Safety of Novel Targeted Therapies in Oncology.

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T-cell bispecific antibodies to bypass MHC class I loss in breast cancer

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Targeting HER3 for cancer treatment: a new horizon for an old target

Human epidermal growth factor receptor 3 (HER3) is a member of the human epidermal growth factor receptors family, having as its main ligands neuregulins 1 and 2. Although its poor tyrosine kinase activity entails a weak oncogenic power on its own, HER3 can heterodimerize with HER2 and/or epidermal growth factor receptor (EGFR), leading to a drastic enhancement of transphosphorylation and activation of downstream signaling pathways, ultimately promoting oncogenesis, metastatic dissemination, and drug resistance. Given its ubiquitous expression across solid tumors, multiple efforts have been done to therapeutically target HER3 by blocking either the ligand binding domain or its dimerization with other receptors. Treatment with anti-HER3 monoclonal antibodies or bispecific antibodies, both as single agents and in combination with other compounds, unfortunately led to unsatisfactory results across several tumor types. The HER3-directed delivery of cytotoxic payloads through antibody-drug conjugates has recently demonstrated encouraging activity in several tumor types, however, suggesting a potential role for the therapeutic targeting of HER3 in cancer treatment

A clinical perspective on escalating or de-escalating adjuvant therapy in HER2+ breast cancer

Introduction: Patients with early HER2-positive breast cancer (BC) benefit from HER2-targeted systemic therapy. The endorsed standard adjuvant treatment for patients with early HER2-positive breast cancer is chemotherapy plus trastuzumab administered for 1 year. Areas covered: Several trials have investigated modifications of the standard treatment in terms of de-escalation by either shortening the duration or giving less resource-demanding regimens and in terms of escalation by either adding a second anti-HER2 agent or extending the duration of HER2-targeted treatment for more than 12\ua0months. In this perspective, we would offer a comprehensive view of these trials and discuss their findings. Expert commentary: At the current state of knowledge, there are still open questions regarding the management of HER2+ BC patients, such as the most adequate duration of trastuzumab therapy, the optimal chemotherapy regimen that should be combined with trastuzumab, and the addition of a second anti-HER2 agent. Growing evidences suggest that some HER2+ BC patients may not need chemotherapy. If these patients could be recognized upfront, optimal response could potentially be reached with HER2-targeted therapy alone

immunizing against breast cancer a new swing for an old sword

Summary Therapeutic potential of vaccination has been explored in many clinical trials involving patients with breast cancer. A large variety of cancer immunogens have been tested. The majority of clinical vaccination studies have been carried out in patients with metastatic breast cancer, characterized by extremely aggressive malignant tumors, resistant to all standard cytotoxic treatments and with longest-lasting disease. With active specific immunotherapy, tumor-associated antigens coupled to appropriate adjuvant can elicit a powerful antitumor responses. The potential advantages of therapeutic cancer vaccines are that they can augment an established immunogenic response to the tumor (which is generally weak in breast cancer), they target specific tumor antigens (although there are few), they are potentially non-toxic, they can be combined with conventional therapies and/or other immunotherapies, and they elicit immunologic memory to prevent recurrence of the tumor. It is unclear whether therapeutic vaccines for cancer prolong survival. Data of clinical activity have been observed by using vaccines targeting HER-2/neu protein, human telomerase reverse transcriptase, carcinoembryonic antigen (CEA), and carbohydrate antigen given after stem cell rescue. A better understanding of the relation between innate and adaptive immune responses, and of the immune escape mechanisms employed by tumor cells, the discovery of mechanisms underlying immunological tolerance, and acknowledgment of the importance of both cell-mediated and humoral adaptive immunity for the control of tumour growth are necessary for leading to a more comprehensive immunotherapeutic approach in breast cancer

A review of the CTRC-AACR San Antonio Breast Cancer Symposium 2012

The annual San Antonio Breast Cancer Symposium (SABC) is a multidisciplinary conference that covers basic molecular and cellular biology, epidemiology, diagnosis and treatment of all types of breast cancer and premalignant breast disease. In 2012, this meeting was held at the Henry B. Gonzalez Convention Center in San Antonio, Texas, United States, from 4 to 8 December. The symposium consisted of lectures within six general sections covering a range of topics in breast cancer research. These included discussions on research of breast cancer posters, a large number of specialist sessions, and several minisymposia. The report below describes much of the research presented in those general lecture sessions

From precision medicine to cancer care through the immunome: Highlights from the European Society of Medical Oncology Congress, Madrid, 26-30th September 2014

The recognition that cancer is a 'spectrum' of diseases, and that medical oncologists should achieve 'convergence' from 'divergence' to treat cancer patients was the main theme of the 2014 European Society of Medical Oncology (ESMO) Congress. The meeting assembled 19,859 participants from nearly 134 countries worldwide. The educational content was centered on precision medicine in cancer care, from mutational burden to the immunome, through the epigenome and the proteome. Precision medicine has been defined as the tailoring of medical treatment to the characteristics of an individual patient. Knowing an individual's genomics has created a remarkable and unprecedented opportunity to improve medical treatment and develop preventative strategies to preserve health. Clinical oncologists across the range of diseases recognise that for precision medicine to take hold, it will require intensive, rigorous validation that these new approaches do indeed improve patient outcomes. Not all molecular alterations are predictive of response to a specific targeted treatment nor are they all druggable, raising issues of cost - benefit, validation of specific biomarkers, and of managing patient expectations. Addressing all these issues will be essential for the medical community to embrace any given opportunities. Along with it, it will also require educational programmes that squarely address the knowledge chasm that currently exists for practicing physicians. The promise of genomic and precision medicine has created greater demands for both those providing the scientific expertise - bioinformatics, statisticians, molecular biologists - and those delivering clinical care - physicians, nurses, psychologists - to the patients. This ESMO 2014 report will highlight the major findings of this outstanding meeting

Agnostic evaluation of ipilimumab and nivolumab association: a metanalysis

Background: Ipilimumab and Nivolumab, targeting the molecules CTLA-4, PD-1, respectively,have shown efficacy against several types of cancer. Despite these results, only a small percentage of patients maintains a long-lasting effect. Even Ipilimumab, in combination with nivolumab, has demonstrated a significant clinical benefit in multiple tumor types. However, no trial has been designed with the primary endpoint to compare the efficacy of nivolumab plus ipilimumab combined, compared to nivolumab alone. Hence, the added value of ipilimumab in the combination has not clearly been established yet. The aim of this study was to demonstrate the superiority of the combination strategy compared to the single agent therapy. Materials and methods: We performed a meta-analysis of Phase I-II-III Clinical Trials, published from 2010 up to 2020, in which the combination of ipilimumab plus nivolumab was compared to nivolumab alone. We extracted ORR, OS and PFS HR on the basis of treatment from the subgroup analysis of each trial. Results: A total of 7 trials were included in the present meta-analysis. Overall, 1313 patients were treated with the nivolumab plus ipilimumab combination compared to 1110 patients treated with nivolumabalone. All trials reported the Objective response rate(ORR), no heterogeneity was found among studies and the pooled Odds Ratio was highly in favor of the nivolumab plus ipilimumab combination with respect to nivolumab alone (1.683; 95% CI: 1.407-2.012; P < 0.0001). Three studies were considered for Progression free survival (PFS) analysis, and the pooled Hazard Ratio favored the combination of nivolumab plus ipilimumab with respect to nivolumab alone (0.807; 95% CI: 0.719-0.907; P < 0.0001). The Overall survival(OS) endpoint was considered only in 2 trials, and the pooled HR favored, also in this case, the combination of nivolumab plus ipilimumab with respect to nivolumab alone (0.87; 95% CI: 0.763-0.997; P = 0.045)