Background

There is a lack of data exploring the use and optimal timing of immunotherapy and chemoradiation therapy (CRT) in node-positive cervical cancer. Further translational research into mechanisms of response and resistance to immunotherapy in advanced cervical cancer is warranted.

Primary objectives

To determine if sequencing of atezolizumab and CRT result in differential immune activation, as determined by clonal expansion of T cell receptor beta (TCRB) repertoires in peripheral blood on day 21.

Study hypothesis

There is a difference for clonal expansion of T cell receptor beta repertoires in the peripheral blood at day 21 between the priming and concurrent atezolizumab and CRT in Arm A vs the concurrent atezolizumab and CRT in Arm B.

Trial design

Locally advanced cervical cancer patients with lymph node-positive disease will be randomized on this open-label, randomized trial with two experimental arms. Arm A will get one dose of atezolizumab prior to cisplatin CRT, and then two subsequent doses of atezolizumab during the CRT, and Arm B will get three doses during CRT. Patients will be followed for 2 years to assess outcomes.

Major inclusion/exclusion criteria

Patients must have histologically confirmed, newly diagnosed advanced cervical cancer (squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma): FIGO 2009 clinical stages IB2/IIA with positive para-aortic nodes, or FIGO 2009 clinical stages IIB/IIIB/IVA with positive pelvic or para-aortic lymph nodes. Exclusion criteria include those who had a prior hysterectomy or lymph node dissection.

Primary endpoints

Clonal expansion of TCRB) repertoires in peripheral blood on day 21.

Sample size

The sample size will be 40 patients.

Estimated dates for completing accrual and presenting results

We estimate accrual to finish by the summer of 2020 with presentation of results to follow in 2021.

Trial registration

NCT03738228.

Radiation therapy exerts a tumoricidal local effect as well as both local and systemic immunomodulation. Immune checkpoint blockade has become a widely used treatment modality across cancer types with a rapidly growing list of agents and US Food and Drug Administration-approved indications. Moreover, there may be synergy between radiation therapy and immune checkpoint blockade. Various strategies have been used, but the optimal sequencing of these therapies is unclear. In this review, the authors discuss the major mechanisms of available immune checkpoint inhibitors and explore the available preclinical and clinical evidence regarding treatment sequencing. They also review safety considerations and conclude with possible future directions.

PURPOSE: Despite therapeutic advances in the treatment of ovarian cancer (OC), 5-year survival remains low, and patients eventually die from recurrent, chemotherapy-resistant disease. The National Cancer Gynecologic Cancer Steering Committee identified the integration of scientifically defined subgroups as a top strategic priority in clinical trial planning. METHODS: A group of experts was convened to review the scientific literature in OC to identify validated predictive biomarkers that could inform patient selection and treatment stratification. Here, we report on these findings and their potential for use in future clinical trial design on the basis of hierarchal evidence grading. RESULTS: The biomarkers were classified on the basis of mechanistic targeting, including DNA repair and replication stress, immunotherapy and tumor microenvironment, oncogenic signaling, and angiogenesis. Currently, BRCA mutations and homologous recombination deficiency to predict poly (ADP-ribose) polymerase inhibitor response are supported in OC by the highest level of evidence. Additional biomarkers of response to agents targeting the pathways above have been identified but require prospective validation. CONCLUSION: Although a number of biomarkers of response to various agents in OC have been described in the literature, high-level evidence for the majority is lacking. This report highlights the unmet need for identification and validation of predictive biomarkers to guide therapy and future trial design in OC.

Abstract Background Numerous pre-clinical studies and clinical trials demonstrated that induction of antibodies to the β-amyloid peptide of 42 residues (Aβ42) elicits therapeutic effects in Alzheimer's disease (AD). However, an active vaccination strategy based on full length Aβ42 is currently hampered by elicitation of T cell pathological autoreactivity. We attempt to improve vaccine efficacy by creating a novel chimeric flu vaccine expressing the small immunodominant B cell epitope of Aβ42. We hypothesized that in elderly people with pre-existing memory Th cells specific to influenza this dual vaccine will simultaneously boost anti-influenza immunity and induce production of therapeutically active anti-Aβ antibodies. Methods Plasmid-based reverse genetics system was used for the rescue of recombinant influenza virus containing immunodominant B cell epitopes of Aβ42 (Aβ1-7/10). Results Two chimeric flu viruses expressing either 7 or 10 aa of Aβ42 (flu-Aβ1-7 or flu-Aβ1-10) were generated and tested in mice as conventional inactivated vaccines. We demonstrated that this dual vaccine induced therapeutically potent anti-Aβ antibodies and anti-influenza antibodies in mice. Conclusion We suggest that this strategy might be beneficial for treatment of AD patients as well as for prevention of development of AD pathology in pre-symptomatic individuals while concurrently boosting immunity against influenza.

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.