Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer

Garon, Edward B.; Rizvi, Naiyer A.; Hui, Rina; Leighl, Natasha B.; Balmanoukian, Ani Sarkis; Eder, Joseph P.; Patnaik, Amita; Aggarwal, Charu; Gubens, Matthew A.; Horn, Leora; Carcereny, Enric; Ahn, Myung‐Ju; Felip, Enriqueta; Lee, Jong-Seok; Hellmann, Matthew D.; Hamid, Omid; Goldman, Jonathan W.; Soria, Jean‐Charles; Dolled‐Filhart, Marisa; Rutledge, Ruth Z.; Zhang, Jin; Lunceford, Jared; Rangwala, Reshma; Lubiniecki, Gregory M.; Roach, Charlotte; Emancipator, Kenneth; Gandhi, Leena

doi:10.1056/nejmoa1501824

Cited by 5,240 publications

(4,445 citation statements)

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“…Antibodies that block negative immune regulatory pathways (checkpoint inhibitors) 5 , including CTLA-4 (cytotoxic T-lymphocyte–associated antigen 4) and PD-1 (programmed cell death 1) receptors, improve survival in patients with advanced disease such as melanoma, bladder, squamous cell head and neck and non-small-cell lung cancer 6–11 . A key clinical approach to improving cancer immunotherapy has been to combine radiotherapy with checkpoint inhibitors to induce the abscopal effect, a phenomenon where local tumor treatment produces systemic regression of metastatic lesions 12 .…”

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confidence: 99%

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

et al. 2017

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Immunotherapy holds tremendous promise for improving cancer treatment1. Administering radiotherapy with immunotherapy has been shown to improve immune responses and can elicit an “abscopal effect”2. Unfortunately, response rates for this strategy remain low3. Herein, we report an improved cancer immunotherapy approach that utilizes antigen-capturing nanoparticles (AC-NPs). We engineered several AC-NPs formulations and demonstrated that the set of protein antigens captured by each AC-NP formulation is dependent upon NP surface properties. We showed that AC-NPs deliver tumor specific proteins to antigen-presenting cells and significantly improve the efficacy of αPD-1 treatment using the B16F10 melanoma model, generating up to 20% cure rate as compared to 0% without AC-NPs. Mechanistic studies revealed that AC-NPs induced an expansion of CD8+ cytotoxic T cells and increased both CD4+/Treg and CD8+/Treg ratios. Our work presents a novel strategy for improving cancer immunotherapy with nanotechnology.

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confidence: 99%

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

et al. 2017

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“…Moreover, this may also induce an indiscriminate reactivation of antigen-experienced T cells, including functionally silenced yet potentially deleterious autoreactive T cells, leading to severe autoimmune-related adverse events during and after treatment. 8 , 12 , 22 …”

Section: Discussionmentioning

confidence: 99%

“…In particular, PD-L1-blocking antibodies, such as atezolizumab, avelumab, and durvalumab, showed prominent clinical activity in patients with advanced stage melanoma 8-10 and non-small-cell lung carcinoma (NSCLC). 11 , 12 However, the efficacy of current conventional monospecific PD-L1-blocking antibodies is potentially hampered due to on-target/off-tumor binding to numerous normal cell types that also express PD-L1. In this respect, binding to PD-L1-expressing cells in blood or other tissue may prevent antibody extravasation and accumulation at the site of the tumor.…”

Section: Introductionmentioning

confidence: 99%

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

et al. 2018

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PD-L1-blocking antibodies produce significant clinical benefit in selected cancer patients by reactivating functionally-impaired antigen-experienced anticancer T cells. However, the efficacy of current PD-L1-blocking antibodies is potentially reduced by ‘on-target/off-tumor’ binding to PD-L1 widely expressed on normal cells. This lack of tumor selectivity may induce a generalized activation of all antigen-experienced T cells which may explain the frequent occurrence of autoimmune-related adverse events during and after treatment.To address these issues, we constructed a bispecific antibody (bsAb), designated PD-L1xEGFR, to direct PD-L1-blockade to EGFR-expressing cancer cells and to more selectively reactivate anticancer T cells. Indeed, the IC50 of PD-L1xEGFR for blocking PD-L1 on EGFR+ cancer cells was ∼140 fold lower compared to that of the analogous PD-L1-blocking bsAb PD-L1xMock with irrelevant target antigen specificity. Importantly, activation status, IFN-γ production, and oncolytic activity of anti-CD3xanti-EpCAM-redirected T cells was enhanced when cocultured with EGFR-expressing carcinoma cells. Similarly, the capacity of PD-L1xEGFR to promote proliferation and IFN-γ production by CMVpp65-directed CD8+ effector T cells was enhanced when cocultured with EGFR-expressing CMVpp65-transfected cancer cells. In contrast, the clinically-used PD-L1-blocking antibody MEDI4736 (durvalumab) promoted T cell activation indiscriminate of EGFR expression on cancer cells. Additionally, in mice xenografted with EGFR-expressing cancer cells 111In-PD-L1xEGFR showed a significantly higher tumor uptake compared to 111In-PD-L1xMock. In conclusion, PD-L1xEGFR blocks the PD-1/PD-L1 immune checkpoint in an EGFR-directed manner, thereby promoting the selective reactivation of anticancer T cells. This novel targeted approach may be useful to enhance efficacy and safety of PD-1/PD-L1 checkpoint blockade in EGFR-overexpressing malignancies.

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“…1,4,5 The T cell-centric mechanisms behind each immune checkpoint protein suggest that correlates of lymphocytic infiltration in the tumor microenvironment may better inform patient response. 6 Early immune-related biomarkers that have been identified for anti-PD-1/anti-PD-L1 include CD8 + T cell density 7 and intratumoral PD-L1 expression, 8 while the expression of immune-related genes has been associated with response to anti-CTLA-4. 9,10 In addition to markers of immune infiltration, a higher tumor mutation burden (TMB) has been associated with response to both therapies, implicating the neoantigen-driven immune reaction as a common factor involved in immune checkpoint blockade response.…”

Section: Introductionmentioning

confidence: 99%

A B cell-derived gene expression signature associates with an immunologically active tumor microenvironment and response to immune checkpoint blockade therapy

2018

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Immune checkpoint inhibitors have shown great potential in treating solid tumors, inducing durable remission and prolonged survival time in responders. Despite their promise, a large fraction of patients remains unresponsive to these treatments highlighting the need for biomarkers that can predict patient sensitivity. Pre-treatment gene expression profiles for patients receiving immune checkpoint inhibitors have recently become available, establishing a new medium by which to discover biomarkers that predict therapy response. In this study, we mined for transcriptomic correlates of response by applying immune cell-derived gene expression signatures to publicly available datasets containing matched gene expression and response efficacy information. These datasets were comprised of urothelial carcinoma patients receiving anti-PD-L1 (n = 25), melanoma patients receiving anti-PD-1 (n = 28), and melanoma patients receiving anti-CTLA-4 (n = 42). We identified one signature, derived from a subpopulation of B cells, with scores that were significantly and reproducibly elevated in patients experiencing clinical benefit following therapy targeting the PD-1/PD-L1 axis and were additionally elevated in patients responsive to anti-CTLA-4 therapy. Multivariate models revealed that this signature was associated with response independent of other response-predictive biomarkers, including tumor mutation burden. Functional annotation of the signature revealed it to be associated with features indicative of an immunologically active microenvironment, including B and T cell activation as well as antigen presentation activity. The preliminary findings presented detail a transcriptomic signature associated with response to multiple checkpoint inhibitors and suggest novel biological associations that warrant further investigation.

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Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer

Cited by 5,240 publications

References 36 publications

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

A B cell-derived gene expression signature associates with an immunologically active tumor microenvironment and response to immune checkpoint blockade therapy

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