Standard therapies: solutions for improving therapeutic effects of immune checkpoint inhibitors on colorectal cancer

Liang, Tingting; Tong, Wei; Ma, Siyang; Chang, Pengyu

doi:10.1080/2162402x.2020.1773205

Cited by 3 publications

(4 citation statements)

References 81 publications

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“…For example, previous work has shown that EGFR inhibitor erlotinib improves the efficacy of anti–PD-1 antibody in EGFR -mutated non–small cell lung cancer by decreasing CD4 + effector T reg infiltration in the TME ( 52 ). In colorectal cancers, anti-EGFR therapy in combination with chemotherapy results in increased cytotoxic T cell infiltration ( 54 ), leading some to argue that anti-EGFR treatments should be combined with ICIs in this cancer ( 55 ). That said, we are the first to offer a likely mechanism of action for these observations, including the central role of immunosuppressive chemokines and EGR1, both of which can serve as potential biomarkers for patient selection in other tumors.…”

Section: Discussionmentioning

confidence: 99%

EGFR is a master switch between immunosuppressive and immunoactive tumor microenvironment in inflammatory breast cancer

et al. 2022

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Inflammatory breast cancer (IBC), the most aggressive breast cancer subtype, is driven by an immunosuppressive tumor microenvironment (TME). Current treatments for IBC have limited efficacy. In a clinical trial (NCT01036087), an anti-EGFR antibody combined with neoadjuvant chemotherapy produced the highest pathological complete response rate ever reported in patients with IBC having triple-negative receptor status. We determined the molecular and immunological mechanisms behind this superior clinical outcome. Using novel humanized IBC mouse models, we discovered that EGFR-targeted therapy remodels the IBC TME by increasing cytotoxic T cells and reducing immunosuppressive regulatory T cells and M2 macrophages. These changes were due to diminishing immunosuppressive chemokine expression regulated by transcription factor EGR1. We also showed that induction of an immunoactive IBC TME by an anti-EGFR antibody improved the antitumor efficacy of an anti–PD-L1 antibody. Our findings lay the foundation for clinical trials evaluating EGFR-targeted therapy combined with immune checkpoint inhibitors in patients with cancer.

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Section: Discussionmentioning

confidence: 99%

EGFR is a master switch between immunosuppressive and immunoactive tumor microenvironment in inflammatory breast cancer

et al. 2022

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“… 255 , 260–263 Yet, as of now the difficulty in generating cDC1/2 from patients in large amounts remains a hurdle for cDC-based DC vaccinations. Simultaneously, DC vaccine research also needs to account for challenges that are also plaguing success of ICBs in the clinic, e.g., deep immunosuppressive niches within the TME of lymphocytes-depleted solid tumors, 249 , 264–266 adaptive or acquired emergence of antigen-loss variant versions of cancer cells, 267–270 and the patient-to-patient immune heterogeneity (owing to immune haplotypes, archetypes, ethnicities, as well as microbiome variations). 271 , 272 Manufacturing and production costs associated with DC vaccines also need to be considered and reduced, possibly through higher automation, to ease overall practicability.…”

Section: Discussionmentioning

confidence: 99%

Trial watch: Dendritic cell (DC)-based immunotherapy for cancer

et al. 2022

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Dendritic cell (DC)-based vaccination for cancer treatment has seen considerable development over recent decades. However, this field is currently in a state of flux toward niche-applications, owing to recent paradigm-shifts in immuno-oncology mobilized by T cell-targeting immunotherapies. DC vaccines are typically generated using autologous (patient-derived) DCs exposed to tumor-associated or -specific antigens (TAAs or TSAs), in the presence of immunostimulatory molecules to induce DC maturation, followed by reinfusion into patients. Accordingly, DC vaccines can induce TAA/TSA-specific CD8 + /CD4 + T cell responses. Yet, DC vaccination still shows suboptimal anti-tumor efficacy in the clinic. Extensive efforts are ongoing to improve the immunogenicity and efficacy of DC vaccines, often by employing combinatorial chemo-immunotherapy regimens. In this Trial Watch, we summarize the recent preclinical and clinical developments in this field and discuss the ongoing trends and future perspectives of DC-based immunotherapy for oncological indications.

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“…For example, a phase II study reported that as a second- or later-line therapy for metastatic PDAC, durvalumab (an anti-PD-L1 drug) alone and durvalumab plus tremelimumab (an anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) drug) had objective response rate (ORR) values of 0% and 3.1%, respectively [ 56 ] ( Table 2 ). Prior to this study, in order to improve the effectiveness of ICB therapy, a phase I study employed stereotactic body radiation therapy (SBRT) in combination with ICB therapy (in this case pembrolizumab) to upregulate the expression of the genes encoding PD-L1 and MHC-I in tumor cells and improve the production of tumor-associated antigens (TAAs) by recruiting tumoricidal T cells and by improving the production of IFN-γ by CD8 + T cells [ 18 ] as a strategy against metastatic cancers, and this combination achieved an ORR of 13.2% among enrolled patients [ 57 ]. However, this study only included three patients with metastatic PDAC, and their ORR to this strategy was not reported.…”

Section: Current Status Of Immune Checkpoint Blockade Therapy For Pdacmentioning

confidence: 99%

“…Similarly, KRAS mutation is able to cause immunosuppression in CRAC tumors as well. However, unlike in PDAC, the published data suggest that CRAC patients with this phenotype can benefit from a combinational strategy featuring conventional therapy plus an ICB drug [ 18 ]. Importantly, despite having KRAS mutation, PDACs, CRACs and LUACs differ in their tumor immune status ( Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

KRAS Mutation Dictates the Cancer Immune Environment in Pancreatic Ductal Adenocarcinoma and Other Adenocarcinomas

Gao

Chang

2021

Cancers

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Generally, patients with pancreatic ductal adenocarcinoma, especially those with wide metastatic lesions, have a poor prognosis. Recently, a breakthrough in improving their survival has been achieved by using first-line chemotherapy, such as gemcitabine plus nab-paclitaxel or oxaliplatin plus irinotecan plus 5-fluorouracil plus calcium folinate. Unfortunately, regimens with high effectiveness are still absent in second- or later-line settings. In addition, although immunotherapy using checkpoint inhibitors definitively represents a novel method for metastatic cancers, monotherapy using checkpoint inhibitors is almost completely ineffective for pancreatic ductal adenocarcinomas largely due to the suppressive immune milieu in such tumors. Critically, the genomic alteration pattern is believed to impact cancer immune environment. Surprisingly, KRAS gene mutation is found in almost all pancreatic ductal adenocarcinomas. Moreover, KRAS mutation is indispensable for pancreatic carcinogenesis. On these bases, a relationship likely exists between this oncogene and immunosuppression in this cancer. During pancreatic carcinogenesis, KRAS mutation-driven events, such as metabolic reprogramming, cell autophagy, and persistent activation of the yes-associated protein pathway, converge to cause immune evasion. However, intriguingly, KRAS mutation can dictate a different immune environment in other types of adenocarcinoma, such as colorectal adenocarcinoma and lung adenocarcinoma. Overall, the KRAS mutation can drive an immunosuppression in pancreatic ductal adenocarcinomas or in colorectal carcinomas, but this mechanism is not true in KRAS-mutant lung adenocarcinomas, especially in the presence of TP53 inactivation. As a result, the response of these adenocarcinomas to checkpoint inhibitors will vary.

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Standard therapies: solutions for improving therapeutic effects of immune checkpoint inhibitors on colorectal cancer

Cited by 3 publications

References 81 publications

EGFR is a master switch between immunosuppressive and immunoactive tumor microenvironment in inflammatory breast cancer

EGFR is a master switch between immunosuppressive and immunoactive tumor microenvironment in inflammatory breast cancer

Trial watch: Dendritic cell (DC)-based immunotherapy for cancer

KRAS Mutation Dictates the Cancer Immune Environment in Pancreatic Ductal Adenocarcinoma and Other Adenocarcinomas

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