Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease

Liu, Jing; Blake, Stephen J.; Yong, Michelle C.R.; Harjunpää, Heidi; Ngiow, Shin Foong; Takeda, Kazuyoshi; Young, Arabella; O’Donnell, Jake S.; Allen, Stacey; Smyth, Mark J.; Teng, Michele W.L.

doi:10.1158/2159-8290.cd-16-0577

Cited by 629 publications

(522 citation statements)

References 51 publications

Supporting

Mentioning

489

Contrasting

Unclassified

Order By: Relevance

“…Preclinical tumor studies in mice had underpinned this concept. 28 Studies in mice had also shown the importance of dendritic cells in the antitumor effects of PD-1 pathway blockade, which suggested that PD-1 blockade not only worked to directly unleash intratumoral T-cell killing but also enhanced tumor antigen–driven priming of T cells. 29 Indeed, PD-1 blockade had been shown to enhance the early stages of T-cell activation in lymph nodes.…”

Section: Discussionmentioning

confidence: 99%

Neoadjuvant PD-1 Blockade in Resectable Lung Cancer

et al. 2018

View full text Add to dashboard Cite

BACKGROUND Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non–small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. METHODS In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses. RESULTS Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab. CONCLUSIONS Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood. (Funded by Cancer Research Institute–Stand Up 2 Cancer and others; ClinicalTrials.gov number, NCT02259621.)

show abstract

Section: Discussionmentioning

confidence: 99%

Neoadjuvant PD-1 Blockade in Resectable Lung Cancer

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Human NK cell activation and culture The B lymphoblastoid cell line (B-LCL) used to activate NK cells in culture has been described elsewhere (55 Experimental tumor models B16F10 (ATCC), RM-1 (provided by Pamela Russell, University of Sydney, Sydney, Australia), and E0771 (provided by Robin Anderson, Peter MacCallum Cancer Centre, Melbourne, Australia) cell lines have all been previously described (26,59). The cell lines were maintained in complete DMEM (cDMEM) containing 10% FBS, 100 U/ml penicillin, 100 μg/ml streptomycin, and 2 mM glutamax (Gibco, Thermo Fisher Scientific).…”

Section: Discussionmentioning

confidence: 99%

NK cell heparanase controls tumor invasion and immune surveillance

Putz

Mayfosh

Kos

et al. 2017

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

“…As such in mice, increased efficacy of neoadjuvant versus adjuvant immunotherapy has been observed. 87 The I-SPY 2 randomised phase II trial investigated the impact on pCR rate following treatment with the combination of pembrolizumab with standard neoadjuvant CT (paclitaxel followed by doxorubicin and cyclophosphamide) in high risk TNBC and ER-positive/HER2-negative BC (NCT01042379) 39 (table 3). In preliminary analyses, the addition of pembrolizumab increased the likelihood of pCR achievement compared with paclitaxel, particularly in the TNBC subgroup.…”

Section: Pd-1/pd-l1 Blockade In the Neoadjuvant And Adjuvant Settingsmentioning

confidence: 99%

Targeting immune checkpoints in breast cancer: an update of early results

et al. 2017

View full text Add to dashboard Cite

The immune tumour microenvironment has been shown to play a crucial role in the development and progression of cancer. Expression of gene signatures, reflecting immune activation, and the presence of tumour-infiltrating lymphocytes were associated with favourable outcomes in HER2-positive and triple-negative breast cancer. Recently, immunotherapy with immune checkpoint blockade induced long-lasting responses and improved survival in hard-to-treat malignancies (ie, melanoma and non-small cell lung cancer) and are changing treatment paradigms in a variety of neoplastic diseases. Immune checkpoint blockade has been evaluated in breast cancer, particularly in the triple-negative subtype, with promising results observed in monotherapy or in combination with chemotherapy in the metastatic and neoadjuvant settings. However, identification of patients who are most likely to benefit from immune checkpoint blockade remains challenging, with many patients not responding to treatments and a significant financial cost. The combination of immune checkpoint blockade with conventional cancer treatments such as chemotherapy, radiotherapy, targeted therapies or with other immunotherapies is a promising strategy to potentiate its efficacy in breast cancer although further research is required to effectively identify who will respond to these immunotherapies. In this review we report the most recent results that emerged from trials testing immune checkpoint blockade and potential predictive biomarkers and emphasise the new strategies that are under clinical development in breast cancer.

show abstract

Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease

Cited by 629 publications

References 51 publications

Neoadjuvant PD-1 Blockade in Resectable Lung Cancer

Neoadjuvant PD-1 Blockade in Resectable Lung Cancer

NK cell heparanase controls tumor invasion and immune surveillance

Targeting immune checkpoints in breast cancer: an update of early results

Contact Info

Product

Resources

About