Antibody–drug conjugates (ADCs) have high specificity with lesser off-target effects, thus providing improved efficacy over traditional chemotherapies. A total of 14 ADCs have been approved for use ...against cancer by the US Food and Drug Administration (FDA), with more than 100 ADCs currently in clinical trials. Of particular interest ADCs targeting immune antigens PD-L1, B7-H3, B7-H4 and integrins. Specifically, we describe ADCs in development along with the gene and protein expression of these immune checkpoints across a wide range of cancer types. let url = window.clickTag || window.clickTag1 || window.clickTag2 || window.clickTag3 || window.clickTag4 || window.bsClickTAG || window.bsClickTAG1 || window.bsClickTAG2 || window.url || ''; if(typeof url == 'string'){ document.body.dataset'perxceptAdRedirectUrl' = url;}
•Antibody-drug conjugates (ADCs) offer a targeted approach to cancer therapy, with high specificity and reduced off-target effects, thereby enhancing efficacy over traditional chemotherapy methods.•The US Food and Drug Administration (FDA) has currently approved 14 ADCs for cancer treatment, with over 100 more currently undergoing clinical trials.•Each ADC is composed of three key components: an antibody, a chemical linker, and a cytotoxic payload.•The advent of immune checkpoint inhibition has significantly improved outcomes for cancer patients, underscoring the critical importance of targeting immune checkpoints in cancer therapy•The article delves into the development of ADCs targeting four immune checkpoints - B7-H3, B7-H4, PD-L1, and integrins.
Cancer immunotherapy and tumor microenvironment have been at the forefront of research over the past decades. Targeting immune checkpoints especially programmed death 1 (PD-1)/programmed death ligand ...1 (PD-L1) has made a breakthrough in treating advanced malignancies. However, the low response rate brings a daunting challenge, changing the focus to dig deeply into the tumor microenvironment for alternative therapeutic targets. Strikingly, the inhibitory immune checkpoint lymphocyte activation gene-3 (LAG-3) holds considerable potential. LAG-3 suppresses T cells activation and cytokines secretion, thereby ensuring immune homeostasis. It exerts differential inhibitory impacts on various types of lymphocytes and shows a remarkable synergy with PD-1 to inhibit immune responses. Targeting LAG-3 immunotherapy is moving forward in active clinical trials, and combination immunotherapy of anti-LAG-3 and anti-PD-1 has shown exciting efficacy in fighting PD-1 resistance. Herein, we shed light on the significance of LAG-3 in the tumor microenvironment, highlight its role to regulate different lymphocytes, interplay with other immune checkpoints especially PD-1, and emphasize new advances in LAG-3-targeted immunotherapy.
The emergence of programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1)–targeted therapy has demonstrated the importance of the PD-L1: PD-1 interaction in inhibiting anticancer T-cell immunity ...in multiple human cancers, generating durable responses and extended overall survival. However, not all patients treated with PD-L1/PD-1–targeted therapy experience tumor shrinkage, durable responses, or prolonged survival. To extend such benefits to more cancer patients, it is necessary to understand why some patients experience primary or secondary immune escape, in which the immune response is incapable of eradicating all cancer cells. Understanding immune escape from PD-L1/PD-1–targeted therapy will be important to the development of rational immune-combination therapy and predictive diagnostics and to the identification of novel immune targets. Factors that likely relate to immune escape include the lack of strong cancer antigens or epitopes recognized by T cells, minimal activation of cancer-specific T cells, poor infiltration of T cells into tumors, downregulation of the major histocompatibility complex on cancer cells, and immunosuppressive factors and cells in the tumor microenvironment. Precisely identifying and understanding these mechanisms of immune escape in individual cancer patients will allow for personalized cancer immunotherapy, in which monotherapy and combination immunotherapy are chosen based on the presence of specific immune biology. This approach may enable treatment with immunotherapy without inducing immune escape, resulting in a larger proportion of patients obtaining clinical benefit.
Regulatory T cells (Tregs) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral Treg stability and function but is dispensable for peripheral immune ...tolerance. Treg-restricted Nrp1 deletion results in profound tumor resistance due to Treg functional fragility. Thus, identifying the basis for Nrp1 dependency and the key drivers of Treg fragility could help to improve immunotherapy for human cancer. We show that a high percentage of intratumoral NRP1+ Tregs correlates with poor prognosis in melanoma and head and neck squamous cell carcinoma. Using a mouse model of melanoma where Nrp1-deficient (Nrp1–/–) and wild-type (Nrp1+/+) Tregs can be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1–/– Tregs produce interferon-γ (IFNγ), which drives the fragility of surrounding wild-type Tregs, boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFNγ-induced Treg fragility is required for response to anti-PD1, suggesting that cancer therapies promoting Treg fragility may be efficacious.
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•Increased percentage of human NRP1+ intratumoral Tregs correlates with poor prognosis•Nrp1-deficient Tregs undermine the function of wild-type Tregs via IFNγ•Hypoxia may drive IFNγ-induced Treg fragility via Hif1α in the tumor microenvironment•IFNγ-mediated Treg functional fragility is required for response to PD1 blockade
Driving Treg fragility in the tumor microenvironment is critical for the efficacy of cancer checkpoint blockade therapy.
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