Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy
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Maarten Swart1, Inge Verbrugge2, Joost B Beltman1
1Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University , Leiden , Netherlands.
Abstract:
In healthy individuals, immune-checkpoint molecules prevent autoimmune responses and limit immune cell-mediated tissue damage. Tumors frequently exploit these molecules to evade eradication by the immune system. Over the past years, immune-checkpoint blockade of cytotoxic T lymphocyte antigen-4 and programed death-1 emerged as promising strategies to activate antitumor cytotoxic T cell responses. Although complete regression and long-term survival is achieved in some patients, not all patients respond. This review describes promising, novel combination approaches involving immune-checkpoint blockade in the context of the cancer-immunity cycle, aimed at increasing response rates to the single treatments. Specifically, we discuss combinations that promote antigen release and presentation, that further amplify T cell activation, that inhibit trafficking of regulatory T cells or MSDCs, that stimulate intratumoral T cell infiltration, that increase cancer recognition by T cells, and that stimulate tumor killing.
Insights
Immune checkpoint blockade (ICB) shows promise in cancer treatment but not all patients respond. Novel combination strategies are being explored to enhance ICB efficacy by targeting the cancer-immunity cycle.
Area of Science:
- Immunology
- Oncology
- Cancer immunotherapy
Background:
- Immune checkpoints, such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1), are crucial for preventing autoimmunity.
- Tumors often hijack these checkpoints to evade immune surveillance and destruction.
- While immune-checkpoint blockade (ICB) has improved outcomes for some cancer patients, response rates remain suboptimal.
Approach:
- This review examines innovative combination therapies designed to augment the effectiveness of ICB.
- These strategies are analyzed within the framework of the cancer-immunity cycle, aiming to overcome treatment resistance.
- Focus areas include enhancing antigen presentation, T-cell activation, immune cell trafficking, and tumor cell killing.
Key Points:
- Combination approaches aim to overcome limitations of single-agent ICB by synergistically engaging multiple steps of the cancer-immunity cycle.
- Strategies discussed include promoting tumor antigen release and presentation, boosting T-cell activation, and modulating the tumor microenvironment.
- Inhibiting regulatory T cells and myeloid-derived suppressor cells (MDSCs) is also explored to enhance anti-tumor immunity.
Conclusions:
- Novel combination strategies involving ICB hold significant potential to improve response rates and patient outcomes in cancer immunotherapy.
- Targeting various stages of the cancer-immunity cycle offers a rational approach to enhance the efficacy of current ICB treatments.
- Further research into these combination therapies is crucial for advancing cancer treatment paradigms.
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