Immune-based therapies for cancer are generating substantial interest because of the success of immune checkpoint inhibitors. This study aimed to enhance anticancer immunity by exploiting the capacity of dendritic cells (DCs) to initiate T cell immunity by efficient uptake and presentation of endocytosed material. Delivery of tumor-associated antigens to DCs using receptor-specific monoclonal antibodies (mAbs) in the presence of DC-activating agents elicits robust antigen-specific immune responses in preclinical models. DEC-205 (CD205), a molecule expressed on DCs, has been extensively studied for its role in antigen processing and presentation. CDX-1401 is a vaccine composed of a human mAb specific for DEC-205 fused to the full-length tumor antigen NY-ESO-1. This phase 1 trial assessed the safety, immunogenicity, and clinical activity of escalating doses of CDX-1401 with the Toll-like receptor (TLR) agonists resiquimod (TLR7/8) and Hiltonol (poly-ICLC, TLR3) in 45 patients with advanced malignancies refractory to available therapies. Treatment induced humoral and cellular immunity to NY-ESO-1 in patients with confirmed NY-ESO-1–expressing tumors across various dose levels and adjuvant combinations. No dose-limiting or grade 3 toxicities were reported. Thirteen patients experienced stabilization of disease, with a median duration of 6.7 months (range, 2.4+ to 13.4 months). Two patients had tumor regression (~20% shrinkage in target lesions). Six of eight patients who received immune-checkpoint inhibitors within 3 months after CDX-1401 administration had objective tumor regression. This first-in-human study of a protein vaccine targeting DCs demonstrates its feasibility, safety, and biological activity and provides rationale for combination immunotherapy strategies including immune checkpoint blockade.

/pdf/induction-of-antigen-specific-immunity-with-a-vaccine-4102y99rb8.pdf

Induction of Antigen-Specific Immunity with a Vaccine Targeting NY-ESO-1 to the Dendritic Cell Receptor DEC-205

Macrophages are one of the immune populations frequently found in colorectal tumors and high macrophage infiltration has been associated with both better and worst prognosis. Importantly, according to microenvironment stimuli, macrophages may adopt different polarization profiles, specifically the pro-inflammatory or M1 and the anti-inflammatory or M2, which display distinct functions. Therefore, concomitantly with the number of tumor-associated macrophages (TAMs), their characterization is fundamental to unravel their relevance in cancer. Here, we profiled macrophages in a series of 150 colorectal cancer (CRC) cases by immunohistochemistry, using CD68 as a macrophage lineage marker, CD80 as a marker of pro-inflammatory macrophages, and CD163 as a marker of anti-inflammatory macrophages. Quantifications were performed by computer-assisted analysis in the intratumoral region, tumor invasive front, and matched tumor adjacent normal mucosa (ANM). Macrophages, specifically the CD163+ ones, were predominantly found at the tumor invasive front, whereas CD80+ macrophages were almost exclusively located in the ANM, which suggests a predominant anti-inflammatory polarization of TAMs. Stratification according to tumor stage revealed that macrophages, specifically the CD163+ ones, are more prevalent in stage II tumors, whereas CD80+ macrophages are predominant in less invasive T1 tumors. Specifically in stage III tumors, higher CD68, and lower CD80/CD163 ratio associated with decreased overall survival. Importantly, despite the low infiltration of CD80+ cells in colorectal tumors, multivariate logistic regression revealed a protective role of these cells regarding the risk for relapse. Overall, this work supports the involvement of distinct microenvironments, present at the intra-tumor, invasive front and ANM regions, on macrophage modulation, and uncovers their prognostic value, further supporting the relevance of including macrophage profiling in clinical settings.

/pdf/the-two-faces-of-tumor-associated-macrophages-and-their-2fhfz9fv78.pdf

The two faces of tumor-associated macrophages and their clinical significance in colorectal cancer

Immunotherapy has emerged as a new standard of care, showing survival benefit for solid tumours in multiple disease sites and indications. The survival improvements seen in diseases that were highly resistant to traditional therapies, with a poor prognosis, are unprecedented. Although the benefits observed in clinical trials are undeniable, not all patients derive those benefits, leading to emerging combination strategies and an ongoing quest for biomarker selection. Here, we summarize the current evidence for immunotherapy in the treatment of solid tumours, and we discuss emerging strategies at the forefront of research. We discuss future challenges that will be encountered as experience and knowledge continue to expand in this rapidly emerging field.

https://www.mdpi.com/1718-7729/25/5/3840/pdf

Current landscape of immunotherapy in the treatment of solid tumours, with future opportunities and challenges.

The gut microbiota and the bile acid pool play pivotal roles in maintaining intestinal homeostasis. Bile acids are produced in the liver from cholesterol and metabolized in the intestine by the gut microbiota. Gut dysbiosis has been reported to be associated with colorectal cancer. However, the interplay between bile acid metabolism and the gut microbiota during intestinal carcinogenesis remains unclear. In the present study, we investigated the potential roles of bile acids and the gut microbiota in the cholic acid (CA; a primary bile acid)-induced intestinal adenoma-adenocarcinoma sequence. Apc min/+ mice, which spontaneously develop intestinal adenomas, were fed a diet supplemented with 0.4% CA for 12 weeks. Mice that were fed a normal diet were regarded as untreated controls. In CA-treated Apc min/+ mice, the composition of the gut microbiota was significantly altered, and CA was efficiently transformed into deoxycholic acid (a secondary bile acid) by the bacterial 7α-dehydroxylation reaction. The intestinal adenoma-adenocarcinoma sequence was observed in CA-treated Apc min/+ mice and was accompanied by an impaired intestinal barrier function and IL-6/STAT3-related low-grade inflammation. More importantly, microbiota depletion using an antibiotic cocktail globally compromised CA-induced intestinal carcinogenesis, suggesting a leading role for the microbiota during this process. Overall, our data suggested that the crosstalk between bile acids and the gut microbiota mediated intestinal carcinogenesis, which might provide novel therapeutic strategies against intestinal tumor development.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/mc.22999

Interplay between bile acids and the gut microbiota promotes intestinal carcinogenesis.

Gastrointestinal (GI) malignancies are the most prevalent tumors worldwide, with increasing incidence and mortality. Although surgical resection, chemotherapy, radiotherapy, and molecular targeted therapy have led to significant advances in the treatment of GI cancer patients, overall survival is still low. Therefore, alternative strategies must be identified to improve patient outcomes. In the tumor microenvironment, tumor cells can escape the host immune response through the interaction of PD-1 and PD-L, which inhibits the function of T cells and tumor-infiltrating lymphocytes while increasing the function of immunosuppressive T regulatory cells. The use of an anti-PD-1/PD-L blockade enables reprogramming of the immune system to efficiently identify and kill tumor cells. In recent years, the efficacy of PD-1/PD-L blockade has been demonstrated in many tumors, and this treatment is expected to be a pan-immunotherapy for tumors. Here, we review the signaling pathway underlying the dysregulation of PD-1/PD-L in tumors, summarize the current clinical data for PD-1/PD-L inhibitors in GI malignancies, and discuss road toward precision immunotherapy in relation to PD-1/PD-L blockade. The preliminary data for PD-1/PD-L inhibitors are encouraging, and the precision immunotherapy of PD-1/PD-L inhibitors will be a viable and pivotal clinical strategy for GI cancer therapy.

/pdf/pd-1-pd-l-blockade-in-gastrointestinal-cancers-lessons-35zpltv2ns.pdf

PD-1/PD-L blockade in gastrointestinal cancers: lessons learned and the road toward precision immunotherapy

The large bowel shows biomolecular, anatomical and bacterial changes that proceed from the proximal to the distal tract. These changes account for the different behaviour of colon cancers arising from the diverse sides of the colon-rectum as well as for the sensitivity to the therapy, including immunotherapy. The gut microbiota plays an important role in the modulation of the immune response and differs between the right colon cancer and the left colorectal cancer. The qualitative and quantitative difference of the commensal bacteria between the right side and the left side induces epigenetic changes in the intestinal epithelial cells as well as in the resident immune population. The second player in the pathological homeostasis of colorectal cancer is the differences of the genetic features of cancer cells and the different effects that microsatellite instability, chromosomal instability and the CpG island methylator phenotype induce on the immunological organisation of the tumour microenvironment. The third player is the immunological composition of the tumour microenvironment, which changes under the influence of both genetic structures and gut microbiota. All these three players influence each other. This review describes these three aspects, highlights their interactions and discusses data from reported clinical trials.

Heterogeneity of colon cancer: from bench to bedside.

Researchers realised that standard criteria for response assessment are unsuitable for immunotherapy.1

They observed that: (1) time to response may be longer for immunotherapy; (2) response may occur after an initial pseudoprogression; (3) discontinuation of treatment may be inappropriate in case of progressive disease (PD) unless PD is confirmed after at least 4 weeks; (4) clinically insignificant PD, such as small new lesions in presence of other responsive lesions, should not be considered and (5) durable stable disease may represent antitumour activity.2

Therefore, Wolchok et al 2 proposed immune-related response criteria (irRC) to evaluate patients undergoing immunotherapy:

Overall, irRC are based on three main principles: 

1. Tumour burden : devalues the importance of each target lesion in favour of the whole ‘quantity’ of disease.

2. Confirmation : any response, other than stable disease, requires to be …

Immune-related response criteria: light and shadows

In reply to immune desert in head and neck squamous cell carcinoma: A review of challenges and opportunities for modulating the tumor immune microenvironment.

The combination of cisplatin and fluoruracil with cetuximab is the only regimen showing survival benefit in first-line therapy of relapsed-metastatic head and neck cancer (R-M HNC) in the past 30 years.1 Similarly, cetuximab is the only target agent significantly improves results of radiotherapy in locally advanced head and neck cancer (L-A HNC).2 

Cetuximab, a chimeric monoclonal antibody , can induce infusion reactions (IRs) that may be severe and life threatening.3 In clinical studies, severe IRs are uncommon.1 2 On the contrary, retrospective studies addressing this matter report higher incidence of severe IR.

We must take into account that patients recruited into clinical studies join strict inclusion criteria and so they might poorly represent the real world population.4 

In this issue of ESMO Open , Coloma et al 5 reports a large series of 428 patients treated in the real-world setting with either cetuximab in combination with radiotherapy for L-A HNC, or in combination with chemotherapy for …

Incidence of cetuximab-related infusion reaction in head and neck cancer patients: may we predict it?

Background: In search of potential biomarkers of drug responsiveness the tumour suppressor PLK2 has been identified as a mediator of taxane sensitivity in some tumour types, based on its role of G2M checkpoint regulation. Objective: The current study set out to evaluate PLK2 methylation in breast cancer treated with neo-adjuvant chemotherapy including a taxane, as a biomarker of disease progression. Methods: Silencing of PLK2 in MCF-7 cells followed by taxane treatment was assessed using apoptotic readout for proof of principle. DNA was extracted from 64 cases of diagnostic surgical FFPE sections. Using pyrosequencing, levels of PLK2  promoter methylation were measured. Results: Silencing of PLK2 resulted in a significantly reduced apoptotic response following paclitaxel treatment (compared with scramble transfected controls). An association with higher levels of CpG island promoter methylation was seen for those cases with a progression-free survival (PFS) of less than 12 months. Kaplan-Meier analysis showed there was an association between overall survival (OS) and level of methylation ( p = .06). Conclusions: Thus, based on data obtained from this pilot study, further larger studies evaluating the utility of PLK2 methylation as a potential predictive biomarker in breast cancer are warranted.

/pdf/methylated-plk2-is-a-prognostic-biomarker-in-taxane-treated-22rczmqnld.pdf

Methylated PLK2 is a prognostic biomarker in taxane-treated breast cancers

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