A first-in-human trial on the safety and immunogenicity of COVID-eVax, a cellular response-skewed DNA vaccine against COVID-19.

The COVID-19 pandemic and the need for additional safe, effective, and affordable vaccines gave new impetus into development of vaccine genetic platforms. Here we report the findings from the phase 1, first-in-human, dose-escalation study of COVID-eVax, a DNA vaccine encoding the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Sixty-eight healthy adults received two doses of 0.5, 1, or 2 mg 28 days apart, or a single 2-mg dose, via intramuscular injection followed by electroporation, and they were monitored for 6 months. All participants completed the primary safety and immunogenicity assessments after 8 weeks. COVID-eVax was well tolerated, with mainly mild to moderate solicited adverse events (tenderness, pain, bruising, headache, and malaise/fatigue), less frequent after the second dose, and it induced an immune response (binding antibodies and/or T cells) at all prime-boost doses tested in up to 90% of the volunteers at the highest dose. However, the vaccine did not induce neutralizing antibodies, while particularly relevant was the T cell-mediated immunity, with a robust Th1 response. This T cell-skewed immunological response adds significant information to the DNA vaccine platform and should be assessed in further studies for its protective capacity and potential usefulness also in other therapeutic areas, such as oncology.

Why not? Motivations for entering a volunteer register for clinical trials during the COVID-19 pandemic.

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.

Social capital and willingness to participate in COVID-19 vaccine trials: an Italian case-control study.

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.

Comparison of tumor microenvironment in primary and paired metastatic ER+/HER2- breast cancers: results of a pilot study.

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.

GRAd-COV2 vaccine provides potent and durable humoral and cellular immunity to SARS-CoV-2 in randomized placebo-controlled phase 2 trial.

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccine portfolios. GRAd-COV2 is a gorilla adenovirus-based COVID-19 vaccine candidate encoding prefusion-stabilized spike. The safety and immunogenicity of GRAd-COV2 is evaluated in a dose- and regimen-finding phase 2 trial (COVITAR study, ClinicalTrials.gov: NCT04791423) whereby 917 eligible participants are randomized to receive a single intramuscular GRAd-COV2 administration followed by placebo, or two vaccine injections, or two doses of placebo, spaced over 3 weeks. Here, we report that GRAd-COV2 is well tolerated and induces robust immune responses after a single immunization; a second administration increases binding and neutralizing antibody titers. Potent, variant of concern (VOC) cross-reactive spike-specific T cell response peaks after the first dose and is characterized by high frequencies of CD8s. T cells maintain immediate effector functions and high proliferative potential over time. Thus, GRAd vector is a valuable platform for genetic vaccine development, especially when robust CD8 response is needed.

Metronomic Chemotherapy for Metastatic Breast Cancer Treatment: Clinical and Preclinical Data between Lights and Shadows.

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.

Personalised Therapies for Metastatic Triple-Negative Breast Cancer: When Target Is Not Everything.

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.

How to Treat HR+/HER2- Metastatic Breast Cancer Patients after CDK4/6 Inhibitors: An Unfinished Story.

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.

Metronomic Chemotherapy.

Metronomic chemotherapy treatment (mCHT) refers to the chronic administration of low doses chemotherapy that can sustain prolonged, and active plasma levels of drugs, producing favorable tolerability and it is a new promising therapeutic approach in solid and in hematologic tumors. mCHT has not only a direct effect on tumor cells, but also an action on cell microenvironment, by inhibiting tumor angiogenesis, or promoting immune response and for these reasons can be considered a multi-target therapy itself. Here we review the state of the art of mCHT use in some classical tumour types, such as breast and no small cell lung cancer (NSCLC), see what is new regarding most recent data in different cancer types, such as glioblastoma (GBL) and acute myeloid leukemia (AML), and new drugs with potential metronomic administration. Finally, a look at the strategic use of mCHT in the context of health emergencies, or in low -and middle-income countries (LMICs), where access to adequate healthcare is often not easy, is mandatory, as we always need to bear in in mind that equity in care must be a compulsory part of our medical work and research.

The Role for Tocilizumab in COVID-19 Patients: Reflections on Monza Cohort Data.

The severe acute respiratory syndrome coronavirus 2 pandemic has dominated the global health scenario from the beginning of 2020 and still represents a major health emergency. Cytokine inhibitors as tocilizumab have been used to treat COVID-19 severe pneumonia with conflicting results. We performed a retrospective study whose results can contribute to the general overview regarding the role of these agents in severe COVID-19 pneumonia, suggesting an interesting, even not statistically significant evidence of the effectiveness of tocilizumab treatment in this disease and sow a seed of reflection about their use in future waves of pandemic. We compared two cohorts of patients treated with local standard of care and with tocilizumab in the experimental one. With a median follow-up of 92 days, deaths were 6 and 16 in the tocilizumab and the standard of care group, respectively. With a longer follow-up than previous studies, a trend in difference with regards to mortality of the groups was observed.

Efficacy and safety of vinorelbine-capecitabine oral metronomic combination in elderly metastatic breast cancer patients: VICTOR-1 study.

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).