Gabriele Antonarelli

Bio: Gabriele Antonarelli is an academic researcher from European Institute of Oncology. The author has contributed to research in topics: Adverse effect & Immunotherapy. The author has an hindex of 1, co-authored 2 publications receiving 1 citations. Previous affiliations of Gabriele Antonarelli include University of Milan.

Safety of COVID-19 mRNA Vaccines in Patients with Cancer Enrolled in Early-Phase Clinical Trials

Abstract: Pivotal trials of COVID-19 vaccines did not include cancer patients, with questions remaining about their safety and efficacy in this population. Patients enrolled in early-phase clinical trials receive novel treatments with unknown efficacy and safety profiles. Studies on the safety of COVID-19 vaccines in these patients are urgently required. This is a retrospective, real-world, cohort study of patients receiving anticancer treatments and COVID-19 vaccines between 1 February and 25 June 2021 at the Division of New Drugs Development for Innovative Therapies of the European Institute of Oncology. One hundred thirteen patients were enrolled, 40 in early-phase clinical trials, and 20 under novel immunotherapy agents. Nearly three-quarters of the patients experienced at least one adverse event (AE) after the first dose (1D) (74.3%) and second dose (2D) (72.6%). Most of the AEs were local (67.3% 1D and 61.9% after 2D), while 31.8% (1D) and 38.1% (2D) of the patients had systemic AEs. No AEs above grade 2 were observed. Therefore, COVID-19 vaccines appear to be safe in patients enrolled in early-phase clinical trials, including patients receiving novel immunotherapy compounds. All cancer patients should be prioritized for COVID-19 vaccination, regardless of ongoing treatments or enrollment in early-phase trials.

Investigational immunomodulatory drugs for enhancement of triple negative breast cancer (TNBC) immunotherapy: early phase development.

Abstract: Introduction Immunotherapy through the blockade of PD1-PDL1 axis has shown to improve outcomes in advanced and early triple negative breast cancer (TNBC). To further enhance immune-stimulation, and ultimately improve patient outcomes, a wide variety of next-generation immunotherapies (NGIO) is being developed for this disease. Areas covered In the present article, we discuss the immune landscape of TNBC and recapitulate the rationale and available clinical evidence of NGIO under early phase development for TNBC, highlighting challenges and opportunities in this emerging field of research. Expert opinion Multiple immunotherapeutic strategies beyond PD-(L)1 blockade have been tested for TNBC, including the targeting of further inhibitory checkpoints, the agonism of costimulatory molecules, the intratumoral administration of immunotherapies and cancer vaccines. Most of these strategies have demonstrated to be safe in early clinical trials, with some exhibiting early signs of antitumor activity. To optimally harness the potential of NGIO, a refined patient selection based on emerging immune biomarkers will be required, through an adaptation of immunotherapeutic strategies based on patient and tumor characteristics. More mature data from ongoing clinical trials, added to the progressively increasing knowledge on breast cancer immune landscape, will hopefully clarify the role of NGIO for the treatment of TNBC.

CAR-T cell therapy for triple-negative breast cancer and other solid tumors: preclinical and clinical progress

Abstract: ABSTRACT Introduction Most breast cancer-related deaths arise from triple-negative breast cancer (TNBC). Molecular heterogeneity, aggressiveness and the lack of effective therapies are major hurdles to therapeutic progress. Chimeric antigen receptor (CAR)-T cells have emerged as a promising immunotherapeutic strategy in TNBC. This approach combines the antigen specificity of an antibody with the effector function of T cells. Areas covered This review examines the opportunities provided by CAR-T cell therapies in solid tumors. Emerging targets, ongoing clinical trials, and prospective clinical implications in TNBC are considered later. An emphasis is placed on the key challenges and possible solutions for this therapeutic approach. Expert Opinion A challenge for CAR-T cell therapy is the selection of the optimal targets to minimize on-target/off-tumor toxicity. Tumor escape via antigen loss and intrinsic heterogeneity is a further hurdle. TROP2, GD2, ROR1, MUC1 and EpCAM are promising targets. Persistence and trafficking to tumor cells may be enhanced by the implementation of CARs with a chemokine receptor and/or constitutively activated interleukin receptors. Fourth-generation CARs (TRUCKs) may redirect T-cells for universal cytokine-mediated killing. Combinatorial approaches and the application of CARs to other immune cells could revert the suppressive immune environment that characterizes solid neoplasms.

mRNA vaccines: The future of prevention of viral infections?

Abstract: Messenger RNA (mRNA) vaccines against COVID‐19 are the first authorized biological preparations developed using this platform. During the pandemic, their administration has been proven to be a life‐saving intervention. Here, we review the main advantages of using mRNA vaccines, identify further technological challenges to be met during the development of the mRNA platform, and provide an update on the clinical progress on leading mRNA vaccine candidates against different viruses that include influenza viruses, human immunodeficiency virus 1, respiratory syncytial virus, Nipah virus, Zika virus, human cytomegalovirus, and Epstein‐Barr virus. The prospects and challenges of manufacturing mRNA vaccines in low‐income countries are also discussed. The ongoing interest and research in mRNA technology are likely to overcome some existing challenges for this technology (e.g., related to storage conditions and immunogenicity of some components of lipid nanoparticles) and enhance the portfolio of vaccines against diseases for which classical formulations are already authorized. It may also open novel pathways of protection against infections and their consequences for which no safe and efficient immunization methods are currently available.

Novel immune targets for the treatment of triple-negative breast cancer.

Abstract: Introduction . Although immune checkpoint inhibitors (ICIs), especially those exploiting the PD1-PD-L1 axis, have recently been granted landmark regulatory approvals in TNBC, they provide benefit only to a subset of TNBC patients. To impact mechanisms of primary and secondary resistance to the anti-tumor immune response, novel targets such as ICOS, LAG3 and TIM3 are currently being explored at preclinical and early-phase clinical levels. Areas covered This article examines the landscape of the immune therapeutics investigated in early-phase clinical trials for TNBC. Preclinical rationale is provided for each immune target, predominant expression, and function. Clinical implications and preliminary available trial results are discussed and finally, we reflect on aspects of future expectations and challenges in this field. Expert opinion Several immune strategies have been investigated in TNBC, including co-inhibitory molecules beyond PD1-PD-L1 axis, co-stimulatory checkpoints, cancer vaccines, adoptive cell transfer, combination therapies, as well as different routes of administration. Most of approaches showed signs of anti-cancer activity and a good safety profile in early-phase clinical trials. Since IO provided benefit only to a small subgroup of TNBC patients so far, identifying predictive biomarkers is a priority to refine patient-selection. Data from ongoing clinical trials, with the gradually improving interpretation of the breast tumor immune environment will hopefully refine the role of new immune targets for the treatment of TNBC.

Safety of two-dose COVID-19 vaccination (BNT162b2 and CoronaVac) in adults with cancer: a territory-wide cohort study

Abstract: The World Health Organization has defined a list of adverse events of special interest (AESI) for safety surveillance of vaccines. AESI have not been adequately assessed following COVID-19 vaccination in patients with cancer contributing to vaccine hesitancy in this population. We aimed to evaluate the association between BNT162b2 and CoronaVac vaccines and the risk of AESI in adults with active cancer or a history of cancer.We conducted a territory-wide cohort study using electronic health records managed by the Hong Kong Hospital Authority and vaccination records provided by the Department of Health. Patients with a cancer diagnosis between January 1, 2018, and September 30, 2021, were included and stratified into two cohorts: active cancer and history of cancer. Within each cohort, patients who received two doses of BNT162b2 or CoronaVac were 1:1 matched to unvaccinated patients using the propensity score. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for AESI 28 days after the second vaccine dose.A total of 74,878 patients with cancer were included (vaccinated: 25,789 [34%]; unvaccinated: 49,089 [66%]). Among patients with active cancer, the incidence of AESI was 0.31 and 1.02 per 10,000 person-days with BNT162b2 versus unvaccinated patients and 0.13 and 0.88 per 10,000 person-days with CoronaVac versus unvaccinated patients. Among patients with history of cancer, the incidence was 0.55 and 0.89 per 10,000 person-days with BNT162b2 versus unvaccinated patients and 0.42 and 0.93 per 10,000 person-days with CoronaVac versus unvaccinated patients. Neither vaccine was associated with a higher risk of AESI for patients with active cancer (BNT162b2: HR 0.30, 95% CI 0.08-1.09; CoronaVac: 0.14, 95% CI 0.02-1.18) or patients with history of cancer (BNT162b2: 0.62, 95% CI 0.30-1.28; CoronaVac: 0.45, 95% CI 0.21-1.00).In this territory-wide cohort study of patients with cancer, the incidence of AESI following vaccination with two doses of either BNT162b2 or CoronaVac vaccines was low. The findings of this study can reassure clinicians and patients with cancer about the overall safety of BNT162b2 and CoronaVac in patients with cancer, which could increase the COVID-19 vaccination rate in this vulnerable group of patients.

Immunotherapy for Metastatic Triple Negative Breast Cancer: Current Paradigm and Future Approaches

Abstract: In approximately 15-20% of the patients diagnosed with breast cancer, it comprises the triple negative (TN) subtype, which until recently lacked targets for specific treatments and is known for its aggressive clinical behavior in patients with metastatic disease. TNBC is considered the most immunogenic breast cancer subtype due to higher levels of tumor infiltrating lymphocytes (TILs), tumor mutational burden and PD-L1 expression, providing a rationale for immunotherapy. The addition of pembrolizumab to chemotherapy as first-line treatment resulted in significantly improved PFS and OS for PD-L1 positive mTNBC, leading to FDA approval. However, response rate of ICB in unselected patients is low. Ongoing (pre)clinical trials aim to further optimize ICB efficacy and widen its application beyond PD-L1 positive breast tumors. Novel immunomodulatory approaches to induce a more inflamed tumor microenvironment include dual checkpoint blockade, bispecific antibodies, immunocytokines, adoptive cell therapies, oncolytic viruses, and cancer vaccines. Preclinical data for these novel strategies seems promising, but solid clinical data to further support its application for mTNBC is awaited. Biomarkers capturing the degree of immunogenicity such as but not limited to TILs, CD8 T cell levels, and IFNg signatures could support deciding which therapeutic strategy is most appropriate for which patient. Given 1) the accumulating therapy options for patients with metastatic disease and 2) the heterogeneity of mTNBC from inflamed to immune-desert tumors, the challenge is to work towards immunomodulatory strategies for specific subgroups of patients with TNBC to enable personalized (immuno)therapy for patients with metastatic disease.