A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma

Huang, Alexander C.; Orlowski, Robert; Xu, Xiaowei; Mick, Rosemarie; George, Sangeeth M.; Yan, Patrick; Manne, Sasikanth; Kraya, Adam; Wubbenhorst, Bradley; Dorfman, Liza M.; D’Andrea, Kurt; Wenz, Brandon M.; Liu, Shujing; Chilukuri, Lakshmi; Kozlov, Andrew; Carberry, Mary; Giles, Lydia; Kier, Melanie Wain; Quagliarello, Felix; McGettigan, Suzanne; Kreider, Kristin; Annamalai, Lakshmanan; Zhao, Qing; Mogg, Robin; Xu, Wei; Blumenschein, Wendy M.; Yearley, Jennifer H.; Linette, Gerald P.; Amaravadi, Ravi K.; Schuchter, Lynn M.; Herati, Ramin S.; Bengsch, Bertram; Nathanson, Katherine L.; Farwell, Michael D.; Karakousis, Giorgos C.; Wherry, E. John; Mitchell, Tara C.

doi:10.1038/s41591-019-0357-y

Cited by 542 publications

(457 citation statements)

References 39 publications

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“…Our findings suggest that the increased surface expression of CTLA‐4 is uniquely maintained in CD4 + TIL after activation followed by 14–21 day culture. Similar findings were reported in melanoma comparing TIL phenotypes ex vivo following exposure to a single dose of anti‐PD1; however both studies reported a positive correlation with the presence of CD8 + PD‐1 hi CTLA‐4 hi , not with the CD4 population .While the observation that patients who experienced tumor regression to anti‐PD‐1 therapy do not experience a sustained elevation of CTLA‐4 on CD4 + TIL is interesting, additional patients who experienced tumor regression would be needed to see if the pattern holds. Nevertheless, it does suggest that inhibition through CTLA‐4 may limit the efficacy of the therapy and argues for testing the combination of anti‐PD‐1 and CTLA‐4 blockade in rare solid tumors.…”

Section: Resultssupporting

confidence: 71%

Exposure to anti‐PD‐1 causes functional differences in tumor‐infiltrating lymphocytes in rare solid tumors

Creasy

Forget

Singh³

et al. 2019

Eur J Immunol

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The pervasive use of therapeutic antibodies targeting programmed cell death protein 1 (PD-1) to boost anti-tumor immunity has positioned this approach to become the standard-of-care for some solid tumor malignancies. However, little is known as to how blockade of PD-1 may alter the function or phenotype of tumor-infiltrating lymphocytes (TIL). We used our ongoing Phase II clinical trial of pembrolizumab for patients with rare solid tumors from various types (NCT02721732) with matched core biopsies taken at baseline and after initial dose of anti-PD-1 (15-21 days post-dose) to elucidate this question. One fresh core needle biopsy was used to propagate TIL ex vivo to analyze phenotype and function using flow cytometry in both CD8 + and CD4 + TIL populations. An enriched CTLA-4 expression in the CD4 + TIL population was observed in TIL expanded from the on-treatment samples compared to TIL expanded from the matched baseline (n = 22, p = 0.0007) but was not observed in patients who experienced tumor regression. Impact on functionality was evaluated by measuring secretion of 65 soluble factors by expanded TIL from 26 patients at baseline and on-treatment. The CD8 + TIL population demonstrated a diminished cytokine secretion profile post-pembrolizumab. Overall, our study assesses the ramifications of one dose of anti-PD-1 on TIL in rare solid tumor types.Keywords: Anti-PD-1 r CTLA-4 r Immunotherapy r Rare solid tumors r TIL Additional supporting information may be found online in the Supporting Information section at the end of the article.

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Section: Resultssupporting

confidence: 71%

Exposure to anti‐PD‐1 causes functional differences in tumor‐infiltrating lymphocytes in rare solid tumors

Creasy

Forget

Singh³

et al. 2019

Eur J Immunol

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“…10c). These results suggest that it may be feasible, though challenging, to monitor the clonal tumor-specific T cell response to checkpoint blockade in the blood 49,50 .…”

Section: Resultsmentioning

confidence: 99%

Clonal replacement of tumor-specific T cells following PD-1 blockade

Yost

Satpathy

Wells

et al. 2019

Preprint

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Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of cancer patients. However, which tumor-specific T cells are mobilized following checkpoint blockade remains unclear. Here, we performed paired single-cell RNA-and T cell receptor (TCR)-sequencing on 79,046 cells from site-matched tumors from patients with basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) preand post-anti-PD-1 therapy. Tracking TCR clones and transcriptional phenotypes revealed a coupling of tumor-recognition, clonal expansion, and T cell dysfunction: the T cell response to treatment was accompanied by clonal expansions of CD8 + CD39 + T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, this expansion did not derive from pre-existing tumor infiltrating T cell clones; rather, it comprised novel clonotypes, which were not previously observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8 + T cells, compared to other distinct T cell phenotypes, and was evident in BCC and SCC patients. These results, enabled by single-cell multi-omic profiling of clinical samples, demonstrate that pre-existing tumor-specific T cells may be limited in their capacity for re-invigoration, and that the T cell response to checkpoint blockade relies on the expansion of a distinct repertoire of T cell clones that may have just recently entered the tumor.

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“…After therapy, an increase of Ki-67+, PD-1+, CD8+ T cells displaying an effectorlike phenotype (HLA-DR+, CD38+, Bcl-2 low ), costimulatory molecules (CD28+, CD27+, ICOS+), high levels of PD-1 and co-expression of CTLA-4 was observed in patients responding to therapy (135,140). In the same patients, the expansion of CD39+, CD8+ T cells was observed a few days after a single dose of anti-PD-1 in a neoadjuvant setting (145). Tracking TCR clones and transcriptional phenotypes in basal cell carcinoma (BCC)…”

Section: Cd8+ T Cellsmentioning

confidence: 90%

Single-Cell Approaches to Profile the Response to Immune Checkpoint Inhibitors

et al. 2020

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Novel treatments based upon the use of immune checkpoint inhibitors have an impressive efficacy in different types of cancer. Unfortunately, most patients do not derive benefit or lasting responses, and the reasons for the lack of therapeutic success are not known. Over the past two decades, a pressing need to deeply profile either the tumor microenvironment or cells responsible for the immune response has led investigators to integrate data obtained from traditional approaches with those obtained with new, more sophisticated, single-cell technologies, including high parameter flow cytometry, single-cell sequencing and high resolution imaging. The introduction and use of these technologies had, and still have a prominent impact in the field of cancer immunotherapy, allowing delving deeper into the molecular and cellular crosstalk between cancer and immune system, and fostering the identification of predictive biomarkers of response. In this review, besides the molecular and cellular cancer-immune system interactions, we are discussing how cutting-edge single-cell approaches are helping to point out the heterogeneity of immune cells in the tumor microenvironment and in blood.

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A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma

Cited by 542 publications

References 39 publications

Exposure to anti‐PD‐1 causes functional differences in tumor‐infiltrating lymphocytes in rare solid tumors

Exposure to anti‐PD‐1 causes functional differences in tumor‐infiltrating lymphocytes in rare solid tumors

Clonal replacement of tumor-specific T cells following PD-1 blockade

Single-Cell Approaches to Profile the Response to Immune Checkpoint Inhibitors

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