Optimizing Sequence of PD-L1 Immune-Checkpoint Inhibitors and Radiation Therapy in Bladder Cancer

2020 ◽  
Vol 6 (3) ◽  
pp. 295-302
Author(s):  
Côme Tholomier ◽  
Gautier Marcq ◽  
Surashri Shinde-Jadhav ◽  
Mina Ayoub ◽  
Jia Min Huang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Radiation Therapy ◽  
Tumor Growth ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Combined Therapy ◽  
Tumor Growth Rate ◽  
Significant Difference ◽  
Rate Of Response

BACKGROUND: New bladder preserving strategies are needed for muscle invasive bladder cancer (MIBC). Combined therapy of immune-checkpoint inhibitors and radiation was shown to have synergistic antitumoral effects in preclinical studies. OBJECTIVES: We aim to evaluate whether the sequence of administration of this combined therapy impacts antitumoral response. METHODS: We developed an in-vivo syngeneic MIBC mouse model where murine bladder cancer cells (MB49) were injected subcutaneously in the right flank of C57BL/6 mice. Mice were then randomized to the following treatments: control, anti-programmed cell death ligand 1 (PD-L1) alone, radiation alone (XRT) consisting of 6.25 Gy x2 fractions, concurrent anti-PD-L1 with XRT, neoadjuvant anti-PD-L1 followed by XRT, or XRT followed by adjuvant anti-PD-L1 therapy. Tumor growth, survival, and rate of response were analyzed. RESULTS: Total of 60 mice were randomized. One-way analysis of variance showed statistically significant difference in tumor growth rate across the treatment arms (p = 0.029). Importantly, timing of immunotherapy (neoadjuvant, concurrent, or adjuvant) did not alter either tumor growth or survival (p > 0.05). The rate of response was also similar in each combination arm (p > 0.05). CONCLUSION: Combining anti-PD-L1 immunotherapy and radiation therapy offers optimal antitumoral responses. Timing of immunotherapy (neoadjuvant, concurrent, or adjuvant) does not appear to affect outcomes. Whether the toxicity profile differs across various sequential deliveries of combination therapy requires further evaluation.

scholarly journals Hyperprogressive disease rarely occurs during checkpoint inhibitor treatment for advanced melanoma

2020 ◽  
Author(s):  
M. Schuiveling ◽  
E. H. J. Tonk ◽  
R. J. Verheijden ◽  
K. P. M. Suijkerbuijk
Keyword(s):  
Tumor Growth ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Evaluation Criteria ◽  
Tumor Burden ◽  
Advanced Melanoma ◽  
Tumor Growth Rate ◽  
Biological Entity ◽  
Melanoma Patients

Abstract Introduction Hyperprogression, characterized by a rapid acceleration in tumor growth, is a novel pattern of progression recently described in patients treated with immune checkpoint inhibitors. This study aims to assess the incidence of hyperprogression in patients with advanced melanoma treated with checkpoint inhibitors. Methods Clinical and radiological findings of all advanced melanoma patients who started checkpoint inhibitors between January 2013 and March 2019 in a tertiary academic center in the Netherlands were analyzed. Change in tumor burden was calculated by assessing volumetric tumor growth using the criteria as defined by immune Response Evaluation Criteria in Solid Tumors version 1.1. Hyperprogression was defined as a time to treatment failure less than 2 months with doubling of tumor burden and a twofold increase in tumor growth rate during treatment. Possible hyperprogression was defined as the presence of the first two criteria in the absence of a pre-baseline scan. Results Out of 206 treatment episodes in 168 patients, 75 were evaluable for hyperprogression and 87 for possible hyperprogression. Hyperprogression was observed in one patient (1.3%) and possible hyperprogression was observed in one patient (1.1%). Conclusion Hyperprogression is rare in melanoma patients treated with immune checkpoint inhibitors. Our data question if hyperprogression really is a biological entity in metastatic melanoma.

Determination of clinical benefit among patients with radiological stable disease to immune checkpoint inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9041-9041
Author(s):  
Jia Luo ◽  
Song Wu ◽  
Hira Rizvi ◽  
Qu Zhang ◽  
Jacklynn V. Egger ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
External Validation ◽  
Objective Response ◽  
Proliferation Index ◽  
Tumor Growth Rate ◽  
Discovery Cohort ◽  
Similar Survival

9041 Background: SD is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs) and likely represents a heterogenous mix of responders and non-responders. This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. The ability to distinguish whom among patients with SD is actually benefiting from treatment would facilitate drug development and improve precision in correlative research. Methods: A systematic review was performed to characterize SD in ICI trials. SD and objective response was compared to proliferation index using TCGA gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of NSCLC treated with ICIs and had RECIST assessment. In patients with best overall response (BOR) of SD, serial cutpoints of two variables, % BOR and PFS, were tested to define a subgroup with similar survival as PR-minor (patients with partial response [PR] and % shrinkage < median among responders). Results were then tested in two external validation cohorts (n = 326, n = 381). Results: Among trials of ICIs (59 studies, 14,280 patients), SD ranged from 16-42% in different tumor types and was associated with disease-specific proliferation index (Spearman rho = -0.75, p = 0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of 1220 patients with NSCLC who were treated with ICIs, 26% had SD, 19% had PR/CR, and 55% had PD. Outcomes among those with SD ranged widely (OS range 0.5-76 months, PFS range 0.2-49 months). The subset of SD with PFS > 6 months and no tumor growth mirrored PR-minor (OS HR 1.0) and was proposed as the definition of “SD-responder”. SD-responders (n = 87) represented 7% (95% CI 6-9%) of the overall population and 28% (95% CI 23-33%) of the SD population. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab. Conclusions: RECIST-defined SD to immunotherapy is common, heterogenous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS > 6 months and no tumor growth (̃1/3 of SD) may be considered “SD responders.” This definition may improve the efficiency of and insight derivable from clinical and translational research.

scholarly journals Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer

2021 ◽  
Vol 22 (10) ◽  
pp. 5207
Author(s):  
Chi Yan ◽  
Jinming Yang ◽  
Nabil Saleh ◽  
Sheau-Chiann Chen ◽  
Gregory D. Ayers ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Mtor Pathway ◽  
Complete Regression ◽  
Mtor Inhibition

Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. Results: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. Conclusion: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.

scholarly journals Perioperative Systemic Treatment for Muscle-Invasive Bladder Cancer: Current Evidence and Future Perspectives

2021 ◽  
Vol 22 (13) ◽  
pp. 7201
Author(s):  
In-Ho Kim ◽  
Hyo-Jin Lee
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Systemic Treatment ◽  
Checkpoint Inhibitors ◽  
Invasive Bladder Cancer ◽  
Current Evidence ◽  
Future Perspectives ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

Radical cystectomy is the primary treatment for muscle-invasive bladder cancer; however, approximately 50% of patients develop metastatic disease within 2 years of diagnosis, which results in dismal prognosis. Therefore, systemic treatment is important to improve the prognosis of muscle-invasive bladder cancer. Currently, several guidelines recommend cisplatin-based neoadjuvant chemotherapy before radical cystectomy, and adjuvant chemotherapy is recommended in patients who have not received neoadjuvant chemotherapy. Immune checkpoint inhibitors have recently become the standard treatment option for metastatic urothelial carcinoma. Owing to their clinical benefits, several immune checkpoint inhibitors, with or without other agents (including other immunotherapy, cytotoxic chemotherapy, and emerging agents such as antibody drug conjugates), are being extensively investigated in perioperative settings. Several studies for perioperative immunotherapy have shown that immune checkpoint inhibitors have promising efficacy with relatively low toxicity, and have explored the predictive molecular biomarkers. Herein, we review the current evidence and discuss the future perspectives of perioperative systemic treatment for muscle-invasive bladder cancer.

MO153RENAL FUNCTIONS OUTCOME IN METASTATIC NON SMALL LUNG CARCINOMA PATIENTS: THE RISK OF AKI IN FIRST LINE THERAPY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Francesco Trevisani ◽  
Federico Di Marco ◽  
Francesco Fiorio ◽  
Monica Cattaneo ◽  
Erika Rijavec ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Combined Therapy ◽  
Overweight And Obesity ◽  
Categorical Variables ◽  
Rank Test ◽  
First Line ◽  
Metastatic Nsclc ◽  
Platinum Based Chemotherapy

Abstract Background and Aims The optimal use of immune and target therapies, the optimal use of standard chemotherapy (CT) is of paramount importance, especially for patients affected by chronic kidney disease (CKD) who require dose adjustment according to the glomerular filtration rate (GFR) to avoid acute kidney injury (AKI) establishment. Immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy (CT) are options for the palliative treatment of metastatic non-small cell lung cancer (NSCLC). Recently, CT in combination with immune-checkpoint inhibitors has become the treatment of choice for this setting of patients. Therefore, it is fundamental to investigate the potential nephrotoxic effects of both treatments and their potential additive effects on renal function. Aim of our study was to compare the nephrotoxic effect of both ICIs and CT (cisplatin and carboplatin-based) in a consecutive cohort of patients affected by metastatic NSCLC. Method A consecutive cohort of 126 patients treated in first-line for NSLCL was enrolled in a single tertiary Hospital between 2018 and 2020. Inclusion criteria were: age (&gt; 18 years old), eGFR (&gt; 15 ml/min/1.73), histological diagnosis of metastatic NSCLC. Each patient underwent immunotherapy or CT according to clinical conditions, comorbidities and programmed death ligand 1 (PD-L1) expression status. eGFR (using CKD-EPI formula 2009) was detected at baseline and after each cycle of immunotherapy or CT (using cisplatin or carboplatin) in order to determine the correct renal status using the K-DIGO 2012 guidelines for AKI stages and CKD classes. Pts were subdivided into CKD categories G according to their eGFR values before and after the treatment. AKI onset was evaluated by rise in creatine levels according to K-DIGO criteria. Clinical stage according to cTNM (AJCC TNM system-2019) was collected at baseline before the first treatment. Comorbidities (e.g., diabetes, blood hypertension, overweight and obesity) were also included. Comparison between numerical variables was performed using linear regressions; between groups using Kruskal-Wallis rank sum test for numerical variables and Pearson’s Chi square test for categorical variables. Log rank test was used to test differences between groups in terms of AKI onset during the therapy. Results Clinical and pathological characteristics are reported in table 1. From the analysis, no significative differences were detected between Immunotherapy and CT group for age, gender, basal serum creatinine, basal eGFR, basal BMI, diagnosis of diabetes, hypertension, basal CKD G group or overall AKI onset. Treatment cycles were significantly different between the two groups (p&lt;0.001) with a short median number of cycles for the CT group. No significative difference in terms of decay of eGFR calculated as final-basal values was detected (p=0.8). AKI onset over cycles was significantly different between the two groups (p=0.02), observing a higher risk of developing earlier AKI for CT group (cisplatin or carboplatin) (13,9%) with respect to immunotherapy (7,4%) (figure 1 and 2). Conclusion Our study highlights that both cisplatin and carboplatin-based CT displays an augmented incidence of AKI development after a lower number of therapy cycles in respect of immunotherapy. The nephrotoxic effects of combined therapy for NSLCL should be always evaluated by nephrologist during the treatment of NSLCL patients to avoid an augmented risk of AKI derived from the combination of immunotherapy and CT in first line.

RNF43 mutations to predict survival from treatment with immune checkpoint inhibitors and are associated with a high tumor mutation burden in bladder cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16528-e16528
Author(s):  
Liping Li ◽  
Mengmei Yang ◽  
Mengli Huang
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Negative Regulator ◽  
Wilcoxon Test ◽  
Wild Type ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
The Impact

e16528 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1/L1 have been approved as first-line treatment for cisplatin-ineligible patients and as second-line therapy for patients with metastatic urothelial carcinoma of the bladder. Biomarkers can help select patients who are more likely to response to ICIs. RNF43 is an E3 ubiquitin ligase that acts as a negative regulator of Wnt/β-catenin signaling pathway. In colorectal cancer (CRC) patients treated with immune checkpoint inhibitors (ICIs), RNF43 mutations predicted longer overall survival (OS). The impact of RNF43 mutations on the efficiency of ICIs in bladder cancer(BLC) remains to be explored. Methods: We downloaded the mutation and clinical data of 211 BLC patients treated with ICIs from the immunotherapeutic cohort published by Samstein et al. (2019). OS analyses were conducted using Kaplan-Meier curves and log-rank tests. Wilcoxon test was used for the comparison of TMB. We also downloaded a TCGA cohort for prognostic analysis. The correlations between RNF43 and immune infiltrates were analyzed in the TIMER2.0 database. Statistical significance was set at p = 0.05. Results: RNF43 mutations were identified in 4.3%(9/211) and 3%(13/438) BLC patients in the immunotherapeutic and TCGA cohort, respectively. In the immunotherapeutic cohort, patients with RNF43 mutations had significantly longer OS (25 months vs 8 months; p = 0.015) and higher tumor mutation burden(TMB, 42.3 vs 7.9; p = 3.15E-06) than RNF43-wild-type patients. Different from this, no significant difference was found in OS between RNF43-mutant and RNF43-wild-type BLC patients with standard treatment in the TCGA cohort (p = 0.696). These results indicated that RNF43 was not a prognostic factor but a predictive biomarker of survival in BLC treated with ICIs. No difference was observed in subsets of immune cells between RNF43-mutant and the RNF43-wide-type BLC patients, including neutrophils, macrophages, CD8+ T cells, Tregs, B cells and NK cells. Conclusions: RNF43 mutations may be a predictor of survival benefit from ICIs in bladder cancer and correlated with higher TMB. Further studies in other ICI-treated cohorts are needed to confirm these results.

Urothelial carcinoma in the era of immune checkpoint inhibitors

Immunotherapy ◽  
2021 ◽  
Author(s):  
Nadine Khalife ◽  
Claude Chahine ◽  
Manal Kordahi ◽  
Tony Felefly ◽  
Hampig Raphael Kourie ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Invasive Disease ◽  
Line Treatment ◽  
First Line ◽  
Metastatic Urothelial Carcinoma ◽  
Muscle Invasive

Bladder cancer is the seventh most frequent cancer worldwide. The majority of patients present with nonmuscle invasive disease, while 20% of the patients are diagnosed with muscle-invasive bladder cancer. The treatment of nonmuscle invasive disease is endoscopic resection followed by intravesical adjuvant treatment for high risk patients. The standard treatment of localized muscle-invasive disease is neoadjuvant chemotherapy followed by radical cystectomy. Platinum-based chemotherapy is the first-line treatment in locally advanced or metastatic urothelial carcinoma. Immune checkpoint inhibitors have been approved for the treatment of metastatic urothelial carcinoma as second-line treatment or first-line in platinum-ineligible patients. Recently, pembrolizumab have been approved in BCG-refractory nonmuscle invasive bladder cancer. This review summarizes the current evidence concerning immunotherapy in the treatment of urothelial carcinoma.

The Current Role of Immunotherapy in mCRPC: A Systematic Review

2021 ◽  
Vol 8 (7) ◽  
Author(s):  
Dalibey H ◽  
◽  
Hansen TF ◽  
Zedan AH ◽  
◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Systematic Review ◽  
Overall Survival ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Specific Antigen ◽  
Treatment Modalities ◽  
Significant Difference

Background: The development of immunotherapy has shown promising results in several malignant diseases, including prostate cancer, calling for a systematic review of the current literature. This review aims to evaluate the present data and prospects of immune checkpoint inhibitors in metastatic Castration Resistant Prostate Cancer (mCRPC). Methods: Articles were identified via a systematic search of the electronic database Pubmed, in accordance with the PICO process and following the PRISMA guidelines. Articles in English studying immune checkpoint inhibitors in patients with mCRPC published between March 2010 and March 2020 were eligible for inclusion. Endpoints of interest were Overall Survival (OS), Progression-Free Survival (PFS), clinical Overall Response Rate (ORR), and Prostate-Specific Antigen (PSA) response rate. Results: Ten articles were identified as eligible for inclusion. The studies primarily explored the use of Ipilimumab, a CTLA-4 inhibitor, and Pembrolizumab, a PD-1 inhibitor. These drugs were both used either as monotherapy or in combination with other treatment modalities. The largest trial included in the review demonstrated no significant difference in overall survival between the intervention and placebo. However, two studies presented promising data combing immunotherapy and immune vaccines. Grade 3 and 4 adverse events ranging from 10.1% to 82.3%, whit diarrhea, rash, and fatigue were the most frequently reported. Forty relevant ongoing trials were identified exploring immunotherapy with or without a parallel treatment modality. Conclusion: Overall, the current data shows that the effect of immune checkpoint inhibitors as monotherapy may have limited impact on mCRPC, and the results from ongoing combinational trials are eagerly awaited.

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