scholarly journals SCIDOT-30. GLITIPNI: A PHASE 1B CLINICAL TRIAL COMBINING SURGICAL RESECTION WITH DIRECT INTRACEREBRAL INJECTION OF IMMUNE CHECKPOINT INHIBITORS IN PATIENTS WITH RECURRENT GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi277-vi278
Author(s):  
Johnny Duerinck ◽  
Gil Awada ◽  
Julia Katharina Schwarze ◽  
Ines Dufait ◽  
Stephanie Peeters ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Immune Checkpoint ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Median Number ◽  
Recurrent Glioblastoma ◽  
Experimental Therapy ◽  
Intracerebral Injection ◽  
Postoperative Fever ◽  
Intracerebral Administration

Abstract INTRODUCTION Intravenous (iv) administration of PD-1 blocking mAb is largely ineffective for the treatment of recurrent glioblastoma (rGB). Combination of iv-ipilimumab (IPI) plus nivolumab (NIVO) is associated with a high incidence of irAE. Intracerebral (ic) administration of immune-checkpoint inhibiting mAb following the resection of rGB could be a more effective and safer alternative to iv-dosing. METHODS Patients underwent maximal safe resection of their rGB followed by ic-injection of 10mg IPI (cohort-1) or 5mg IPI plus 10mg NIVO (cohort-2) in the wall of the resection cavity. In both cohorts 10mg nivolumab was administered iv for a max of 6 doses, starting 1 day pre-operatively. RESULTS 21 pts were included (3 in C-1, 18 in C-2; 8F/13M; median age 56y [range 38–72]; 17 de novo GB, 4 secGB). All patients underwent maximal safe surgical resection followed by ic-injection of IPI and NIVO as planned. Median number of iv-administrations of NIVO was 5 (range 1–8). Treatment was generally well tolerated. Postoperatively, 2 patients experienced a G3 symptomatic increase in perilesional cerebral edema with neurological deterioration, reversible upon steroid treatment. One patient had worsening neurological symptoms related to an inflammatory intracerebral cyst at the resection site, requiring surgical decompression 4 months post-study treatment. Most frequent AEs were fatigue (2pts G3, 8pts G2), postoperative fever (11pts G1) and headache (3pts G2); 1pt developed G3 pneumonitis. No other immune-related AEs or treatment-related deaths occurred. After median follow-up of 60 weeks, median PFS is 14.4 weeks (95% CI 11.2–17.6); 11/21 patients are alive, and 1- and 2y-OS% are respectively 46% (95% CI 19- 73%), and15% (95% CI 0–42%). CONCLUSION This is the first study demonstrating the safety and activity of combined surgical resection of rGB with local intracerebral administration of immune checkpoint-inhibiting mAb. Survival compares favorably to historical controls justifying further investigation of this experimental therapy.

scholarly journals ATIM-38. GLITIPNI: A PHASE 1B CLINICAL TRIAL COMBINING SURGICAL RESECTION WITH DIRECT INTRACEREBRAL INJECTION OF IMMUNE CHECKPOINT INHIBITORS IN PATIENTS WITH RECURRENT GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi10-vi10 ◽  
Author(s):  
Johnny Duerinck ◽  
Gil Awada ◽  
Julia Katharina Schwarze ◽  
Ines Dufait ◽  
Stephanie Peeters ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Immune Checkpoint ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Median Number ◽  
Recurrent Glioblastoma ◽  
Experimental Therapy ◽  
Intracerebral Injection ◽  
Postoperative Fever ◽  
Intracerebral Administration

Abstract INTRODUCTION Intravenous (iv) administration of PD-1 blocking mAb is largely ineffective for the treatment of recurrent glioblastoma (rGB). Combination of iv-ipilimumab (IPI) plus nivolumab (NIVO) is associated with a high incidence of irAE. Intracerebral (ic) administration of immune-checkpoint inhibiting mAb following the resection of rGB could be a more effective and safer alternative to iv-dosing. METHODS Patients underwent maximal safe resection of their rGB followed by ic-injection of 10mg IPI (cohort-1) or 5mg IPI plus 10mg NIVO (cohort-2) in the wall of the resection cavity. In both cohorts 10mg nivolumab was administered iv for a max of 6 doses, starting 1 day pre-operatively. RESULTS 21 pts were included (3 in C-1, 18 in C-2; 8F/13M; median age 56y [range 38–72]; 17 de novo GB, 4 secGB). All patients underwent maximal safe surgical resection followed by ic-injection of IPI and NIVO as planned. Median number of iv-administrations of NIVO was 5 (range 1–8). Treatment was generally well tolerated. Postoperatively, 2 patients experienced a G3 symptomatic increase in perilesional cerebral edema with neurological deterioration, reversible upon steroid treatment. One patient had worsening neurological symptoms related to an inflammatory intracerebral cyst at the resection site, requiring surgical decompression 4 months post-study treatment. Most frequent AEs were fatigue (2pts G3, 8pts G2), postoperative fever (11pts G1) and headache (3pts G2); 1pt developed G3 pneumonitis. No other immune-related AEs or treatment-related deaths occurred. After median follow-up of 60 weeks, median PFS is 14.4 weeks (95% CI 11.2–17.6); 11/21 patients are alive, and 1- and 2y-OS% are respectively 46% (95% CI 19- 73%), and15% (95% CI 0–42%). CONCLUSION This is the first study demonstrating the safety and activity of combined surgical resection of rGB with local intracerebral administration of immune checkpoint-inhibiting mAb. Survival compares favorably to historical controls justifying further investigation of this experimental therapy.

scholarly journals Neoadjuvant immunotherapy in resectable head and neck cancer: oral cavity carcinoma as a potential research model

2021 ◽  
Vol 13 ◽  
pp. 175883592098406
Author(s):  
Vanesa Gutiérrez Calderón ◽  
Alexandra Cantero González ◽  
Laura Gálvez Carvajal ◽  
Yolanda Aguilar Lizarralde ◽  
Antonio Rueda Domínguez
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Cavity ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Surgical Resection ◽  
Squamous Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Research Model

Squamous cell carcinoma of oral cavity (OCSCC) accounts for approximately 25% of cases of head and neck squamous cell carcinoma (HNSCC). Tobacco and alcohol consumption are the main risk factors for both cancers. Surgical resection, combined with adjuvant radiotherapy or radiochemotherapy in patients with high risk of relapse, is the key element in management in the initial stages. However, despite the availability of aggressive multidisciplinary treatments, advanced resectable OCSCC carries poor prognosis; only half of the patients are disease-free 5 years after the surgery. Immunotherapy based on the use of immune checkpoint inhibitors has been proven to be effective in a wide variety of tumours, including recurrent and metastatic HNSCC. These positive results resulted in investigations into its effectiveness in earlier stages of the disease with OCSCC emerging as an interesting research model because of the accessible location of the tumours. This article reviews the potential advantages of emerging immunotherapeutic agents [mainly monoclonal antibodies against programmed cell death-1 ( PD-1) immune checkpoint inhibitors] as neoadjuvant treatment for OCSCC at locoregional stages as well as the ongoing clinical trials, challenges in evaluating tumour response, and possible predictive biomarkers of response with highlights regarding the role of oral microbiota as modulators of immune response. The efficacy and safety of anti- PD-1 drugs in these patients have been proven in preliminary trials. If there is a decrease in the relapse rate and an improvement in the overall survival after surgical resection in ongoing trials, preoperative immunotherapy may be established as a treatment option for patients with early stages of the disease.

scholarly journals Overcoming Resistance to Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinomas

2021 ◽  
Vol 11 ◽  
Author(s):  
Lucas V. dos Santos ◽  
Carina M. Abrahão ◽  
William N. William
Keyword(s):  
Head And Neck ◽  
Squamous Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Clinical Work ◽  
Squamous Cell Carcinomas ◽  
Clinical Activity

Preclinical data suggest that head and neck squamous cell carcinomas (HNSCC) may evade immune surveillance and induce immunosuppression. One mechanism of immune evasion involves the expression of programmed death ligand-1 (PD-L1) in tumor and immune cells, which is, to date, the only biomarker routinely used in clinical practice to select patients with advanced HNSCCs more likely to benefit from anti-PD-1 therapy. Nonetheless, PD-L1 expression alone incompletely captures the degree of sensitivity of HNSCCs to PD-1 inhibitors. Most patients exposed to anti-PD-1 antibodies do not respond to therapy, suggesting the existence of mechanisms of de novo resistance to immunotherapy. Furthermore, patients that initially respond to PD-1 inhibitors will eventually develop acquired resistance to immunotherapy through mechanisms that have not yet been completely elucidated. In this article, we will provide an overview of the immune landscape of HNSCCs. We will briefly describe the clinical activity of inhibitors of the PD-1/PD-L1 axis in this disease, as well as biomarkers of benefit from these agents that have been identified so far. We will review pre-clinical and clinical work in cancers in general, and in HNSCCs specifically, that have characterized the mechanisms of de novo and acquired resistance to immunotherapy. Lastly, we will provide insights into novel strategies under investigation to overcome resistance to immune checkpoint inhibitors.

scholarly journals ATIM-20. A RETROSPECTIVE STUDY EVALUATING THE SAFETY AND SURVIVAL OF THE COMBINATION OF PD-1 IMMUNE CHECKPOINT BLOCKADE AND BEVACIZUMAB IN RECURRENT GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi5-vi5
Author(s):  
Joshua Friedman ◽  
Adilia Hormigo
Keyword(s):  
Retrospective Study ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Recurrent Disease ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Immune Checkpoint Blockade ◽  
Recurrent Glioblastoma ◽  
Grade 3 ◽  
Recurrent Gbm

Abstract INTRODUCTION Immune checkpoint inhibitors (ICI) have demonstrated clinical efficacy in a variety of cancers. It is known that cancer including glioblastoma (GBM) induces an immunosuppression. Bevacizumab by normalizing blood vessels in the tumor can facilitate immune surveillance and potentially improve the efficacy of ICI in GBM patients. We analyze GBM patients with recurrent disease treated with ICI and bevacizumab. METHODS We retrospectively review records of patients diagnosed with recurrent GBM treated at our institution with Pembrolizumab or Nivolumab and bevacizumab and evaluate for tolerance and outcomes. RESULTS Twenty-one patients, 12 men and 9 women with median age 62 (range 36–78) and KPS 70 (range 60–90) were treated with a median of 10 ICI cycles (range 4–29) and 5 of bevacizumab (range 0–21). A total of 8 patients (38%) had immune-related adverse events (IRAE): 3 grade 1, 3 grade 2 and 2 grade 3. A patient with pneumonitis required cessation of ICI. Median OS for the 21 patients was 22 months (range 6–41). The 7 patients that had MGMT detected in their tumors had a median OS of 27 months (range 23–41) compared to a survival of 21 months (range 6–24) for the 13 patients that had MGMT undetected. One had undetermined MGMT and her OS was 21 months. The median survival for all the patients from onset of ICI was 10 months (range 1–25) and 10 of them (47.6%) survived > 12 months. DISCUSSION The development of IRAE was common but self-limiting, allowing continuation of the treatment in all but one patient. The combination of ICI and bevacizumab increased survival. Our data needs to be interpreted with caution, as it is a retrospective analysis of a small group of patients. However, these results warrant prospective studies using the combination of ICI and bevacizumab to treat recurrent GBM.

Infections in patients receiving immune checkpoint inhibitors.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 155-155
Author(s):  
Sutthichai Sae-Tia ◽  
Jarushka Naidoo ◽  
Seema Mehta
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Viral Infections ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Laboratory Data ◽  
Hematologic Malignancies ◽  
Systemic Corticosteroids ◽  
Improved Outcomes ◽  
Infectious Diseases Consultation

155 Background: Immune checkpoint inhibitors (ICIs) - anti-PD-1 (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, avelumab), anti-CTLA-4 (ipilimumab) - have improved outcomes for several malignancies. ICIs may cause immune-related adverse events (irAEs), often treated with immunosuppression. The incidence of infections arising de novo during ICI therapy or from immunosuppression for irAEs is not well described. Methods: In- and outpatients receiving ICIs were referred for Infectious Diseases consultation between 6/2011-6/2018. Twenty-five were randomly selected for retrospective summarization of the spectrum of infections. Diagnosis of infection was made by the primary oncologist, based upon clinical/radiographic/laboratory data. Results: Solid tumor (24, 96%) and hematologic malignancies (1, 4%) were represented (Table). All 25 had infections. 15 (60%) were male; median age 58 years (29-97). 17 (68%) had irAEs: pneumonitis (10, 40%), thyroiditis (5, 20%), colitis (5, 20%), hepatitis (4, 16%), dermatitis (4, 16%) and myocarditis (1, 4%). 17 (68%) patients developed +1 irAE. 50% with pneumonitis were concurrently treated for pneumonia. Of the 25, 17 (72%) developed de novo infections on ICIs; whereas others were receiving systemic corticosteroids (7, 28%) or infliximab (1, 4%). Initial infections included pneumonia (13, 52%), bacteremia (3, 12%), sinusitis (2, 8%), wound infection (2, 8%), viral infections (HSV, CMV, HCV; 1, 4% each) and 1 (4%) each of empyema, UTI, peritonitis, osteomyelitis, and meningitis. 44% (11) developed a second infection within 60 days of the first. Conclusions: Patients receiving ICIs for cancer developed a myriad of infections, both de novo during ICI therapy, or consequent to immunosuppression for irAEs. Second infections are common, occurring in nearly half the patients. Awareness of this is vital for early diagnosis and appropriate management. Patients with suspected ICI-related infection. (n=25). [Table: see text]

scholarly journals Immune checkpoint inhibitors in combination with radiotherapy as salvage treatment for relapsed/refractory classical Hodgkin lymphoma: A retrospective analysis in 12 patients

2021 ◽  
Vol 13 (2) ◽  
Author(s):  
Elisa Lucchini ◽  
Chiara Rusconi ◽  
Mario Levis ◽  
Francesca Ricci ◽  
Armando Santoro ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Median Number ◽  
Brentuximab Vedotin ◽  
Salvage Treatment ◽  
Classical Hodgkin Lymphoma ◽  
Highly Active

The rate of complete remission (CR) with the anti-PD1 immune checkpoint inhibitors (ICI) nivolumab (N) and pembrolizumab (P) in patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) is low (20-30%), and the majority of patients eventually relapse. One strategy to improve their outcome is to combine ICI with radiotherapy (ICI-RT), taking advantage of a supposed synergistic effect. We retrospectively collected data of 12 adult patients with R/R cHL treated with ICI-RT delivered during or within 8 weeks from the start or after the end of ICI. Median age at ICI-RT was 37 years, 50% had previously received an autologous stem cell transplantation (SCT) and 92% brentuximab vedotin. RT was given concurrently, before or after ICI in 4, 1 and 7 patients. Median RT dose was 30Gy, for a median duration of 22 days. Median number of ICI administrations was 15. Overall response and CR rate were 100% and 58%. Nine patients received subsequent SCT consolidation (7 allogeneic and 2 autologous). After a median follow-up of 18 months, 92% of patients were in CR. No major concerns about safety were reported. ICI-RT combination appears to be a feasible and highly active bridge treatment to transplant consolidation.

scholarly journals A Systematic Review on the Therapeutic Potentiality of PD-L1-Inhibiting MicroRNAs for Triple-Negative Breast Cancer: Toward Single-Cell Sequencing-Guided Biomimetic Delivery

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1206
Author(s):  
Mahdi Abdoli Shadbad ◽  
Sahar Safaei ◽  
Oronzo Brunetti ◽  
Afshin Derakhshani ◽  
Parisa Lotfinejad ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Oncogenic Signaling ◽  
Single Cell Sequencing ◽  
Oncogenic Signaling Pathways ◽  
Tumoral Cells

The programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) is a well-established inhibitory immune checkpoint axis in triple-negative breast cancer (TNBC). Growing evidence indicates that tumoral PD-L1 can lead to TNBC development. Although conventional immune checkpoint inhibitors have improved TNBC patients’ prognosis, their effect is mainly focused on improving anti-tumoral immune responses without substantially regulating oncogenic signaling pathways in tumoral cells. Moreover, the conventional immune checkpoint inhibitors cannot impede the de novo expression of oncoproteins, like PD-L1, in tumoral cells. Accumulating evidence has indicated that the restoration of specific microRNAs (miRs) can downregulate tumoral PD-L1 and inhibit TNBC development. Since miRs can target multiple mRNAs, miR-based gene therapy can be an appealing approach to inhibit the de novo expression of oncoproteins, like PD-L1, restore anti-tumoral immune responses, and regulate various intracellular singling pathways in TNBC. Therefore, we conducted the current systematic review based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to provide a comprehensive and unbiased synthesis of currently available evidence regarding the effect of PD-L1-inhibiting miRs restoration on TNBC development and tumor microenvironment. For this purpose, we systematically searched the Cochrane Library, Embase, Scopus, PubMed, ProQuest, Web of Science, Ovid, and IranDoc databases to obtain the relevant peer-reviewed studies published before 25 May 2021. Based on the current evidence, the restoration of miR-424-5p, miR-138-5p, miR-570-3p, miR-200c-3p, miR-383-5p, miR-34a-5p, miR-3609, miR-195-5p, and miR-497-5p can inhibit tumoral PD-L1 expression, transform immunosuppressive tumor microenvironment into the pro-inflammatory tumor microenvironment, inhibit tumor proliferation, suppress tumor migration, enhance chemosensitivity of tumoral cells, stimulate tumor apoptosis, arrest cell cycle, repress the clonogenicity of tumoral cells, and regulate various oncogenic signaling pathways in TNBC cells. Concerning the biocompatibility of biomimetic carriers and the valuable insights provided by the single-cell sequencing technologies, single-cell sequencing-guided biomimetic delivery of these PD-L1-inhibiting miRs can decrease the toxicity of traditional approaches, increase the specificity of miR-delivery, enhance the efficacy of miR delivery, and provide the affected patients with personalized cancer therapy.

scholarly journals Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Shuang Qin ◽  
Linping Xu ◽  
Ming Yi ◽  
Shengnan Yu ◽  
Kongming Wu ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Immune Checkpoint Molecules

Abstract The emergence of immune checkpoint inhibitors (ICIs), mainly including anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies (mAbs), has shaped therapeutic landscape of some type of cancers. Despite some ICIs have manifested compelling clinical effectiveness in certain tumor types, the majority of patients still showed de novo or adaptive resistance. At present, the overall efficiency of immune checkpoint therapy remains unsatisfactory. Exploring additional immune checkpoint molecules is a hot research topic. Recent studies have identified several new immune checkpoint targets, like lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), and so on. The investigations about these molecules have generated promising results in preclinical studies and/or clinical trials. In this review, we discussed the structure and expression of these newly-characterized immune checkpoints molecules, presented the current progress and understanding of them. Moreover, we summarized the clinical data pertinent to these recent immune checkpoint molecules as well as their application prospects.

Clinical outcomes of patients with non-small cell lung cancer (NSCLC) receiving chemotherapy after immune checkpoint blockade.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9082-9082 ◽  
Author(s):  
Claud Grigg ◽  
Brian D. Reuland ◽  
Adrian G. Sacher ◽  
Randy Yeh ◽  
Naiyer A. Rizvi ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Objective Response ◽  
Poor Performance ◽  
Response Rates ◽  
Median Number ◽  
Immune Checkpoint Blockade ◽  
Poor Performance Status ◽  
Chemotherapy Response

9082 Background: Objective response rates (ORR) to chemotherapy beyond the first-line for advanced NSCLC are low (5-10%). Pre-clinical studies suggest that some chemotherapies may act, in part, through immune mediated mechanisms. Additionally, results from phase I/II studies of chemotherapy combined with immune checkpoint inhibitors (ICIs) suggest high response rates ( > 50%) and potential synergy. It is unknown whether chemotherapy is more efficacious when given after ICIs. Methods: We reviewed demographics, imaging, treatment history, and clinical course for all patients at our institution with a diagnosis of metastatic NSCLC who received at least one dose of nivolumab, pembrolizumab, atezolizumab, or durvalumab prior to December 8, 2016. Patients who received any subsequent chemotherapy were included for analysis. Objective response was determined by RECIST v1.1, and date of progression was determined radiographically or clinically (treatment discontinuation with documented clinical deterioration). Results: 145 patients received at least one dose of any ICI, and 38 patients received subsequent chemotherapy. The median age was 68 years (range 44-88). Six chemotherapy-naïve patients received carboplatin + pemetrexed +/- bevacizumab. There were 3 partial responses (PR) including one exceptional response that is ongoing after 2 years. Among 32 chemotherapy non-naïve patients, the median number of prior chemotherapy regimens was 2 (range 1-6). Post-ICI chemotherapy included docetaxel + ramucirumab (n = 12), vinorelbine (n = 7), gemcitabine-based chemotherapy (n = 6), carboplatin doublets (n = 4), pemetrexed + bevacizumab (n = 2), and paclitaxel (n = 1). Six patients had documented poor performance status and died within 1 month of starting treatment. The ORR was 25% (1CR, 7PR), median time to progression was 116 days, and 9 patients (28%) experienced stable disease (SD) or better lasting > 150 days. Exceptional responses occurred across regimens. Nine patients received a further line of chemotherapy, with 3 ongoing PR or SD lasting > 100 days. Conclusions: For NSCLC, chemotherapy response rates may be higher when administered after an ICI.

DNA methylation profiling in patients with head and neck squamous cell carcinoma treated with immune checkpoint inhibitors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18527-e18527
Author(s):  
Angelika Martina Starzer ◽  
Gerwin Heller ◽  
Erwin Tomasich ◽  
Katharina Feldmann ◽  
Teresa Hatziioannou ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Median Number ◽  
Neck Squamous Cell Carcinoma

e18527 Background: Biomarkers for response prediction to immune checkpoint inhibitors in head and neck squamous cell carcinoma (HNSCC) patients are needed for a personalized therapy regimen. Therefore, we investigated the predictive potential of inflammatory biomarkers and DNA methylation. Methods: We profiled the methylation status of 850.000 CpG sites in formalin-fixed, paraffin-embedded primary HNSCC samples collected before ICI therapy start using Infinium Methylation EPIC microarrays. Tumor-infiltrating lymphocytes (TILs) and programmed cell death ligand 1 (PD-L1) expression were analyzed employing immunohistochemistry staining. Methylation profile, TIL density and PD-L1 expression were correlated with best radiological response to ICI treatment. Results: 29 patients (median age of 61; range 28-80) years; 8 (27.6%) females, 21 (72.4%) males) with HNSCC were included. Median number of prior systemic therapies was 1 (range 0-3). Median number of ICI applications was 6 (range 1-45). 2/29 (6.9%) patients achieved an objective response (complete response or partial response) under anti-PD-1 therapy. Median progression-free survival (PFS) and median overall survival (OS) were 3.3 months (range 0-28.8) and 7.2 months (range 0-29.4), respectively. 7/29 (24.1%) patients were still alive and one of these patients was still on ICI therapy at data cut-off. Methylation analyses revealed a combination of methylation changes (both hypo- and hypermethylation) that was predictive for response to ICI. 11/27 (40.7%) patients had PD-L1 expressing tumor cells ( > 1% PD-L1 expression). Median density of CD8+ TILs was 423.49 cells/mm2 tumor (range 5.71-11528.43 cells/mm2) and median density of CD3+ TILs was 794.82 cells/mm2 tumor (range 1.68-8811.74 cells/mm2). There was no correlation of PD-L1 expression, density of CD8+ or CD3+ TILs with response or disease control (p > 0.05). Conclusions: In contrast to PD-L1 expression and TIL density, methylation profiles were associated with response to ICI treatment in HNSCC patients.

Sign in / Sign up

Export Citation Format

Share Document