Chronic inflammation is a well‐known tumor‐enabling capacity, which allows nascent tumors to acquire all the hallmark capabilities, including the escape from immunosurveillance. Soluble and cellular ...inflammatory mediators constitute the complex network of the tumor microenvironment, in which tumors grow and with which constantly interact. Myeloid cells (e.g., tumor associated macrophages) are pivotal players of the tumor microenvironment and are characterized by plasticity, which consists of the ability to acquire distinct phenotypes in response to the microenvironment in which they reside. Neutrophils are emerging as important players of tumor microenvironment, given their heterogeneity and plasticity. Increasing evidence suggests a dual role for neutrophils in modulating tumor behavior and highlights the need for a reassessment of neutrophil functions in cancer initiation and progression.
Tremendous innovation is underway among a rapidly expanding repertoire of promising personalized immune-based treatments. Therapeutic cancer vaccines (TCVs) are attractive systemic immunotherapies ...that activate and expand antigen-specific CD8+ and CD4+ T cells to enhance anti-tumor immunity. Our review highlights key issues impacting TCVs in clinical practice and reports on progress in development. We review the mechanism of action, immune-monitoring, dosing strategies, combinations, obstacles, and regulation of cancer vaccines. Most trials of personalized TCVs are ongoing and represent diverse platforms with predominantly early investigations of mRNA, DNA, or peptide-based targeting strategies against neoantigens in solid tumors, with many in combination immunotherapies. Multiple delivery systems, routes of administration, and dosing strategies are used. Intravenous or intramuscular administration is common, including delivery by lipid nanoparticles. Absorption and biodistribution impact antigen uptake, expression, and presentation, affecting the strength, speed, and duration of immune response. The emerging trials illustrate the complexity of developing this class of innovative immunotherapies. Methodical testing of the multiple potential factors influencing immune responses, as well as refined quantitative methodologies to facilitate optimal dosing strategies, could help resolve uncertainty of therapeutic approaches. To increase the likelihood of success in bringing these medicines to patients, several unique development challenges must be overcome.
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Shemesh et al. present a detailed review of the tremendous innovation underway among a rapidly expanding repertoire of personalized cancer vaccines (PCVs) in phase 1 or 2 development. The findings reveal PCVs as substantially complex immunotherapies with unique challenges requiring forward-thinking approaches to influence their translational success.
Immunotherapy, represented by immune checkpoint inhibitors (ICI), is transforming the treatment of cancer. However, only a small percentage of patients show response to ICI, and there is an unmet ...need for biomarkers that will identify patients who are more likely to respond to immunotherapy. The fundamental basis for ICI response is the immunogenicity of a tumor, which is primarily determined by tumor antigenicity and antigen presentation efficiency. Here, we propose a method to measure tumor immunogenicity score (TIGS), which combines tumor mutational burden (TMB) and an expression signature of the antigen processing and presenting machinery (APM). In both correlation with pan-cancer ICI objective response rates (ORR) and ICI clinical response prediction for individual patients, TIGS consistently showed improved performance compared to TMB and other known prediction biomarkers for ICI response. This study suggests that TIGS is an effective tumor-inherent biomarker for ICI-response prediction.
Chimeric antigen receptor (CAR) T cell therapy is revolutionizing cancer immunotherapy for patients with B cell malignancies and is now being developed for solid tumors and chronic viral infections. ...Although clinical trials have demonstrated the curative potential of CAR T cell therapy, a substantial and well-established limitation is the heightened contraction and transient persistence of CAR T cells during prolonged antigen exposure. The underlying mechanism(s) for this dysfunctional state, often termed CAR T cell exhaustion, remains poorly defined. Here, we report that exhaustion of human CAR T cells occurs through an epigenetic repression of the T cell’s multipotent developmental potential. Deletion of the de novo DNA methyltransferase 3 alpha (DNMT3A) in T cells expressing first- or second-generation CARs universally preserved the cells’ ability to proliferate and mount an antitumor response during prolonged tumor exposure. The increased functionality of the exhaustion-resistant DNMT3A knockout CAR T cells was coupled to an up-regulation of interleukin-10, and genome-wide DNA methylation profiling defined an atlas of genes targeted for epigenetic silencing. This atlas provides a molecular definition of CAR T cell exhaustion, which includes many transcriptional regulators that limit the “stemness” of immune cells, including CD28, CCR7, TCF7, and LEF1. Last, we demonstrate that this epigenetically regulated multipotency program is firmly coupled to the clinical outcome of prior CAR T cell therapies. These data document the critical role epigenetic mechanisms play in limiting the fate potential of human T cells and provide a road map for leveraging this information for improving CAR T cell efficacy.
Blockade of the protein–protein interaction between the transmembrane protein programmed cell death protein 1 (PD‐1) and its ligand PD‐L1 has emerged as a promising immunotherapy for treating ...cancers. Using the technology of mirror‐image phage display, we developed the first hydrolysis‐resistant D‐peptide antagonists to target the PD‐1/PD‐L1 pathway. The optimized compound DPPA‐1 could bind PD‐L1 at an affinity of 0.51 μM in vitro. A blockade assay at the cellular level and tumor‐bearing mice experiments indicated that DPPA‐1 could also effectively disrupt the PD‐1/PD‐L1 interaction in vivo. Thus D‐peptide antagonists may provide novel low‐molecular‐weight drug candidates for cancer immunotherapy.
Protein chemical synthesis and mirror‐image phage display were combined to develop a proteolysis‐resistant D‐peptide antagonist (DPPA‐1) which targets the immune checkpoint protein PD‐L1 (the ligand for PD‐1, the programmed cell death protein 1). DPPA‐1 was found to inhibit the PD‐1/PD‐L1 protein–protein interaction at the cellular level. IgV=immunoglobulin‐like variable.
Overexpression of the B7-H1 (PD-L1) molecule in the tumor microenvironment (TME) is a major immune evasion mechanism in some patients with cancer, and antibody blockade of the B7-H1/PD-1 interaction ...can normalize compromised immunity without excessive side-effects. Using a genome-scale T cell activity array, we identified Siglec-15 as a critical immune suppressor. While only expressed on some myeloid cells normally, Siglec-15 is broadly upregulated on human cancer cells and tumor-infiltrating myeloid cells, and its expression is mutually exclusive to B7-H1, partially due to its induction by macrophage colony-stimulating factor and downregulation by IFN-γ. We demonstrate that Siglec-15 suppresses antigen-specific T cell responses in vitro and in vivo. Genetic ablation or antibody blockade of Siglec-15 amplifies anti-tumor immunity in the TME and inhibits tumor growth in some mouse models. Taken together, our results support Siglec-15 as a potential target for normalization cancer immunotherapy.
Cancer neoantigens derived from random somatic mutations in tumor tissue represent an attractive type of targets for the cancer immunotherapies including cancer vaccine. Vaccination against the ...tumor-specific neoantigens minimizes the potential induction of central and peripheral tolerance as well as the risk of autoimmunity. Neoantigen-based cancer vaccines have recently showed marked therapeutic potential in both preclinical and early-phase clinical studies. However, significant challenges remain in the effective and faithful identification of immunogenic neoepitopes and the efficient and safe delivery of the subunit vaccine components for eliciting potent and robust anticancer T cell responses. In this mini review, we provide a brief overview of the recent advances in the development of neoantigen-based cancer vaccines focusing on various vaccine delivery strategies for targeting and modulating antigen-presenting cells. We discuss current delivery approaches, including direct injection,
-pulsed dendritic cell vaccination, and biomaterial-assisted vaccination for enhancing the efficiency of neoantigen vaccines and present a perspective on future directions.
Physiologically relevant human models that recapitulate the challenges of solid tumors and the tumor microenvironment (TME) are highly desired in the chimeric antigen receptor (CAR)-T cell field. We ...developed a breast cancer-on-chip model with an integrated endothelial barrier that enables the transmigration of perfused immune cells, their infiltration into the tumor, and concomitant monitoring of cytokine release during perfused culture over a period of up to 8 days. Here, we exemplified its use for investigating CAR-T cell efficacy and the ability to control the immune reaction with a pharmacological on/off switch. Additionally, we integrated primary breast cancer organoids to study patient-specific CAR-T cell efficacy. The modular architecture of our tumor-on-chip paves the way for studying the role of other cell types in the TME and thus provides the potential for broad application in bench-to-bedside translation as well as acceleration of the preclinical development of CAR-T cell products.
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•Tumor-on-chip recapitulating 3D microenvironment with vasculature-like perfusion•Model for CAR-T cell infusion, recruitment, and infiltration into solid tumors•Allows for monitoring of dynamic cytokine release over more than 1 week•Enables in vitro assessment of safety and efficacy in a patient-specific manner
Maulana et al. developed an advanced tumor-on-chip model that recreates chimeric antigen receptor (CAR)-T cell infusion, recruitment, and infiltration into solid tumors. Perfused culture enables the monitoring of patient-specific safety and efficacy parameters for over 1 week. The model provides novel opportunities for mechanistic studies of CAR-T cell function in a human-relevant setting.
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