Immune Modulation in Cancer with Antibodies

Page, David B.; Postow, Michael A.; Callahan, Margaret K.; Allison, James P.; Wolchok, Jedd D.

doi:10.1146/annurev-med-092012-112807

Cited by 465 publications

(394 citation statements)

References 121 publications

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“…Blockade of the suppressive signals via anti-CTLA-4, anti-PD-1, and anti-PD-L1 agents has shown clinical benefit (3). Dual blockade of immunosuppressive pathways via anti-CTLA-4 and anti-PD-1 or via anti-PD-1 and anti-LAG-3 has entered clinical trials (3,4). Modulation of stimulatory signals by 4-1BB, OX40, or GITR pathway is still in the early stages of clinical evaluation (30).…”

Section: Discussionmentioning

confidence: 99%

“…5 days apart. In the study of treating larger tumors (range of 126-350 mm 3 ), antibodies were given four times i.p. 3 days apart.…”

Section: Immune-cell Phenotyping Using Flow Cytometrymentioning

confidence: 99%

“…Anti-PD-1 treatment alone did not alter Eomes expression (18% Eomes þ CD8 þ T cells). CD4 þ T cells from control groups 3 . A, mice were randomized on day 8, and anti-4-1BB (1 mg/kg)/anti-PD-1 (10 mg/kg) mAbs were dosed on days 8, 11, and 14 (indicated by arrows).…”

Section: Anti-4-1bb/anti-pd-1 Combination Induced T-cell Effector/ Mementioning

confidence: 99%

“…The combination of two checkpoint inhibitors, anti-CTLA-4 and anti-PD-1, increased the response rate up to 53% in a phase I trial with advanced melanoma; however, severe treatment-related adverse events (grade ! 3) were also reported in 53% of cases and treatment was discontinued in 21% of the patients (3,4). Although these results are promising, it is clear that increasing the frequency of response while limiting toxicities will be crucial for the success of combinatorial cancer immunotherapy in a wider population of patients with cancer.…”

Section: Introductionmentioning

confidence: 96%

“…Targeting the programmed death 1/programmed cell death ligand 1 (PD-1/PD-L1) axis resulted in a higher response rate of up to 37%, whereas treatment-related grade ! 3 toxicity rates were 9% to 33% in the melanoma cohorts of multiple phase I trials (3). The combination of two checkpoint inhibitors, anti-CTLA-4 and anti-PD-1, increased the response rate up to 53% in a phase I trial with advanced melanoma; however, severe treatment-related adverse events (grade !…”

Section: Introductionmentioning

confidence: 99%

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Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector/Memory CD8 T Cells in a Poorly Immunogenic Tumor Model

Chen

Lee

Fisher

et al. 2015

Cancer Immunology Research

236

167

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Immunotherapies targeting the programmed death 1 (PD-1) coinhibitory receptor have shown great promise for a subset of patients with cancer. However, robust and safe combination therapies are still needed to bring the benefit of cancer immunotherapy to broader patient populations. To search for an optimal strategy of combinatorial immunotherapy, we have compared the antitumor activity of the anti-4-1BB/anti-PD-1 combination with that of the anti-PD-1/anti-LAG-3 combination in the poorly immunogenic B16F10 melanoma model. Pronounced tumor inhibition occurred only in animals receiving anti-PD-1 and anti-4-1BB concomitantly, while combining anti-PD-1 with anti-LAG-3 led to a modest degree of tumor suppression. The activity of the anti-4-1BB/anti-PD-1 combination was dependent on IFNg and CD8 þ T cells. Both 4-1BB and PD-1 proteins were elevated on the surface of CD8 þ T cells by anti-4-1BB/anti-PD-1 cotreatment. In the tumor microenvironment, an effective antitumor immune response was induced as indicated by the increased CD8 þ /Treg ratio and the enrichment of genes such as Cd3e, Cd8a, Ifng, and Eomes. In the spleen, the combination treatment shaped the immune system to an effector/memory phenotype and increased the overall activity of tumor-specific CD8 þ CTLs, reflecting a long-lasting systemic antitumor response. Furthermore, combination treatment in C57BL/6 mice showed no additional safety signals, and only minimally increased severity of the known toxicity relative to 4-1BB agonist alone. Therefore, in the absence of any cancer vaccine, anti-4-1BB/anti-PD-1 combination therapy is sufficient to elicit a robust antitumor effector/memory T-cell response in an aggressive tumor model and is therefore a candidate for combination trials in patients.

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Section: Discussionmentioning

confidence: 99%

“…5 days apart. In the study of treating larger tumors (range of 126-350 mm 3 ), antibodies were given four times i.p. 3 days apart.…”

Section: Immune-cell Phenotyping Using Flow Cytometrymentioning

confidence: 99%

Section: Anti-4-1bb/anti-pd-1 Combination Induced T-cell Effector/ Mementioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector/Memory CD8 T Cells in a Poorly Immunogenic Tumor Model

Chen

Lee

Fisher

et al. 2015

Cancer Immunology Research

236

167

View full text Add to dashboard Cite

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CNOT4 enhances the efficacy of anti‐PD‐1 immunotherapy in a model of non‐small cell lung cancer

Zhang

Han

et al. 2020

FEBS Open Bio

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Nano‐Oncologicals: A Tortoise Trail Reaching New Avenues

Dacoba

Anthiya

Berrecoso

et al. 2021

Adv Funct Materials

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Research efforts towards cancer therapeutics have resulted in the development of a variety of pharmacological molecules, including small synthetic molecules and biological drugs (RNA-based therapies and monoclonal antibodies-mAbs), intended to target tumor or immune-related cells, or their signaling mediators. The majority of them present important biopharmaceutical problems related to their difficulties for overcoming biological barriers and reach their targets. Nanotechnology has been, for more than 60 years, trying to solve these problems. As knowledge in drug discovery, molecular biology, and biomaterials advances, there has been significant progress in the adequate design of nanodelivery strategies that may significantly contribute to the exploitation of the new therapies. This review provides a critical overview of the current potential of nanotechnology to solve problems associated with the different categories of drugs. Starting with the general concept of passive and active targeting, it presents the distinct advantages that delivery technologies have shown to date for improving the therapeutic outcome of small drugs with cytotoxic activity, RNA-and mAb-based therapies. Moreover, it precisely describes the benefits of combining immunotherapies and nanotechnology. The most advanced technologies are put into perspective in relation to their translational pathway and the future avenues for nano-oncologicals.

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Immune Modulation in Cancer with Antibodies

Cited by 465 publications

References 121 publications

Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector/Memory CD8 T Cells in a Poorly Immunogenic Tumor Model

Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector/Memory CD8 T Cells in a Poorly Immunogenic Tumor Model

CNOT4 enhances the efficacy of anti‐PD‐1 immunotherapy in a model of non‐small cell lung cancer

Nano‐Oncologicals: A Tortoise Trail Reaching New Avenues

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