scholarly journals Radiation as an In Situ Auto-Vaccination: Current Perspectives and Challenges

Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 100 ◽  
Author(s):  
Goto
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Local Treatment ◽  
Combination Therapies ◽  
Antitumor Effects ◽  
Radiation Induced ◽  
Antigen Presenting

Radiotherapy is generally considered to be a local treatment, but there have been reports of rare cases demonstrating abscopal effects in which antitumor effects have been observed in cancer lesions other than the irradiated site. This result is more likely to occur when immune checkpoint inhibitors are used in addition to radiotherapy. Certain radiation-induced chemokines and cytokines have immune-enhancing effects. Immune checkpoint inhibitors may strengthen these effects by stimulating antigen-presenting cells and effector cytotoxic T cells. To date, there is no consensus regarding the applicability of the abscopal effect in the clinical setting, including optimal methods for combining immune checkpoint inhibitors and irradiation. In this review, we highlight the evidence for interactions between cancer immunotherapy and radiotherapy and discuss the potential of such interactions for use in designing novel combination therapies.

scholarly journals IMMU-04. IMMUNE-RELATED ADVERSE EVENTS STRONGLY PREDICT SUPERIOR OUTCOMES IN BRAIN METASTASES PATIENTS RECEIVING LOCAL TREATMENT AND IMMUNE CHECKPOINT INHIBITORS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii105-ii105
Author(s):  
Alexander Hulsbergen ◽  
Asad Lak ◽  
Yu Tung Lo ◽  
Nayan Lamba ◽  
Steven Nagtegaal ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Adverse Events ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Local Treatment ◽  
Sensitivity Analyses ◽  
Immortal Time Bias ◽  
The Brain

Abstract INTRODUCTION In several cancers treated with immune checkpoint inhibitors (ICIs), a remarkable association between the occurrence of immune-related adverse events (irAEs) and superior oncological outcomes has been reported. This effect has hitherto not been reported in the brain. This study aimed to investigate the relation between irAEs and outcomes in brain metastases (BM) patients treated with both local treatment to the brain (LT; i.e. surgery and/or radiation) and ICIs. METHODS This study is a retrospective cohort analysis of patients treated for non-small cell lung cancer (NSCLC) BMs in a tertiary institution in Boston, MA. Outcomes of interest were overall survival (OS) and intracranial progression-free survival (IC-PFS), measured from the time of LT. Sensitivity analyses were performed to account for immortal time bias (i.e., patients who live longer receive more cycles of ICIs and thus have more opportunity to develop an irAE). RESULTS A total of 184 patients were included; 62 (33.7%) were treated with neurosurgical resection and 122 (66.3%) with upfront brain radiation. irAEs occurred in 62 patients (33.7%). After adjusting for lung-Graded Prognostic Assessment, type of LT, type of ICI, newly diagnosed vs. recurrent BM, BM size and number, targetable mutations, and smoking status, irAEs were strongly associated with better OS (HR 0.33, 95% CI 0.19 – 0.58, p < 0.0001) and IC-PFS (HR 0.41; 95% CI 0.26 – 0.65; p = 0.0001). Landmark analysis including only patients who received more than 3 cycles of ICI (n = 133) demonstrated similar results for OS and IC-PFS, as did sensitivity analysis adjusting for the number of cycles administered (HR range 0.36 – 0.51, all p-values < 0.02). CONCLUSIONS After adjusting for known prognostic factors, irAEs strongly predict superior outcomes after LT in NSCLC BM patients. Sensitivity analysis suggests that this is unlikely due to immortal time bias.

scholarly journals Combinatorial benefit without synergy in recent clinical trials of immune checkpoint inhibitors

2020 ◽  
Author(s):  
Adam C. Palmer ◽  
Benjamin Izar ◽  
Peter K. Sorger
Keyword(s):  
Clinical Trials ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Combination Therapies ◽  
Anti Tumor Activity

ABSTRACTHundreds of clinical trials are testing whether combination therapies can increase the anti-tumor activity of Immune Checkpoint Inhibitors (ICIs). We find that the benefits of recently reported and approved combinations involving ICIs are fully accounted for by increasing the chance of a single-agent response (drug independence), with no requirement for additive or synergistic efficacy. Thus, the degree of success of combinations involving ICIs with other therapies is largely predictable.

Incidence and Economic Burden of Infections in Cancer Patients Receiving Immune Checkpoint Inhibitors: A Retrospective Cohort Study

2020 ◽  
Author(s):  
Swarna Nalluru ◽  
Paramrajan Piranavan ◽  
Anvesh Narimiti ◽  
Ahmad D. Siddiqui ◽  
George M. Abraham
Keyword(s):  
Risk Factors ◽  
Cancer Patients ◽  
Economic Burden ◽  
Immune Checkpoint ◽  
Average Cost ◽  
Immune Checkpoint Inhibitors ◽  
Multidisciplinary Approach ◽  
Checkpoint Inhibitors ◽  
Antitumor Effects ◽  
Cost Per Admission

Abstract BACKGROUNDAlong with antitumor effects, Immune Checkpoint Inhibitors (ICPI) have shown great potential in treating chronic infections such as HIV, Hepatitis B and malaria, in ex-vivo studies. However, several case reports and case series have suggested an increased infection risk in cancer patients. The purpose of our study was to assess the risk of infections in cancer patients receiving ICPI. We also attempted to evaluate the role of a multidisciplinary approach (Oncology and Infectious disease specialists) and the cost associated with treatment. METHODS:Records on all cancer patients over age ≥18 years old who had received at least one dose of ICPI between 2015 to 2018 at a major community teaching hospital in the central Massachusetts region were reviewed. Several risk factors associated with infection were identified. A two-tailed, unpaired t-test was used to analyze the association between risk factors and infection. We calculated the cumulative length of stay (LOS) and cost per admission with a multidisciplinary vs. non-multidisciplinary approach. The calculated total average cost per admission was compared to a matched population (without an oncologic diagnosis) admitted with infections similar to that in our study, to compare the economic burden. RESULTSRetrospective chart review of 169 cancer patients receiving ICPI showed sixty-two episodes of infection in thirty-seven (21.8%) patients and a mortality rate of 3.5% due to associated complications. Risk factors like COPD, prior chemotherapy and steroid use were significantly associated (P<0.05) with infections. Further sub-group analysis showed increase in cumulative LOS from 5.9 to 8.1 days but approximately similar average cost per admission ($52,047 vs. $54,510) with non-multidisciplinary vs. multidisciplinary approach. The calculated total cost per admission during an episode of infection in this cohort of patients was $35,484; three-fold higher when matched to similar infections in a general non-oncologic population ($11,527). CONCLUSIONSA significant incidence of infections and associated health care resource utilization continues to prevail in cancer patients despite the utility of ICPI. A multidisciplinary approach to manage the infections and associated complications in cancer patients receiving ICPI increased the cumulative LOS but not the average cost per admission.

Incidence and economic burden of infections in cancer patients receiving immune checkpoint inhibitors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e19365-e19365
Author(s):  
swarna sri nalluru ◽  
Paramarajan Piranavan ◽  
Anvesh Narimiti ◽  
Shanil Shah ◽  
Ahmad Daniyal Siddiqui ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cancer Patients ◽  
Economic Burden ◽  
Immune Checkpoint ◽  
Average Cost ◽  
Immune Checkpoint Inhibitors ◽  
Multidisciplinary Approach ◽  
Checkpoint Inhibitors ◽  
Antitumor Effects ◽  
Cost Per Admission

e19365 Background: Along with antitumor effects, Immune Checkpoint Inhibitors (ICPI) have shown great potential in treating chronic infections such as HIV, Hepatitis B, and malaria, in ex-vivo studies. However, several case reports and case series suggested increased infection risk in cancer patients receiving ICPI. The purpose of our study is to assess the risk of infections in cancer patients receiving ICPI. We also attempted to evaluate the role of a multidisciplinary approach (Oncology and Infectious disease specialists) and the cost associated with treatment. Methods: Records on all cancer patients over age ≥18 years old who had received at least one dose of ICPI from 2015 to 2018 at two major community teaching hospitals in the Central Massachusetts region were reviewed. Several risk factors associated with infection were identified. Two-tailed unpaired t-test was used to analyze the association between risk factors and infection. We calculated the average length of stay (LOS) and cost per admission with a multidisciplinary vs. non-multidisciplinary approach. The calculated total average cost per admission was compared with a random set of non-oncologic population admitted with similar infections noted in our study to estimate the economic burden. Results: Thirty-seven (21.8%) patients developed sixty-two episodes of infection. Microbiological confirmation was available in 13 episodes. Risk factors like COPD (P = 0.01), prior chemotherapy (P = 0.03), and steroid use (P = 0.003) were significantly associated with infections. An infection-associated mortality rate was noted to be 2.3%. With the involvement of multidisciplinary team, the average LOS increased from 5.9 to 8.1 days. Yet, the average cost per admission approximately remained the same (52,047$ vs. 54,510$). Upon comparison with a non-oncologic patient, the average cost per admission for an infection in cancer patients receiving ICPI increased from 11,527$ to 35,484$. Conclusions: Surprisingly, a significant incidence of infections and associated health care resource utilization continue to prevail in cancer patients despite the utility of ICPI. Although the economic burden due to the infections in this set of patients is remarkably high when compared to the general population, the multidisciplinary approach did not increase the hospital costs.

scholarly journals Predictive Biomarkers of Immune Checkpoint Inhibitor Response in Breast Cancer: Looking beyond Tumoral PD-L1

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1863
Author(s):  
Nan Chen ◽  
Nicole Higashiyama ◽  
Valentina Hoyos
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Large Scale ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Predictive Biomarkers

Immune checkpoint inhibitors utilize the immune system to kill cancer cells and are now widely applied across numerous malignancies. Pembrolizumab has two breast-specific indications in triple-negative disease. Currently, programmed death ligand-1 (PD-L1) expression on tumor and surrounding immune cells is the only validated predictive biomarker for immune checkpoint inhibitors (ICIs) in breast cancer; however, it can be imprecise. Additional biomarkers are needed to identify the patient population who will derive the most benefit from these therapies. The tumor immune microenvironment contains many biomarker candidates. In tumor cells, tumor mutational burden has emerged as a robust biomarker across malignancies in general, with higher burden cancers demonstrating improved response, but will need further refinement for less mutated cancers. Preliminary studies suggest that mutations in breast cancer gene 2 (BRCA-2) are associated with increased immune infiltration and response to ICI therapy. Other genomic alterations are also being investigated as potential predictive biomarkers. In immune cells, increased quantity of tumor-infiltrating lymphocytes and CD8+ cytotoxic T cells have correlated with response to immunotherapy treatment. The role of other immune cell phenotypes is being investigated. Peripherally, many liquid-based biomarker strategies such as PD-L1 expression on circulating tumor cells and peripheral immune cell quantification are being studied; however, these strategies require further standardization and refinement prior to large-scale testing. Ultimately, multiple biomarkers utilized together may be needed to best identify the appropriate patients for these treatments.

scholarly journals Immunotherapy and Metastatic Renal Cell Carcinoma: A Review of New Treatment Approaches

Life ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 24
Author(s):  
Nikhita Kathuria-Prakash ◽  
Claire Drolen ◽  
Christopher A. Hannigan ◽  
Alexandra Drakaki
Keyword(s):  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
New Combination ◽  
Combination Therapies ◽  
New Treatment

Introduction: Renal cell carcinomas (RCC) have been treated with immunotherapy for decades; the use of immune checkpoint inhibitors represents the most recent advance. In this review, we compare these new RCC immunotherapies, with a focus on achieving durable complete responses (CR). Review: Sorafenib and sunitinib were the first Food and Drug Administration (FDA)-approved targeted agents for RCC, with sunitinib eventually becoming the standard-of-care agent against which novel therapies are compared. In the last five years, many combination therapies based on the use of immune checkpoint inhibitors (ICIs) and receptor tyrosine kinase inhibitors (TKIs), including ipilimumab/nivolumab, nivolumab/cabozantinib, avelumab/axitinib, pembrolizumab/axitinib, and pembrolizumab/lenvatinib, have demonstrated superior overall survival (OS) and progression-free survival (PFS) compared to sunitinib. Ongoing clinical trials of hypoxia-induced factor-2 alpha (HIF-2a) inhibitors, chimeric antigen receptor T cell (CAR-T) therapy targeting CD70, and other new combination therapies have also shown promise and are currently under investigation. Conclusions: Many new combination therapies are approved for RCC treatment, and CR rates suggest that, in the era of immunotherapy, it may be possible to achieve durable responses and survival benefit in patients with metastatic RCC.

scholarly journals How Immunotherapy Has Changed the Continuum of Care in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4719
Author(s):  
Giulia Martini ◽  
Davide Ciardiello ◽  
Fernando Paragliola ◽  
Valeria Nacca ◽  
Walter Santaniello ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Local Treatment ◽  
Continuum Of Care ◽  
Future Research ◽  
Marginal Effect ◽  
Local Ablation ◽  
The Continuum

Hepatocellular carcinoma (HCC) is one of the leading causes of death worldwide. The use of local treatment, such as surgical resection, liver transplant, and local ablation, has improved the survival of patients with HCC detected at an early stage. Until recently, the treatment of patients with metastatic disease was limited to the use of the multikinase inhibitor (MKI) sorafenib with a marginal effect on survival outcome. New target approaches, such as the oral MKI lenvatinib in first-line treatment and regorafenib, ramucirumab, and cabozantinib in later lines of therapy, have demonstrated efficacy in patients with preserved liver function (Child–Pugh class A) and good performance status. On the other hand, the implementation of immune checkpoint inhibitors directed against PD-1 (nivolumab and pembrolizumab), PD-L1 (atezolizumab), and anti-CTLA4 (ipilimumab) in the management of advanced HCC has strongly changed the continuum of care of HCC. Future research should include the evaluation of molecular biomarkers that can help patient selection and provide new insight on potential combined approaches. In this review, we provide an overview of the clinical evidence of the use of immune checkpoint inhibitors in HCC, and discuss how immunotherapy has been implemented into the continuum of HCC care.

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