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.

scholarly journals Rethinking immune checkpoint blockade: ‘Beyond the T cell’

2021 ◽  
Vol 9 (1) ◽  
pp. e001460 ◽  
Author(s):  
Xiuting Liu ◽  
Graham D Hogg ◽  
David G DeNardo
Keyword(s):  
Immune System ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.

scholarly journals 522 Transcriptomic changes in cancer patients treated with immune-checkpoint inhibitors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A552-A552
Author(s):  
Dmitrii Shek ◽  
Bo Gao ◽  
Joey Lai ◽  
Won-Hee Yoon ◽  
Tania Moujaber ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Differentially Expressed Genes ◽  
Immune Checkpoint ◽  
Functional Annotation ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Link Type ◽  
Pre Treatment ◽  
Grade 3 ◽  
Transcriptomic Changes

BackgroundImmune-checkpoint inhibitors (ICIs) are monoclonal antibodies that block inhibitory CTLA-4/PD-1 signalling pathways and thus boost cytotoxic T cell antitumor activity. ICIs have been proven effective in various malignancies, but there is a lack of knowledge regarding factors associated with ICI efficacy and safety. This study aims to examine transcriptomic changes in cancer patients treated with ICIs and their potential association with related clinical outcomes.MethodsThis is a prospective multicentre cohort study (NCT04631731) recruiting cancer patients treated with (1) ICI monotherapy; (2) ICI dual therapy; (3) ICI + kinase inhibitor; (4) ICI + platinum-doublet chemotherapy. Peripheral blood is collected at baseline and 6–8 weeks after first ICI treatment as well as after the development of immune-related adverse events (irAEs, grade 2 and higher). Whole transcriptome sequencing (Novaseq S4 300 cycle lane, Illumina) was performed and followed by functional annotation using the ConsensusPath-DB platform.Results22 patients were recruited to the study and had paired blood taken. Two patients had developed grade 3–4 irAEs. RNA sequencing analysis identified 3,000 genes that were significantly dysregulated at week 6–8 after ICI commencement as compared to pre-treatment in n=20 recruited patients without irAEs (figure 1). Functional annotation established that 132 pathways were associated with the identified set of dysregulated genes. Among them: (1) pre-NOTCH processing in Golgi, (2) Interleukin-15 signalling; (3) STAT5 activation, and (4) RORA activation of gene expression possessed a gene set enrichment of at least 80% and p<0.01. In 2 patients with grade 3 immune-mediated hepatitis, both treated with combination of CTLA-4/PD-1 inhibitors, analysis revealed that 360 and 325 were 2-fold up- and downregulated respectively upon onset of toxicity as compared to both pre-treatment and 1-week post-steroid treatment. Interestingly, this gene set possessed minimal overlap when compared to genes dysregulated in patients without irAEs. Moreover, functional annotation established different pathways that were associated with toxicity. The highest enrichment scores belonged to pathways regulating cell cycle and apoptotic pathways driven by CDC25A, p53 and BCL-2, among others.Abstract 522 Figure 1Volcano plot representing the differentially expressed genesThe figure representing differentially expressed genes elucidated in this pilot study. N=3000 genes were significantly dysregulated between pre- and week 6–8 post-IO commencement.ConclusionsThe preliminary analysis of the first 22 patients recruited to NCT04631731 confirms that ICI treatment interferes with expression of coding and non-coding RNAs. Importantly, patients with and without irAEs show different patterns of transcriptomic changes as well as variability among activated cellular pathways. This data emphasises the need for further exploration and validation of transcriptomic changes in a larger cohort. In the near future, RNA signatures may be utilised as biomarkers to rapidly and accurately diagnose irAEs.AcknowledgementsN/ATrial RegistrationClinicalTrials.Gov identification number: NCT04631731ReferencesN/AEthics ApprovalThis study has been approved by the Western Sydney Local Health District (WSLHD) Human Research Ethics Committee on the November 9th, 2020 to be conducted at Blacktown and Westmead Public Hospitals of the WSLHD, Sydney, NSW, Australia.ConsentEach participant recruited to this translational study has provided written consent approved on the November 6th, 2020 (MASTER version) by the WSLHD HREC.

scholarly journals 237 Infectious complications in patients with non-small cell lung cancer treated with anti-PD(L)1 immune checkpoint inhibitors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A253-A253
Author(s):  
Matthew Guo ◽  
Aanika Balaji ◽  
Joseph Murray ◽  
Joshua Reuss ◽  
Seema Mehta Steinke ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Infectious Complications ◽  
Small Cell ◽  
Small Cell Lung ◽  
Grade 3

BackgroundImmune checkpoint inhibitors (ICI) are standard treatment for stage III/IV non-small cell lung cancer (NSCLC). ICIs may cause immune-related adverse events (irAEs) often requiring corticosteroids or other immunosuppressive therapy and are associated with increased risk of opportunistic infections.1 2 The burden of infectious complications in NSCLC patients (pts) treated with ICIs is poorly described.MethodsWe retrospectively reviewed NSCLC pts treated with ICIs between 2016–2020 at a large tertiary academic center. An infectious complication related to ICIs was defined as a pathogen-confirmed or clinically diagnosed infection requiring antimicrobials during or within 3 months of ICI discontinuation. High-grade infections were defined as those requiring IV antibiotics (grade 3), life-threatening or requiring ICU stay (grade 4), or resulting in death (grade 5). irAEs were defined by the treating provider and treated according to standard guidelines. Patient demographics, treatment data, cancer outcomes, infectious complications, and irAE details were annotated in an IRB-approved database. An AE treated as both an infection and/or irAE with antibiotics and immunosuppression was coded as a concomitant irAE/infection event. The association between patient features and infectious complications was examined using logistic regression. Treatment and disease characteristics for concomitant irAE with infection were also described.Results302 ICI-treated NSCLC pts were included. 211 pts received PD-1 monotherapy and 91 received PD-1 therapy with CTLA-4 therapy, chemotherapy, or other investigational therapy. The majority (175/302, 57.9%) had a documented infection (bacterial=138, viral=17, fungal=19, mycobacterial=1) during or within 3 months of ICI discontinuation. Grade ≥3 infections occurred in 33.4% of pts (101/302). Pulmonary infections were most common (35.4%), followed by gastrointestinal, urinary, and skin (<10%, each). A subset of pts were treated as having concomitant irAE/infection events (63/302, 20.9%). Among 63 pts who experienced irAEs, pneumonitis occurred most commonly (47/63, 74.6%) followed by colitis (7/63, 11.1%); other irAEs (hepatitis, myocarditis, thyroiditis) occurred in <3 patients each. A concomitant event was associated with a trend toward higher odds of hospitalization (OR 3.91, CI 0.5–30.76) when adjusted for grade ≥3 infection. Similarly, steroid use within one month prior to infection, was also associated with a trend toward higher odds of hospitalization (OR 8.88, CI 0.81–97.15), adjusted for grade ≥3 infection.ConclusionsIn this retrospective study of NSCLC pts treated with ICIs, the majority experienced infections during or within 3 months of ICI discontinuation. The most common infections were bacterial pulmonary in origin. Concomitant irAE/infection was associated with trend toward higher odds of hospitalization.ReferencesHamashima R, Uchino J, Morimoto Y, et al. Association of immune checkpoint inhibitors with respiratory infections: a review. Cancer Treatment Reviews 2020;90:102109. doi:10.1016/j.ctrv.2020.102109Lu M, Zhang L, Li Y, et al. Recommendation for the diagnosis and management of immune checkpoint inhibitor related infections. Thorac Cancer 2020;11(3):805–809. doi:10.1111/1759-7714.13313Ethics ApprovalThis retrospective chart review study has obtained ethics approval from the Institutional Review Board at the Johns Hopkins School of Medicine (number: IRB00129424).

Volume increase of spleen in melanoma patients undergoing immune checkpoint blockade

Immunotherapy ◽  
2021 ◽  
Author(s):  
Laura Susok ◽  
Dominik Reinert ◽  
Carsten Lukas ◽  
Eggert Stockfleth ◽  
Thilo Gambichler
Keyword(s):  
Immune Checkpoint ◽  
Cutaneous Melanoma ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Clinical Parameters ◽  
Spleen Volume ◽  
Volume Increase ◽  
Computer Tomographic ◽  
Melanoma Patients

Aim: To find out whether treatment with immune checkpoint inhibitors (ICIs) results in volume increase of the spleen. Patient & methods: We studied 49 stage III and IV melanoma patients with an indication for ICIs. Computer tomographic-assisted volumetry of spleens was performed. Results: After 3 months, median spleen volume was significantly increased when compared with the baseline volume. At 3 months, the increase of spleen volume was significantly associated with the use of ipilimumab and ipilimumab plus nivolumab. There was no significant association between spleen volume increase and clinical parameters. Conclusion: The median spleen volume of patients with cutaneous melanoma increases during the first months of ICI treatment, which was particularly attributable to the use of anti-CTLA-4 and anti-CTLA-4/anti-PD-1 regimens.

scholarly journals Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3629
Author(s):  
Hsiao-Ling Chen ◽  
Yu-Kang Tu ◽  
Hsiu-Mei Chang ◽  
Tai-Huang Lee ◽  
Kuan-Li Wu ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Small Cell ◽  
Randomized Controlled ◽  
Extensive Stage ◽  
Grade 3

Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard cytotoxic chemotherapy with etoposide and platinum (EP). Several randomized controlled trials have shown that patients with ED-SCLC who received a combination of EP plus immune checkpoint inhibitors (ICIs) had superior survival compared with those who received EP alone. We conducted a systematic review and network meta-analysis to provide a ranking of ICIs for our primary endpoints in terms of overall survival (OS), progression free survival (PFS), and objective response rate (ORR), as well as our secondary endpoint in terms of adverse events. The fractional polynomial model was used to evaluate the adjusted hazard ratios for the survival indicators (OS and PFS). Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being best (Prbest) reference. EP plus nivolumab, atezolizumab or durvalumab had significant benefits compared with EP alone in terms of OS (Hazard Ratio HR = 0.67, 95% Confidence Interval CI = 0.46–0.98 for nivolumab, HR = 0.70, 95% CI = 0.54–0.91 for atezolizumab, HR = 0.73, 95% CI = 0.59–0.90 for durvalumab) but no significant differences were observed for pembrolizumab or ipilimumab. The probability of nivolumab being ranked first among all treatment arms was highest (SCURA = 78.7%, Prbest = 46.7%). All EP plus ICI combinations had a longer PFS compared with EP alone (HR = 0.65, 95% CI = 0.46–0.92 for nivolumab, HR = 0.77, 95% CI = 0.61–0.96 for atezolizumab, HR = 0.78, 95% CI = 0.65–0.94 for durvalumab, HR = 0.75, 95% CI = 0.61–0.92 for pembrolizumab), and nivolumab was ranked first in terms of PFS (SCURA = 85.0%, Prbest = 66.8%). In addition, nivolumab had the highest probability of grade 3–4 adverse events (SUCRA = 84.8%) in our study. We found that nivolumab had the best PFS and OS in all combinations of ICIs and EP, but nivolumab also had the highest probability of grade 3–4 adverse events in our network meta-analysis. Further head-to head large-scale phase III randomized controlled studies are needed to verify our conclusions.

Immune-related adverse events associated with immune checkpoint inhibitors in patients with cancer

2020 ◽  
pp. 030089162095346
Author(s):  
Nilay Sengul Samanci ◽  
Duygu Ilke Cikman ◽  
Kerem Oruc ◽  
Sahin Bedir ◽  
Emir Çelik ◽  
...  
Keyword(s):  
Adverse Events ◽  
Health Care Providers ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Care Providers ◽  
Patients With Cancer ◽  
Combination Treatments ◽  
Grade 3

Introduction: With the widespread use of immune checkpoint inhibitors (ICIs), we are facing challenges in the management of immune-related adverse events (irAEs). We aimed to characterize the spectrum of toxicity, management, and outcomes for irAEs. Methods: Patients who were treated with at least one ICI in clinical trials, expanded access programs, or routine clinical practice were included. Clinical and laboratory parameters were collected retrospectively to determine the incidence of irAEs, methods of management, and treatment outcomes. Results: A total of 255 patients were screened retrospectively. Of these, 71 (27.8%) patients developed irAEs. More than 2 different types of irAEs were detected in 16 (6.2%) out of 255 patients. A total of 3177 doses were given to 255 patients. In 93 (2.9%) of the 3177 doses, 1 episode of irAEs was experienced. A total of 22 out of 93 (23.7%) episodes were reported as grade 1, 49 (52.7%) as grade 2, 19 (20.4%) as grade 3, and 3 (3.2%) as grade 4. The most frequently seen irAEs were pneumonitis, hepatitis, and hypothyroidism. With regard to treatment, 39 out of 93 episodes (42%) of any grade irAEs occurred after anti–programmed cell death-1 therapy, 47 (50.5%) occurred following administration of anti–programmed death-ligand 1, and 7 (7.5%) occurred after combination treatments. Conclusion: With the increased use of immunotherapeutic agents, increased awareness and early recognition are required for effective management of irAEs. Our experience as a single institution might be of use for health care providers in oncology.

scholarly journals Comparative risk of serious and fatal treatment-related adverse events caused by 19 immune checkpoint inhibitors used in cancer treatment: a network meta-analysis

2020 ◽  
Vol 12 ◽  
pp. 175883592094092 ◽  
Author(s):  
Tingting Liu ◽  
Bo Jin ◽  
Jun Chen ◽  
Hui Wang ◽  
Shuiyu Lin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cancer Treatment ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Combinatorial Therapy ◽  
Grade 5 ◽  
Comparative Risk ◽  
Grade 3

Background: This network meta-analysis assessed the comparative risk of grade 3–5 and grade 5 treatment-related adverse events (TRAEs) for immune checkpoint inhibitors (ICIs), either alone or in combination with other modalities, for cancer treatment. Methods: PubMed, Embase, Cochrane Library, Web of Science, and recent predominant oncology congresses were searched for relevant phase II and phase III randomized controlled trials (RCTs). As outcomes, grade 3–5, and grade 5 TRAE outcomes were reported as odds ratios and 95% confidence intervals. Results: In 67 RCTs involving 36,422 patients and 19 ICIs, the incidence of grade 3–5 and grade 5 TRAEs was 17.9% and 0.8% with ICI monotherapy and 46.3% and 1.4%, respectively, with combinatorial therapy. Pneumonitis was the most common cause of grade 5 TRAEs following either monotherapy (16.3%) or combinatorial therapy (11.4%). Regarding grade 3–5 TRAEs, atezolizumab + chemotherapy (CT) and antiangiogenic therapy (AT) (atezolizumab + CAT), pembrolizumab + CT, ipilimumab + CT, and atezolizumab + CT were more toxic than any ICI monotherapy, pembrolizumab or nivolumab + radiotherapy (RT), and ICIs dual therapy (durvalumab + tremelimumab and nivolumab + ipilimumab). Tremelimumab, ipilimumab, durvalumab, and pembrolizumab were, however, associated with higher grade 5 TRAEs than combinatorial treatments. Atezolizumab + CAT was the most toxic and nivolumab + RT was the least toxic of combinatorial treatments; among monotherapies, tremelimumab and avelumab were the most and least toxic, respectively. The toxicity ranking changed with type of grade 3–5 TRAEs. Conclusions: Compared with combinatorial therapy, ICI monotherapy caused lower grade 3–5 TRAEs, but some monotherapies resulted in a higher incidence of fatal TRAEs. Atezolizumab + CAT and nivolumab + RT were the most and least toxic of combinatorial treatments, respectively, and tremelimumab and avelumab were the most and least toxic of the monotherapies, respectively.

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