scholarly journals Improving the Odds in Advanced Breast Cancer With Combination Immunotherapy: Stepwise Addition of Vaccine, Immune Checkpoint Inhibitor, Chemotherapy, and HDAC Inhibitor in Advanced Stage Breast Cancer

2021 ◽  
Vol 10 ◽  
Author(s):  
Margaret E. Gatti-Mays ◽  
Sofia R. Gameiro ◽  
Yohei Ozawa ◽  
Karin M. Knudson ◽  
Kristin C. Hicks ◽  
...  

Breast tumors commonly harbor low mutational burden, low PD-L1 expression, defective antigen processing/presentation, and an immunosuppressive tumor microenvironment (TME). In a malignancy mostly refractory to checkpoint blockade, there is an unmet clinical need for novel combination approaches that increase tumor immune infiltration and tumor control. Preclinical data have guided the development of this clinical trial combining 1) BN-Brachyury (a poxvirus vaccine platform encoding the tumor associated antigen brachyury), 2) bintrafusp alfa (a bifunctional protein composed of the extracellular domain of the TGF-βRII receptor (TGFβ “trap”) fused to a human IgG1 anti-PD-L1), 3), entinostat (a class I histone deacetylase inhibitor), and 4) T-DM1 (ado-trastuzumab emtansine, a standard of care antibody-drug conjugate targeting HER2). We hypothesize that this tetratherapy will induce a robust immune response against HER2+ breast cancer with improved response rates through 1) expanding tumor antigen-specific effector T cells, natural killer cells, and immunostimulatory dendritic cells, 2) improving antigen presentation, and 3) decreasing inhibitory cytokines, regulatory T cells, and myeloid-derived suppressor cells. In an orthotopic HER2+ murine breast cancer model, tetratherapy induced high levels of antigen-specific T cell responses, tumor CD8+ T cell/Treg ratio, and augmented the presence of IFNγ- or TNFα-producing CD8+ T cells and IFNγ/TNFα bifunctional CD8+ T cells with increased cytokine production. Similar effects were observed in tumor CD4+ effector T cells. Based on this data, a phase 1b clinical trial evaluating the stepwise addition of BN-Brachyury, bintrafusp alfa, T-DM1 and entinostat in advanced breast cancer was designed. Arm 1 (TNBC) receives BN-Brachyury + bintrafusp alfa. Arm 2 (HER2+) receives T-DM1 + BN-Brachyury + bintrafusp alfa. After safety is established in Arm 2, Arm 3 (HER2+) will receive T-DM1 + BN-Brachyury + bintrafusp alfa + entinostat. Reimaging will occur every 2 cycles (1 cycle = 21 days). Arms 2 and 3 undergo research biopsies at baseline and after 2 cycles to evaluate changes within the TME. Peripheral immune responses will be evaluated. Co-primary objectives are response rate and safety. All arms employ a safety assessment in the initial six patients and a 2-stage Simon design for clinical efficacy (Arm 1 if ≥ three responses of eight then expand to 13 patients; Arms 2 and 3 if ≥ four responses of 14 then expand to 19 patients per arm). Secondary objectives include progression-free survival and changes in tumor infiltrating lymphocytes. Exploratory analyses include changes in peripheral immune cells and cytokines. To our knowledge, the combination of a vaccine, an anti-PD-L1 antibody, entinostat, and T-DM1 has not been previously evaluated in the preclinical or clinical setting. This trial (NCT04296942) is open at the National Cancer Institute (Bethesda, MD).

2005 ◽  
Vol 4 (6) ◽  
pp. 338-340
Author(s):  
Xiaoqing LIU ◽  
Santai SONG ◽  
Zefei JIANG ◽  
Weilian LI ◽  
Weixia WANG ◽  
...  

2017 ◽  
Vol 77 (08) ◽  
pp. 870-878 ◽  
Author(s):  
Markus Wallwiener ◽  
Felix Heindl ◽  
Sara Brucker ◽  
Florin-Andrei Taran ◽  
Andreas Hartkopf ◽  
...  

Abstract Purpose Patient-reported outcomes (PROs) have been incorporated into clinical trials for many symptoms and medical conditions. A transition from paper-based capture of PROs to electronic PROs (ePROs) has recently started. This study reports on the feasibility of ePRO assessment in a prospective registry including molecular data for patients with advanced breast cancer. Methods As part of the PRAEGNANT network, patients were invited by clinical trial staff, physicians, and nurses to complete three standardized Internet-based questionnaires (EQ 5D 5 L, CES-D and IPAQ). Feasibility was assessed by the staff members who assigned the user accounts by the patients. The completeness of the questionnaires was also assessed. Results Fifteen of 17 patients who were asked agreed to participate to complete the PRO questionnaires (EQ-5D-5L and CES-D). However, the IPAQ (physical activity) questionnaire was only validly completed by 9 patients. Feasibility was ranked better by the physicians and dedicated clinical trial staff than by the nursing staff. Conclusions Incorporating ePRO questionnaires into an advanced breast cancer registry is feasible, and no major hurdles were reported. Involving stakeholders from the start, the application is tailored to the capacities and abilities of both patients and clinical staff. The patientsʼ compliance was better with some questionnaires, but others may present difficulties.


1964 ◽  
Vol 50 (6) ◽  
pp. 445-456 ◽  
Author(s):  
Sergio Di Pietro ◽  
Bruno Salvatori

Twenty-two women with advanced breast cancer underwent clinical trial with a new hormonal compound, 4-hydroxy-17 α-methyl - 19 - nortestosterone (HMNT), in order to evaluate the antitumor activity of this steroid. The age of the patients ranged from 39 to 72 years; the compound was administrated i.m. at the dose of 50 mg a day, regularly and continuously, as long as a new progression of the neoplastic lesions was observed (in one case the treatment went on over a period of 13 months). An objective regression of the lesions was obtained in 8 of the 22 patients treated. The most impressive clinical feature of this new drug seems to consist in a more marked effect in premenopausal women, under 50 years of age. The compound proved to be practically free of virilizing action and of other unwanted side-effects, at least at the doses employed in this study.


2020 ◽  
Vol 26 (12) ◽  
pp. 2420-2423
Author(s):  
Takaaki Masuda ◽  
Atsushi Nonami ◽  
Fumiaki Tanaka ◽  
Yuki Ando ◽  
Masatoshi Eto ◽  
...  

1988 ◽  
Vol 74 (1) ◽  
pp. 53-56 ◽  
Author(s):  
Tiping Zhao ◽  
Guifen He

An antiandrogenic agent flutamide was used in the treatment of one male and 14 female postmenopausal breast cancer patients. Only a mild and transient response was seen in 2 female patients. Therefore, flutamide cannot be used solely in the treatment of female postmenopausal breast cancer.


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