Tyrosine kinase inhibitors in sarcoma treatment.

Sarcomas are a group of rare mesenchymal malignant tumors that arise from transformed cells of the mesenchymal connective tissue, which are challenging to treat. The majority of sarcomas are soft tissue sarcomas (STSs; 75%) and this heterogeneous group of tumors is further comprised of gastrointestinal stromal tumors (~15%) and bone sarcomas (10%). Although surgery remains the current primary therapeutic approach for localized disease, recurrent, metastatic and refractory sarcomas require cytotoxic chemotherapy, which usually yields poor results. Therefore the efficiency of sarcoma treatment imposes a difficult problem. Furthermore, even though progress has been made towards understanding the underlying molecular signaling pathways of sarcoma, there are limited treatment options. The aim of the present study was therefore to perform a systematic literature review of the available clinical evidence regarding the role of tyrosine kinase inhibitors (TKIs) in patients with recurrent or refractory STSs and bone sarcomas over the last two decades. Tyrosine kinases are principal elements of several intracellular molecular signaling pathways. Deregulation of these proteins has been implicated in driving oncogenesis via the crosstalk of pivotal cellular signaling pathways and cascades, including cell proliferation, migration, angiogenesis and apoptosis. Subsequently, small molecule TKIs that target these proteins provide a novel potential therapeutic approach for several types of tumor by offering significant clinical benefits. Among the eligible articles, there were 45 prospective clinical trials, primarily multicentric, single arm, phase II and non-randomized. Numerous studies have reported promising results regarding the use of TKIs, mainly resulting in disease control in patients with STSs. The lack of randomized clinical trials demonstrates the ambiguous efficiency of various studied treatment options, which therefore currently limits the approved drugs used in clinical practice. Research both in clinical and preclinical settings is needed to shed light on the underlying molecular drivers of sarcomagenesis and will identify novel therapeutic approaches for pretreated patients.

Systematic Review of Recurrent Osteosarcoma Systemic Therapy.

Osteosarcoma is the most frequent primary bone cancer, mainly affecting those of young ages. Although surgery combined with cytotoxic chemotherapy has significantly increased the chances of cure, recurrent and refractory disease still impose a tough therapeutic challenge. We performed a systematic literature review of the available clinical evidence, regarding treatment of recurrent and/or refractory osteosarcoma over the last two decades. Among the 72 eligible studies, there were 56 prospective clinical trials, primarily multicentric, single arm, phase I or II and non-randomized. Evaluated treatment strategies included cytotoxic chemotherapy, tyrosine kinase and mTOR inhibitors and other targeted agents, as well as immunotherapy and combinatorial approaches. Unfortunately, most treatments have failed to induce objective responses, albeit some of them may sustain disease control. No driver mutations have been recognized, to serve as effective treatment targets, and predictive biomarkers of potential treatment effectiveness are lacking. Hopefully, ongoing and future clinical and preclinical research will unlock the underlying biologic mechanisms of recurrent and refractory osteosarcoma, expanding the therapeutic choices available to pre-treated osteosarcoma patients.

Immunotherapy in Nonendemic Nasopharyngeal Carcinoma: Real-World Data from Two Nonendemic Regions.

BACKGROUND: nasopharyngeal carcinoma (NPC) is a complex disease entity that mainly predominates in endemic regions. Real-world data with immunotherapy from nonendemic regions are limited. METHODS: we collected data from patients with recurrent/metastatic (R/M) NPC treated at a center in Greece and 8 centers in Italy. Between 2016 and 2021, 46 patients who were treated with at least one cycle of immune checkpoint inhibitors (ICI) were identified. Herein, we present our results and a review of the literature. RESULTS: assessment of response was available in 42 patients. Overall, 11 patients responded to immunotherapy (Overall Response Rate-ORR 26.2%). Three patients had complete response (CR), and 8 patients had partial response (PR). Disease control rate (DCR) was 61.9%. Median Progression Free Survival (PFS) was 5.6 months and median Overall Survival (OS) was 19.1 months. Responders to ICI improved PFS and OS as compared to that of nonresponders. A lower probability of responding to ICI was shown in patients with more than three metastatic sites (p = 0.073), metastatic disease at initial diagnosis, (p = 0.039) or EBV DNA positive before ICI initiation, (p = 0.074). Decline in EBV DNA levels was found to be statistically significant associated with best response to ICI (p = 0.049). Safety was manageable. CONCLUSIONS: among 46 patients with R/M NPC treated with immunotherapy in two nonendemic regions, ORR was 26.2% and durable responses were observed. Low disease burden could serve as a biomarker for response to ICI.

Prognostic Biomarkers in Early-stage Gastric Adenocarcinoma Treated With Adjuvant Chemoradiotherapy.

BACKGROUND/AIM: Early-stage gastric cancer has a high risk of recurrence, despite trimodality therapy with surgery, chemotherapy and radiation. To improve patient selection for adjuvant chemoradiotherapy, we evaluated the prognostic significance of immunohistochemical and genetic biomarkers in patients with resected gastric adenocarcinoma. PATIENTS AND METHODS: Tumors from 119 patients were subjected to immunohistochemistry for 12 protein biomarkers, as well as next-generation sequencing. Clinical and biomarker data were available for 91 patients. RESULTS: EBV-positive tumors and tumors with mutations had higher intratumoral CD8 tumor-infiltrating lymphocyte density (p=0.009 and p=0.017, respectively). PIK3CA mutations were correlated with VEGFA overexpression (p=0.042), while KRAS mutations and HER2 expression were mutually exclusive (p=0.036). PTEN expression univariately confirmed longer overall survival (HR=0.27; p=0.046), while there was a trend between the presence of KRAS mutations and inferior disease-free and overall survival. CONCLUSION: PTEN protein expression and KRAS mutations may predict disease outcome in early-stage gastric cancer. These results need to be further validated in larger cohorts.

Programmed death 1 regulates memory phenotype CD4 T cell accumulation, inhibits expansion of the effector memory phenotype subset and modulates production of effector cytokines.

Memory phenotype CD4 T cells are found in normal mice and arise through response to environmental antigens or homeostatic mechanisms. The factors that regulate the homeostasis of memory phenotype CD4 cells are not clear. In the present study we demonstrate that there is a marked accumulation of memory phenotype CD4 cells, specifically of the effector memory (T(EM)) phenotype, in lymphoid organs and tissues of mice deficient for the negative co-stimulatory receptor programmed death 1 (PD-1). This can be correlated with decreased apoptosis but not with enhanced homeostatic turnover potential of these cells. PD-1 ablation increased the frequency of memory phenotype CD4 IFN-γ producers but decreased the respective frequency of IL-17A-producing cells. In particular, IFN-γ producers were more abundant but IL-17A producing cells were more scarce among PD-1 KO T(EM)-phenotype cells relative to WT. Transfer of peripheral naïve CD4 T cells suggested that accumulated PD-1 KO T(EM)-phenotype cells are of peripheral and not of thymic origin. This accumulation effect was mediated by CD4 cell-intrinsic mechanisms as shown by mixed bone marrow chimera experiments. Naïve PD-1 KO CD4 T cells gave rise to higher numbers of TEM-phenotype lymphopenia-induced proliferation memory cells. In conclusion, we provide evidence that PD-1 has an important role in determining the composition and functional aspects of memory phenotype CD4 T cell pool.

Programmed death-1 shapes memory phenotype CD8 T cell subsets in a cell-intrinsic manner.

Memory phenotype T cells, found in unimmunized mice, display phenotypic and functional traits of memory cells and provide essential protection against infections, playing a role in both innate and adaptive immune responses. Mechanisms governing homeostasis of these memory phenotype T cells remain ill-defined. In this study, we reveal a crucial role of the negative costimulator programmed death-1 (PD-1) in regulating developmental fates of memory phenotype cells. Thus, in lymphoid organs and tissues of PD-1 knockout (KO) mice a marked accumulation of functional effector memory (T(EM)) phenotype CD8 T cells was observed. T(EM) phenotype cells from PD-1 KO mice exhibit decreased proliferation but increased survival potential. These cells could produce effector molecules constitutively, in response to phorbol esters or through bystander activation by innate stimuli. Similarly, in lymphopenia-induced proliferating CD8 T cells, whereby normally naive T cells acquire a memory phenotype, skewing toward a T(EM) phenotype was prominent in the absence of PD-1. Acquisition of the T(EM) phenotype was a CD8 T cell-intrinsic phenomenon as demonstrated by mixed bone marrow transfer experiments. Importantly, adoptively transferred PD-1 KO CD8 central memory T (T(CM)) cells converted into the T(EM) phenotype, indicating that PD-1 sets a major checkpoint in the T(CM) to T(EM) phenotype differentiation process. This was reflected by distinct patterns of gene expression of PD-1 KO T(CM) phenotype cells revealed by global transcriptional analysis. Additionally, adoptively transferred PD-1 KO T(EM) phenotype cells converted to a lesser degree to a T(CM) phenotype. Collectively, these data suggest that PD-1 shapes memory phenotype CD8 T cell subsets.

T cells as sources and targets of TNF: implications for immunity and autoimmunity.

TNF is a pleiotropic cytokine produced by many cell types upon different stimuli and in various physiological and pathological conditions. In this review, we focus on the role of TNF in T cell responses as demonstrated by in vitro and in vivo observations in mice and humans. TNF has an impact on all aspects of T cell biology such as development in the thymus, peripheral homeostasis, primary antigenic responses, apoptosis, effector functions, memory cell formation and tolerance induction and maintenance. In most cases, TNF has an immunostimulatory role in T cell responses; however, under certain conditions, TNF can exert immunomodulatory effects on T cells. We also review how T cell-derived TNF is an important component of T cell immunity as exemplified by many studies involving intracellular pathogens and tumors. Finally, we summarize how TNF T cells interplay contributes to pathology in autoimmune disorders and what is known about the effect of widely used TNF blockers on T cell differentiation/function.

An essential role for TNF in modulating thresholds for survival, activation, and tolerance of CD8+ T cells.

TNF and its receptors p55 and p75 are known to be important in the homeostasis of the peripheral immune system. Previous studies have presented apparently contradictory evidence for an in vivo role of TNF in T cells. In this study, we analyzed TNF-deficient mice crossed with the F5 TCR-transgenic animals. We show that endogenous TNF modulates several aspects of homeostasis of peripheral F5 CD8 T cells. We found that F5/TNF(-/-)mice had reduced numbers of peripheral F5 T cells, F5/TNF(-/-) CD8 T cells exhibited reduced survival potential, and furthermore that T cell-derived TNF is required for optimum recovery of naive CD8 T cells in lymphopenic hosts, suggesting its involvement in the survival of peripheral CD8 T cells. Both peptide activation and ensuing Ag-induced apoptosis are quantitatively reduced in TNF(-/-) CD8 T cells. The latter observations can be related to decreased binding activities of NF-kappaB and NF-ATp observed in Ag-stimulated F5/TNF(-/-) T cells. Finally, in a CD8 T cell tolerance model, endogenous TNF was necessary for several parameters of CD8 T cell tolerance induction. Collectively, our results provide evidence that endogenous TNF modulates thresholds in several ligand-driven T cell responses.