Cancer response to immunotherapy depends on the infiltration of CD8
T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these ...factors. We show that LIF assumes a crucial role in the regulation of CD8
T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8
T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival.
Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas
. ...More than a decade ago, combination therapy with the anti-HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for patients with these types of tumours
. Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer
, there are preclinical
and clinical
rationales for adding pembrolizumab in HER2-positive disease. Here we describe results of the protocol-specified first interim analysis of the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for unresectable or metastatic, HER2-positive gastric or gastro-oesophageal junction adenocarcinoma
( https://clinicaltrials.gov , NCT03615326). We show that adding pembrolizumab to trastuzumab and chemotherapy markedly reduces tumour size, induces complete responses in some participants, and significantly improves objective response rate.
Aflibercept is a targeted anti-VEGF therapy used to treat patients with metastatic colorectal cancer (mCRC) following progression on oxaliplatin-based regimens. This
study evaluated the effect of ...prior bevacizumab treatment and growth factor levels on patient outcomes associated with aflibercept in the VELOUR phase III trial.
Baseline biomarker plasma concentrations were measured using a bead-based multiplex assay. Patients were grouped according to prior bevacizumab treatment, second-line treatment, and serum biomarker concentrations, and analyzed for overall survival (OS) and progression-free survival (PFS).
Plasma samples were available for 553 patients (placebo
= 265; aflibercept
= 288), of which 169 had received prior bevacizumab. Nine biomarkers implicated in angiogenesis or bevacizumab resistance correlated with prior bevacizumab therapy. VEGF-A and placental growth factor (PlGF) were the most significantly increased in patients who had received prior bevacizumab compared with those who had not received prior bevacizumab. In the placebo group, patients with high VEGF-A (>144 pg/mL) levels at baseline had worse OS and PFS compared with patients with lower levels at baseline (9.6 vs. 12.9 months). This was also seen in patients who received placebo and had high baseline PlGF (>8 pg/mL; 9.7 vs. 11.7 months). In the aflibercept group, prolonged OS and PFS were observed regardless of baseline VEGF-A or PlGF levels.
High VEGF-A and PlGF serum levels may underlie development of resistance to bevacizumab in patients with mCRC. Aflibercept retains its activity regardless of baseline VEGF-A and PlGF levels and may be an effective second-line treatment for patients with bevacizumab-induced resistance.
It is well established that the PI3K pathway plays a central role in various cellular processes that can contribute to the malignant phenotype. Accordingly, pharmacological inhibition of key nodes in ...this signaling cascade has been a focus in developmental therapeutics. To date, agents targeting upstream receptor tyrosine kinases are best studied and have achieved greatest clinical success. Further downstream, despite efficacy in certain tumor types, the rapalogs have been somewhat disappointing in the clinic. Novel inhibitors of PI3K, Akt, and mTORC1 and 2 are now passing through early phase clinical trials. It is hoped that these agents will circumvent some of the shortcomings of the rapalogs and lead to meaningful benefits for cancer patients.
Colorectal cancer was one of the first solid tumors to be classified on the basis of molecular profiling. Microsatellite instability has allowed researchers to distinguish a specific subtype of ...colorectal cancer that has a clearly identified molecular origin (mismatch repair deficiency), arises on a hereditary and sporadic basis, is linked to a clear clinicopathologic profile, and has prognostic implications. Inconclusive predictive data along with a paucity of targeted drug development have prevented this molecular classification system from being implemented in the clinical setting. New high-throughput genomic data have validated it, thus stressing the fact that it is ready to be applied clinically.
Application of a molecular classification of colorectal cancer in the clinical arena is an unmet promise. Recent results of large-scale genomic analyses have provided confirmation and further insights into the molecular biology of already known colorectal cancer subgroups. The quintessential example is the microsatellite instability subgroup, which has been well characterized during the past 2 decades. Future drug development and clinical research initiatives in colorectal oncology should consider these and other known cancer subgroups and start targeting these selected patient populations.
The fibroblast growth factor receptor (FGFR) pathway plays a major role in several biological processes, from organogenesis to metabolism homeostasis and angiogenesis. Several aberrations, including ...gene amplifications, point mutations, and chromosomal translocations have been described across solid tumors. Most of these molecular alterations promote multiple steps of carcinogenesis in FGFR oncogene-addicted cells, increasing cell proliferation, angiogenesis, and drug resistance. Data suggest that upregulation of FGFR signaling is a common event in many cancer types. The FGFR pathway thus arises as a potential promising target for cancer treatment. Several FGFR inhibitors are currently under development. Initial preclinical results have translated into limited successful clinical responses when first-generation, nonspecific FGFR inhibitors were evaluated in patients. The future development of selective and unselective FGFR inhibitors will rely on a better understanding of the tissue-specific role of FGFR signaling and identification of biomarkers to select those patients who will benefit the most from these drugs. Further studies are warranted to establish the predictive significance of the different FGFR-aberrations and to incorporate them into clinical algorithms, now that second-generation, selective FGFR inhibitors exist.
The current COVID-19 pandemic challenges oncologists to profoundly re-organize oncological care in order to dramatically reduce hospital visits and admissions and therapy-induced immune-related ...complications without compromising cancer outcomes. Since COVID-19 is a novel disease, guidance by scientific evidence is often unavailable, and impactful decisions are inevitably made on the basis of expert opinions. Here we report how the seven comprehensive cancer centers of Cancer Core Europe have organized their healthcare systems at an unprecedented scale and pace to make their operations 'pandemic proof'. We identify and discuss many commonalities, but also important local differences, and pinpoint critical research priorities to enable evidence-based remodeling of cancer care during the COVID-19 pandemic. Also, we discuss how the current situation offers a unique window of opportunity for assessing the effects of de-escalating anticancer regimens, which may fast-forward the development of more-refined and less-toxic treatments. By sharing our joint experiences, we offer a roadmap for proceeding and aim to mobilize the global research community to generate the data that are critically needed to offer the best possible care to patients.
Recent discoveries of genomic alterations that underlie and promote the malignant phenotype, together with an expanded repertoire of targeted agents, have provided many opportunities to conduct ...hypothesis-driven clinical trials. The ability to profile each unique cancer for actionable aberrations by using high-throughput technologies in a cost-effective way provides unprecedented opportunities for using matched therapies in a selected patient population. The major challenges are to integrate and make biologic sense of the substantial genomic data derived from multiple platforms. We define two different approaches for the analysis, interpretation, and clinical applicability of genomic data: (1) the genomically stratified model originates from the "one test-one drug" paradigm and is currently being expanded with an upfront multicategorical approach following recent advances in multiplexed genotyping platforms; and (2) the comprehensive assessment model is based on whole-genome, -exome, and -transcriptome data and allows identification of novel drivers and subsequent therapies in the experimental setting. Tumor heterogeneity and evolution of the diverse populations of cancer cells during cancer progression, influenced by the effects of systemic treatments, will need to be addressed in the new scenario of early drug development. Logistical issues related to prescreening strategies and trial allocation, in addition to concerns in the economic and ethical domains, must be taken into consideration. Here we present a historical view of how increased understanding of cancer genomics has been translated to the clinic and discuss the prospects and challenges for further implementation of a personalized treatment strategy for human solid tumors.
Colorectal cancers comprise a complex mixture of malignant cells, nontransformed cells, and microorganisms. Fusobacterium nucleatum is among the most prevalent bacterial species in colorectal cancer ...tissues. Here we show that colonization of human colorectal cancers with Fusobacterium and its associated microbiome—including Bacteroides, Selenomonas, and Prevotella species—is maintained in distal metastases, demonstrating microbiome stability between paired primary and metastatic tumors. In situ hybridization analysis revealed that Fusobacterium is predominantly associated with cancer cells in the metastatic lesions. Mouse xenografts of human primary colorectal adenocarcinomas were found to retain viable Fusobacterium and its associated microbiome through successive passages. Treatment of mice bearing a colon cancer xenograft with the antibiotic metronidazole reduced Fusobacterium load, cancer cell proliferation, and overall tumor growth. These observations argue for further investigation of antimicrobial interventions as a potential treatment for patients with Fusobacterium-associated colorectal cancer.
Brain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the ...degree and phenotype of the immune cell infiltration has been used to predict response to ICI. However, the anatomical location of brain lesions limits access to tumor material to characterize the immune phenotype. Here, we characterize immune cells present in brain lesions and matched cerebrospinal fluid (CSF) using single-cell RNA sequencing combined with T cell receptor genotyping. Tumor immune infiltration and specifically CD8
T cell infiltration can be discerned through the analysis of the CSF. Consistently, identical T cell receptor clonotypes are detected in brain lesions and CSF, confirming cell exchange between these compartments. The analysis of immune cells of the CSF can provide a non-invasive alternative to predict the response to ICI, as well as identify the T cell receptor clonotypes present in brain metastasis.
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