Mechanisms of Primary and Secondary Resistance to Immune Checkpoint Inhibitors in Cancer

Seto, Tiffany; Sam, Danny; Pan, Minggui

doi:10.3390/medsci7020014

Cited by 40 publications

(46 citation statements)

References 122 publications

(136 reference statements)

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“…In our series, one patient with JAK2 mutation was non-responder, which is consistent with previous studies. The predictive value of tumor mutation burden had been confirmed in specific cancer types, including melanoma [32,33]. In Forschner's study, a cutoff value of 23.1 Mut/Mb was utilized to separate the TMB of metastatic melanoma patients into TMB low or intermediate and TMB high, which was found effective in predicting the response and overall survival under combined CTLA-4 and PD-1 antibody therapy.…”

Section: Discussionmentioning

confidence: 99%

Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study

Shen

Chen

et al. 2020

Cancer Immunol Immunother

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Background The presence of liver metastasis correlates with poor therapeutic response of PD-1 blockade therapy in melanoma. A novel treatment protocol by combining cryoablation with transarterial infusion of pembrolizumab (CATAP) was proposed, and its feasibility and safety was assessed among this group of patients. Methods This registered ambispective cohort study enrolled fifteen melanoma patients with multiple hepatic metastases who received planned two-stage CATAP therapy: in the combined stage, subtotal cryoablation on day 1, in which one to two intrahepatic lesions were ablated completely with other lesions left untreated, sequentially combined transarterial infusion of pembrolizumab on day 3, every three weeks, for at least one cycle; in the infusion stage, arterial infusion of pembrolizumab was recommended at three-week interval until disease progression. The primary endpoint was objective response rate by RECIST (version 1.1); secondary end points included progression-free survival (PFS) and safety; exploratory endpoints were changes of cytokines and immune cell compositions in peripheral blood samples. Results Of the 15 patients enrolled, no grade 3-4 adverse events or major complications were observed. One patient (6.7%) achieved complete response, and 3 (20.0%) achieved partial response. The overall response rates of CATAP for the entire cohort and patients with cutaneous melanoma were 26.7% (95% confidence interval (CI) 4.3-49.0%) and 33.3% (95% CI 2.5-64.1%), respectively. Clinical response was observed in a proportion of patients (2/6; 33.3%) who failed first-line intravenous pembrolizumab treatment. The median overall PFS time and hepatic PFS time were 4.0 (95% CI 2.5-5.5) and 5.73 (95% CI 1.1-10.4) months, respectively. A significant increase in CD3-CD16 + CD56 + cells (natural killer cells; P = 0.0124) and a marginally significant decrease in CD4 + CD25 + cells (regulatory T cells; P = 0.0546) were observed three weeks after the first cycle of treatment in the combined stage. Conclusions The CATAP therapy demonstrated positive clinical activity and a favorable safety profile for melanoma patients with liver metastasis.

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Section: Discussionmentioning

confidence: 99%

Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study

Shen

Chen

et al. 2020

Cancer Immunol Immunother

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“…It was demonstrated that PDL-1 high exhausted CD8+ T cells respond poorly to PDL-1 blockade [10]. Besides T cells, myeloid-derived suppressor cells (MDSC) and tumor-associated M2 macrophages (TAMs) play a role in negative immune regulation [6,8,11]. Finally, adaptive upregulation of alternative immune checkpoints such as TIM-3 or Lag-3 was shown to be responsible for primary CPI resistance [6,12].…”

Section: Primary Resistancementioning

confidence: 99%

“…Epigenetic modifications of immune-related genes or mutations in the interferon gamma pathway, the JAK pathway or constitutive PDL-1 expression also lead to a negative immune-response [8]. Additionally, low antigenicity of the tumor cell, which is mediated by a low tumor mutational burden or alterations in the antigen-presenting machinery, results in a lack of immune cell recognition [11].…”

Section: Primary Resistancementioning

confidence: 99%

“…Likewise, the immune-related gene expression profile of the tumor can be altered. Interferon gamma pathway mutations and loss of antigen presentation proteins leading to a lack of T cell recognition have been described [11]. In melanoma patients, who initially responded to CPI, but relapsed, a truncating beta 2 microglobulin mutation was detected by whole exome sequencing.…”

Section: Secondary Resistancementioning

confidence: 99%

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Resistance to immune checkpoint inhibitors. Next steps and combinational approaches

Fuereder

2019

memo

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Immuno-oncology and in particular checkpoint inhibitor (CPI) treatment has become a novel promising cancer therapy strategy in recent years. However, still a minority of patients respond to checkpoint blockade. Primary and secondary resistance to CPI is a challenge in the daily clinical routine. Combination strategies have been tested in various clinical trials in order to address this issue. Data available from these trials indicate improved activity depending on the tumor type. This review article focuses on the molecular background for resistance to CPI, gives an overview of current clinical data of CPI combination studies and points out potential strategies to overcome CPI resistance depending on the immune phenotype.

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“…Resistance to immunotherapy can be classified as primary (or innate) and secondary or acquired [12][13][14][15]. Some authors also refer to an intermediate phenotype that is adaptive resistance [16].…”

Section: Introductionmentioning

confidence: 99%

Primary Resistance to PD-1-Based Immunotherapy—A Study in 319 Patients with Stage IV Melanoma

Amaral

Seeber

Mersi

et al. 2020

Cancers

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Background: Primary resistance to immunotherapy can be observed in approximately 40–65% of the stage IV melanoma patients treated with immune checkpoint inhibitors. A minority of the patients receive a second-line therapy, and the clinical benefit is small. Patients and methods: Stage IV melanoma patients treated with first-line PD-1-based immunotherapy between January 2015 and December 2018 were investigated. Primary resistance was defined as progressive disease (PD) at the time of the first tumor assessment after starting immunotherapy. Patients with complete response, partial response, and stable disease were classified as having disease control (DC). Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan–Meier estimator. Univariate and multivariate logistic regression analyses were performed to determine prognostic factors associated with OS. Results: Three hundred and nineteen patients were included, and 40% had primary resistance to immunotherapy. The median follow-up time was 22 months. Patients with primary resistance had 1-, 2-, and 3-year OS rates of 41%, 15%, and 10%, respectively, compared to 91%, 81%, and 65% for the patients who achieved DC. The following independently significant prognostic factors for OS were identified: protein S100B level and primary tumor localization. There was a statistically significant difference for OS (p < 0.0001) but not for PFS (p = 0.230) when analyzing risk groups formed with a combination of these two variables (low-, intermediate-, and high-risk subgroups). Conclusions: Melanoma patients with primary resistance to immunotherapy have a dismal prognosis. Response at the first tumor assessment after starting immunotherapy is a stronger prognostic factor for the further course of the disease than pretreatment risk factors.

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Mechanisms of Primary and Secondary Resistance to Immune Checkpoint Inhibitors in Cancer

Cited by 40 publications

References 122 publications

Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study

Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study

Resistance to immune checkpoint inhibitors. Next steps and combinational approaches

Primary Resistance to PD-1-Based Immunotherapy—A Study in 319 Patients with Stage IV Melanoma

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