A feasibility study of combined epigenetic and vaccine therapy in advanced colorectal cancer with pharmacodynamic endpoint

Bever, Katherine M.; Thomas, Dwayne L.; Zhang, Jiajia; Rivera, Ernie A. Diaz; Rosner, Gary L.; Zhu, Qingfeng; Nauroth, Julie M.; Christmas, Brian J.; Thompson, Elizabeth D.; Anders, Robert A.; Judkins, Carol; Liu, Mei-Zheng; Jaffee, Elizabeth M.; Ahuja, Nita; Li, Zheng; Azad, Nilofer S.

doi:10.1186/s13148-021-01014-8

Cited by 15 publications

(12 citation statements)

References 37 publications

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“…Two early phase clinical trials combining anti-PD1 checkpoint inhibitors with azacytidine (DNA methyltransferase inhibitor) or vorinostat (HDAC inhibitor) plus standard chemoradiation are currently underway in IDHmutant gliomas (NCT03684811) and newly diagnosed GBM (NCT03426891), respectively. Additionally, several clinical trials testing combination epigenetic and immune therapy have been conducted or are currently underway in a variety of cancers, however, durable clinical effects are rare and often restricted to small subsets of patients (224)(225)(226)(227)(228)(229)(230)(231)(232)(233)(234)(235)(236). However, ongoing clinical trials may provide insight into mechanisms of resistance and opportunities for therapeutic improvement.…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Exploring glioblastoma stem cell heterogeneity: Immune microenvironment modulation and therapeutic opportunities

2022

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Despite its growing use in cancer treatment, immunotherapy has been virtually ineffective in clinical trials for gliomas. The inherently cold tumor immune microenvironment (TIME) in gliomas, characterized by a high ratio of pro-tumor to anti-tumor immune cell infiltrates, acts as a seemingly insurmountable barrier to immunotherapy. Glioma stem cells (GSCs) within these tumors are key contributors to this cold TIME, often functioning indirectly through activation and recruitment of pro-tumor immune cell types. Furthermore, drivers of GSC plasticity and heterogeneity (e.g., reprogramming transcription factors, epigenetic modifications) are associated with induction of immunosuppressive cell states. Recent studies have identified GSC-intrinsic mechanisms, including functional mimicry of immune suppressive cell types, as key determinants of anti-tumor immune escape. In this review, we cover recent advancements in our understanding of GSC-intrinsic mechanisms that modulate GSC-TIME interactions and discuss cutting-edge techniques and bioinformatics platforms available to study immune modulation at high cellular resolution with exploration of both malignant (i.e., GSC) and non-malignant (i.e., immune) cell fractions. Finally, we provide insight into the therapeutic opportunities for targeting immunomodulatory GSC-intrinsic mechanisms to potentiate immunotherapy response in gliomas.

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Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Exploring glioblastoma stem cell heterogeneity: Immune microenvironment modulation and therapeutic opportunities

2022

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“…Several epigenetic drugs, including DAC, are already in clinical use for treatment of CRC [ 64 , 65 ]. In addition, anti-PD-1/PD-L1 therapy has emerged as one of the most promising immunotherapies for CRC patients with microsatellite instability (MSI) [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

Functional characterization of age-dependent p16 epimutation reveals biological drivers and therapeutic targets for colorectal cancer

Yang

Chen

Lee

et al. 2023

J Exp Clin Cancer Res

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Background Methylation of the p16 promoter resulting in epigenetic gene silencing—known as p16 epimutation—is frequently found in human colorectal cancer and is also common in normal-appearing colonic mucosa of aging individuals. Thus, to improve clinical care of colorectal cancer (CRC) patients, we explored the role of age-related p16 epimutation in intestinal tumorigenesis. Methods We established a mouse model that replicates two common genetic and epigenetic events observed in human CRCs: Apc mutation and p16 epimutation. We conducted long-term survival and histological analysis of tumor development and progression. Colonic epithelial cells and tumors were collected from mice and analyzed by RNA sequencing (RNA-seq), quantitative PCR, and flow cytometry. We performed single-cell RNA sequencing (scRNA-seq) to characterize tumor-infiltrating immune cells throughout tumor progression. We tested whether anti-PD-L1 immunotherapy affects overall survival of tumor-bearing mice and whether inhibition of both epigenetic regulation and immune checkpoint is more efficacious. Results Mice carrying combined Apc mutation and p16 epimutation had significantly shortened survival and increased tumor growth compared to those with Apc mutation only. Intriguingly, colon tumors with p16 epimutation exhibited an activated interferon pathway, increased expression of programmed death-ligand 1 (Pdl1), and enhanced infiltration of immune cells. scRNA-seq further revealed the presence of Foxp3+ Tregs and γδT17 cells, which contribute to an immunosuppressive tumor microenvironment (TME). Furthermore, we showed that a combined therapy using an inhibitor of DNA methylation and a PD-L1 immune checkpoint inhibitor is more effective for improving survival in tumor-bearing mice than blockade of either pathway alone. Conclusions Our study demonstrated that age-dependent p16 epimutation creates a permissive microenvironment for malignant transformation of polyps to colon cancer. Our findings provide a mechanistic rationale for future targeted therapy in patients with p16 epimutation.

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“…GVAX demonstrated a modulatory effect on the antitumor response in a phase II trial targeting pMMR advanced CRC patients ( 36 ). In order to further improve GVAX, epigenetic therapy has been tried to enhance immunologic activity in both preclinical and clinical trials (NCT01966289) ( 43 , 44 ).…”

Section: Different Types Of Colorectal Cancer Vaccinesmentioning

confidence: 99%

Colorectal cancer vaccines: The current scenario and future prospects

et al. 2022

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Colorectal cancer (CRC) is one of the most common cancers worldwide. Current therapies such as surgery, chemotherapy, and radiotherapy encounter obstacles in preventing metastasis of CRC even when applied in combination. Immune checkpoint inhibitors depict limited effects due to the limited cases of CRC patients with high microsatellite instability (MSI-H). Cancer vaccines are designed to trigger the elevation of tumor-infiltrated lymphocytes, resulting in the intense response of the immune system to tumor antigens. This review briefly summarizes different categories of CRC vaccines, demonstrates the current outcomes of relevant clinical trials, and provides particular focus on recent advances on nanovaccines and neoantigen vaccines, representing the trend and emphasis of CRC vaccine development.

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A feasibility study of combined epigenetic and vaccine therapy in advanced colorectal cancer with pharmacodynamic endpoint

Cited by 15 publications

References 37 publications

Exploring glioblastoma stem cell heterogeneity: Immune microenvironment modulation and therapeutic opportunities

Exploring glioblastoma stem cell heterogeneity: Immune microenvironment modulation and therapeutic opportunities

Functional characterization of age-dependent p16 epimutation reveals biological drivers and therapeutic targets for colorectal cancer

Colorectal cancer vaccines: The current scenario and future prospects

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