Mechanism and strategies of immunotherapy resistance in colorectal cancer

Shan, Jiqi; Han, Dong Hun; Shen, Chunyi; Lei, Qi; Zhang, Yi

doi:10.3389/fimmu.2022.1016646

Cited by 32 publications

(18 citation statements)

References 144 publications

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“…These patients had microsatellite stable status, for whom immunotherapy is not indicated. Several factors involved in the TME of patients with colorectal cancer, such as accumulation of Tregs, MDSCs, and immunosuppressive cytokines, have been reported to determine resistance to immunotherapy [ 47 ]. In this regard, results from the phase 3 SUNLIGHT study (NCT0437187), conducted in patients with refractory metastatic colorectal cancer, showed a modest increase in median overall survival (OS) with third-line bevacizumab plus trifluridine/tipiracil compared to trifluridine/tipiracil alone (10.8 months vs 7.5 months), and the overall response rate was only 6.3% [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

First-in-human phase 1 clinical trial of anti-core 1 O-glycans targeting monoclonal antibody NEO-201 in treatment-refractory solid tumors

Cole

Morelli

Fantini³

et al. 2023

J Exp Clin Cancer Res

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Background NEO201 is a humanized IgG1 monoclonal antibody (mAb) generated against tumor-associated antigens from patients with colorectal cancer. NEO-201 binds to core 1 or extended core 1 O-glycans expressed by its target cells. Here, we present outcomes from a phase I trial of NEO-201 in patients with advanced solid tumors that have not responded to standard treatments. Methods This was a single site, open label 3 + 3 dose escalation clinical trial. NEO-201 was administered intravenously every two weeks in a 28-day cycle at dose level (DL) 1 (1 mg/kg), DL 1.5 (1.5 mg/kg) and DL 2 (2 mg/kg) until dose limiting toxicity (DLT), disease progression, or patient withdrawal. Disease evaluations were conducted after every 2 cycles. The primary objective was to assess the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of NEO-201. The secondary objective was to assess the antitumor activity by RECIST v1.1. The exploratory objectives assessed pharmacokinetics and the effect of NEO-201 administration on immunologic parameters and their impact on clinical response. Results Seventeen patients (11 colorectal, 4 pancreatic and 2 breast cancers) were enrolled; 2 patients withdrew after the first dose and were not evaluable for DLT. Twelve of the 15 patients evaluable for safety discontinued due to disease progression and 3 patients discontinued due to DLT (grade 4 febrile neutropenia [1 patient] and prolonged neutropenia [1 patient] at DL 2, and grade 3 prolonged (> 72 h) febrile neutropenia [1 patient] at DL 1.5). A total of 69 doses of NEO-201 were administered (range 1–15, median 4). Common (> 10%) grade 3/4 toxicities occurred as follows: neutropenia (26/69 doses, 17/17 patients), white blood cell decrease (16/69 doses, 12/17 patients), lymphocyte decrease (8/69 doses, 6/17 patients). Thirteen patients were evaluable for disease response; the best response was stable disease (SD) in 4 patients with colorectal cancer. Analysis of soluble factors in serum revealed that a high level of soluble MICA at baseline was correlated with a downregulation of NK cell activation markers and progressive disease. Unexpectedly, flow cytometry showed that NEO-201 also binds to circulating regulatory T cells and reduction of the quantities of these cells was observed especially in patients with SD. Conclusions NEO-201 was safe and well tolerated at the MTD of 1.5 mg/kg, with neutropenia being the most common adverse event. Furthermore, a reduction in the percentage of regulatory T cells following NEO-201 treatment supports our ongoing phase II clinical trial evaluating the efficiency of the combination of NEO-201 with the immune checkpoint inhibitor pembrolizumab in adults with treatment-resistant solid tumors. Trial registration NCT03476681. Registered 03/26/2018. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

First-in-human phase 1 clinical trial of anti-core 1 O-glycans targeting monoclonal antibody NEO-201 in treatment-refractory solid tumors

Cole

Morelli

Fantini³

et al. 2023

J Exp Clin Cancer Res

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“…Taken together, similar acquired immune responses might be activated in the primary tumor site in patients with CAM. Effective induction of adaptive immune responses against tumor cells plays a critical role in protection from cancer, while the upregulation of PD-1/PD-L1 plays an important role in evading tumor immune responses ( 39 ). Since PD-1/PD-L1 expression levels were positively correlated with expansion of TLSs/TILs in the cancer tissue ( 40 ), it is worth assessing a potential relationship between PD-1/PD-L1 expression and development of CAM in future studies.…”

Section: Discussionmentioning

confidence: 99%

Tertiary lymphoid structures in the primary tumor site of patients with cancer-associated myositis: A case–control study

Kadota

Gono²,

Κunugi³

et al. 2023

Front. Med.

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ObjectiveTo investigate histologic features of immunological components in the primary tumor site of patients with cancer-associated myositis (CAM) by focusing on tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs), which play major roles in antitumor immunity.MethodsCancer-associated myositis patients were selected from the single-center idiopathic inflammatory myopathy cohort based on the availability of primary tumor specimens obtained before the introduction of immunomodulatory agents. Control cancer subjects without CAM were selected from the cancer tissue repository at a ratio of 1:2 matched for demographics and cancer characteristics of CAM cases. A series of immunohistochemical analyses was conducted using sequential tumor sections. TLS was defined as an ectopic lymphoid-like structure composed of DC-LAMP+ mature dendritic cells, CD23+ follicular dendritic cells (FDCs) and PNAd+ high endothelial venules. TLS distribution was classified into the tumor center, invasive margin, and peritumoral area.ResultsSix CAM patients and 12 matched non-CAM controls were eligible for the study. There was no apparent difference in the density or distribution of TILs between the groups. TLSs were found in 3 CAM patients (50%) and 4 non-CAM controls (33%). TLSs were exclusively located at the tumor center or invasive margin in CAM cases but were mainly found in the peritumoral area in non-CAM controls. FDCs and class-switched B cells colocalized with follicular helper T cells were abundantly found in the germinal center-like area of TLSs from CAM patients compared with those from non-CAM controls.ConclusionThe adaptive immune response within TLSs in the primary tumor site might contribute to the pathogenic process of CAM.

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“…Compared to the pMMR/MSS phenotype, The dMMR/MSI-H phenotype generally shows higher levels of TMB and immune cell infiltration ( 51 ). It has been shown that immunotherapy is effective in some cases of dMMR/MSI-H CRC, while many patients in the pMMR/MSS phenotype show resistance ( 52 ). For ICB, although dozens of clinical trials have demonstrated the effectiveness of ICB and it has received several FDA approvals, its response has been limited to patients with dMMR/MSI-H CRC ( 53 ).…”

Section: Strategies For Gut Microbiota To Increase the Efficiency Of ...mentioning

confidence: 99%

Gut microbiota: A novel and potential target for radioimmunotherapy in colorectal cancer

Yuan

Gui²,

Wang³

et al. 2023

Front. Immunol.

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Colorectal cancer (CRC) is one of the most common cancers, with a high mortality rate, and is a major burden on human health worldwide. Gut microbiota regulate human immunity and metabolism through producing numerous metabolites, which act as signaling molecules and substrates for metabolic reactions in various biological processes. The importance of host-gut microbiota interactions in immunometabolic mechanisms in CRC is increasingly recognized, and interest in modulating the microbiota to improve patient’s response to therapy has been raising. However, the specific mechanisms by which gut microbiota interact with immunotherapy and radiotherapy remain incongruent. Here we review recent advances and discuss the feasibility of gut microbiota as a regulatory target to enhance the immunogenicity of CRC, improve the radiosensitivity of colorectal tumor cells and ameliorate complications such as radiotoxicity. Currently, great breakthroughs in the treatment of non-small cell lung cancer and others have been achieved by radioimmunotherapy, but radioimmunotherapy alone has not been effective in CRC patients. By summarizing the recent preclinical and clinical evidence and considering regulatory roles played by microflora in the gut, such as anti-tumor immunity, we discuss the potential of targeting gut microbiota to enhance the efficacy of radioimmunotherapy in CRC and expect this review can provide references and fresh ideas for the clinical application of this novel strategy.

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Mechanism and strategies of immunotherapy resistance in colorectal cancer

Cited by 32 publications

References 144 publications

First-in-human phase 1 clinical trial of anti-core 1 O-glycans targeting monoclonal antibody NEO-201 in treatment-refractory solid tumors

First-in-human phase 1 clinical trial of anti-core 1 O-glycans targeting monoclonal antibody NEO-201 in treatment-refractory solid tumors

Tertiary lymphoid structures in the primary tumor site of patients with cancer-associated myositis: A case–control study

Gut microbiota: A novel and potential target for radioimmunotherapy in colorectal cancer

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