Combination Immune Checkpoint Inhibition and SBRT for Advanced Pancreatic Cancer

2019 ◽  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Checkpoint ◽  
Advanced Pancreatic Cancer ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition

A pilot study of immune checkpoint inhibition in combination with radiation therapy in patients with metastatic pancreatic cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15786-e15786 ◽  
Author(s):  
Austin G. Duffy ◽  
Oxana V. Makarova-Rusher ◽  
David E Kleiner ◽  
Christine Alewine ◽  
William Douglas Figg ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Monoclonal Antibody ◽  
Radiation Therapy ◽  
Pilot Study ◽  
Immune Checkpoint ◽  
Advanced Pancreatic Cancer ◽  
Primary Objective ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Eligibility Criteria

e15786 Background: Durvalumab is a human IgG1 monoclonal antibody directed against PD-L1. Tremelimumab is a selective human IgG2 monoclonal antibody against CTLA-4. Several studies have documented an increase in peripheral antitumor immunity following radiation. The hypothesis of this study is that the effect of immune checkpoint inhibition (ICI) can be enhanced by radiation in pancreatic adenocarcinoma (PAC). Methods: Patients with histologically confirmed metastatic PC with primary in-situ or metastatic SBRT-amenable disease are being enrolled to this pilot study. Primary objective to determine safety, tolerability and feasibility of immune checkpoint inhibition [comprising either Durvalumab alone (Cohort A), or combined durvalumab and tremelimumab (Cohort B)] in combination with stereotactic body radiation therapy (SBRT) at two different schedules (8Gy/single fraction or 25Gy in 5 fractions). Select eligibility criteria are as follows: at least 1 measurable metastatic lesion by RECIST 1.1 accessible for biopsy. No limit to the number of prior chemotherapy regimens; ECOG ≤ 1; Life expectancy of greater than 3 months. Acceptable organ and bone marrow function. No active autoimmune disorders. Results: N = 24 patients with chemorefractory metastatic PC have so far been enrolled; M/F = 13/11; Median age = 61. Treatment was well tolerated. No DLT encountered. The most common toxicity was fatigue (G1/2) in all patients in DL2. 5/24 pts had early discontinuation ( < 4 wks) due to rapid PD. No objective responses have been seen. 5 pts (21%) had SD as best response. Conclusions: Immune checkpoint inhibition in combination with SBRT in advanced pancreatic cancer is safe and feasible. Preliminarily no objective responses have been seen for these schedules of SBRT with durvalumab. The study is continuing with evaluation of SBRT with dual checkpoint inhibition (durvalumab and tremelimumab). Clinical trial information: NCT02311361.

A pilot study of immune checkpoint inhibition (tremelimumab and/or MEDI4736) in combination with radiation therapy in patients with unresectable pancreatic cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS470-TPS470
Author(s):  
Austin G. Duffy ◽  
Oxana V. Makarova-Rusher ◽  
Drew Pratt ◽  
David E Kleiner ◽  
Christine Alewine ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Monoclonal Antibody ◽  
Radiation Therapy ◽  
Pilot Study ◽  
Immune Checkpoint ◽  
Human Monoclonal Antibody ◽  
Unresectable Pancreatic Cancer ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Early Stage Disease

TPS470 Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and causes inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. MEDI4736 is a human monoclonal antibody directed against PD-L1. Blockage of ligation between PD-L1 and PD1 induces local immune activation and prevents anergy and exhaustion of effector T-cells. Several studies have documented an increase in peripheral antitumor immunity following radiation. This effect is evidently too weak to be clinically relevant, but has the potential to be boosted by immune modulation. The underlying hypothesis of this study is that the effect of immune checkpoint inhibition (accomplished via tremelimumab and/or MEDI4736) treatment can be enhanced by radiation in patients with advanced pancreatic carcinoma. Whilst radiation treatment in pancreas cancer is commonly employed in limited or early stage disease, if radiation can enhance the effect of immune checkpoint inhibition to produce systemic anti-tumor effects the combination could become an effective treatment modality for patients with advanced disease. Methods: Patients with histologically confirmed metastatic pancreatic cancer with primary in-situ (or locally-recurrent) disease are being enrolled to this pilot study. The primary objectives are to determine the safety, tolerability and feasibility of immune checkpoint inhibition [comprising either MEDI4736 alone (Cohort A), Tremelimumab (Cohort B) or combined MEDI4736 and Tremelimumab (Cohort C)] in combination with stereotactic body radiation therapy (SBRT) in patients with unresectable pancreatic cancer. Select eligibility criteria are as follows: at least 1 measurable metastatic lesion by RECIST 1.1 criteria and accessible for biopsy. No prior radiation therapy to the pancreas allowed. There is no limit to the number of prior chemotherapy regimens received; ECOG ≤ 1; Life expectancy of greater than 3 months. Acceptable organ and bone marrow function. No active or prior documented autoimmune or inflammatory disorders. Clinical trial information: NCT02311361.

scholarly journals Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer

2017 ◽  
Author(s):  
Valeria Quaranta ◽  
Carolyn Rainer ◽  
Sebastian R. Nielsen ◽  
Meirion Raymant ◽  
Muhammad Shamsher Ahmed ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cell ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Tumour Microenvironment ◽  
Ductal Adenocarcinoma ◽  
Metastatic Tumour ◽  
Metastatic Progression ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition

AbstractThe ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumour microenvironment that suppresses and/or excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immuno-protective role of the metastatic tumour microenvironment in pancreatic cancer is not completely understood. In this study we find that macrophage-derived granulin contributes to cytotoxic CD8+ T cell exclusion in metastatic livers. Mechanistically, we find that granulin expression by macrophages is induced in response to colony stimulating factor-1. Genetic depletion of granulin reduces the formation a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumours are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin depleted tumours restored the anti-tumour immune defence and dramatically decreased metastatic tumour burden. These findings suggest that targeting granulin may serve as a potential therapeutic strategy to restore CD8+ T cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumours, which are refractory to immune checkpoint inhibitors, into tumours that respond to immune checkpoint inhibition therapies.

scholarly journals Macrophage-Derived Granulin Drives Resistance to Immune Checkpoint Inhibition in Metastatic Pancreatic Cancer

2018 ◽  
Vol 78 (15) ◽  
pp. 4253-4269 ◽  
Author(s):  
Valeria Quaranta ◽  
Carolyn Rainer ◽  
Sebastian R. Nielsen ◽  
Meirion L. Raymant ◽  
Muhammad S. Ahmed ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Checkpoint ◽  
Metastatic Pancreatic Cancer ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition

Sinonasal Mucosal Melanoma: A Comparison of Outcomes between Surgical Resection and Immune Checkpoint Inhibition

2020 ◽  
Author(s):  
Shivangi Lohia ◽  
Stephanie Flukes ◽  
Alexander N. Shoushtari ◽  
Akash D. Shah ◽  
Ian Ganly ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Immune Checkpoint ◽  
Mucosal Melanoma ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition

scholarly journals PD-L1 lncRNA splice isoform promotes lung adenocarcinoma progression via enhancing c-Myc activity

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shuang Qu ◽  
Zichen Jiao ◽  
Geng Lu ◽  
Bing Yao ◽  
Ting Wang ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Lung Adenocarcinoma ◽  
Solid Tumors ◽  
Immune Checkpoint ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Non Coding Rna ◽  
Adenocarcinoma Cells ◽  
Lung Adenocarcinoma Cells ◽  
Long Non Coding Rna

Abstract Background Although using a blockade of programmed death-ligand 1 (PD-L1) to enhance T cell immune responses shows great promise in tumor immunotherapy, the immune-checkpoint inhibition strategy is limited for patients with solid tumors. The mechanism and efficacy of such immune-checkpoint inhibition strategies in solid tumors remains unclear. Results Employing qRT-PCR, Sanger sequencing, and RNA BaseScope analysis, we show that human lung adenocarcinoma (LUAD) all produce a long non-coding RNA isoform of PD-L1 (PD-L1-lnc) by alternative splicing, regardless if the tumor is positive or negative for the protein PD-L1. Similar to PD-L1 mRNA, PD-L1-lnc in various lung adenocarcinoma cells is significantly upregulated by IFNγ. Both in vitro and in vivo studies demonstrate that PD-L1-lnc increases proliferation and invasion but decreases apoptosis of lung adenocarcinoma cells. Mechanistically, PD-L1-lnc promotes lung adenocarcinoma progression through directly binding to c-Myc and enhancing c-Myc transcriptional activity. Conclusions In summary, the PD-L1 gene can generate a long non-coding RNA through alternative splicing to promote lung adenocarcinoma progression by enhancing c-Myc activity. Our results argue in favor of investigating PD-L1-lnc depletion in combination with PD-L1 blockade in lung cancer therapy.

scholarly journals Thinking Small: Small Molecules as Potential Synergistic Adjuncts to Checkpoint Inhibition in Melanoma

2021 ◽  
Vol 22 (6) ◽  
pp. 3228
Author(s):  
Alexander C. Chacon ◽  
Alexa D. Melucci ◽  
Shuyang S. Qin ◽  
Peter A. Prieto
Keyword(s):  
Skin Cancer ◽  
Small Molecules ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Treatment Resistance ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Specific Effector ◽  
Melanoma Treatment ◽  
Therapeutic Responses

Metastatic melanoma remains the deadliest form of skin cancer. Immune checkpoint inhibition (ICI) immunotherapy has defined a new age in melanoma treatment, but responses remain inconsistent and some patients develop treatment resistance. The myriad of newly developed small molecular (SM) inhibitors of specific effector targets now affords a plethora of opportunities to increase therapeutic responses, even in resistant melanoma. In this review, we will discuss the multitude of SM classes currently under investigation, current and prospective clinical combinations of ICI and SM therapies, and their potential for synergism in melanoma eradication based on established mechanisms of immunotherapy resistance.

Sign in / Sign up

Export Citation Format

Share Document