DNA Repair Gene Mutations as Predictors of Immune Checkpoint Inhibitor Response beyond Tumor Mutation Burden

Hsiehchen, David; Hsieh, Antony; Samstein, Robert M.; Lu, Tianshi; Beg, Muhammad Shaalan; Gerber, David E.; Wang, Tao; Morris, Luc G.T.; Zhu, Min

doi:10.1016/j.xcrm.2020.100034

Cited by 54 publications

(39 citation statements)

References 39 publications

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“…Additionally, only a fraction of patients with PD-L1-positive, metastatic TNBC respond to ICB [ 6 , 7 ]. DNA instability has emerged as a predictor of response to ICB alone and in combination with chemotherapy and DNA-damaging agents [ 8 ]. These observations culminated in the U.S. Food and Drug Administration (FDA) pan-approval of pembrolizumab for unresectable or metastatic cancers of any tissue origin with microsatellite instability (MSI+) or mismatch repair deficiency (MMR-) [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Tumor mutational burden as a predictor of immunotherapy response in breast cancer

O'Meara

Tolaney

2021

Oncotarget

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Tumor mutational burden (TMB) is a promising tool to help define patients with triple-negative breast cancer (TNBC) most likely to benefit from immune checkpoint blockade (ICB) therapies. Roughly reflecting the degree of neo-antigens that tumors present to immune cells, TMB associates with multiple measures of tumoral immunogenicity and has proven clinically useful in cancers with relatively high mutation burden. TNBC carries higher TMB than other breast cancer subtypes, and recent data suggest that high-TMB TNBC cases may derive particular benefit from ICB in combination with chemotherapy (GeparNuevo, IMpassion130) or even ICB alone (KEYNOTE-119, TAPUR). Given the recent approval of pembrolizumab and atezolizumab in combination with chemotherapy for PD-L1-positive, metastatic TNBC, standardizing TMB calculation methods and cut-off values is of critical importance to deploy this clinical biomarker.

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Section: Introductionmentioning

confidence: 99%

Tumor mutational burden as a predictor of immunotherapy response in breast cancer

O'Meara

Tolaney

2021

Oncotarget

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“…Analysis of biopsies for potential genomic predictive biomarkers of response noted all tumors had low TMB and there were no clear mutations associated with response. Although a couple of patients with response had tumors with multiple mutations in DNA damage and repair pathway genes, there was no consistent pattern of response as has been recently demonstrated in a larger series of tumors treated by immune checkpoint inhibitors 31 . Analysis of the transcriptome demonstrated signi cant expression of multiple repeat RNAs with concordant elevation of interferon response genes in patients with disease control or response.…”

Section: Discussionmentioning

confidence: 80%

Radiation Induced Checkpoint Immunotherapy Response in Refractory Colorectal and Pancreatic Adenocarcinoma

Parikh¹,

Szabolcs²,

Allen³

et al. 2020

Preprint

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Immune checkpoint blockade has limited efficacy in microsatellite stable (MSS) colorectal (CRC) and pancreatic (PDAC) cancer. Preclinical models have demonstrated the use of radiation to activate the innate immune response and stimulate responsiveness to immune checkpoint blockade. Here, we describe a Phase 2 trial of radiation therapy combined with combined anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab) antibodies in MSS CRC and PDAC. In the per protocol analysis disease control rate was 37% (10/27) in CRC and 29% (5/17) in PDAC with an overall response rate of 15% (4/27) and 18% (3/17), respectively. Whole exome and RNA sequencing of biopsies from 17 patients revealed low tumor mutational burden in all tumors, but a notable upregulation of interferon stimulated genes with concordant high expression of multiple repeat RNA transcripts in responders. Altogether, this study provides foundational human proof of concept of radiation with combination immune checkpoint blockade therapy in otherwise immunotherapy resistant cancers.

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“…While checkpoint inhibitor monotherapy is not the way forward for all mCRPC patients, checkpoint inhibitors may be of value in specific subgroups (NCT04104893) [33–35] or in combination with other therapies (NCT02861573). Subgroups of interest include patients with a high tumor mutational burden [34] or DNA damage repair deficiency [35–37]. The data on combination strategies of radium-223 with immunotherapy is scarce.…”

Section: Discussionmentioning

confidence: 99%

Immunophenotyping reveals longitudinal changes in circulating immune cells during radium-223 therapy in patients with metastatic castration-resistant prostate cancer

Creemers¹,

Doelen²,

Wilpe³

et al. 2020

Preprint

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PurposeRadium-223 improves overall survival (OS) in men with bone metastatic castration-resistant prostate cancer (mCRPC). While the exact mechanism behind this survival benefit remains unclear, radium-induced immunological mechanisms might contribute to the OS advantage. We performed a comprehensive evaluation of the immunological changes in mCRPC patients by phenotyping the peripheral blood mononuclear cells (PBMCs) during radium-223 therapy.Experimental DesignIn this prospective, single-arm, exploratory study, PBMCs of 30 mCRPC patients were collected before, during, and after treatment with radium-223. Lymphocyte and monocyte counts were analyzed to get insight into general immune cell trends. Next, we analyzed changes in T cell subsets, myeloid-derived suppressor cells (MDSCs), and immune checkpoint expression using linear regression models. Per subset, the 6-month change (% of baseline) was determined. Bootstrapped 95% confidence intervals were used to measure the degree of uncertainty of our findings.ResultsWe observed a substantial decrease in absolute lymphocyte counts (−0.12 * 10^9 cells/L per injection, 95% CI: -0.143 - -0.102). Simultaneously, an increase was observed in the proportion of T cells that expressed costimulatory (ICOS) or inhibitory (TIM-3, PD-L1, and PD-1) checkpoint molecules. Moreover, the fraction of two immunosuppressive subsets – the regulatory T cells and the monocytic MDSCs – increased throughout treatment. These findings were not more pronounced in patients with an ALP response during therapy.ConclusionImmune cell subsets in patients with mCRPC changed during radium-223 therapy, which warrants further research into the possible immunological consequences of these changes.

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DNA Repair Gene Mutations as Predictors of Immune Checkpoint Inhibitor Response beyond Tumor Mutation Burden

Cited by 54 publications

References 39 publications

Tumor mutational burden as a predictor of immunotherapy response in breast cancer

Tumor mutational burden as a predictor of immunotherapy response in breast cancer

Radiation Induced Checkpoint Immunotherapy Response in Refractory Colorectal and Pancreatic Adenocarcinoma

Immunophenotyping reveals longitudinal changes in circulating immune cells during radium-223 therapy in patients with metastatic castration-resistant prostate cancer

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