•Chemotherapy induces microbiome disruption, inflammation, and cognitive decline.•The resulting microbiome disruption relates to cognitive decline and inflammation.•Those cognitively impaired have ...unique chemotherapy-induced microbiome alterations.
Chemotherapy is notorious for causing behavioral side effects (e.g., cognitive decline). Notably, the gut microbiome has recently been reported to communicate with the brain to affect behavior, including cognition. Thus, the aim of this clinical longitudinal observational study was to determine whether chemotherapy-induced disruption of the gut microbial community structure relates to cognitive decline and circulating inflammatory signals. Fecal samples, blood, and cognitive measures were collected from 77 patients with breast cancer before, during, and after chemotherapy. Chemotherapy altered the gut microbiome community structure and increased circulating TNF-α. Both the chemotherapy-induced changes in microbial relative abundance and decreased microbial diversity were related to elevated circulating pro-inflammatory cytokines TNF-α and IL-6. Participants reported subjective cognitive decline during chemotherapy, which was not related to changes in the gut microbiome or inflammatory markers. In contrast, a decrease in overall objective cognition was related to a decrease in microbial diversity, independent of circulating cytokines. Stratification of subjects, via a reliable change index based on 4 objective cognitive tests, identified objective cognitive decline in 35% of the subjects. Based on a differential microbial abundance analysis, those characterized by cognitive decline had unique taxonomic shifts (Faecalibacterium, Bacteroides, Fusicatenibacter, Erysipelotrichaceae UCG-003, and Subdoligranulum) over chemotherapy treatment compared to those without cognitive decline. Taken together, gut microbiome change was associated with cognitive decline during chemotherapy, independent of chemotherapy-induced inflammation. These results suggest that microbiome-related strategies may be useful for predicting and preventing behavioral side effects of chemotherapy.
Abstract
Background: Advanced breast cancer (BC) and endometrial cancer (EC) have limited treatment options with no treatments improving survival. ONC201 is the founding member of a novel class of ...anticancer drugs called impiridones. The drug is orally bioavailable and crosses the blood brain barrier. Preclinical studies have demonstrated that ONC201 selectively kills various cancer cells, including all subtypes of BC and EC, while having little effect on normal cells. An on-going Phase 1 study of ONC201 has demonstrated clinical benefit in some solid tumors, including EC and glioblastomas.
Trial Design: Phase 2 single arm study of ONC201 with 3 cohorts: Cohort 1, female and male hormone receptor positive breast cancer (HR+BC); Cohort 2, female and male triple negative breast cancer (TNBC); and Cohort 3, EC. All patients will receive ONC201 at the recommended Phase 2 dose of 625mg by mouth q7 days (1 cycle = 28 days). Patients will undergo a baseline biopsy as well as a biopsy after 5 doses of ONC201 (C2D2). Patients will be evaluated for response every two cycles (8 weeks) by RECIST 1.1.
Eligibility Criteria: Measurable disease with >1 biopsiable lesion, willing to undergo biopsies. Cohort 1 (HR+BC) requires prior treatment with >2 lines of hormonal treatment. No prior treatment required for the other cohorts. Patients must have ECOG 0-1 and adequate organ function. Patients with asymptomatic or brain metastases treated > 4 weeks from study entry are eligible. Exclusion criteria include: symptomatic CNS metastases, radiotherapy ≤ 4 weeks from study entry, HIV, Hepatitis B or Hepatitis C.
Specific Aims: Primary objectives for this study are progression free survival (PFS) at 8 months for Cohort 1 (HR+BC) and overall response rate (ORR) for Cohorts 2 and 3 (TNBC and EC). Secondary objectives include safety, clinical benefit rate (CBR = partial response + complete response + stable disease), and overall survival.
Statistical Methods: This study has been designed to pause prior to full accrual to allow for evaluation of futility prior to proceeding to full accrual. In Cohort 1, if >1 of 5 patients is progression-free at 8 months, then we will recruit up to 24 patients. In Cohort 2, if >2 of 10 patients has clinical benefit then we will recruit up to 29 patients. For Cohort 3, if 1 of 13 patients has clinical benefit, then we will recruit up to 25 patients. Additional evaluations of tumor or blood samples performed will be done in an exploratory fashion, with results presented without any formal adjustment for multiple comparisons.
Target Accrual: 24 patients with HR+BC, 29 patients with TNBC, and 25 patients with EC.This trial will open Summer 2017 at the National Institutes of Health (Bethesda, MD).
Contact Information: Principal Investigator Alexandra S Zimmer, MD; alexandra.zimmer@nih.gov
Citation Format: Gatti-Mays ME, Greer Y, Steinberg S, Soltani S, Collins J, Olson M, Ojemuyiwa M, Annunziata C, Lee J-M, Nunes A, Lipkowitz S, Zimmer A. A phase 2 study of ONC201 in recurrent/refractory metastatic breast cancer and advanced endometrial carcinoma abstract. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-04.
Abstract
Background: Long-term follow-up of neoadjuvant studies demonstrates poor clinical outcomes in patients with TNBC who do not achieve pathologic complete response, with only 35% remaining free ...of recurrence at 10 years. The addition of adjuvant capecitabine in the CREATE-X study prolonged disease free survival and overall survival (OS) in patients with HER2 negative breast cancer with residual invasive disease, with more striking benefit in patients with TNBC. Checkpoint inhibitors have not been approved in breast cancer yet, but recent studies suggest a benefit in combination with chemotherapy and low burden of disease. In the current study, we will evaluate the role of chemoimmunotherapy in the adjuvant setting for patients with TNBC with residual disease after neoadjuvant therapy. We will also investigate the role of the peripheral immunoscore (PIS) in predicting the benefit of immune checkpoint inhibition with or without chemotherapy.
Trial design: OXEL is a pilot open-label three arm randomized study of nivolumab, capecitabine or the combination as adjuvant therapy for 45 patients with residual TNBC after adequate neoadjuvant chemotherapy. Patients enrolled will be randomly assigned to 1 of 3 treatment arms: nivolumab 360 mg iv q3weeks for x 6 cycles; capecitabine 1250mg/m2 po bid D1-D14 q3 weeks x 6 cycles; nivolumab 360mg iv q3weeks + capecitabine 1250mg/m2 po bid D1-D14 q3 weeks x 6 cycles.
Main eligibility criteria: Patients ≥18 years of age with TNBC and ≥1cm of residual disease in the breast and/or node positive disease; receipt of neoadjuvant taxane +/- anthracycline, or platinum, and having completed definitive resection of primary tumor, with no prior use of capecitabine, fluorouracil or immunotherapy, and with no active autoimmune disease or chronic use of systemic steroids.
Specific aims: The primary endpoint is assessing the immunologic effects of capecitabine, nivolumab or the combination in the adjuvant setting by PIS. Additional endpoints include toxicity assessment, distant recurrence free survival (DRFS) and OS at 3-years, association between changes in PIS and circulating tumor DNA at different timepoints with clinical outcome variables and characterization of the immune contexture in residual tumors.
Statistical methods: The study is designed to assess the change in PIS at 6 weeks from baseline in each arm. The sample size of 15 per arm (45 total for 3 arms) will provide preliminary results. A sample size of 15 per arm will have 85% power to detect an effect size of 1 (the difference of the change in PIS from baseline to week 6 between two arms divided by the standard deviation) at 5% significance level.
Present accrual and target accrual: The Institutional Review Board at Georgetown University Medical Center has approved the study. Clinicaltrials.gov NCT03487666. Enrollment of the first patient is expected in July 2018 with a total of 45 patients planned to be recruited. Recruitment sites are MedStar Georgetown University Hospital, MedStar Washington Hospital Center, Hackensack University Medical Center. This trial is supported by Bristol-Meyers Squibb, P30CA051008-25 from NCI, Inivata and the Nina Hyde Center for Breast Cancer Research.
Citation Format: Khoury K, Isaacs C, Gatti-Mays ME, Donahue RN, Schlom J, Wang H, Gallagher C, Graham D, Warren R, Dilawari A, Swain SM, Pohlmann PR, Lynce F. Nivolumab or capecitabine or combination therapy as adjuvant therapy for triple negative breast cancer (TNBC) with residual disease following neoadjuvant chemotherapy: The OXEL study abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-04-01.
Lessons Learned
Concurrent ETBX‐011, ETBX‐051, and ETBX‐061 can be safely administered to patients with advanced cancer.
All patients developed CD4+ and/or CD8+ T‐cell responses after vaccination to ...at least one tumor‐associated antigen (TAA) encoded by the vaccine; 5/6 patients (83%) developed MUC1‐specific T cells, 4/6 (67%) developed CEA‐specific T cells, and 3/6 (50%) developed brachyury‐specific T cells.
The presence of adenovirus 5‐neutralizing antibodies did not prevent the generation of TAA‐specific T cells.
Background
A novel adenovirus‐based vaccine targeting three human tumor‐associated antigens—CEA, MUC1, and brachyury—has demonstrated antitumor cytolytic T‐cell responses in preclinical animal models of cancer.
Methods
This open‐label, phase I trial evaluated concurrent administration of three therapeutic vaccines (ETBX‐011 = CEA, ETBX‐061 = MUC1 and ETBX‐051 = brachyury). All three vaccines used the same modified adenovirus 5 (Ad5) vector backbone and were administered at a single dose level (DL) of 5 × 1011 viral particles (VP) per vector. The vaccine regimen consisting of all three vaccines was given every 3 weeks for three doses then every 8 weeks for up to 1 year. Clinical and immune responses were evaluated.
Results
Ten patients enrolled on trial (DL1 = 6 with 4 in the DL1 expansion cohort). All treatment‐related adverse events were temporary, self‐limiting, grade 1/2 and included injection site reactions and flu‐like symptoms. Antigen‐specific T cells to MUC1, CEA, and/or brachyury were generated in all patients. There was no evidence of antigenic competition. The administration of the vaccine regimen produced stable disease as the best clinical response.
Conclusion
Concurrent ETBX‐011, ETBX‐051, and ETBX‐061 can be safely administered to patients with advanced cancer. Further studies of the vaccine regimen in combination with other agents, including immune checkpoint blockade, are planned.
Therapeutic cancer vaccines have gained significant popularity in recent years as new approaches for specific oncologic indications emerge. Three therapeutic cancer vaccines are FDA approved and one ...is currently approved by the EMA as monotherapy with modest treatment effects. Combining therapeutic cancer vaccines with other treatment modalities like radiotherapy (RT), hormone therapy, immunotherapy, and/or chemotherapy have been investigated as a means to enhance immune response and treatment efficacy. There is growing preclinical and clinical data that combination of checkpoint inhibitors and vaccines can induce immunogenic intensification with favorable outcomes. Additionally, novel methods for identifying targetable neoantigens hold promise for personalized vaccine development. In this article, we review the rationale for various therapeutic combinations, clinical trial experiences, and future directions. We also highlight the most promising developments that could lead to approval of novel therapeutic cancer vaccines.
HuMax-IL8 (now known as BMS-986253) is a novel, fully human monoclonal antibody that inhibits interleukin-8 (IL-8), a chemokine that promotes tumor progression, immune escape, epithelial-mesenchymal ...transition, and recruitment of myeloid-derived suppressor cells. Studies have demonstrated that high serum IL-8 levels correlate with poor prognosis in many malignant tumors. Preclinical studies have shown that IL-8 blockade may reduce mesenchymal features in tumor cells, making them less resistant to treatment.
Fifteen patients with metastatic or unresectable locally advanced solid tumors were enrolled in this 3 + 3 dose-escalation trial at four dose levels (4, 8, 16, or 32 mg/kg). HuMax-IL8 was given IV every 2 weeks, and patients were followed for safety and immune monitoring at defined intervals up to 52 weeks.
All enrolled patients (five chordoma, four colorectal, two prostate, and one each of ovarian, papillary thyroid, chondrosarcoma, and esophageal) received at least one dose of HuMax-IL8. Eight patients had received three or more prior lines of therapy and five patients had received prior immunotherapy. Treatment-related adverse events occurred in five patients (33%), mostly grade 1. Two patients receiving the 32 mg/kg dose had grade 2 fatigue, hypophosphatemia, and hypersomnia. No dose-limiting toxicities were observed, and maximum tolerated dose was not reached. Although no objective tumor responses were observed, 11 patients (73%) had stable disease with median treatment duration of 24 weeks (range, 4-54 weeks). Serum IL-8 was significantly reduced on day 3 of HuMax-IL8 treatment compared to baseline (p = 0.0004), with reductions in IL-8 seen at all dose levels.
HuMax-IL8 is safe and well-tolerated. Ongoing studies are evaluating the combination of IL-8 blockade and other immunotherapies.
NCTN, NCT02536469. Registered 23 August 2015, https://clinicaltrials.gov/ct2/show/NCT02536469?term=NCT02536469&rank=1 .
Lessons Learned
Modified vaccinia Ankara‐Bavarian Nordic (MVA‐BN)‐Brachyury followed by fowlpox virus‐BN‐Brachyury was well tolerated upon administration to patients with advanced cancer.
Sixty‐three ...percent of patients developed CD4+ and/or CD8+ T‐cell responses to brachyury after vaccination.
BN‐Brachyury vaccine also induced T‐cell responses against CEA and MUC1, which are cascade antigens, that is, antigens not encoded in the vaccines.
Background
Brachyury, a transcription factor, plays an integral role in the epithelial–mesenchymal transition, metastasis, and tumor resistance to chemotherapy. It is expressed in many tumor types, and rarely in normal tissues, making it an ideal immunologic target. Bavarian Nordic (BN)‐Brachyury consists of vaccination with modified vaccinia Ankara (MVA) priming followed by fowlpox virus (FPV) boosting, each encoding transgenes for brachyury and costimulatory molecules.
Methods
Patients with metastatic solid tumors were treated with two monthly doses of MVA‐brachyury s.c., 8 × 108 infectious units (IU), followed by FPV‐brachyury s.c., 1 × 109 IU, for six monthly doses and then every 3 months for up to 2 years. The primary objective was to determine safety and tolerability.
Results
Eleven patients were enrolled from March 2018 to July 2018 (one patient was nonevaluable). No dose‐limiting toxicities were observed. The most common treatment‐related adverse event was grade 1/2 injection‐site reaction observed in all patients. Best overall response was stable disease in six patients, and the 6‐month progression‐free survival rate was 50%. T cells against brachyury and cascade antigens CEA and MUC1 were detected in the majority of patients.
Conclusion
BN‐Brachyury vaccine is well tolerated and induces immune responses to brachyury and cascade antigens and demonstrates some evidence of clinical benefit.
BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-βRII (a TGF-β ‘trap’) fused to a human IgG1 mAb ...blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa.MethodsIn these phase 1 (NCT02517398) and phase 2 trials (NCT03427411), 59 patients with advanced, pretreated, checkpoint inhibitor-naive HPV-associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; other endpoints included safety.ResultsAs of April 17, 2019 (phase 1), and October 4, 2019 (phase 2), the confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was 30.5% (95% CI, 19.2% to 43.9%; five complete responses); eight patients had stable disease (disease control rate, 44.1% (95% CI, 31.2% to 57.6%)). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of 35.6% (95% CI, 23.6% to 49.1%). An additional patient with vulvar cancer had an unconfirmed response. Forty-nine patients (83.1%) experienced treatment-related adverse events, which were grade 3/4 in 16 patients (27.1%). No treatment-related deaths occurred.ConclusionBintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of bintrafusp alfa in patients with advanced, pretreated HPV-associated cancers.
Breast cancer has historically been a disease for which immunotherapy was largely unavailable. Recently, the use of immune checkpoint inhibitors (ICIs) in combination with chemotherapy for the ...treatment of advanced/metastatic triple-negative breast cancer (TNBC) has demonstrated efficacy, including longer progression-free survival and increased overall survival in subsets of patients. Based on clinical benefit in randomized trials, ICIs in combination with chemotherapy for the treatment of some patients with advanced/metastatic TNBC have been approved by the United States (US) Food and Drug Administration (FDA), expanding options for patients. Ongoing questions remain, however, about the optimal chemotherapy backbone for immunotherapy, appropriate biomarker-based selection of patients for treatment, the optimal strategy for immunotherapy treatment in earlier stage disease, and potential use in histological subtypes other than TNBC. To provide guidance to the oncology community on these and other important concerns, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew upon the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for breast cancer, including diagnostic testing, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence-based and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with breast cancer.
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