Association of differential expression of immunoregulatory molecules and presence of targetable mutations may inform rational design of clinical trials

Szeto, Christopher; Kurzrock, Razelle; Kato, Shumei; Goloubev, Alexey; Veerapaneni, Saihitha; Preble, Andrea; Reddy, Satyanarayan K.; Adashek, Jacob J.

doi:10.1016/j.esmoop.2022.100396

Cited by 11 publications

(9 citation statements)

References 55 publications

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“…Prior data has also suggested that differential expression of immunoregulatory molecules coincides with specific genomic alterations and that these data may be exploitable for therapeutic trial design. 34 , 35 Our data also indicate that tumor types with the highest proportion of TIL-PD-1–positive specimens were diffuse large B-cell lymphoma (∼97% TIL-PD-1–positive), bladder and peritoneum (∼84%), esophagus, head and neck, melanoma, and mesothelioma (∼80%) ( Supplemental Fig. S4 ), making them potentially amenable to ICB treatment.…”

Section: Discussionmentioning

confidence: 52%

Tumor Infiltrating Lymphocyte Expression of PD-1 Predicts Response to Anti-PD-1/PD-L1 Immunotherapy

Bevins

Okamura

Montesion³

et al. 2022

Journal of Immunotherapy and Precision Oncology

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Introduction Many studies have focused on the role of programmed death receptor ligand 1 (PD-L1) expression in predicting immunotherapy outcomes. Limited clinical data are available regarding the role of programmed death receptor 1 (PD-1; the PD-L1 receptor) expressing tumor-infiltrating lymphocytes (TILs) in PD-1/PD-L1 antibody responsiveness. However, preclinical studies demonstrate that TILs expressing PD-1 contribute to tumor immune evasion. Methods This study analyzed the association between TIL-PD-1 status and outcome after immune checkpoint blockade (ICB) therapy. We evaluated 123 patients with various solid tumors treated with monoclonal antibodies targeting the PD-1/PD-L1 signaling axis. Additionally, 8706 solid tumor specimens were assessed for TIL-PD-1 and tumor mutational burden (TMB) status. Results The presence of PD-1-expressing TILs in tumors was associated with increased median progression-free survival (7.0 vs 1.9 months; p = 0.006) and overall survival (18.1 vs 8.0 months; p = 0.04) after treatment with ICB. TIL-PD-1–positive patients had an objective response rate (ORR) of 41% (95% CI, 24–61; N = 12/29) compared with 17% (95% CI, 4–43; N = 3/17) for TIL-PD-1–negative patients (p = 0.18). Analyzed as continuous variables, TIL-PD-1 and TMB showed a weak correlation in 8706 solid tumor samples (Pearson r = 0.074); when analyzed as categorical variables (cutoffs: TIL-PD-1 ≥ 1% and TMB ≥ 10 mutations/Mb), the two variables are correlated (p < 0.0001). TIL-PD-1–positive status is also associated with enrichment of pathologic variants within several genes, most notably TP53 (adjusted p < 0.05). Conclusion TIL-PD-1 positivity in tumors (≥ 1%) is associated with significantly longer progression-free and overall survival after ICB. ClinicalTrials.gov ID: NCT02478931

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Section: Discussionmentioning

confidence: 52%

Tumor Infiltrating Lymphocyte Expression of PD-1 Predicts Response to Anti-PD-1/PD-L1 Immunotherapy

Bevins

Okamura

Montesion³

et al. 2022

Journal of Immunotherapy and Precision Oncology

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“…Other approaches include choosing drugs to impact as many alterations as possible directly; this strategy has shown efficacy in clinical trials [3,7], but may be limited by the number of drugs needed for patients with multiple molecular alterations. Additional strategies include evaluation of real-world data on similar patients, including digital cancer twins [67], and functional ex vivo assessment of drug impact[68], as well as the use of transcriptomics to determine synthetic lethal and immune interactions [69][70][71].…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Cancer: slaying the nine-headed Hydra

Adashek¹,

Subbiah²,

Westphalen³

et al. 2023

Annals of Oncology

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“…[14][15][16] Expression of LAG-3 is also differentially upregulated, regardless of tumor histology, when alterations are present in CDKN2A, EZH2, and MPL genes. 17 There have been multiple interventional clinical trials employing LAG-3 inhibitors (Table 1). 3,[18][19][20][21][22][23][24] However, trials including LAG-3-blocking drugs seem to have modest effects on outcomes.…”

Section: Introductionmentioning

confidence: 99%

“…Both high TMB and MSI‐H status have been associated with responsiveness to anti‐PD‐1/PD‐L1 checkpoint inhibitors 14–16 . Expression of LAG‐3 is also differentially upregulated, regardless of tumor histology, when alterations are present in CDKN2A , EZH2 , and MPL genes 17 …”

Section: Introductionmentioning

confidence: 99%

LAG‐3 transcriptomic expression patterns across malignancies: Implications for precision immunotherapeutics

et al. 2023

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Background: Lymphocyte activation gene 3 (LAG-3) or CD223 is a transmembrane protein that serves as an immune checkpoint which attenuates T-cell activation. Many clinical trials of LAG-3 inhibitors have had modest effects, but recent data indicate that the LAG-3 antibody relatlimab, together with nivolumab (anti-PD-1), provided greater benefit than nivolumab alone in patients with melanoma. Methods: In this study, the RNA expression levels of 397 genes were assessed in 514 diverse cancers at a clinical-grade laboratory (OmniSeq: https://www.omnis eq.com/). Transcript abundance was normalized to internal housekeeping gene profiles and ranked (0-100 percentile) using a reference population (735 tumors; histologies).Results: A total of 116 of 514 tumors (22.6%) had high LAG-3 transcript expression (≥75 percentile rank). Cancers with the greatest proportion of high LAG-3 transcripts were neuroendocrine (47% of patients) and uterine (42%); colorectal had among the lowest proportion of high LAG-3 expression (15% of patients) (all

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Association of differential expression of immunoregulatory molecules and presence of targetable mutations may inform rational design of clinical trials

Cited by 11 publications

References 55 publications

Tumor Infiltrating Lymphocyte Expression of PD-1 Predicts Response to Anti-PD-1/PD-L1 Immunotherapy

Tumor Infiltrating Lymphocyte Expression of PD-1 Predicts Response to Anti-PD-1/PD-L1 Immunotherapy

Cancer: slaying the nine-headed Hydra

LAG‐3 transcriptomic expression patterns across malignancies: Implications for precision immunotherapeutics

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