Search

Tregs are able of suppressing tumor-specific effector cells, such as lymphocytes CD8+, CD4+ and Natural Killer cells. Different drugs, especially different schedules of administration, like metronomic chemotherapy (mCHT), seem to be able to increase anticancer immunity, by acting on downregulation of Tregs. Most of the data available regarding the immunomodulating effect of mCHT have been obtained with Cyclophosphamide (CTX). Aim of the present study was to explore the effects of mVRL and mCAPE administration, alone or in combination, on T cells. Observation of 13 metastatic breast cancer patients lasted controlling for 56 days, where Treg frequencies and function, spontaneous anti-tumor T-cell responses were monitored, as well as the clinical outcome. No depletion in Treg absolute numbers, or percentage of T lymphocytes, was observed. Only in 5 patients, a modest and transient depletion of Tregs was observed during the first 14 days of treatment. To better describe the effect on Tregs, we subsequently looked at the variations in Memory, Naïve and Activated Treg subpopulations: we observed a trend in reduction for memory Treg (Treg MEM) and an increase for Treg Naïve (Treg NAIVE) and Treg Activated (Treg ACT) components. We finally analyzed the average trend of Treg in the Treg depleted patients and non-depleted ones, without fiding any significant differences. The trend of the Treg MEM appeared different, showing a reduction during the first 14 days, followed by an increase at the levels before treatment at Day 56 in the group of depleted patients and a progressive substantial reduction in the group of non-depleted patients along the entire course of treatment. Opposed to the data known, treatment with mVRL w/o mCAPE did not show any effect on Tregs.

Additional file 1.

Backgrounds Healthy volunteers play a key role in clinical trials and it is crucial to develop recruitment strategies that capitalise on their motivations and maximise their participation. The COVID-19 pandemic has shown the importance of finding motivated healthy volunteers for the development of new vaccines. Public registers represent a promising way to promote the participation of healthy volunteers in the research field, but their adoption is still limited. The current study aimed to explore the motivations of healthy volunteers to enrol in an Italian public register for clinical trials during the COVID-19 pandemic and their attitude toward participating in a phase 1 COVID-19 vaccine clinical trial. The impacts of different enrolling interview modalities (in person, by phone, by mail) on motivation, understanding of information and trust in researchers were also investigated. Methods An online survey investigating experience with COVID-19, motivations to enrol, trust in researchers, political and healthcare authorities and pharmacological companies was presented to people applying as healthy volunteers in the public register for clinical trials at Phase 1 Unit Research Centre of ASST Monza, Italy, and considering to participate in a COVID-19 vaccine clinical trial. Data were collected in June 2021. Results Altruistic motivations were the main driver for enrolling in the public register, while self-interested motivations were secondary. No gender differences were found. As for enrolling modalities, no differences emerged between in-person and interviews for motivation to enrol, understanding of information and trust in researchers. Email modality led to significantly lower volunteers’ satisfaction and understanding of information but similar trust in research. Conclusions This study supports the validity of different interview modalities (in person and by phone) for the enrolment of healthy volunteers for clinical trials and highlights the positive role of public registers for the recruitment procedures.

Background What leads healthy people to enter in a volunteer register for clinical trials? This study aimed to investigate the relationship between the decision to volunteer in clinical trials for a COVID-19 vaccine and social capital, in a sample of healthy volunteers in Italy. Since social capital is characterized by trust, reciprocity, and social and political participation, we claim that it is key in leading individuals to actively take action to protect public health, and to take a risk for the (potential) benefit not only of themselves but for the entire community. Methods This study was conducted through the administration of a questionnaire to healthy volunteers registered for a phase 1 clinical trial for a COVID-19 vaccine in the Unit Research Centre of ASST-Monza, in September 2020. The primary purpose of a phase 1 study is to evaluate the safety of a new drug candidate before it proceeds to further clinical studies. To approximate a case–control study, we randomly matched the 318 respondents to healthy volunteers (cases) with 318 people randomly selected by Round 9 of the European Social Survey (controls), using three variables, which we considered to be associated with the decision to volunteer: gender, age, and education level. To execute this matching procedure, we used the “ccmatch” module in STATA. Results The findings highlight the positive impact of social capital in the choice of healthy individuals to volunteer in COVID-19 vaccine clinical trials. Controlling for possible confounding factors, some exemplary results show that people with a high level of general trust have a greater likelihood of volunteering compared to people with low trust (OR = 2.75, CI = 1.58–4.77); we also found that it is more probable that volunteers are people who have actively taken action to improve things compared with people who have not (for individuals who did three or more actions: OR = 7.54, CI = 4.10–13.86). People who reported voting (OR = 3.91, CI = 1.70–8.99) and participating in social activities more than other people of their age (OR = 2.89, CI = 1.82–4.60) showed a higher probability to volunteer. Conclusions Together with the adoption of urgent health measures in response to COVID-19, government policymakers should also promote social capital initiatives to encourage individuals to actively engage in actions aimed at protecting collective health. Our findings make an empirical contribution to the research on vaccines and its intersection with social behaviour, and they provide useful insights for policymakers to manage current and future disease outbreaks and to enhance the enrolment in vaccine trials.

Metronomic chemotherapy (mCHT), defined as continuous administration of low-dose chemotherapeutic agents with no or short regular treatment-free intervals, was first introduced to the clinic in international guidelines in 2017, and, since then, has become one of the available strategies for the treatment of advanced breast cancer (ABC). Despite recent successes, many unsolved practical and theoretical issues remain to be addressed. The present review aims to identify the “lights and shadows” of mCHT in preclinical and clinical settings. In the preclinical setting, several findings indicate that one of the most noticeable effects of mCHT is on the tumor microenvironment, which, over the last twenty years, has been demonstrated to be pivotal in supporting tumor cell survival and proliferation. On the other hand, the direct effects on tumor cells have been less well-defined. In addition, critical items to be addressed are the lack of definition of an optimal biological dose (OBD), the method of administration of metronomic schedules, and the recognition and validation of predictive biomarkers. In the clinical context—where mCHT has mainly been used in a metastatic setting—low toxicity is the most well-recognised light of mCHT, whereas the type of study design, the absence of randomised trials and uncertainty in terms of doses and drugs remain among the shadows. In conclusion, growing evidence indicates that mCHT is a suitable treatment option for selected metastatic breast cancer (MBC) patients. Moreover, given its multimodal mechanisms of action, its addition to immunological and targeted therapies might represent a promising new approach to the treatment of MBC. More preclinical data are needed in this regard, which can only be obtained through support for translational research as the key link between basic science and patient care.

Triple-negative breast cancer—defined by the absence of oestrogen/progesterone receptors and human epidermal growth factor receptor 2 expression—is a complex and heterogeneous type of tumour characterised by poor prognosis, aggressive behaviour and lack of effective therapeutic strategies. The identification of new biomarkers and molecular signatures is leading to development of new therapeutic strategies including immunotherapy, targeted therapy and antibody-drug conjugates (ADCs). Against a background where chemotherapy has always been considered the standard of care, evolution towards a precision medicine approach could improve TNBC clinical practice in a complex scenario, with many therapeutic options and new drugs. The aim of this review was to focus on emerging therapeutic targets and their related specific therapy, discussing available and emerging drugs, underlining differences in approval by American and European regulatory authorities and showing the future perspective in the large number of ongoing clinical trials.

CDK4/6 inhibitors in association with endocrine therapy represent the best therapeutic choice for either endocrine-sensitive or resistant hormone-receptor-positive advanced breast cancer patients. On the contrary, the optimal therapeutic strategy after the failure of CDK4/6 inhibitors-based treatment still remains an open question worldwide. In this review, we analyze the most studied mechanisms of resistance to CDK4/6 inhibitors treatment, as well as the most significant results of retrospective and prospective trials in the setting of progression after CDK4/6 inhibitors, to provide the reader a comprehensive overview from both a preclinical and especially a clinical perspective. In our opinion, an approach based on a deeper knowledge of resistance mechanisms to CDK4/6 inhibitors, but also on a careful analysis of what is done in clinical practice, can lead to a better definition of prospective randomized trials, to implement a personalized sequence approach, based on molecular analyses.

Background Tumor microenvironment (TME) is a dynamic setting and changes in TILs and their subpopulations are potential candidates to influence the metastatic process. Aim of this pilot study is to describe the changes occurring between primary breast cancers and their paired metastases in terms of TILs composition. To assess if these changes influence the process of metastasis development, we used a control group of patients. Methods We retrospectively identified 18 Luminal patients, for whom primary and metastatic tissue were available (cases) and 18 paired-matched patients (controls), not relapsed after at least 9 years of follow-up, and we quantified TILs and their composition (i.e. T CD8+ and CD4+/FOXP3+). The presence of TILs was defined as ≥10%. Results Our results showed that the microenvironment composition of relapsed patients was poor of TILs (median = 5%, I-III quartiles = 0.6–5%), CD8+ (2.5%, 0–5%) and CD4+/FOXP3 + (0%, 0–0.6%) in the primary tumor. Comparable results were observed in their related metastases (TILs 3.8%, 0.6–5%; CD8+ 0%, 0–1.3%; CD4+/FOXP3+ 0%,0–1.9%). On the contrary, the microenvironment in the control group was richer of TILs (5%, 5–17.5%) in comparison to cases, both in primary tumor (p = 0.035) and related metastases (p = 0.018). Although CD8+ in controls were similar to cases at primary tumor (p = 0.6498), but not at metastasis (p = 0.0223), they expressed only one part on the TILs subpopulations (p = 0.0060), while TILs in the cases at primary tumor were almost completely CD8+ (p = 0.5034). Conclusions These findings suggest that the lack of activation of immune system in the primary tumor might influence the multifactor process of cancer progression.

Purpose Elderly patients with metastatic breast cancer are expected to derive similar benefits from chemotherapy as younger patients, but are more likely to experience therapy-related toxicity. Data from the VICTOR-1 study showed that metronomic therapy with vinorelbine and capecitabine was effective and well tolerated in patients with metastatic breast cancer. This analysis determined the efficacy and safety of the metronomic combination of oral vinorelbine and capecitabine in a subgroup of VICTOR-1 study patients aged ≥70 years. Methods Eighteen of the 32 patients enrolled in VICTOR-1 were aged ≥70 years. Objective response and clinical benefit rates were calculated and toxicity was determined using the NCI-CTCAE criteria. Results All patients had at least 1 comorbidity (4 had 2 comorbidities), and 77.7% were taking concomitant medication. Eight patients (44%) had received ≥1 chemotherapy regimens for metastatic disease and most (78%) had ≥2 metastatic sites. Grade 1-2 adverse events occurred in 45.8% of cycles, whereas the incidence of grade 3 and grade 4 events was very low (1.5% and 0.7%, respectively). Median time to progression was 10.5 months (range 1-40). The objective response rate was 33% and the clinical benefit rate was 67%. Conclusions The all-oral metronomic combination of vinorelbine and capecitabine had an acceptable efficacy profile and appears to be better tolerated than standard treatment schedules in elderly metastatic breast cancer patients (age ≥70 years).

Non-small-cell lung cancer is still considered a difficult disease to manage because of its aggressiveness and resistance to common therapies. Chemotherapy remains the gold standard in nearly 80% of lung cancers, but clinical outcomes are discouraging, and the impact on median overall survival (OS) barely reaches 12 months. At the end of the last century, the discovery of oncogene-driven tumours completely changed the therapeutic landscape in lung cancers, harbouring specific gene mutations/translocations. Epidermal growth factors receptor (EGFR) common mutations first and anaplastic lymphoma kinase (ALK) translocations later led new insights in lung cancer biology knowledge. The use of specific tyrosine kinases inhibitors overturned the biological behaviour of EGFR mutation positive tumours and became a preclinical model to understand the heterogeneity of lung cancers and the mechanisms of drug resistance. In this review, we summarise the employment of targeted agents against the most representative biomolecular alterations and provide some criticisms of the therapeutic strategies.