The Spectrum of Benefit from Checkpoint Blockade in Hypermutated Tumors

Rousseau, Benoît; Foote, Michael B.; Maron, Steven Brad; Diplas, Bill H.; Lu, Steve; Argilés, Guillem; Cercek, Andrea; Díaz, Luis A.

doi:10.1056/nejmc2031965

Cited by 147 publications

(79 citation statements)

References 3 publications

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“…14 Marabelle et al have demonstrated the association of TMB with outcomes in patients with advanced solid tumors. 34 Similar results have been obtained in hypermutated tumors 35 and TMB as an indicator for cytolytic activity and prognosis in malignant melanoma and other tumors. 36,37…”

Section: Heterogeneity Of Pd-l1 Expressionsupporting

confidence: 69%

Immunological tumor heterogeneity and diagnostic profiling for advanced and immune therapies

Huss

Schmid

Manesse³

et al. 2021

Adv Cell Gene Ther

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Immunotherapies have changed the way how we treat cancer at all stages. The understanding of the immune system in individual tumor specimens guides the selection of immune-modulating agents such as immune checkpoint inhibitors alone or in combination with other therapeutic agents that target, modulate or unleash the patient's immune system. Despite the similar histopathological diagnosis, each tumor is unique at its primary site and site of metastasis, also depending on previous treatment regimens or genetic alterations, such as chromosomal instability or acquired mutations. The clinically well-established use of PD-1/PD-L1 inhibitors already requires the assessment of

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Section: Heterogeneity Of Pd-l1 Expressionsupporting

confidence: 69%

Immunological tumor heterogeneity and diagnostic profiling for advanced and immune therapies

Huss

Schmid

Manesse³

et al. 2021

Adv Cell Gene Ther

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show abstract

“…This is consistent with other studies reporting that response to immunotherapy does not correlate with high TMB in all patients [40]. The use of TMBhigh status as a biomarker to predict ICI response in OAC has been challenged further by recent studies that have shown no benefit for ICI use in mismatch-repair proficient, TMB-high cancers [41,42]. In TMBhigh tumours where CD8 + T-cell levels are not associated with neoantigen load, such as OC, treatment with ICIs is associated with a significantly lower response rate, and trend towards worse overall survival (OS) compared to TMB-low tumours [42].…”

Section: Genomic Features Of Oac and Associated Immune Responsessupporting

confidence: 87%

Understanding the immuno-biology of oesophageal adenocarcinoma: Towards improved therapeutic approaches

Lonie

Barbour

Dolcetti

2021

Cancer Treatment Reviews

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With an incidence that is constantly rising, oesophageal adenocarcinoma (OAC) is becoming an increasing health burden worldwide. Although significant advances in treatment regimens have improved patient outcomes, survival rates for this deadly cancer remain unsatisfactory. This highlights the need to improve current therapeutic approaches and develop novel therapeutic strategies for treating OAC patients. The advent of immunotherapy has revolutionised treatment across a range of malignancies, however outcomes in OAC show modest results. The inherent resistance of OAC to treatment reflects the complex genomic landscape of this cancer, which displays a lack of ubiquitous driver mutations and large-scale genomic alterations along with high tumour and immune heterogeneity. Research into the immune landscape of OAC is limited, and elucidation of the mechanisms surrounding the immune responses to this complex cancer will result in improved therapeutic approaches. This review explores what is known about the immuno-biology of OAC and explores promising therapeutic avenues that may improve responses to immunotherapeutic regimens.

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“…MSI metastatic CRC are characterized by poorer prognosis, and they are usually resistant to common cytotoxic and targeted agents [ 24 , 29 , 30 ]. Interestingly, while MSS mCRCs exhibit primary resistance to CPIs, MSI mCRC are greatly sensitive to CPIs [ 16 , 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers

Amodio

Mauri

Reilly

et al. 2021

Cancers

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Immune checkpoint inhibitors (CPIs) represent an effective therapeutic strategy for several different types of solid tumors and are remarkably effective in mismatch repair deficient (MMRd) tumors, including colorectal cancer (CRC). The prevalent view is that the elevated and dynamic neoantigen burden associated with the mutator phenotype of MMRd fosters enhanced immune surveillance of these cancers. In addition, recent findings suggest that MMRd tumors have increased cytosolic DNA, which triggers the cGAS STING pathway, leading to interferon-mediated immune response. Unfortunately, approximately 30% of MMRd CRC exhibit primary resistance to CPIs, while a substantial fraction of tumors acquires resistance after an initial benefit. Profiling of clinical samples and preclinical studies suggests that alterations in the Wnt and the JAK-STAT signaling pathways are associated with refractoriness to CPIs. Intriguingly, mutations in the antigen presentation machinery, such as loss of MHC or Beta-2 microglobulin (B2M), are implicated in initial immune evasion but do not impair response to CPIs. In this review, we outline how understanding the mechanistic basis of immune evasion and CPI resistance in MMRd CRC provides the rationale for innovative strategies to increase the subset of patients benefiting from CPIs.

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The Spectrum of Benefit from Checkpoint Blockade in Hypermutated Tumors

Cited by 147 publications

References 3 publications

Immunological tumor heterogeneity and diagnostic profiling for advanced and immune therapies

Immunological tumor heterogeneity and diagnostic profiling for advanced and immune therapies

Understanding the immuno-biology of oesophageal adenocarcinoma: Towards improved therapeutic approaches

Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers

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