Immunotherapy in pancreatic adenocarcinoma—overcoming barriers to response

Rosenberg, Ari J.; Mahalingam, Devalingam

doi:10.21037/jgo.2018.01.13

Cited by 43 publications

(36 citation statements)

References 135 publications

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“…The efficacy of immunotherapy in pancreatic cancer is widely hampered by its low immunogenic potential compared with melano-ma (23) and its largely immunosuppressive microenvironment dominated by Treg and MDSC infiltration (16,23). Our results, however, demonstrate that neoTx can reverse these premises and reactivate the local immune response.…”

Section: Discussionmentioning

confidence: 69%

Neoadjuvant Therapy Remodels the Pancreatic Cancer Microenvironment via Depletion of Protumorigenic Immune Cells

Reyes

Teller

Muckenhuber

et al. 2020

Clinical Cancer Research

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Purpose: Neoadjuvant therapy (neoTx) has dramatically improved the prognosis of patients with locally advanced and borderline resectable pancreatic ductal adenocarcinoma, yet its mechanisms of action on tumor cells and the tumor microenvironment are still unknown. Here, we aimed to characterize the multiple facets of neoTx-induced alterations in the pancreatic cancer microenvironment. Experimental Design: We performed the currently most comprehensive histopathologic analysis of desmoplasia, angiogenesis, neural invasion, and immune cell infiltration at the tumor-host interface of pancreatic cancer after neoTx (n ¼ 37) versus after primary resection (n ¼ 37) through quantitative IHC and double immunofluorescence using automated and software-based quantification algorithms. Results: We demonstrate that, independently of the applied pretreatment, neoadjuvant regimes are able to reverse the immu-nosuppressive behavior of malignant cells on pancreatic cancer microenvironment. Here, neoTx-driven selective depletion of regulatory T cells and myeloid-derived suppressor cells was associated with enrichment of antitumor immune cells in the peritumoral niche, decreased stromal activation, and less neural invasion. Importantly, the degree of this antitumor immune remodeling correlates to the degree of histopathologic response to neoTx. Survival analysis revealed that the tumor proliferation rate together with the activation of the stroma and the intratumoral infiltration with CD4 þ T cells and natural killer cells constitute as independent prognostic factors for neoadjuvantly treated pancreatic cancer. Conclusions: NeoTx is not only cytotoxic but has pleiotropic, beneficial effects on all cellular and noncellular components of pancreatic cancer. Combinational approaches including immunotherapy may unleash long-term and more effective antitumor responses and improve prognosis of pancreatic cancer.

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Section: Discussionmentioning

confidence: 69%

Neoadjuvant Therapy Remodels the Pancreatic Cancer Microenvironment via Depletion of Protumorigenic Immune Cells

Reyes

Teller

Muckenhuber

et al. 2020

Clinical Cancer Research

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“…Pelareorep was shown to supplement gemcitabine monotherapy and these results should be validated with a larger randomized clinical trial to remove potential selection bias, which is inherent in a smaller single-arm study as the one we present here. There are currently a growing list of clinical studies addressing the combination of immunotherapy with chemotherapy, poly-ADP ribose polymerase (PARP) inhibitors, oncolytic therapy, or other novel therapies in patients with advanced pancreatic cancer [ 41 ]. These findings also have implications in future studies of pelareorep in combination with checkpoint blockade in pancreatic adenocarcinoma, as immuno-oncolytic virus therapy upregulates PD-L1 in the tumor.…”

Section: Discussionmentioning

confidence: 99%

A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma

Mahalingam

Goel

Aparo

et al. 2018

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naïve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that pelareorep complements single agent gemcitabine in PDAC.

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“…In addition, a large amount of MDSCs existing at the day 2 initiation phase of immune response might be involved in this blockage effect as well. TME is believed to play a critical role in resistance to immunotherapy in pancreatic cancer [ 38 ]. This concept is supported by our above findings as well.…”

Section: Discussionmentioning

confidence: 99%

Nano-Pulse Stimulation for the Treatment of Pancreatic Cancer and the Changes in Immune Profile

Guo

Burcus

Hornef

et al. 2018

Cancers

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A Pancreatic cancer is a notorious malignant neoplasm with an extremely poor prognosis. Current standard of care is rarely effective against late-stage pancreatic cancer. In this study, we assessed nanopulse stimulation (NPS) as a local treatment for pancreatic cancer in a syngeneic mouse Pan02 pancreatic cancer model and characterized corresponding changes in the immune profile. A single NPS treatment either achieved complete tumor regression or prolonged overall survival in animals with partial tumor regression. While this is very encouraging, we also explored if this local ablation effect could also result in immune stimulation, as was observed when NPS led to the induction of immune-mediated protection from a second tumor challenge in orthotopic mouse breast and rat liver cancer models. In the Pan02 model, there were insufficient abscopal effects (1/10) and vaccine-like protective effects (1/15) suggesting that NPS-induced immune mechanisms in this model were limited. To evaluate this further, the immune landscape was analyzed. The numbers of both T regulatory cells (Tregs) and myeloid derived suppressor cells (MDSCs) in blood were significantly reduced, but memory (CD44+) T-cells were absent. Furthermore, the numbers of Tregs and MDSCs did not reduce in spleens compared to tumor-bearing mice. Very few T-cells, but large numbers of MDSCs were present in the NPS treated tumor microenvironment (TME). The number of dendritic cells in the TME was increased and multiple activation markers were upregulated following NPS treatment. Overall, NPS treatments used here are effective for pancreatic tumor ablation, but require further optimization for induction of immunity or the need to include effective combinational NPS therapeutic strategy for pancreatic cancer.

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Immunotherapy in pancreatic adenocarcinoma—overcoming barriers to response

Cited by 43 publications

References 135 publications

Neoadjuvant Therapy Remodels the Pancreatic Cancer Microenvironment via Depletion of Protumorigenic Immune Cells

Neoadjuvant Therapy Remodels the Pancreatic Cancer Microenvironment via Depletion of Protumorigenic Immune Cells

A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma

Nano-Pulse Stimulation for the Treatment of Pancreatic Cancer and the Changes in Immune Profile

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