Throughout our life, long‐lived somatic stem cells (SSC) regenerate adult tissues both during homeostatic processes and repair after injury. The role of aberrant regulation of SSC has also recently ...gained prominence in the field of cancer research. Following malignant transformation, so termed cancer stem cells (CSC), endowed with the same properties as SSC (i.e. the ability to both self‐renew and generate differentiated progenitors), play a major part in tumor initiation, therapy resistance and ultimately relapse. The same signaling pathways involved in regulating SSC maintenance are involved in the regulation of CSC. CSC exist in a wide array of tumor types, including leukemias, and brain, breast, prostate and colon tumors. Consequently, one of the key goals in cancer research over the past decade has been to develop therapeutic strategies to safely eliminate the CSC population without damaging the endogenous SSC population. A major hurdle to this goal lies in the identification of the key mechanisms that distinguish CSC from the normal endogenous tissue stem cells. This review will discuss the discovery of the specific CBP/catenin antagonist ICG‐001 and the ongoing clinical development of the second generation CBP/catenin antagonist PRI‐724. Importantly, specific CBP/catenin antagonists appear to have the ability to safely eliminate CSC by taking advantage of an intrinsic differential preference in the way SSC and CSC divide.
The same signaling pathways involved in regulating somatic stem cells (SSC) are also involved in the regulation of cancer stem cells (CSC). Consequently, one of the key goals in cancer research over the past decade has been to develop therapeutic strategies to safely eliminate the CSC population without damaging the endogenous SSC population. This review focusses on the discovery of specific CBP/catenin antagonists that appear to have the ability to safely eliminate CSCs by taking advantage of an intrinsic differential preference in the way SSCs and CSCs divide.
Learning Objectives
After completing this course, the reader will be able to:
Discuss the physiology of the different clinical hypersensitivity and infusion reactions to monoclonal antibodies and ...chemotherapy.
Select appropriate prevention and treatment strategies for hypersensitivity reactions.
Describe the differences between acquired and acute hypersensitivity reactions.
Background.
Like nearly all systemic cancer therapies, monoclonal antibodies are associated with hypersensitivity reactions. This article reviews the characteristics and management of hypersensitivity reactions to monoclonal antibodies and commonly used chemotherapy agents.
Methods.
MEDLINE was searched for recent studies and reviews pertaining to hypersensitivity reactions with monoclonal antibodies (cetuximab, rituximab, trastuzumab, panitumumab, bevacizumab), platinum compounds (carboplatin, oxaliplatin), and taxanes (paclitaxel, docetaxel). Emphasis was placed on articles that provided practical information on hypersensitivity reaction management. Data found in the literature were supplemented with information from the package insert for each agent.
Results.
Severe hypersensitivity reactions are rare, with an incidence of ≤5%, provided patients receive proper premedication, close monitoring, and prompt intervention when symptoms occur. Hypersensitivity reactions to platinum compounds are generally consistent with type 1 hypersensitivity, occurring after multiple cycles of therapy. Reactions to taxanes and monoclonal antibodies produce similar symptoms, but are generally immediate, occurring during the first few minutes of the first or second infusion. However, 10%–30% of reactions to monoclonal antibodies are delayed, and may occur in later infusions, indicating the importance of close observation of the patient following administration. Mild‐to‐moderate reactions can be managed by temporary infusion interruption, reduction of the infusion rate, and symptom management. Rechallenge should be considered after complete resolution of all symptoms. Severe reactions may require treatment discontinuation.
Conclusion.
Hypersensitivity or infusion reactions to platinum compounds are acquired; reactions to taxanes and monoclonal antibodies are immediate and typically occur during the first few minutes of the first infusion. The different time of onset should be considered when developing strategies for preventing and managing hypersensitivity reactions. The decision to rechallenge or discontinue treatment after a reaction occurs depends on the severity of the reaction and other clinical factors.
Disclosure of potential conflicts of interest is found at the end of this article.
TAS-102, a combination of trifluridine and tipiracil in which tipiracil interferes with the deactivation of trifluridine, improved overall and progression-free survival in patients whose disease had ...progressed after treatment with fluorouracil-containing drug combinations.
Fluoropyrimidines have long represented the cornerstone of treatment for colorectal cancer.
1
Such compounds act primarily as inhibitors of thymidylate synthase, the rate-limiting enzyme in the synthesis of pyrimidine nucleotides.
2
Fluorouracil has been combined with folinic acid (also known as leucovorin) to enhance the capacity of fluorouracil to bind to thymidylate synthase.
2
The addition of irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) to fluorouracil and folinic acid, in combination with either a vascular endothelial growth factor inhibitor (bevacizumab) or an epidermal growth factor inhibitor (e.g., cetuximab or panitumumab) if the tumor contains a wild-type
RAS
gene, represents contemporary standard therapy and has extended . . .
•Chemokines induce chemotaxis, promote differentiation of immune cells, and cause tissue extravasation.•The CXCL9, -10, -11/CXCR3 axis regulates immune cell migration, differentiation, and activation ...through paracrine axis.•The axis induces tumor growth and metastasis through autocrine axis.•Preclinical researches are defining the axis as a promising target for cancer treatment.•Other immune consistent pathways strongly crosslink with this axis.
Chemokines are proteins which induce chemotaxis, promote differentiation of immune cells, and cause tissue extravasation. Given these properties, their role in anti-tumor immune response in the cancer environment is of great interest. Although immunotherapy has shown clinical benefit for some cancer patients, other patients do not respond. One of the mechanisms of resistance to checkpoint inhibitors may be chemokine signaling. The CXCL9, -10, -11/CXCR3 axis regulates immune cell migration, differentiation, and activation, leading to tumor suppression (paracrine axis). However, there are some reports that show involvements of this axis in tumor growth and metastasis (autocrine axis). Thus, a better understanding of CXCL9, -10, -11/CXCR3 axis is necessary to develop effective cancer control. In this article, we summarize recent evidence regarding CXCL9, CXCL10, CXCL11/CXCR3 axis in the immune system and discuss their potential role in cancer treatment.
Metastatic colorectal carcinoma (mCRC) is a heterogeneous disease with differing outcomes and clinical responses and poor prognosis. CRCs can be characterised by their primary tumour location within ...the colon. The left-sided colon, derived from the hindgut, includes the distal third of the transverse colon, splenic flexure, descending colon, sigmoid colon and rectum. The right-sided colon, derived from the midgut, includes the proximal two-thirds of the transverse colon, ascending colon and caecum. Sometimes, the rectum is described separately, despite originating from the hindgut, and in many clinical series, the left-sided colon includes only tumours within and distal to the splenic flexure. Differences in the microbiome, clinical characteristics and chromosomal and molecular characteristics have been reported between the right and left side of the colon, regardless of how this is defined. There is now strong evidence from clinical studies in patients with mCRC for the prognostic effect of primary tumour location. The impact of primary colonic tumour location on response to treatment is now under investigation in a large number of clinical studies in patients with mCRC.
In this review, we summarise the microbiome, clinical, chromosomal and molecular differences associated with the primary location of CRC. We present an overview of the proven prognostic impact of primary tumour location for patients with mCRC and discuss emerging data for the predictive impact of primary tumour location on clinical outcome.
•Colorectal carcinomas (CRCs) can be characterised by primary tumour location within the colon and rectum.•Clinical, chromosomal and molecular features differ by primary tumour location.•Primary tumour location has a proven prognostic effect in patients with metastatic mCRC.•Primary CRC location may predict response to epidermal growth factor receptor inhibitors.
Worldwide, colorectal cancer has a higher incidence rate in men than in women, suggesting a protective role for sex hormones in the development of the disease. Preclinical data support a role for ...estrogen and its receptors in the initiation and progression of colorectal cancer and establishes that protective effects of estrogen are exerted through ERβ. Hormone replacement therapy (HRT) in postmenopausal women as well as consumption of soy reduces the incidence of colorectal cancer. In the Women's Health Initiative trial, use of HRT in postmenopausal women reduced the risk of colon cancer by 56% 95% confidence interval (CI), 0.38-0.81; P = 0.003. A recent meta-analysis showed that in women, consumption of soy reduced the risk of colon cancer by 21% (95% CI, 0.03-0.35; P = 0.026). In this review, using the preclinical data, we translate the findings in the clinical trials and observational studies to define the role of estrogen in the prevention of colorectal cancer. We hypothesize that sometime during the tumorigenesis process ERβ expression in colonocytes is lost and the estrogen ligand, HRT, or soy products, exerts its effects through preventing this loss. Thus, in the adenoma-to-carcinoma continuum, timing of HRT is a significant determinant of the observed benefit from this intervention. We further argue that the protective effects of estrogen are limited to certain molecular subtypes. Successful development of estrogen modulators for prevention of colorectal cancer depends on identification of susceptible colorectal cancer population(s). Thus, research to better understand the estrogen pathway is fundamental for clinical delivery of these agents.
Nivolumab received US Food and Drug Administration approval as a single agent or in combination with ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) ...metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on CheckMate 142. Presented are results of nivolumab plus low-dose ipilimumab in the first-line therapy cohort from the phase II CheckMate 142 study.
Patients with no prior treatment in the metastatic setting for MSI-H/dMMR CRC were treated with nivolumab every 2 weeks plus low-dose ipilimumab every 6 weeks until disease progression. The primary end point was objective response rate (investigator assessment; RECIST v1.1).
Median age of treated patients was 66 years (N = 45). Median follow-up was 29.0 months. Objective response rate and disease control rate were 69% (95% CI, 53 to 82) and 84% (95% CI, 70.5 to 93.5), respectively, with 13% complete response rate. Median duration of response was not reached; 74% of responders had ongoing responses at data cutoff. Median progression-free survival and median overall survival were not reached with minimum follow-up of 24.2 months (24-month rates, 74% and 79%, respectively). Clinical benefit was observed regardless of baseline demographic and tumor characteristics, including
or
mutation status. In a post hoc analysis, of 14 patients who discontinued treatment and did not receive subsequent therapy, 10 remained progression-free. Patient-reported outcomes were stable over the treatment period. Grade 3-4 treatment-related adverse events occurred in 22% of patients; 13% discontinued because of any-grade treatment-related adverse events.
Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated as a first-line treatment for MSI-H/dMMR mCRC. Based on these promising data, randomized studies are warranted.
The efficacy of immunotherapy varies widely among different gastrointestinal cancers. Response to immune checkpoint inhibitors is shown to correlate with tumor mutation load (TML), mismatch repair ...deficiency (dMMR) status, and programmed cell death-ligand 1 (PD-L1) expression. Herein, we quantify TML, dMMR, and PD-L1 expression and determine their interrelationship in gastrointestinal cancers. Here, a total of 4,125 tumors from 14 different gastrointestinal cancer sites were studied using validated assays. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor specimens using the NextSeq platform. TML was calculated using only somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Microsatellite instability (MSI) was assessed using direct analysis of altered known MSI loci in the target regions of the sequenced genes. PD-L1 expression was analyzed by IHC. Interestingly, right-sided colon and small-bowel adenocarcinomas had the highest prevalence of TML-high tumors (14.6% and 10.2%, respectively). Pancreatic neuroendocrine tumors and gastrointestinal stromal tumors had the lowest rates of TML-high (1.3% and 0%, respectively). TML-high was strongly associated with MSI-H (
< 0.0001). However, all TML-high anal cancers (8.3%) were microsatellite stable (MSS). Higher PD-L1 expression was more likely to be seen in MSI compared with MSS tumors (20.6% vs. 7.8%,
< 0.0001).
TML-high rate varied widely among gastrointestinal cancers. Although MSI is conceivably the main driver for TML-high, other factors may be involved. Future clinical trials are needed to evaluate whether the integration of TML, MSI, and PD-L1 could better identify potential responders to immunotherapy.
.
Microsatellite instability‐high (MSI‐H) and tumor mutational burden (TMB) are predictive biomarkers for immune‐checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of ...MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI‐H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592‐gene panel; a subset of MSI‐H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/MSH6 expression) and gene‐specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co‐expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P < .0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P < .0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P < .0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI.
What's new?
Immunotherapy based on checkpoint inhibitors shows promising results in a variety of cancer types, but still benefits a minority of patients. High microsatellite instability (MSI) and tumor mutational burden (TMB) have both been identified as biomarkers predictive of response to checkpoint inhibitors. Here, the authors investigated how the underlying causes of MSI influence TMB. Tumors lacking the mismatch repair protein duo MLH1/PMS2 had lower TMB than those lacking a different protein heterodimer, MLH2/MSH6. Even among tumors lacking the same mismatch repair proteins, the tissue of origin influenced mutational burden.
Exosomes are naturally occurring membranous vesicles secreted by various types of cells. Given their unique and important biological and pharmacological properties, exosomes have been emerging as a ...promising form of nanomedicine acting via efficient delivery of endogenous and exogenous therapeutics. Here we explore a new concept of utilizing endogenously derived exosomes as artificial controllers of cellular immunity to redirect and activate cytotoxic T cells toward cancer cells for killing. This was achieved through genetically displaying two distinct types of antibodies on exosomal surface. The resulting s ynthetic m ultivalent a ntibodies r e t argeted exo somes (SMART-Exos), which express monoclonal antibodies specific for T-cell CD3 and cancer cell-associated epidermal growth factor receptor (EGFR), were shown to not only induce cross-linking of T cells and EGFR-expressing breast cancer cells but also elicit potent antitumor immunity both in vitro and in vivo. This proof-of-concept study demonstrates a novel application of exosomes in cancer immunotherapy and may provide a general and versatile approach for the development of a new class of cell-free therapy.
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