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      Randomized, Double‐Blind, Placebo‐Controlled Phase II Study of Yeast‐Brachyury Vaccine (GI‐6301) in Combination with Standard‐of‐Care Radiotherapy in Locally Advanced, Unresectable Chordoma

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          Abstract

          Background

          Brachyury is a transcription factor overexpressed in chordoma and is associated with chemotherapy resistance and epithelial‐to‐mesenchymal transition. GI‐6301 is a recombinant, heat‐killed Saccharomyces cerevisiae yeast‐based vaccine targeting brachyury. A previous phase I trial of GI‐6301 demonstrated a signal of clinical activity in chordomas. This trial evaluated synergistic effects of GI‐6301 vaccine plus radiation.

          Materials and Methods

          Adults with locally advanced, unresectable chordoma were treated on a randomized, placebo‐controlled trial. Patients received three doses of GI‐6301 (80 × 10 7 yeast cells) or placebo followed by radiation, followed by continued vaccine or placebo until progression. Primary endpoint was overall response rate, defined as a complete response (CR) or partial response (PR) in the irradiated tumor site at 24 months. Immune assays were conducted to evaluate immunogenicity.

          Results

          Between May 2015 and September 2019, 24 patients enrolled on the first randomized phase II study in chordoma. There was one PR in each arm; no CRs were observed. Median progressive‐free survival for vaccine and placebo arms was 20.6 months (95% confidence interval [CI], 5.7–37.5 months) and 25.9 months (95% CI, 9.2–30.8 months), respectively. Hazard ratio was 1.02 (95% CI, 0.38–2.71). Vaccine was well tolerated with no vaccine‐related serious adverse events. Preexisting brachyury‐specific T cells were detected in most patients in both arms. Most patients developed T‐cell responses during therapy, with no difference between arms in frequency or magnitude of response.

          Conclusion

          No difference in overall response rate was observed, leading to early discontinuation of this trial due to low conditional power to detect statistical difference at the planned end of accrual.

          Implications for Practice

          Chordoma is a rare neoplasm lacking effective systemic therapies for advanced, unresectable disease. Lack of clinically actionable somatic mutations in chordoma makes development of targeted therapy quite challenging. While the combination of yeast‐brachyury vaccine (GI‐6301) and standard radiation therapy did not demonstrate synergistic antitumor effects, brachyury still remains a good target for developmental therapeutics in chordoma. Patients and their oncologists should consider early referral to centers with expertise in chordoma (or sarcoma) and encourage participation in clinical trials.

          Abstract

          The use of a therapeutic cancer vaccine that stimulates the immune system to fight brachyury‐expressing cancer cells is a promising alternative to targeted molecular therapies. This article evaluates the concurrent use of a yeast‐brachyury vaccine in combination with radiation therapy in patients with advanced or metastatic chordoma.

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          Most cited references43

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          New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

          Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.
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            The basics of epithelial-mesenchymal transition.

            The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.
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              Combining radiotherapy and cancer immunotherapy: a paradigm shift.

              The therapeutic application of ionizing radiation has been largely based on its cytocidal power combined with the ability to selectively target tumors. Radiotherapy effects on survival of cancer patients are generally interpreted as the consequence of improved local control of the tumor, directly decreasing systemic spread. Experimental data from multiple cancer models have provided sufficient evidence to propose a paradigm shift, whereby some of the effects of ionizing radiation are recognized as contributing to systemic antitumor immunity. Recent examples of objective responses achieved by adding radiotherapy to immunotherapy in metastatic cancer patients support this view. Therefore, the traditional palliative role of radiotherapy in metastatic disease is evolving into that of a powerful adjuvant for immunotherapy. This combination strategy adds to the current anticancer arsenal and offers opportunities to harness the immune system to extend survival, even among metastatic and heavily pretreated cancer patients. We briefly summarize key evidence supporting the role of radiotherapy as an immune adjuvant. A critical appraisal of the current status of knowledge must include potential immunosuppressive effects of radiation that can hamper its capacity to convert the irradiated tumor into an in situ, individualized vaccine. Moreover, we discuss some of the current challenges to translate this knowledge to the clinic as more trials testing radiation with different immunotherapies are proposed.
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                Author and article information

                Contributors
                gulleyj@mail.nih.gov
                Journal
                Oncologist
                Oncologist
                10.1002/(ISSN)1549-490X
                ONCO
                theoncologist
                The Oncologist
                John Wiley & Sons, Inc. (Hoboken, USA )
                1083-7159
                1549-490X
                09 March 2021
                May 2021
                : 26
                : 5 ( doiID: 10.1002/onco.v26.5 )
                : e847-e858
                Affiliations
                [ 1 ] Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda Maryland USA
                [ 2 ] Neuro‐Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda Maryland USA
                [ 3 ] Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda Maryland USA
                [ 4 ] Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health Bethesda Maryland USA
                [ 5 ] Clinical Image Processing Service, National Institutes of Health Bethesda Maryland USA
                [ 6 ] University of Chicago Chicago Illinois USA
                [ 7 ] Precision Biosciences Durham North Carolina USA
                Author notes
                [*] [* ]Correspondence: James L Gulley, M.D., Ph.D., Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, USA. Telephone: 301‐480‐7164; e‐mail: gulleyj@ 123456mail.nih.gov
                [†]

                Contributed equally.

                Author information
                https://orcid.org/0000-0003-1313-6065
                https://orcid.org/0000-0002-1349-5917
                https://orcid.org/0000-0001-5106-8636
                https://orcid.org/0000-0002-7550-4938
                https://orcid.org/0000-0002-8280-551X
                https://orcid.org/0000-0001-7932-4072
                https://orcid.org/0000-0002-6569-2912
                Article
                ONCO13720
                10.1002/onco.13720
                8100546
                33594772
                c84a991c-58b5-45dd-9d85-4a3539457d6a
                Published 2021. This article is a U.S. Government work and is in the public domain in the USA.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 08 November 2020
                : 05 February 2021
                Page count
                Figures: 3, Tables: 5, Pages: 12, Words: 8222
                Categories
                43
                20
                25
                New Drug Development and Clinical Pharmacology
                New Drug Development and Clinical Pharmacology
                Custom metadata
                2.0
                May 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:06.05.2021

                Oncology & Radiotherapy
                chordoma,immunotherapy,therapeutic vaccine,radiation therapy,randomized clinical trial

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