Immune Checkpoint Blockade Therapy: Merits and Demerits

Sugiura, Keiji; Sugiura, Mariko

doi:10.4172/2155-9554.1000372

Cited by 2 publications

(2 citation statements)

References 38 publications

(54 reference statements)

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“…This provides a rational for using combined BRAF/MEK inhibition instead of BRAF inhibition alone [ 11 ]. Treatment of melanoma with immune checkpoint inhibitors has a lower response rate compared to treatment with BRAF/MEK inhibitors, but the response tends to be more durable, lasting for years [ 11 – 13 ]. It was therefore suggested that BRAF/MEK-targeted therapy may synergize with the PD-1 pathway blockade to enhance anti-tumor immunity [ 4 , 11 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Combination therapy for melanoma with BRAF/MEK inhibitor and immune checkpoint inhibitor: a mathematical model

Lai

Friedman²

2017

BMC Syst Biol

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BackgroundThe B-raf gene is mutated in up to 66% of human malignant melanomas, and its protein product, BRAF kinase, is a key part of RAS-RAF-MEK-ERK (MAPK) pathway of cancer cell proliferation. BRAF-targeted therapy induces significant responses in the majority of patients, and the combination BRAF/MEK inhibitor enhances clinical efficacy, but the response to BRAF inhibitor and to BRAF/MEK inhibitor is short lived. On the other hand, treatment of melanoma with an immune checkpoint inhibitor, such as anti-PD-1, has lower response rate but the response is much more durable, lasting for years. For this reason, it was suggested that combination of BRAF/MEK and PD-1 inhibitors will significantly improve overall survival time.ResultsThis paper develops a mathematical model to address the question of the correlation between BRAF/MEK inhibitor and PD-1 inhibitor in melanoma therapy. The model includes dendritic and cancer cells, CD 4+ and CD 8+ T cells, MDSC cells, interleukins IL-12, IL-2, IL-6, IL-10 and TGF- β, PD-1 and PD-L1, and the two drugs: BRAF/MEK inhibitor (with concentration γ B) and PD-1 inhibitor (with concentration γ A). The model is represented by a system of partial differential equations, and is used to develop an efficacy map for the combined concentrations (γ B,γ A). It is shown that the two drugs are positively correlated if γ B and γ A are at low doses, that is, the growth of the tumor volume decreases if either γ B or γ A is increased. On the other hand, the two drugs are antagonistic at some high doses, that is, there are zones of (γ B,γ A) where an increase in one of the two drugs will increase the tumor volume growth, rather than decrease it.ConclusionsIt will be important to identify, by animal experiments or by early clinical trials, the zones of (γ B,γ A) where antagonism occurs, in order to avoid these zones in more advanced clinical trials.

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Section: Introductionmentioning

confidence: 99%

Combination therapy for melanoma with BRAF/MEK inhibitor and immune checkpoint inhibitor: a mathematical model

Lai

Friedman²

2017

BMC Syst Biol

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“…This can boost the body's immune response against cancer cells. Unlike radio and chemotherapy which aim to directly interfere with tumor cell growth and survival, Immunotherapy target the tumour indirectly by boosting the antitumor immune response that spontaneously arise in many patients [1] .…”

Section: Introductionmentioning

confidence: 99%

A review on immune checkpoint blockage therapy

shajahan¹,

Dharan²,

Nj³

2020

Int J Res Pharm Hos & Clin. Pharm

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Activating the immune system to eliminate cancer cells and produce clinically relevant response has been a long standing goal of cancer research. Most promising therapeutic approaches of activating antitumor immunity include immune checkpoint inhibitors. Our immune system protect us from disease, killing bacteria and virus. One main type of immune cell called T-cells. T-cells have protein that turn it off. These are called checkpoint. Immune checkpoint are accessory molecules that either promote or inhibit T-cell activation. Checkpoint inhibitor are a type of immunotherapy. They block protein that stops the immune system from attacking the cancer cells. Checkpoint inhibitor are a type of monoclonal antibody or targeted treatment. Immune system cells, such as T-cells and Antigen presenting cells (APCs), defend and protect the body. Immune system play an important role in controlling and eradicating cancer. Cytotoxic T lymphocytes associated protein 4(CTLA-4) and Programmed cell dealth protein (PD-1) are checkpoint protein which is the negative regulation of T-cell immune function. Inhibition of the target, results in increased activation of immune system.

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Immune Checkpoint Blockade Therapy: Merits and Demerits

Cited by 2 publications

References 38 publications

Combination therapy for melanoma with BRAF/MEK inhibitor and immune checkpoint inhibitor: a mathematical model

Combination therapy for melanoma with BRAF/MEK inhibitor and immune checkpoint inhibitor: a mathematical model

A review on immune checkpoint blockage therapy

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