Despite the acknowledged sex-related dimorphism in immune system response, little is known about the effect of patients' sex on the efficacy of immune checkpoint inhibitors as cancer treatments. We ...did a systematic review and meta-analysis to assess the heterogeneity of immune checkpoint inhibitor efficacy between men and women.
We systematically searched PubMed, MEDLINE, Embase, and Scopus, from database inception to Nov 30, 2017, for randomised controlled trials of immune checkpoint inhibitors (inhibitors of PD-1, CTLA-4, or both) that had available hazard ratios (HRs) for death according to patients' sex. We also reviewed abstracts and presentations from all major conference proceedings. We excluded non-randomised trials and considered only papers published in English. The primary endpoint was to assess the difference in efficacy of immune checkpoint inhibitors between men and women, measured in terms of the difference in overall survival log(HR) reported in male and female study participants. We calculated the pooled overall survival HR and 95% CI in men and women using a random-effects model, and assessed the heterogeneity between the two estimates using an interaction test.
Of 7133 studies identified in our search, there were 20 eligible randomised controlled trials of immune checkpoint inhibitors (ipilimumab, tremelimumab, nivolumab, or pembrolizumab) that reported overall survival according to patients' sex. Overall, 11 351 patients with advanced or metastatic cancers (7646 67% men and 3705 33% women) were included in the analysis; the most common types of cancer were melanoma (3632 32%) and non-small-cell lung cancer (3482 31%). The pooled overall survival HR was 0·72 (95% CI 0·65–0·79) in male patients treated with immune checkpoint inhibitors, compared with men treated in control groups. In women treated with immune checkpoint inhibitors, the pooled overall survival HR compared with control groups was 0·86 (95% CI 0·79–0·93). The difference in efficacy between men and women treated with immune checkpoint inhibitors was significant (p=0·0019).
Immune checkpoint inhibitors can improve overall survival for patients with advanced cancers such as melanoma and non-small-cell lung cancer, but the magnitude of benefit is sex-dependent. Future research should guarantee greater inclusion of women in trials and focus on improving the effectiveness of immunotherapies in women, perhaps exploring different immunotherapeutic approaches in men and women.
None.
Direct intralesional injection of specific or even generic agents, has been proposed over the years as cancer immunotherapy, in order to treat cutaneous or subcutaneous metastasis. Such treatments ...usually induce an effective control of disease in injected lesions, but only occasionally were able to demonstrate a systemic abscopal effect on distant metastases. The usual availability of tissue for basic and translational research is a plus in utilizing this approach, which has been used in primis for the treatment of locally advanced melanoma. Melanoma is an immunogenic tumor that could often spread superficially causing in-transit metastasis and involving draining lymph nodes, being an interesting model to study new drugs with different modality of administration from normal available routes. Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for intratumoral injection, that produces granulocyte-macrophage colony-stimulating factor (GM-CSF) and enhances local and systemic antitumor immune responses. After infection, selected viral replication happens in tumor cells leading to tumor cell lysis and activating a specific T-cell driven immune response. For this reason, a probable synergistic effect with immune checkpoints inhibition have been described. Pre-clinical studies in melanoma confirmed that T-VEC preferentially infects melanoma cells and exerts its antitumor activity through directly mediating cell death and by augmenting local and even distant immune responses. T-VEC has been assessed in monotherapy in Phase II and III clinical trials demonstrating a tolerable side-effect profile, a promising efficacy in both injected and uninjected lesions, but a mild effect at a systemic level. In fact, despite improved local disease control and a trend toward superior overall survival in respect to the comparator GM-CSF (which was injected subcutaneously daily for two weeks), responses as a single agent therapy have been uncommon in patients with visceral metastases. For this reason, T-VEC is currently being evaluated in combinations with other immune checkpoint inhibitors such as ipilimumab and pembrolizumab, with interesting confirmation of activity even systemically.
•Thymic epithelial tumors (TETs) are rare tumors.•TETs are genetically heterogeneous and the different histological subtypes of TETs harbor specific and distinctive molecular alterations.•Recent ...studies highlighted new data about the biology and pathogenesis of these tumors.•Immunotherapy and new targeted therapies showed promising efficacy in TETs.
In the last few years, meaningful advances have been made in the knowledge of the biology of Thymic Epithelial Tumors (TETs).
Data available suggest that in most cases, the different histological subtypes could be distinct biological entities, characterized by specific molecular aberrations, rather than representing a histological continuum of diseases.
Recurrent gene mutations in Thymomas and Thymic Carcinoma have been identified, but we still do not know the exact role played by these mutations in TETs pathogenesis.
Relevant new data are now available on the pathogenetic mechanisms underlying the association between TETs and autoimmune diseases that warrant further investigations for the potential therapeutic implications.
The progress in knowledge of the molecular pathways involved in TETs pathogenesis, allowed to identify and to test target therapies potentially active in such diseases.
Platinum-based chemotherapy remains the standard first line treatment for patients with advanced or metastatic TETs.
However, some promising data have been reported on the activity of new target therapies, including anti-angiogenic drugs, Cycline Dependent Kinases and PI3K/mTOR inhibitors, as well as of Immune-checkpoint inhibitors.
A number of new drugs and combinations are currently under evaluation.
The efficacy of new drugs should be balanced with their toxicity profiles, in such complex patients that seem to be more susceptible to develop drug-related toxicities, in particular with immunotherapies.
Abstract
Background
We previously showed that therapy with anti–checkpoints T-lymphocyte-associated protein 4 (anti–CTLA-4) or antiprogrammed cell death protein 1 (anti–PD-1) agents was more ...effective for men as compared with women. However, because the sex-dimorphism of the immune system is complex, involving multiple elements of immune responses, it is possible that women could derive larger benefit than men from strategies other than therapy with immune checkpoint inhibitors (ICIs) alone. Here we investigated whether women could derive larger benefit than men from the combination of chemotherapy and anti-PD-1 or anti-PD-L1.
Methods
We performed two meta-analyses. The first included all randomized controlled trials (RCTs) testing anti-PD1 and anti–PD-L1 plus chemotherapy vs chemotherapy to assess different efficacy between men and women. The second included all RCTs of first-line systemic treatment in advanced non-small cell lung cancer testing anti–PD-1/PD-L1 given either alone or combined with chemotherapy to assess the different efficacy of these two immunotherapeutic strategies according to patients’ sex. For each RCT included in the two meta-analyses, first, a trial-specific ratio of hazard ratios (HRs) was calculated from the ratio of the reported hazard ratios in men and in women; second, these trial-specific ratios of hazard ratios were combined across trials using a random-effects model to obtain a pooled hazard ratios ratio. A pooled HRs ratio estimate lower than 1 indicates a greater treatment effect in men, and higher than 1 a greater effect in women.
Results
Eight RCTs were included in the first meta-analysis. The pooled overall survival hazard ratios (OS-HRs) comparing anti–PD-1/PD-L1 plus chemotherapy vs chemotherapy was 0.76 (95% confidence interval CI = 0.66 to 0.87) for men and 0.48 (95% CI = 0.35 to 0.67) for women. The pooled ratio of the overall survival hazard ratios reported in men vs women was 1.56 (95% CI = 1.21 to 2.01), indicating a statistically significant greater effect for women. Six RCTs were included in the second meta-analysis: three tested an anti-PD-1 alone, whereas three RCTs tested anti-PD-1/PD-L1 plus chemotherapy. The pooled overall survival hazard ratios were 0.78 (95% CI = 0.60 to 1.00) in men and 0.97 (95% CI = 0.79 to 1.19) in women for anti–PD-1 alone, compared with 0.76 (95% CI = 0.64 to 0.91) in men and 0.44 (95% CI = 0.25 to 0.76) in women for anti–PD-1/PD-L1 plus chemotherapy. The pooled ratio of overall survival hazard ratios was 0.83 (95% CI = 0.65 to 1.06) for anti–PD-1 alone, indicating a greater effect in men, and 1.70 (95% CI = 1.16 to 2.49) for anti–PD-1/PD-L1 plus chemotherapy, indicating a greater effect in women.
Conclusion
Women with advanced lung cancer derived a statistically significantly larger benefit from the addition of chemotherapy to anti–PD-1/PD-L1 as compared with men.
The histone demethylase LSD1 is over-expressed in hematological tumors and has emerged as a promising target for anticancer treatment, so that several LSD1 inhibitors are under development and ...testing, in preclinical and clinical settings. However, the complete understanding of their complex mechanism of action is still unreached. Here, we unraveled a novel mode of action of the LSD1 inhibitors MC2580 and DDP-38003, showing that they can induce differentiation of AML cells through the downregulation of the chromatin protein GSE1. Analysis of the phenotypic effects of GSE1 depletion in NB4 cells showed a strong decrease of cell viability in vitro and of tumor growth in vivo. Mechanistically, we found that a set of genes associated with immune response and cytokine-signaling pathways are upregulated by LSD1 inhibitors through GSE1-protein reduction and that LSD1 and GSE1 colocalize at promoters of a subset of these genes at the basal state, enforcing their transcriptional silencing. Moreover, we show that LSD1 inhibitors lead to the reduced binding of GSE1 to these promoters, activating transcriptional programs that trigger myeloid differentiation. Our study offers new insights into GSE1 as a novel therapeutic target for AML.
We previously demonstrated that sex influences response to immune checkpoint inhibitors. In this article, we investigate sex-based differences in the molecular mechanisms of anticancer immune ...response and immune evasion in patients with NSCLC.
We analyzed (i) transcriptome data of 2,575 early-stage NSCLCs from seven different datasets; (ii) 327 tumor samples extensively characterized at the molecular level from the TRACERx lung study; (iii) two independent cohorts of 329 and 391 patients, respectively, with advanced NSCLC treated with anti-PD-1/anti-PD-L1 drugs.
As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune checkpoint molecules, and higher abundance of immune-suppressive cells, including cancer-associated fibroblasts, MDSCs, and regulatory T cells. In contrast, the TME of males was significantly enriched for a T-cell-excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti-PD-1/PD-L1 drugs.
We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men.
Exportin 1 (XPO1) mediates nuclear export of many cellular factors known to play critical roles in malignant processes, and selinexor (KPT-330) is the first XPO1-selective inhibitor of nuclear export ...compound in advanced clinical development phase for cancer treatment. We demonstrated here that inhibition of XPO1 drives nuclear accumulation of important cargo tumor suppressor proteins, including transcription factor FOXO3a and p53 in thymic epithelial tumor (TET) cells, and induces p53-dependent and -independent antitumor activity
Selinexor suppressed the growth of TET xenograft tumors in athymic nude mice via inhibition of cell proliferation and induction of apoptosis. Loss of p53 activity or amplification of XPO1 may contribute to resistance to XPO1 inhibitor in TET. Using mass spectrometry-based proteomics analysis, we identified a number of proteins whose abundances in the nucleus and cytoplasm shifted significantly following selinexor treatment in the TET cells. Furthermore, we found that XPO1 was highly expressed in aggressive histotypes and advanced stages of human TET, and high XPO1 expression was associated with poorer patient survival. These results underscore an important role of XPO1 in the pathogenesis of TET and support clinical development of the XPO1 inhibitor for the treatment of patients with this type of tumors.
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We explored the outcomes of germline
pathogenic/likely pathogenic variants (PVs/LPVs) in the endocrine-sensitive disease treated with first-line standard of care cyclin-dependent kinase 4/6 (CDK4/6) ...inhibitors. Three studies retrospectively showed a reduction in the overall survival (OS) and progression-free survival (PFS) in g
m patients compared to both the germinal
wild type (g
wt) and the untested population. Regarding the efficacy of PI3Kα inhibitors, there are no subgroups or biomarker analyses in which germinal BRCA status was explored. However, the biological interactions between the PIK3CA/AKT/mTOR pathway and
at a molecular level could help us to understand the activity of these drugs when used to treat BC in
PVs/LPVs carriers. The efficacy of trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC) targeting HER2 for HER2-low and HER2-positive (HER2+) BC, has been increasingly described. Unfortunately, data on T-DXd in HER2+ or HER2-low metastatic BC harboring germinal
PVs/LPVs is lacking. Including germinal
status in the subgroup analysis of the registration trials of this ADC would be of great interest, especially in the phase III trial DESTINY-breast04. This trial enrolled patients with HER2-negative (HER2-) and both HR+ and HR- metastatic disease, which can now be categorized as HER2-low. The HER2-low subgroup includes tumors that were previously classified as triple negative, so it is highly likely that some women were germline
PVs/LPVs carriers and this data was not reported. Germline
status will be available for a higher number of individuals with BC in the near future, and data on the prognostic and predictive role of these PVs/LPVs is needed in order to choose the best treatment options.
Metastatic vulvar melanoma is a rare and aggressive disease and survival is usually poor. Vulvar melanomas harbor BRAF V600 mutations only infrequently; consequently, target therapy is a rare ...therapeutic option and immunotherapy usually has only a weak effect. On the other hand, KIT mutations are rare in cutaneous melanomas, but relatively frequent in mucosal melanomas, particularly in vulvar-vaginal melanomas, and can be a therapeutic target. Herein, we report a clinical case of a patient with metastatic vulvar melanoma, harboring an exon 17 c-KIT mutation, treated with avapritinib (BLU-285) – a highly potent and selective oral kinase inhibitor designed to treat imatinib-resistant gastro-intestinal stromal tumors (GIST) by targeting KIT/PDGFRα activation loop mutants (exons 17/18). After failure of the combination of ipilimumab + nivolumab first and then nivolumab alone, the patient received avapritinib 300 mg/daily for central nervous system (CNS), lymph-nodal, right adrenal gland, lung, and subcutaneous metastases. Best response was partial remission, according to RECIST 1.1 criteria. Time to treatment progression was 11 months. Main toxicities were grade 2 cutaneous vasculitis that required avapritinib discontinuation, and grade 2 uveitis of unknown origin, treated by vitrectomy and empiric antibiotic and antiviral therapy due to negative cultural tests. Uveitis was detected at the time of progression and therapy was definitively discontinued. In conclusion, avapritinib proved to be effective even in the presence of a pretreated disease, a high tumor burden, and brain metastases. In our experience, treatment was feasible and toxicity manageable. Considering the lack of effective therapies and the poor outcome of the disease, determination of c-KIT mutations should be performed routinely in cases of metastatic mucosal melanoma.
To provide evidence explaining the poor association between pCR and patients’ long-term outcome at trial-level in neoadjuvant RCTs for breast cancer (BC), we performed a systematic-review and ...meta-analysis of all RCTs testing neoadjuvant treatments for early-BC and reporting the hazard ratio of DFS (HRDFS) for the intervention versus control arm stratified by pathological response type (i.e., pCR yes versus no).
The objective was to explore differences of treatment effects on DFS across patients with and without pCR.
We calculated the pooled HRDFS in the two strata of pathological response (i.e., pCR yes versus no) using a random-effects model, and assessed the difference between these two estimates using an interaction test.
Ten RCTs and 8496 patients were included in the analysis.
Patients obtaining pCR in the intervention-arm had a higher, although not statistically significant, risk of DFS-event as compared with patients obtaining pCR in the control-arm: the pooled HRDFS for the experimental versus control arm was 1.23 (95%CI, 0.91–1.65). On the opposite, the risk of DFS-event was higher for control as compared with the intervention-arm in the stratum of patients without pCR: the pooled HRDFS was 0.86 (95%CI, 0.78–0.95).
Treatment effect on DFS was significantly different according to pathological response type (interaction test p: 0.014).
We reported new evidence that contributes to explaining the poor surrogacy value of pCR at trial-level in neoadjuvant RCTs for early-BC.
•Pathological complete response (pCR) has been shown to be associated with long-term outcome at patient level but not at trial-level in neoadjuvant RCTs for breast cancer (BC).•One explanation could be that new neoadjuvant treatment regimens achieving substantially higher pCR rates might exert a dissociated effect on primary tumors versus micrometastases.•In this meta-analysis of recent RCTs testing neoadjuvant treatments for early-BC patients, there was a numerically higher risk of DFS-event for patients obtaining pCR in the intervention-arm as compared with those obtaining pCR in the control-arm.•On the opposite, the risk of DFS-event was higher for control as compared with the intervention-arm in the stratum of patients without pCR.
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