Immune checkpoint inhibitor response in tumors with LRP1B variants.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14291-e14291
Author(s):  
Jason Zhu ◽  
Matthew D Tucker ◽  
Chester Kao ◽  
Matthew Labriola ◽  
Sachica Cheris ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Suppressor Gene ◽  
Response To Therapy ◽  
Chromosome 2 ◽  
Putative Tumor Suppressor Gene ◽  
Radiographic Response ◽  
Tumor Types

e14291 Background: Low-density lipoprotein receptor-related protein 1B (LRP1B) is a putative tumor suppressor gene spanning > 500 kb on chromosome 2. A melanoma study previously reported enrichment of LRP1B mutations in responders (34%) to immune checkpoint inhibitors (ICIs) compared with non-responders (3%). Deep deletions in LRP1B are frequently observed in non-small cell lung cancer (NSCLC, 12%), head and neck (11%), cervical (9%), bladder (8%), and prostate cancers (8%). This study examines the clinical response to ICIs in a diverse group of tumor types with LRP1B alterations. Methods: We conducted a single center retrospective study inclusive of all patients (pts) with tumors containing any LRP1B variant who were treated with an ICI between 01/2015 and 11/2018. The primary outcome of the study was to describe the clinical outcomes of patients with LRP1B alterations, with respect to radiographic response to therapy, time on therapy, duration of response, and overall survival. Results: 44 pts with an LRP1B variant were treated with an ICI at Duke between 01/2015 and 11/2018. The most common ICIs were pembrolizumab (29/44, 66%) and nivolumab (12/44, 27%). Tumor types included NSCLC (24/44, 55%), renal cell carcinoma (RCC, 5/44, 11%), and prostate cancer (5/44, 11%). 14 (32%) pts had pathogenic variants (PVs) and 30 pts (68%) had variants of uncertain significance (VUS). Among pts with LRP1b PVs, 36% (95%CI 14%-64%) had radiographic responses (5/14, 2 lung, 1 prostate, 1 RCC, 1 endometrial carcinoma), two of whom were MSI high. As a control, the radiographic response rate among patients with a LRP1b VUS was 10% (95%CI 3%-28%). Of those with PVs, 3 pts had stable disease, one of whom has been on CPI therapy for > 22 months and 5 (36%) remain on therapy, with 2 (14%) pts discontinued due to immune toxicities, and 7 (50%) pts discontinued due to disease progression. The median TMB among responders was 12 (2-150.05 mut/Mb) and the median TMB amongst non-responders was 9.5 (6-18 mut/Mb). Conclusions: In a tumor agnostic population of pts harboring LRP1B PVs, 36% of pts have responses to ICI. The majority of responders were MSS and TMB low, which may suggest that PV in LRP1B may independently predict for response to ICI. Prospective and multicenter validation is now needed.

Association of LRP1B pathogenic genomic alterations with favorable outcomes with immune checkpoint inhibitors across multiple tumor types.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3007-3007 ◽  
Author(s):  
Landon Carter Brown ◽  
Ramy Sedhom ◽  
Eric B Schwartz ◽  
Jason Zhu ◽  
Chester Kao ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Density Lipoprotein ◽  
Primary Objective ◽  
Missense Mutations ◽  
Multiple Tumor ◽  
Tumor Types

3007 Background: Low-density lipoprotein receptor-related protein 1b (LRP1b) is a putative tumor suppressor and one of the most frequently altered genes in cancer. Our prior single-center work suggested that LRP1B alterations may enrich for responses to immune checkpoint inhibitors (ICI) in solid tumors including prostate cancer; however, validation of these findings is needed. Methods: We conducted a multicenter, retrospective analysis of patients with LRP1B alterations (on tissue-based next-generation sequencing panels) treated with ICI at Duke, Johns Hopkins (JHU), and University of Michigan (UM). The primary objective was to assess the association between objective response rate (ORR) to ICI and pathogenic LRP1B alterations, defined as deletions or truncating alterations, when compared with LRP1B variants of undetermined significance (VUS), defined as missense mutations not predicted to be pathogenic in COSMIC. Missense changes with a COSCMIC FATHMM score of > 0.8 were categorized separately as likely pathogenic. Summary statistics, ORR, progression free survival (PFS), and overall survival (OS) were calculated. Results: 101 patients (44 Duke, 35 JHU, 22 UM) with LRP1B alterations were treated with ICI. Median age was 61 (range 32-82). The most common tumor types by alteration (pathogenic or likely pathogenic/VUS%) were lung (33/47%), GI (17/13%), prostate (11/7%), sarcoma (2/9%), melanoma (11/0%), and others (26/24%). 93% of patients received single-agent PD-(L)1 inhibition. The ORR for patients with either pathogenic/likely pathogenic alterations, or VUS alterations was 57% and 18%, respectively. After excluding MSI-high or TMB-high ( > 10 mut/Mb) tumors, ORR was 14/25 (56%) and 6/36 (17%), respectively. Pathogenic or likely pathogenic LRP1B alterations were associated with longer PFS (HR 0.39, 95% CI 0.24-0.63) and OS (HR 0.58, 95% CI 0.36-0.95). Conclusions: This multicenter study shows impressive and durable objective response rates to ICI for patients harboring pathogenic LRP1B alterations when compared to those with LRP1B VUS, independent of TMB/MSI status. Further mechanistic insights and prospective validation studies are warranted. [Table: see text]

scholarly journals LRP1B mutations are associated with favorable outcomes to immune checkpoint inhibitors across multiple cancer types

2021 ◽  
Vol 9 (3) ◽  
pp. e001792
Author(s):  
Landon C Brown ◽  
Matthew D Tucker ◽  
Ramy Sedhom ◽  
Eric B Schwartz ◽  
Jason Zhu ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Progression Free Survival ◽  
Preliminary Evidence ◽  
Primary Objective ◽  
Multiple Cancer ◽  
Variants Of Unknown Significance

BackgroundLow-density lipoprotein receptor-related protein 1b (encoded by LRP1B) is a putative tumor suppressor, and preliminary evidence suggests LRP1B-mutated cancers may have improved outcomes with immune checkpoint inhibitors (ICI).MethodsWe conducted a multicenter, retrospective pan-cancer analysis of patients with LRP1B alterations treated with ICI at Duke University, Johns Hopkins University (JHU) and University of Michigan (UM). The primary objective was to assess the association between overall response rate (ORR) to ICI and pathogenic or likely pathogenic (P/LP) LRP1B alterations compared with LRP1B variants of unknown significance (VUS). Secondary outcomes were the associations with progression-free survival (PFS) and overall survival (OS) by LRP1B status.ResultsWe identified 101 patients (44 Duke, 35 JHU, 22 UM) with LRP1B alterations who were treated with ICI. The most common tumor types by alteration (P/LP vs VUS%) were lung (36% vs 49%), prostate (9% vs 7%), sarcoma (5% vs 7%), melanoma (9% vs 0%) and breast cancer (3% vs 7%). The ORR for patients with LRP1B P/LP versus VUS alterations was 54% and 13%, respectively (OR 7.5, 95% CI 2.9 to 22.3, p=0.0009). P/LP LRP1B alterations were associated with longer PFS (HR 0.42, 95% CI 0.26 to 0.68, p=0.0003) and OS (HR 0.62, 95% CI 0.39 to 1.01, p=0.053). These results remained consistent when excluding patients harboring microsatellite instability (MSI) and controlling for tumor mutational burden (TMB).ConclusionsThis multicenter study shows significantly better outcomes with ICI therapy in patients harboring P/LP versus VUS LRP1B alterations, independently of TMB/MSI status. Further mechanistic and prospective validation studies are warranted.

scholarly journals Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 678 ◽  
Author(s):  
Adrien Procureur ◽  
Audrey Simonaggio ◽  
Jean-Emmanuel Bibault ◽  
Stéphane Oudard ◽  
Yann-Alexandre Vano
Keyword(s):  
Cell Death ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Mitotic Cell ◽  
Immunogenic Cell Death ◽  
Dna Damages ◽  
Multiple Tumor ◽  
Tumor Types

The immunogenic cell death (ICD) is defined as a regulated cell death able to induce an adaptive immunity. It depends on different parameters including sufficient antigenicity, adjuvanticity and favorable microenvironment conditions. Radiation therapy (RT), a pillar of modern cancer treatment, is being used in many tumor types in curative, (neo) adjuvant, as well as metastatic settings. The anti-tumor effects of RT have been traditionally attributed to the mitotic cell death resulting from the DNA damages triggered by the release of reactive oxygen species. Recent evidence suggests that RT may also exert its anti-tumor effect by recruiting tumor-specific immunity. RT is able to induce the release of tumor antigens, to act as an immune adjuvant and thus to synergize with the anti-tumor immunity. The advent of new efficient immunotherapeutic agents, such as immune checkpoint inhibitors (ICI), in multiple tumor types sheds new light on the opportunity of combining RT and ICI. Here, we will describe the biological and radiobiological rationale of the RT-induced ICD. We will then focus on the interest to combine RT and ICI, from bench to bedside, and summarize the clinical data existing with this combination. Finally, RT technical adaptations to optimize the ICD induction will be discussed.

scholarly journals Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review

2020 ◽  
Vol 22 (1) ◽  
pp. 190
Author(s):  
Fulvio Borella ◽  
Mario Preti ◽  
Luca Bertero ◽  
Giammarco Collemi ◽  
Isabella Castellano ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
State Of The Art ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Survival Rates ◽  
Younger Women ◽  
Multiple Tumor ◽  
Tumor Types

Vulvar cancer (VC) is a rare neoplasm, usually arising in postmenopausal women, although human papilloma virus (HPV)-associated VC usually develop in younger women. Incidences of VCs are rising in many countries. Surgery is the cornerstone of early-stage VC management, whereas therapies for advanced VC are multimodal and not standardized, combining chemotherapy and radiotherapy to avoid exenterative surgery. Randomized controlled trials (RCTs) are scarce due to the rarity of the disease and prognosis has not improved. Hence, new therapies are needed to improve the outcomes of these patients. In recent years, improved knowledge regarding the crosstalk between neoplastic and tumor cells has allowed researchers to develop a novel therapeutic approach exploiting these molecular interactions. Both the innate and adaptive immune systems play a key role in anti-tumor immunesurveillance. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in multiple tumor types, improving survival rates and disease outcomes. In some gynecologic cancers (e.g., cervical cancer), many studies are showing promising results and a growing interest is emerging about the potential use of ICIs in VC. The aim of this manuscript is to summarize the latest developments in the field of VC immunoncology, to present the role of state-of-the-art ICIs in VC management and to discuss new potential immunotherapeutic approaches.

scholarly journals Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review

2020 ◽  
Vol 21 (17) ◽  
pp. 6176 ◽  
Author(s):  
Yolla Haibe ◽  
Ziad El Husseini ◽  
Rola El Sayed ◽  
Ali Shamseddine
Keyword(s):  
Immune Checkpoint ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Immune Checkpoints ◽  
Therapeutic Approaches ◽  
Standard Chemotherapy ◽  
Primary Resistance ◽  
In The Beginning ◽  
Tumor Types

The treatment landscape in oncology has witnessed a major revolution with the introduction of checkpoint inhibitors: anti-PD1, anti-PDL1 and anti-CTLA-4. These agents enhance the immune response towards cancer cells instead of targeting the tumor itself, contrary to standard chemotherapy. Although long-lasting durable responses have been observed with immune checkpoints inhibitors, the response rate remains relatively low in many cases. Some patients respond in the beginning but then eventually develop acquired resistance to treatment and progress. Other patients having primary resistance never respond. Multiple studies have been conducted to further elucidate these variations in response in different tumor types and different individuals. This paper provides an overview of the mechanisms of resistance to immune checkpoint inhibitors and highlights the possible therapeutic approaches under investigation aiming to overcome such resistance in order to improve the clinical outcomes of cancer patients.

scholarly journals Immunmoduláló antitestek alkalmazása – az onkológia új fejezete

2016 ◽  
Vol 157 (Supplement 2) ◽  
pp. 9-16 ◽  
Author(s):  
Szilvia Szamosi ◽  
László Váróczy ◽  
Zoltán Szekanecz
Keyword(s):  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Hematologic Malignancies ◽  
The United States ◽  
Clinical Development ◽  
Clinical Activity ◽  
The European Union ◽  
Tumor Types

In the past decade major advances in tumor immunology, a better understanding of antigen recognition by T-cells likewise discovering the regulatory inhibitory signals resulted in the development of new immunotherapies with promising durable responses in various solid tumor types and in hematologic malignancies. This review focuses on immunomodulatory antibodies, namely immune checkpoint inhibitor therapy. The prototype of this new class of immune stimulating agents was cytotoxic T-lymphocyte antigen-4 (CTLA-4) antagonists. After demonstrating enhanced survival, ipilimumab was approved first in the United States in 2011, further on in the European Union for second-line (2011) and for first-line therapy (2013) of metastatic melanoma. Additional T-cell intrinsic pathways were identified and targeted for clinical development. Antibodies blocking the PD-1 pathway also showed promising clinical activity and objective tumor response in several types of tumors, including metastatic melanoma, non-small- cell lung cancer. On the other hand antitumor activity is frequently accompanied by significant reversible immune-related adverse events. To explore potential new immune checkpoint targets bring forth several challanges. Future clinical development will involve identifying potential biomarkers anticipating responsiveness to pathway blockade and additional tumor types likely to respond to the therapy. Furthermore, combination strategies, immune checkpoint inhibitors combined with cancer vaccines, targeted inhibitors and traditional chemotherapies are being evaluated in pre-clinical studies. Orv. Hetil., 2016, 157(Suppl. 2), 9–16.

scholarly journals Association between body mass index, dosing strategy, and efficacy of immune checkpoint inhibitors

2021 ◽  
Vol 9 (6) ◽  
pp. e002349
Author(s):  
Murtaza Ahmed ◽  
Mitchell S von Itzstein ◽  
Thomas Sheffield ◽  
Shaheen Khan ◽  
Farjana Fattah ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Clinical Outcomes ◽  
Body Mass ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Fixed Dose ◽  
Radiographic Response ◽  
Dosing Strategy ◽  
High Bmi

BackgroundIncreased body mass index (BMI) has been associated with improved response to immune checkpoint inhibitors (ICIs) in multiple cancer types. We evaluated associations between BMI, ICI dosing strategy, and clinical outcomes.MethodsWe abstracted clinical data on patients with cancer treated with ICI, including age, sex, cancer type, BMI, ICI type, dosing strategy (weight-based or fixed), radiographic response, overall survival (OS), and progression-free survival (PFS). We compared clinical outcomes between low-BMI and high-BMI populations using Kaplan-Meier curves, Cox regressions, and Pearson product-moment correlation coefficients.ResultsA total of 297 patients were enrolled, of whom 40% were women and 59% were overweight (BMI≥25). Of these, 204 (69%) received fixed and 93 (31%) received weight-based ICI dosing. In the overall cohort, overweight BMI was associated with improved PFS (HR 0.69; 95% CI 0.51 to 0.94; p=0.02) and had a trend toward improved OS (HR 0.77; 95% CI 0.57 to 1.04; p=0.08). For both endpoints, improved outcomes in the overweight population were limited to patients who received weight-based ICI dosing (PFS HR 0.53; p=0.04 for weight-based; vs HR 0.79; p=0.2 for fixed dosing) (OS HR 0.56; p=0.03 for weight-based; vs HR 0.89; p=0.54 for fixed dosing). In multivariable analysis, BMI was not associated with PFS or OS. However, the interaction of BMI≥25 and weight-based dosing had a trend toward association with PFS (HR 0.53; 95% CI 0.26 to 1.10; p=0.09) and was associated with OS (HR 0.50; 95% CI 0.25 to 0.99; p=0.05). Patients with BMI<25 tended to have better outcomes with fixed-dose compared with weight-based ICI, while patients with BMI≥25 tended to have better outcomes with weight-based ICI, although these differences did not achieve statistical significance. There was no association between radiographic response and BMI with fixed-dose ICI (p=0.97), but a near-significant trend with weight-based ICI (p=0.1). In subset analyses, the association between BMI, ICI dosing strategy, and clinical outcomes appeared limited to men.ConclusionsThe clinical benefit of ICI in high-BMI populations appears limited to individuals receiving weight-based ICI dosing. Further research into optimal ICI dosing strategies may be warranted.

Markers of immune checkpoint inhibitor efficacy in the AACR Project GENIE database.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15091-e15091
Author(s):  
Yuanchu J Yang ◽  
Sam Rubinstein ◽  
Jeremy Lyle Warner
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Metastatic Breast ◽  
Copy Number Gain ◽  
Ductal Adenocarcinoma ◽  
Cancer Type ◽  
Reference Allele ◽  
Resected Nsclc ◽  
Tumor Types

e15091 Background: Although immune checkpoint inhibitors (ICIs) have been shown to be effective in many tumor types, some highly lethal cancers are not responsive to ICI. Potential biomarkers of ICI response include tumor mutational burden (TMB), which is thought to correlate with increased neoantigen production, and 9p24.1 copy number gain (CNG), which can result in over-expression of programmed death ligand 1 (PD-L1). 9p24.1 CNGs have been described in ICI-sensitive (ICI-S) hematologic malignancies (e.g., Hodgkin lymphoma), but are not well described in solid malignancy. We sought to investigate TMB and 9p24.1 CNG for ICI-S and ICI-resistant (ICI-R) tumor types in the publicly available AACR Project GENIE database, version 7.0. Methods: TMB was calculated by counting somatic mutations with tumor reference allele frequency ≥5% and sequencing depth ≥200X. Samples with < 0.5 MB sequenced were excluded. 9p24.1 CNG was extrapolated from gene-level data. Samples with two or more consecutive gene amplifications in the 9p24.1 region were determined to have 9p24.1 CNG. Samples whose sequencing assay did not include at least two genes in 9p24.1 were excluded. Using an overall response rate (ORR) of ≥10% to define ICI-S, we assessed three ICI-S cancers: hepatobiliary cancer (HBC), melanoma (MEL), non-small cell lung cancer (NSCLC); and two ICI-R types: metastatic breast cancer (MBC) & pancreatic ductal adenocarcinoma (PDAC). Groupwise TMB was compared using Wilcoxon rank-sum and 9p24.1 CNG was compared using Chi-squared. Results: MEL had the highest median TMB but a low 9p24.1 CNG rate; NSCLC had the highest rate of 9p24.1 CNG (Table). PDAC had both the lowest median TMB and 9p24.1 CNG rate. As a group, the ICI-S cancers had higher median TMB (p < .001) and 9p24.1 CNG rate (p < .001). Conclusions: Although rates of 9p24.1 CNG were low across the database as a whole, the NSCLC finding replicates findings described in early stage resected NSCLC (Inoue et al. 2016). Relatively high median TMB in MEL may explain ICI-sensitivity in this cancer type. The combination of low median TMB and low rates of 9p24.1 CNG in PDAC may explain the general lack of efficacy of ICIs in this disease. These findings demonstrate the utility of GENIE as a clinico-genomic database, and also highlight the need to identify better markers of responsiveness to these potentially effective but toxic therapies. [Table: see text]

scholarly journals Multitumor Case Series of Germline BRCA1, BRCA2 and CHEK2-Mutated Patients Responding Favorably on Immune Checkpoint Inhibitors

2021 ◽  
Vol 28 (5) ◽  
pp. 3227-3239
Author(s):  
Lisa Kinget ◽  
Oliver Bechter ◽  
Kevin Punie ◽  
Philip R. Debruyne ◽  
Hilde Brems ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Case Series ◽  
Predictive Biomarkers ◽  
Solid Malignancies ◽  
Tumor Mutational Burden ◽  
Brca1 Brca2 ◽  
Tumor Types ◽  
Selection Of

In recent years, immune checkpoint inhibitors (ICPI) have become widely used for multiple solid malignancies. Reliable predictive biomarkers for selection of patients who would benefit most are lacking. Several tumor types with somatic or germline alterations in genes involved in the DNA damage response (DDR) pathway harbor a higher tumor mutational burden, possibly associated with an increased tumoral neoantigen load. These neoantigens are thought to lead to stronger immune activation and enhanced response to ICPIs. We present a series of seven patients with different malignancies with germline disease-associated variants in DDR genes (BRCA1, BRCA2, CHEK2) responding favorably to ICPIs.

scholarly journals Immune Checkpoint Inhibitor Dosing: Can We Go Lower Without Compromising Clinical Efficacy?

2019 ◽  
pp. 1-5 ◽  
Author(s):  
Alex Renner ◽  
Mauricio Burotto ◽  
Carlos Rojas
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
World Population ◽  
Significant Activity ◽  
New Agents ◽  
Drug Dosing ◽  
New Era ◽  
Number Of Patients ◽  
Tumor Types ◽  
Yearly Cost

In just a few years, immune checkpoint inhibitors have dramatically changed the landscape in oncology, offering durable responses and improved survival for many patients across several tumor types. With more than 3,300 new agents in the immuno-oncology pipeline plus a wide array of combinations being studied, it seems this new era is just getting started. These advances come with a significant caveat: most of the world population does not have access to their benefits, because the yearly cost of a novel anticancer medication can routinely exceed $100,000. There is a large amount of data showing that checkpoint inhibitors have significant activity at doses much lower than those currently approved. We review the evidence for reduced drug dosing as a strategy to increase the number of patients who can be treated and what would be needed to further validate this approach.

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