistance based on differentially expressed proteins associated with pro-tumorigenic biological processes. Statistical analysis of the clinical data identified multiple novel differential clinical parameters between responders and non-responders, either at baseline or by comparing T0 to T1, which may suggest host-mediated effects. Conclusions: Our study demonstrates the potential clinical utility of analyzing the host response to ICI therapy, in particular for the discovery of novel predictive biomarkers for NSCLC patient stratification. Clinical trial information: NCT04056247.

Outcomes of IDH1/2 mutant AML patients treated with IDH1/2 inhibitors: A single institutional experience.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19010-e19010
Author(s):  
Constantine Nick Logothetis ◽  
Chetasi Talati ◽  
Gregoire Calon ◽  
Nathan P Horvat ◽  
Virginia Olivia Volpe ◽  
...  
Keyword(s):  
Adverse Events ◽  
Somatic Mutations ◽  
Demographic Data ◽  
Response Duration ◽  
Initial Response ◽  
Median Number ◽  
Resistance Mechanisms ◽  
Overall Response ◽  
Line Therapy ◽  
Number Of Patients

e19010 Background: Recent studies showed that IDH1/2 are frequently mutated in AML and that aberrant 2-HG elevation driven by the mutant IDH1/2 proteins plays a pivotal role in AML development. Subsequent clinical trials of IDH1/2 inhibitors demonstrated promising outcomes in IDH1/2mut AML patients. In this single institutional retrospective study, we explored the efficacy and safety outcomes of IDH1/2mut AML patients treated with Ivosidenib or Enasidenib. Methods: We retrospectively identified AML patients who had IDH1/2 somatic mutations based on NGS assessments. Clinical and demographic data were extracted from the medical records. Statistical analyses were performed using GraphPad Prism (v.7.03) and SPSS (v.24.0). Results: A total of 43 ( IDH1mut, n = 12; IDH2mut, n = 33; both IDH1/2mut, n = 2) patients were included in the study. Median age at AML diagnosis was 67.6 (24.2-83.3) years and 24 (55.8%) patients were male. Eighteen (42%) patients had secondary AML and 13 (34.2%), 17 (44.7%), and 8 (21.1%) patients had favorable, intermediate, and adverse risk, respectively. A total of 23 (53.5%) and 9 (20.9%) patients received intensive chemotherapy and hypomethylating agents as their 1st line therapy. One patient received Enasidenib as the 1st line therapy and the rest of the patients had relapsed/refractory disease prior to IDH1/2 inhibitor therapy. Median number of treatment prior to IDH1/2 inhibitors was 4 (0-8). The median duration of IDH1/2 inhibitor treatment was 3.2 (0.2-31.6) months ( IDH1 mut, 2.5 [0.7-13.5]; IDH2 mut, 3.4 [0.2-31.6]). Treatment response was assessed in 38 patients and 18 had overall response (CR, n = 7 [18.4%]; PR, n = 11 [28.9%]). Among these, 13 patients had concurrent somatic mutations in FLT3, KRAS, NRAS, or PTPN11. The overall response rate in these patients was not statistically different compared to patients who did not have these mutations (38.5% vs. 40%, p > 0.05). The median PFS was 3.9 (0.4-14.7) months ( IDH1 mut, 5.6 [1.7-11.5] vs. IDH2 mut, 3.7 [0.4-14.7], p > 0.05) and median OS was 7.6 (0.4-44.1) months. The most common reason for IDH1/2 inhibitor discontinuation was disease progression (n = 21) followed by adverse events (n = 3) and allogeneic transplant (n = 2). The adverse events were assessed in 41 patients and the most common adverse events were differentiation syndrome ( IDH1 mut, n = 3; IDH2 mut, n = 5) and leukocytosis ( IDH1 mut, n = 4; IDH2 mut, n = 4) followed by hepatic toxicity ( IDH2 mut n = 7), and QTc prolongation ( IDH1 mut, n = 3). Conclusions: Our study indicates that IDH1/2 inhibitors remain a reasonable option for the refractory/relapsed IDH1/2mut AML. However, significant number of patients failed to show any response and many of the patients who showed initial response had short response duration. These findings warrant further studies to identify underlying resistance mechanisms of IDH1/2 inhibitors and the optimal combination therapeutic strategies.

Imaging features in post-operative lung cancer recurrence

2018 ◽  
Author(s):  
Monia Attia ◽  
Henda Neji ◽  
Mariem Affes ◽  
Soumaya Ben Saad ◽  
Houda Gharsalli ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Recurrence ◽  
Imaging Features

Mechanisms of Resistance to Immune Checkpoint Blockade: Why Does Checkpoint Inhibitor Immunotherapy Not Work for All Patients?

2019 ◽  
pp. 147-164 ◽  
Author(s):  
Charlene M. Fares ◽  
Eliezer M. Van Allen ◽  
Charles G. Drake ◽  
James P. Allison ◽  
Siwen Hu-Lieskovan
Keyword(s):  
Immune Checkpoint ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Mechanisms Of Resistance ◽  
Primary Resistance ◽  
Wide Range ◽  
Clinical Responses ◽  
Tumor Types

The emergence of immune checkpoint blockade therapies over the last decade has transformed cancer treatment in a wide range of tumor types. Unprecedented and durable clinical responses in difficult-to-treat cancer histologies have been observed. However, despite these promising long-term responses, the majority of patients fail to respond to immune checkpoint blockade, demonstrating primary resistance. Additionally, many of those who initially respond to treatment eventually experience relapse secondary to acquired resistance. Both primary and acquired resistance are a result of complex and constantly evolving interactions between cancer cells and the immune system. Many mechanisms of resistance have been characterized to date, and more continue to be uncovered. By elucidating and targeting mechanisms of resistance, treatments can be tailored to improve clinical outcomes. This review will discuss the landscape of immune checkpoint blockade response data, different resistance mechanisms, and potential therapeutic strategies to overcome resistance.

scholarly journals Acquired Resistance to Immune Checkpoint Blockades: The Underlying Mechanisms and Potential Strategies

2021 ◽  
Vol 12 ◽  
Author(s):  
Binghan Zhou ◽  
Yuan Gao ◽  
Peng Zhang ◽  
Qian Chu
Keyword(s):  
Immune Checkpoint ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Immune Checkpoint Blockade ◽  
Treatment Modalities ◽  
Immune Checkpoints ◽  
Number Of Patients ◽  
Clinical Responses ◽  
Underlying Mechanisms ◽  
Definition Of

The immune checkpoint blockade therapy has completely transformed cancer treatment modalities because of its unprecedented and durable clinical responses in various cancers. With the increasing use of immune checkpoint blockades in clinical practice, a large number of patients develop acquired resistance. However, the knowledge about acquired resistance to immune checkpoint blockades is limited and poorly summarized. In this review, we clarify the principal elements of acquired resistance to immune checkpoint blockades. The definition of acquired resistance is heterogeneous among groups or societies, but the expert consensus of The Society for Immunotherapy of Cancer can be referred. Oligo-progression is the main pattern of acquired resistance. Acquired resistance can be derived from the selection of resistant cancer cell clones that exist in the tumor mass before therapeutic intervention or gradual acquisition in the sensitive cancer cells. Specifically, tumor intrinsic mechanisms include neoantigen depletion, defects in antigen presentation machinery, aberrations of interferon signaling, tumor-induced exclusion/immunosuppression, and tumor cell plasticity. Tumor extrinsic mechanisms include upregulation of other immune checkpoints. Presently, a set of treatment modalities is applied to patients with similar clinical characteristics or resistance mechanisms for overcoming acquired resistance, and hence, further research is required.

scholarly journals Therapeutic KRASG12C inhibition drives effective interferon-mediated anti-tumour immunity in immunogenic lung cancers

2021 ◽  
Author(s):  
Edurne Mugarza ◽  
Febe van Maldegem ◽  
Jesse Boumelha ◽  
Christopher Moore ◽  
Sareena Rana ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Cytotoxic T Cells ◽  
Initial Response ◽  
Therapeutic Benefit ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Acquired Drug Resistance ◽  
Tumour Immunity ◽  
Pathway Gene

The recent development and approval of KRASG12C inhibitors promises to change profoundly the clinical management of lung cancer patients harbouring KRASG12C mutations. However, early clinical data indicate that acquired drug resistance can frequently develop after the initial response. Due to the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, targeted KRASG12C inhibition can indirectly affect anti-tumour immunity. This has served as a rationale for combination with immune checkpoint blockade, showing therapeutic benefit in certain immunogenic pre-clinical tumour models. In this study, we characterised how KRASG12C inhibition reverses immune suppression driven by oncogenic KRAS in a number of pre-clinical lung cancer models with varying levels of immunogenicity. Mechanistically, KRASG12C inhibition upregulates interferon pathway gene expression via inhibition of Myc and, in tumours, leads to reduced infiltration of immunosuppressive cells, increased interferon responses and antigen presentation, and also enhanced infiltration and activation of cytotoxic T cells. However, the combination of KRASG12C inhibitors with immune checkpoint blockade only provides synergistic benefit in the most immunogenic tumour model, with KRASG12C inhibition failing to sensitize cold tumours to immunotherapy. In immunogenic tumours, complete responses to KRASG12C inhibition requires tumour cell autonomous interferon gamma signaling. Our data have important implications for the design of clinical trials combining KRASG12C inhibitors with anti-PD-1 drugs and suggest that additional combination strategies will be needed for immunotherapy refractory patients.

scholarly journals Clinical and radiological features of immune checkpoint inhibitor-related pneumonitis in lung cancer and non-lung cancers

2020 ◽  
Vol 93 (1115) ◽  
pp. 20200409 ◽  
Author(s):  
Tomomi W Nobashi ◽  
Yuko Nishimoto ◽  
Yujiro Kawata ◽  
Hidetaka Yutani ◽  
Masaki Nakamura ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Disease Onset ◽  
Chest Ct ◽  
Radiological Features ◽  
Ct Findings ◽  
Number Of Patients ◽  
History Of

Objective: To investigate the clinical and radiological features of immune checkpoint inhibitor-related pneumonitis (ICI-P), a rare but serious pulmonary complication of cancer immunotherapy and to evaluate key differences between lung cancer (LC) and non-LC patients. Methods: 247 patients (LC, n = 151) treated with ICI for malignancies were retrospectively screened in a single institute. The number of patients, history of other immune-related adverse events (irAE), the onset, serum KL-6 levels, and chest CT features (types of pneumonitis, symmetry, laterality, location) were recorded for the ICI-P population and compared for LC and non-LC groups. Results: ICI-P was identified in 26 patients in total (LC, n = 19; non-LC, n = 7). The incidence of other irAE was significantly higher in ICI-P group (63%) compared with patients without ICI-P (34%) (p = 0.0056). An earlier onset of ICI-P was recorded in LC (78 days) compared to non-LC patients (186 days) (p = 0.0034). Serum KL-6 was significantly elevated only in the non-LC group when ICI-P was noticed (p = 0.029). Major CT findings of ICI-P, irrespective of primary disease, were organizing pneumonia pattern and ground glass opacities. LC patients commonly exhibited consolidation and traction bronchiectasis and were prone to asymmetrical shadows (p < 0.001). Non-LC patients were more likely to exhibit symmetrical infiltrations. A small fraction of both groups experienced relapse or moving patterns of ICI-P. Conclusion: ICI-P patients more often experienced other irAE prior to the development of ICI-P. The characteristics of ICI-P can differ in terms of the onset, KL-6 reliability, and chest CT findings between LC and non-LC patients. Advances in knowledge: In ICI-P patients, a history of other irAE can be more frequently observed. Differences in disease onset and radiological patterns between LC and non-LC patients might be helpful to make a diagnosis of ICI-P; however, longitudinal observation of chest CT scans is advised to observe the pneumonitis activity irrespective of cancer types.

scholarly journals Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3729
Author(s):  
Laura Boyero ◽  
Amparo Sánchez-Gastaldo ◽  
Miriam Alonso ◽  
José Francisco Noguera-Uclés ◽  
Sonia Molina-Pinelo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
Immune Checkpoint ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Immune Checkpoint Blockade ◽  
Research Field ◽  
Term Survival ◽  
Number Of Patients

After several decades without maintained responses or long-term survival of patients with lung cancer, novel therapies have emerged as a hopeful milestone in this research field. The appearance of immunotherapy, especially immune checkpoint inhibitors, has improved both the overall survival and quality of life of patients, many of whom are diagnosed late when classical treatments are ineffective. Despite these unprecedented results, a high percentage of patients do not respond initially to treatment or relapse after a period of response. This is due to resistance mechanisms, which require understanding in order to prevent them and develop strategies to overcome them and increase the number of patients who can benefit from immunotherapy. This review highlights the current knowledge of the mechanisms and their involvement in resistance to immunotherapy in lung cancer, such as aberrations in tumor neoantigen burden, effector T-cell infiltration in the tumor microenvironment (TME), epigenetic modulation, the transcriptional signature, signaling pathways, T-cell exhaustion, and the microbiome. Further research dissecting intratumor and host heterogeneity is necessary to provide answers regarding the immunotherapy response and develop more effective treatments for lung cancer.

Sign in / Sign up

Export Citation Format

Share Document