How to schedule VEGF and PD-1 inhibitors in combination cancer therapy?

Lai, Xiulan; Friedman, Avner

doi:10.1186/s12918-019-0706-y

Cited by 24 publications

(11 citation statements)

References 64 publications

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“…In the clinical use, different agents of combination therapies may have different administration schedules due to their respective mechanisms of action and pharmacokinetics, which can increase the burden on medical staff and patients. The simultaneous administration observed to be effective here may be more straightforward and clinically translatable than other described combinations that may require the administration of dual drugs on different schedules (51)(52)(53).…”

Section: Discussionmentioning

confidence: 94%

Engineered IL-7 synergizes with IL-12 immunotherapy to prevent T cell exhaustion and promote memory without exacerbating toxicity

Kang,

Mansurov,

Kurtanich

et al. 2023

Sci. Adv.

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Cancer immunotherapy is moving toward combination regimens with agents of complementary mechanisms of action to achieve more frequent and robust efficacy. However, compared with single-agent therapies, combination immunotherapies are associated with increased overall toxicity because the very same mechanisms also work in concert to enhance systemic inflammation and promote off-tumor toxicity. Therefore, rational design of combination regimens that achieve improved antitumor control without exacerbated toxicity is a main objective in combination immunotherapy. Here, we show that the combination of engineered, tumor matrix-binding interleukin-7 (IL-7) and IL-12 achieves remarkable anticancer effects by activating complementary pathways without inducing any additive immunotoxicity. Mechanistically, engineered IL-12 provided effector properties to T cells, while IL-7 prevented their exhaustion and boosted memory formation as assessed by tumor rechallenge experiments. The dual combination also rendered checkpoint inhibitor (CPI)–resistant genetically engineered melanoma model responsive to CPI. Thus, our approach provides a framework of evaluation of rationally designed combinations in immuno-oncology and yields a promising therapy.

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Section: Discussionmentioning

confidence: 94%

Engineered IL-7 synergizes with IL-12 immunotherapy to prevent T cell exhaustion and promote memory without exacerbating toxicity

Kang,

Mansurov,

Kurtanich

et al. 2023

Sci. Adv.

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“…However, some studies have reported that better results can be achieved by ICB therapy rst. [27]. Together, Optimal dose and schedule selection for combined antiangiogenic and ICB therapy in clinical trials will be critical.…”

Section: Discussionmentioning

confidence: 99%

A Novel Combination of Bevacizumab and Pembrolizumab Stimulates Tumour Immunity Through Vascular Normalisation in Humanised Mouse Model

Qiao

Guo

Meng

et al. 2021

Preprint

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Background: Immunotherapy has dramatically changed the treatment landscape of cancer. Immunotherapies targeting the programmed death 1/programmed death ligand 1 pathway have been shown to lead to durable responses in patients with a variety of cancers. However, combination approaches are required to extend this benefit beyond a subset of patients. Studies have suggested that anti-angiogenic therapy can elicit or enhance tumor immunity response.Therefore, we hypothesised that combining immunotherapy with anti-angiogenic treatment may have a synergistic effect and may enhance the efficacy of both treatments.Methods: We evaluated the combination of bevacizumab (anti-vascular endothelial growth factor monoclonal antibody) and pembrolizumab (anti-programmed death 1 monoclonal antibody) in two mouse models of human non-small cell lung cancer cell lines (H1299 and A549). We monitored tumour growth and examined changes in the tumour vasculature, along with the frequency and phenotype of tumour-infiltrating lymphocytes.Results: The combination of bevacizumab and pembrolizumab synergistically inhibited tumour growth in vivo without overt toxicity in both cell lines. Combination therapy reprogrammed the immune microenvironment by increasing CD8+ cytotoxic T cell infiltration, thereby turning tumours with different phenotypes into inflamed (‘hot’) tumours. This is potentially mediated by vascular normalisation and endothelial cell activation, as demonstrated by a reduction in the number of microvessels and an increase in adhesion molecules.Conclusions: Taken together, our preclinical studies demonstrate that the combination of bevacizumab and pembrolizumab had a synergistic anti-tumour effect and provides a theoretical basis for translating basic research into clinical applications.

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“…Using a continuum, multiscale mechanistic model of drug PK/PD, integrated with tumor growth dynamics, Dogra et al performed virtual (i.e., in silico) clinical trials and identified drug synergism between the PD-L1 inhibitor atezolizumab and nanoparticle-based microRNA-22 therapy in triple negative breast cancer (Dogra et al, 2022). Similarly, Lai et al developed a PDE-based model and simulated the temporal dynamics of vascular tumor growth and immune interactions to optimize the scheduling of anti-VEGF and anti-PD-1 combination therapy (Lai & Friedman, 2019). Their modeling analyses suggested improved treatment outcomes with nonsimultaneous administration of the two therapies, with anti-PD-1 preceding anti-VEGF.…”

Section: Mechanistic Modelsmentioning

confidence: 99%

Immune‐checkpoint inhibitor therapy response evaluation using oncophysics‐based mathematical models

Syed

Cagely

Dogra

et al. 2022

WIREs Nanomed Nanobiotechnol

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The field of oncology has transformed with the advent of immunotherapies. The standard of care for multiple cancers now includes novel drugs that target key checkpoints that function to modulate immune responses, enabling the patient's immune system to elicit an effective anti‐tumor response. While these immune‐based approaches can have dramatic effects in terms of significantly reducing tumor burden and prolonging survival for patients, the therapeutic approach remains active only in a minority of patients and is often not durable. Multiple biological investigations have identified key markers that predict response to the most common form of immunotherapy—immune checkpoint inhibitors (ICI). These biomarkers help enrich patients for ICI but are not 100% predictive. Understanding the complex interactions of these biomarkers with other pathways and factors that lead to ICI resistance remains a major goal. Principles of oncophysics—the idea that cancer can be described as a multiscale physical aberration—have shown promise in recent years in terms of capturing the essence of the complexities of ICI interactions. Here, we review the biological knowledge of mechanisms of ICI action and how these are incorporated into modern oncophysics‐based mathematical models. Building on the success of oncophysics‐based mathematical models may help to discover new, rational methods to engineer immunotherapy for patients in the future. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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How to schedule VEGF and PD-1 inhibitors in combination cancer therapy?

Cited by 24 publications

References 64 publications

Engineered IL-7 synergizes with IL-12 immunotherapy to prevent T cell exhaustion and promote memory without exacerbating toxicity

Engineered IL-7 synergizes with IL-12 immunotherapy to prevent T cell exhaustion and promote memory without exacerbating toxicity

A Novel Combination of Bevacizumab and Pembrolizumab Stimulates Tumour Immunity Through Vascular Normalisation in Humanised Mouse Model

Immune‐checkpoint inhibitor therapy response evaluation using oncophysics‐based mathematical models

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