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960MO - Clinical outcomes and immune responses in a phase I/II study of personalized, neoantigen-directed immunotherapy in patients with advanced MSS-CRC, GEA and NSCLC
- Daniel V. Catenacci (Chicago, IL, United States of America)
Abstract
Background
Induction of a strong neoantigen-specific T-cell response may drive tumor lysis and clinical benefit in patients (pts) with poor responses to checkpoint inhibitors (CPI) alone.
Methods
Pts with advanced MSS-CRC (n=10; ≥ 2 lines of therapy), gastroesophageal adenocarcinoma (GEA; n= 10; ≥ 1 line of therapy), and NSCLC (n=2; post-CPI, ≥ 1 line of therapy) were treated with a patient-specific neoantigen-directed heterologous prime/boost vaccine leveraging 20 neoantigens selected using the EDGETM platform plus 30 mg SC ipilimumab and 480 mg IV nivolumab. Prime is a chimpanzee adenovirus (ChAd) and boosts are self-amplifying mRNA formulated in lipid nanoparticles and a second ChAd administration.
Results
22 pts have been treated. Treatment-related AEs and SAEs were mostly Grade 1-2 and reversible with no DLTs. All evaluated pts have a vaccine-induced, neoantigen-specific T-cell response typically evident after priming and further increased or maintained with boosts. Elicited T-cells were specific for multiple neoantigens (including epitope spreading), cytotoxic and infiltrated the tumor. The best response in 18 evaluable pts per RECIST includes 1 confirmed complete response (GEA; > 4 months [mo]), 4 stable disease (1 CRC >18 mo, 1 CRC > 9 mo, 1 CRC and 1 GEA up to 6 mo), 11 progressive disease (PD), and 2 no measurable disease. CD8+ T-cell responses develop over the first 1-3 mo of vaccination and 8 pts progressed within the first 9 weeks, prior to expected treatment effect. Of 9 pts treated beyond RECIST PD, 4 pts did not have confirmed PD at the next scan. In 9 pts with MSS-CRC with at least one scan, 5 were progression-free per iRECIST beyond 6 mo and 4 of the 5 showed circulating tumor DNA (ctDNA) response (decrease ≥ 50% from baseline) indicating clinical activity in MSS-CRC. Enrollment continues; data will be updated.
Conclusions
Neoantigen-directed prime/boost immunotherapy in combination with CPI is well-tolerated and generates strong and persistent T-cells to multiple neoantigens. Increases in T-cells correlate with a novel pattern of response and clinical benefit characterized by a transient spike then decline in ctDNA, tumor markers, and tumor size, notably in pts with MSS-CRC.
Clinical trial identification
NCT03639714.
Legal entity responsible for the study
Gritstone bio, Inc.
Funding
Gritstone bio, Inc.
Disclosure
D.V. Catenacci: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Five Prime Therapeutics; Financial Interests, Personal, Advisory Board: Genentech/Roche; Financial Interests, Personal, Advisory Board: Gritstone Oncology; Financial Interests, Personal, Advisory Board: Guardant Health; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Taiho Pharmaceutical; Financial Interests, Personal, Advisory Board: Tempus; Financial Interests, Personal, Speaker’s Bureau: Foundation Medicine; Financial Interests, Personal, Speaker’s Bureau: Genentech; Financial Interests, Personal, Speaker’s Bureau: Guardant Health; Financial Interests, Personal, Speaker’s Bureau: Lilly; Financial Interests, Personal, Speaker’s Bureau: Merck; Financial Interests, Personal, Speaker’s Bureau: Tempus. C. Liao: Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Exelixis; Financial Interests, Personal, Advisory Board: Lexicon; Financial Interests, Personal, Advisory Board: Incyte; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Advisory Board: QED; Financial Interests, Personal, Advisory Board: Transthera Therapeutics; Financial Interests, Personal, Advisory Board: Blueprint Medicine; Financial Interests, Personal, Advisory Board: Genentech. S. Maron: Financial Interests, Personal, Advisory Board: Basilea; Financial Interests, Personal, Advisory Board: Daiichi-Sar; Financial Interests, Personal, Advisory Board: Natera; Financial Interests, Personal, Stocks/Shares: Calithera; Non-Financial Interests, Institutional, Other: Guardant; Financial Interests, Institutional, Other: Genentech. B.J. Solomon: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Genentech/Roche; Financial Interests, Institutional, Advisory Board: Pfizer; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Royalties: Veristrat (Biodesix); Financial Interests, Personal, Royalties: UpToDate. A. Mahipal: Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Research Grant: Taiho Pharmaceutical; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: Karyopharm; Financial Interests, Institutional, Research Grant: Novartis. M.L. Johnson: Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: Otsuka; Financial Interests, Institutional, Research Grant: Abbvie; Financial Interests, Institutional, Research Grant: Acerta Pharma; Financial Interests, Institutional, Research Grant: Adaptimmune; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Apexigen; Financial Interests, Institutional, Research Grant: Arcus; Financial Interests, Institutional, Research Grant: Array; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Atreca; Financial Interests, Institutional, Research Grant: BeiGene; Financial Interests, Institutional, Research Grant: Birdie; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Checkpoint Therapeutics; Financial Interests, Institutional, Research Grant: Corvus; Financial Interests, Institutional, Research Grant: CytomX; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Dynavax; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Genentech/Roche; Financial Interests, Institutional, Research Grant: Genocea; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Gritstone Oncology; Financial Interests, Institutional, Research Grant: Guardant; Financial Interests, Institutional, Research Grant: Hengrui; Financial Interests, Institutional, Research Grant: Immunocore; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Jounce; Financial Interests, Institutional, Research Grant: Kadmon; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Loxo; Financial Interests, Institutional, Research Grant: Lycera; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Mirati; Financial Interests, Institutional, Research Grant: Neovia; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: OncoMed; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Regeneron; Financial Interests, Institutional, Research Grant: Ribon; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Shattuck Labs; Financial Interests, Institutional, Research Grant: Stem CentRx; Financial Interests, Institutional, Research Grant: Syndax; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Institutional, Research Grant: Tarveda Therapeutics; Financial Interests, Institutional, Research Grant: TCR2 Therapeutics; Financial Interests, Institutional, Research Grant: University of Michigan; Financial Interests, Institutional, Research Grant: WindMIL. D. Carbone: Financial Interests, Institutional, Research Grant: Gritstone bio, Inc.; Financial Interests, Personal, Research Grant: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Abbvie; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Biocept; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Clovis; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Advisory Board: Foundation Medicine; Financial Interests, Personal, Advisory Board: Genentech/Roche; Financial Interests, Personal, Advisory Board: GlaxoSmithKline; Financial Interests, Personal, Advisory Board: Guardant Health; Financial Interests, Personal, Advisory Board: Helsinn; Financial Interests, Personal, Advisory Board: Incyte; Financial Interests, Personal, Advisory Board: Inivata; Financial Interests, Personal, Advisory Board: Inovio; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis Oncology; Financial Interests, Personal, Advisory Board: Peregrine Pharmaceuticals; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Synta; Financial Interests, Personal, Advisory Board: Loxo; Financial Interests, Personal, Research Grant: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Nexus. B. Johnson: Financial Interests, Personal, Advisory Board: Gritstone bio, Inc.; Financial Interests, Personal, Advisory Board: Incyte; Financial Interests, Personal, Advisory Board: Taiho Oncology; Financial Interests, Personal, Research Grant: Bristol-Myers Squibb; Financial Interests, Personal, Research Grant: Syntrix. S. Roychowdhury: Financial Interests, Institutional, Stocks/Shares: Johnson&Johnson; Financial Interests, Personal, Advisory Board: Abbvie; Financial Interests, Personal, Advisory Board: Incyte; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: QED Therapeutics; Financial Interests, Personal, Research Grant: Ignyta; Financial Interests, Personal, Research Grant: Incyte; Financial Interests, Personal, Research Grant: QED Therapeutics; Financial Interests, Personal, Research Grant: Takeda. K. Mody: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Genentech/Roche; Financial Interests, Personal, Advisory Board: Merrimack; Financial Interests, Personal, Advisory Board: Vicus Therapeutics; Financial Interests, Personal, Research Grant: Agios; Financial Interests, Personal, Research Grant: Ariad; Financial Interests, Personal, Research Grant: ArQule; Financial Interests, Personal, Research Grant: FibroGen; Financial Interests, Personal, Research Grant: MedImmune; Financial Interests, Personal, Research Grant: Senhwa Biosciences; Financial Interests, Personal, Research Grant: Taiho Pharmaceutical; Financial Interests, Personal, Research Grant: TRACON Pharma; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Gritstone Oncology; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Basilea; Financial Interests, Personal, Stocks/Shares: CytoDyn; Financial Interests, Personal, Stocks/Shares: Oncotherapeutics. E. Bournazou: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. D. Schenk: Financial Interests, Personal, Full or part-time Employment: Gritstone bio, Inc. S. Kounlavouth: Financial Interests, Personal, Full or part-time Employment: Gritstone bio, Inc. L. Kraemer: Financial Interests, Personal, Full or part-time Employment: Gritstone bio, Inc. G. Talbot: Financial Interests, Personal, Full or part-time Employment: Gritstone bio, Inc. R. Rousseau: Financial Interests, Personal, Full or part-time Employment: Gritstone bio, Inc.; Financial Interests, Personal, Stocks/Shares: Gritstone bio, Inc. A.R. Ferguson: Financial Interests, Personal, Full or part-time Employment: Gritstone bio, Inc.; Financial Interests, Personal, Stocks/Shares: Gritstone bio, Inc. All other authors have declared no conflicts of interest.
961MO - Safety, efficacy, immunogenicity of arenavirus-based vectors HB-201 and HB-202 in patients with HPV16+ cancers
- Marshall R. Posner (New York, NY, United States of America)
Abstract
Background
Human papillomavirus 16 positive (HPV16+) cancers are caused by stable expression of HPV16-specific E7 and E6 oncoproteins, also a source of immunogenic neoantigens. Replicating arenavirus vectors HB-201 (LCMV) and HB-202 (Pichinde virus), expressing the same non-oncogenic HPV16 E7E6 fusion protein, induce tumour-specific T-cell responses.
Methods
A phase I first-in-human study assessed HB-201 monotherapy and HB-201 & HB-202 alternating 2-vector therapy (HB-201/HB-202) intravenously (IV) with or without 1 intratumoral dose (IT/IV) in HPV16+ cancers. Safety, tolerability, and preliminary anti-tumour activity by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or immune RECIST were evaluated, as well as immunogenicity and pharmacodynamic biomarkers in blood and tumour tissue samples.
Results
The study treated 38 patients (29 with ≥1 efficacy scan) with confirmed HPV16+ cancers with a median (range) of 3 (1–10) prior anticancer therapies. The most common primary cancer site was oropharynx (76%), followed by cervical (7.9%). Eighteen patients received HB-201 monotherapy IV and 9 IT/IV; 11 patients received HB-201/HB-202 alternating therapy. Treatment was generally well tolerated. Twenty patients (53%) reported treatment-related adverse events (all Grade ≤2). Two of 11 evaluable patients treated with HB-201 IV every 3 weeks had partial response (including 1 unconfirmed immune complete response of target lesion) and 6 had stable disease (SD) lasting 1.2–5.9 months. All 6 evaluable patients that received HB-201/HB-202 had SD. HPV16-specific T-cells in peripheral blood were detected at several time points post-administration through direct
Conclusions
Arenavirus-based vectors HB-201 and HB-201/HB-202 appeared well tolerated and showed preliminary anti-tumour activity as single agents in this heavily pretreated population of patients with HPV16+ cancers. Induction of circulating E7E6-specific activated CD8+ T-cells was observed.
Clinical trial identification
NCT04180215.
Editorial acknowledgement
Writing and editorial support was provided by Margaret Van Horn, PhD, of AlphaBioCom, LLC, and was funded by Hookipa Biotech GmbH.
Legal entity responsible for the study
Hookipa Biotech GmbH.
Funding
Hookipa Biotech GmbH.
Disclosure
M.R. Posner: Other, Principal Investigator: Hookipa Pharma; Financial Interests, Advisory Role: BioNTech; Financial Interests, Advisory Role: Kura; Financial Interests, Advisory Board: Cel-Sci; Financial Interests, Advisory Board: Merck; Financial Interests, Advisory Role: Hookipa; Financial Interests; Advisory Role: Naveris; Financial Interests, Institutional, Funding: Formation Biologics; Financial Interests, Institutional, Funding: Innate; Financial Interests, Institutional, Funding: Hookipa Pharma; Financial Interests, Institutional, Funding: Sensei; Financial Interests, Institutional, Funding: Regeneron (Clinical Trials); Financial Interests, Royalties: Alopexx; Financial Interests, Institutional, Royalties: anti-Pseudomonas antibody; Financial Interests, Institutional, Royalties: anti-Staphylococcal monoclonal antibody; Financial Interests, Royalties: UpToDate editor; Financial Interests, Advisory Board: Hookipa Pharma. A.L. Ho: Other, Principal Investigator: Hookipa Pharma; Financial Interests, Institutional, Other, Honoraria: Massachusetts General Hospital; Financial Interests, Institutional, Other, Honoraria: Winship Cancer Center/Emory; Financial Interests, Institutional, Other, Honoraria: Leidos/NIH; Financial Interests, Institutional, Other, Honoraria: ASTRO; Financial Interests, Institutional, Other, Honoraria: Rasopathy conference; Financial Interests, Advisory Role: Eisai; Financial Interests, Advisory Role: Sanofi Genzyme; Financial Interests, Advisory Role: Ayala Pharmaceuticals; Financial Interests, Advisory Role: Regeneron; Financial Interests, Advisory Role: CureVac; Financial Interests, Advisory Role: Klus Pharm; Financial Interests, Advisory Role: Prelude Therapeutics; Financial Interests, Advisory Role: Novartis; Financial Interests, Advisory Role: Kura Oncology; Financial Interests, Advisory Role: AstraZeneca; Financial Interests, Advisory Role: Merck; Financial Interests, Advisory Role: Bristol-Myers Squibb; Financial Interests, Advisory Role: Genentech/Roche; Financial Interests, Advisory Role: Sun Pharmaceuticals; Financial Interests, Advisory Role: TRM Oncology; Financial Interests, Advisory Role: McGivney Global Advisors; Financial Interests, Advisory Role: Rgenta; Financial Interests, Advisory Role: Exelixis; Financial Interests, Advisory Role: Affyimmune; Financial Interests, Advisory Role: Inxmed; Financial Interests, Speaker’s Bureau: Medscape; Financial Interests, Speaker’s Bureau: Novartis; Financial Interests, Speaker’s Bureau: Omniprex America; Financial Interests, Personal, Funding, For Clinical Trials: Allos Therapeutics; Financial Interests, Personal, Funding, For Clinical Trials: Astellas Pharma; Financial Interests, Personal, Funding, For Clinical Trials: AstraZeneca; Financial Interests, Personal, Funding, For Clinical Trials: Ayala Pharmaceuticals; Financial Interests, Personal, Funding, For Clinical Trials: Bayer; Financial Interests, Personal, Funding, For Clinical Trials: Bristol-Myers Squibb; Financial Interests, Personal, Funding, For Clinical Trials: Daiichi Sankyo; Financial Interests, Personal, Funding, For Clinical Trials: Eisai; Financial Interests, Personal, Funding, For Clinical Trials: Elevar Therapeutics; Financial Interests, Personal, Funding, For Clinical Trials: Genentech/Roche; Financial Interests, Personal, Funding, For Clinical Trials: Celldex; Financial Interests, Personal, Funding, For Clinical Trials: Kura Oncology; Financial Interests, Personal, Funding, For Clinical Trials: Lilly; Financial Interests, Personal, Funding, For Clinical Trials: Merck; Financial Interests, Personal, Funding, For Clinical Trials: Novartis; Financial Interests, Personal, Funding, For Clinical Trials: Pfizer; Financial Interests, Personal, Funding, For Clinical Trials: Kura Oncology; Financial Interests, Other, Travel/Accommodation/Expenses: Ayala Pharmaceuticals; Financial Interests, Other, Travel/Accommodation/Expenses: Ignyta; Financial Interests, Other, Travel/Accommodation/Expenses: Janssen Oncology; Financial Interests, Other, Travel/Accommodation/Expenses: Klus Pharma; Financial Interests, Other, Travel/Accommodation/Expenses: Kura Oncology; Financial Interests, Other, Travel/Accommodation/Expenses: Merck; Financial Interests, Other, Travel/Accommodation/Expenses: Shanghai Jia Tong University; Financial Interests, Stocks/Shares: Rgenta; Financial Interests, Member of the Board of Directors: International Thyroid Oncology Group. J. Niu: Other, Principal Investigator: Hookipa Pharma; Financial Interests, Advisory Role: Boehringer Ingelheim; Financial Interests, Advisory Role: Merck; Financial Interests, Advisory Role: AstraZeneca; Financial Interests, Advisory Role: Blueprint Medicines; Financial Interests, Advisory Role: Immvira; Financial Interests, Advisory Role: Johnson&Johnson; Financial Interests, Advisory Role: Takeda; Financial Interests, Advisory Role: Exelixis; Financial Interests, Advisory Role: Beigene; Financial Interests, Advisory Role: Mirati Therapeutics. L. Nabell: Other, Principal Investigator, NCT04180215: Hookipa Pharma. R.S. Leidner: Other, Principal Investigator, NCT04180215: Hookipa Pharma; Financial Interests, Advisory Role: Sanofi/Regeneron; Financial Interests, Advisory Role: AstraZeneca; Financial Interests, Advisory Role: Merck; Financial Interests, Advisory Role: Bristol-Myers Squibb; Financial Interests, Advisory Role: Oncolys Biopharma; Financial Interests, Institutional, Funding: Bristol-Myers Squibb; Financial Interests, Institutional, Funding: MedImmune; Financial Interests, Other, Travel/Accommodation/Expenses: Sanofi/Regeneron; Financial Interests, Other, Travel/Accommodation/Expenses: AstraZeneca; Financial Interests, Other, Travel/Accommodation/Expenses: Merck; Financial Interests, Other, Travel/Accommodation/Expenses: Bristol-Myers Squibb. J. Nieva: Other, Principal Investigator: Hookipa Pharma; Financial Interests, Advisory Role: AstraZeneca; Financial Interests, Advisory Role: Bayer; Financial Interests, Advisory Role: Western Oncolytics; Financial Interests, Advisory Role: Fujirebio Diagnostics; Financial Interests, Advisory Role: Takeda; Financial Interests, Advisory Role: Roche/Genentech; Financial Interests, Advisory Role: Turnstone; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Funding: Genentech; Financial Interests, Stocks/Shares: Epic Sciences; Financial Interests, Stocks/Shares: Cansera; Financial Interests, Royalties: Patent Pending - movement and unexpected health care encounters. D.L. Richardson: Other, Principal Investigator: Hookipa Pharma; Financial Interests, Advisory Role: AstraZeneca; Financial Interests, Advisory Role: Genentech/Roche; Financial Interests, Advisory Role: Deciphera; Financial Interests, Advisory Role: Mersana; Financial Interests, Advisory Role: Tesaro/GlaxoSmithKline; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Genentech/Roche; Financial Interests, Institutional, Funding: Mersana; Financial Interests, Institutional, Funding: Tesaro/GlaxoSmithKline; Financial Interests, Institutional, Funding: Aravive; Financial Interests, Institutional, Funding: ArQule, Inc.; Financial Interests, Institutional, Funding: Decphera; Financial Interests, Institutional, Funding: Harpoon Therapeutics; Financial Interests, Institutional, Funding: Innovent Biologics; Financial Interests, Institutional, Funding: Karyopharm; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Funding: Syros Pharmaceuticals; Financial Interests, Institutional, Funding: Five Prime Therapeutics; Financial Interests, Institutional, Funding: Hookipa Biotech; Financial Interests, Institutional, Funding: FujiFilm; Financial Interests, Institutional, Funding: Shattuck Labs; Financial Interests, Institutional, Funding: Plexxikon. A.T. Pearson: Other, Principal Investigator: Hookipa Pharma; Financial Interests, Advisory Role: Prelude Therapeutics; Financial Interests, Expert Testimony: Smith Haughey Rice & Roegge. D. Wang: Other, Principal Investigator: Hookipa Pharma; Financial Interests, Advisory Role: Castle BioSciences; Financial Interests, Advisory Role: Qurgen; Financial Interests, Other, Travel/Accommodation/Expenses: Castle BioSciences; Financial Interests, Other, Travel/Accommodation/Expenses: Qurgen. K. Chung: Other, Principal Investigator: Hookipa Pharma. D.R. Adkins: Other, Principal Investigator: Hookipa Pharma; Financial Interests, Advisory Role: Merck; Financial Interests, Advisory Role: Cue Biopharma; Financial Interests, Advisory Role: BLU; Financial Interests, Advisory Role: Exelixis; Financial Interests, Advisory Role: Kura; Financial Interests, Advisory Role: Twoxar; Financial Interests, Advisory Role: Vaccinex; Financial Interests, Advisory Role: Zilio; Financial Interests, Advisory Role: Targimmune; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Eli Lilly; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Funding: Celgene/BMS; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Atara Bio; Financial Interests, Institutional, Funding: Blueprint Medicine; Financial Interests, Institutional, Funding: Celldex; Financial Interests, Institutional, Funding: Aduro; Financial Interests, Institutional, Funding: Enzychem; Financial Interests, Institutional, Funding: Kura; Financial Interests, Institutional, Funding: Exelixis; Financial Interests, Institutional, Funding: Innate; Financial Interests, Institutional, Funding: Sensei; Financial Interests, Institutional, Funding: Matrix Biomed; Financial Interests, Institutional, Funding: ISA; Financial Interests, Institutional, Funding: Cofactor; Financial Interests, Institutional, Funding: Cue Biopharma; Financial Interests, Institutional, Funding: Debiopharm; Financial Interests, Institutional, Funding: Epizyme; Financial Interests, Institutional, Funding: Hookipa; Financial Interests, Institutional, Funding: Shanghai De Novo; Financial Interests, Institutional, Funding: Roche. A. Pimentel: Other, Principal Investigator: Hookipa Pharma; Other, Principal Investigator: Turnstone Biologics, Corp; Other, Principal Investigator: Ludwig Institute for Cancer Research, Ltd; Other, Principal Investigator: Isofol Medical AB; Other, Principal Investigator: Hoosier Cancer Research Network, Inc.; Other, Principal Investigator: ECOG-ACRIN; Financial Interests, Advisory Role: Taiho Oncology; Financial Interests, Advisory Role: QED Therapeutics; Financial Interests, Advisory Role: Bristol-Myers Squibb Company; Financial Interests, Stocks/Shares: Pfizer; Financial Interests, Stocks/Shares: BioNTech. S. Wong: Other, Principal Investigator: Hookipa Pharma. C. Iacobucci: Financial Interests, Stocks/Shares: BMS; Financial Interests, Stocks/Shares: Hookipa Pharma; Financial Interests, Full or part-time Employment: Hookipa Pharma. X. Qing: Financial Interests, Stocks/Shares: Hookipa Pharma; Financial Interests, Full or part-time Employment: Hookipa Pharma. K. Katchar: Financial Interests, Stocks/Shares: Hookipa Pharma; Financial Interests, Full or part-time Employment: Hookipa Pharma. K. Schlienger: Financial Interests, Other, Travel/Accommodation/Expenses: Hookipa Pharma; Financial Interests, Full or part-time Employment: Hookipa Pharma. I. Matushansky: Financial Interests, Stocks/Shares: Hookipa Pharma; Financial Interests, Full or part-time Employment: Hookipa Pharma; Financial Interests, Member of the Board of Directors: Crescendo Biologics; Financial Interests, Leadership Role: Hookipa Pharma. S. Fu: Other, Principal Investigator: Hookipa Pharma; Financial Interests, Personal, Funding: Millenium Pharmaceuticals, Inc.; Financial Interests, Personal, Funding: Sorcimed Biopharma, Inc.; Financial Interests, Personal, Funding: Exelixis; Financial Interests, Personal, Funding: BeiGene; Financial Interests, Personal, Funding: Novocure; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Abbisko; Financial Interests, Institutional, Funding: Anaeropharma Science; Financial Interests, Institutional, Funding: Arrien Pharmaceuticals; Financial Interests, Institutional, Funding: BeiGene; Financial Interests, Institutional, Funding: BioAtla, LLC; Financial Interests, Institutional, Funding: Boehringer Ingelheim; Financial Interests, Institutional, Funding: Eli Lilly & Co.; Financial Interests, Institutional, Funding: Hookipa Biotech; Financial Interests, Institutional, Funding: Huya Bioscience International; Financial Interests, Institutional, Funding: IMV, Inc; Financial Interests, Institutional, Funding: Innovent Biologics, Col., Ltd; Financial Interests, Institutional, Funding: Lyvgen Pharma; Financial Interests, Institutional, Funding: MacroGenics; Financial Interests, Institutional, Funding: Medivir AB; Financial Interests, Institutional, Funding: Millennium Pharmaceuticals, Inc.; Financial Interests, Institutional, Funding: Nerviano Medical Sciences; Financial Interests, Institutional, Funding: Neupharma, Inc; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Novocure; Financial Interests, Institutional, Funding: OncoMed Pharmaceuticals; Financial Interests, Institutional, Funding: Parexel International, LLC; Financial Interests, Institutional, Funding: Sellas Life Sciences Group; Financial Interests, Institutional, Funding: Sorcimed Biopharma, Inc.; Financial Interests, Institutional, Funding: Tolero Pharmaceuticals; Financial Interests, Institutional, Funding: National Institutes of Health/National Cancer Institute; Financial Interests, Institutional, Research Grant, P30CA016672 – Core Grant (CCSG Shared Resources): National Cancer Institute/National Institutes of Health; Financial Interests, Full or part-time Employment: MD Anderson - FT. D.G. Pfister: Other, Principal Investigator: Hookipa Pharma; Financial Interests, Advisory Role: Boehringer Ingelheim; Financial Interests, Advisory Role: Celgene; Financial Interests, Advisory Role: Bristol-Myers Squibb; Financial Interests, Advisory Role: Incyte; Financial Interests, Personal, Funding: Boehringer Ingelheim; Financial Interests, Personal, Funding: AstraZeneca; Financial Interests, Personal, Funding: Novartis; Financial Interests, Personal, Funding: MedImmune; Financial Interests, Personal, Funding: Merck; Financial Interests, Personal, Funding: Regeneron; Financial Interests, Personal, Funding: Atara Biotherapeutics; Financial Interests, Personal, Funding: Kura; Financial Interests, Personal, Funding: Esai; Financial Interests, Personal, Funding: Ayala; Financial Interests, Personal, Funding: Plexxikon.
962MO - A phase I clinical trial on intratumoral injection of autologous CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells (myDC) in combination with talimogene laherparepvec (T-VEC) in patients with advanced pretreated melanoma
- Julia Katharina Schwarze (Jette, Belgium)
Abstract
Background
Intratumoral (IT) myDC play a pivotal role in initiating antitumor immune responses within the tumor microenvironment. IT injection of the oncolytic virus T-VEC may lead to the release of tumor antigens and maturation signals that can be captured and processed by CD1c (BDCA-1)+/CD141 (BDCA-3)+ myDC, thereby reinvigorating the cancer immunity cycle.
Methods
Patients (pts) with ICI-refractory melanoma received IT injections of ≥1 non-visceral metastases with T-VEC (106 PFU/mL; max 4 mL) on day 1 followed by IT injection of CD1c (BDCA-1)+ (cohort C1) or CD1c (BDCA-1)+/CD141 (BDCA-3)+ myDC (cohort C2) on day 2. Injection of T-VEC (108PFU/mL; max 4 mL) was repeated on day 21, and Q2w thereafter. In C1, the number of CD1c (BDCA-1)+myDCs was escalated from 0.5x106, to 1x106, and 10x106 cells. In C2, pts received all isolated CD1c (BDCA-1)+/CD141 (BDCA-3)+ myDCs. Primary objectives were safety and feasibility. Immunohistochemistry (IHC), gene expression profiling (GEP), and multiplexed immunofluorescence (mIF) of baseline and on-treatment biopsies was performed.
Results
13 pts were enrolled (C1: n=7 [respectively 2, 2, and 3 pts per dose-level of myDC]; C2: n=6). Pts received the predefined dose of myDCs and a median of 6 (range 3-8) T-VEC injections. Most frequent AEs were fatigue in 11 pts (85%), injection-site pain in 9 pts (69%), fever in 8 pts (62%), and chills and flu-like symptoms in 6 pts (46%). There were no G4 or G5 AEs. AEs of special interest were a G3 eosinophilia and a G2 purpuric rash at the injection-site; 2 pts (C1, dose level 3) developed a pathological complete remission that is ongoing at 24 months following treatment initiation. One pt in C2 had an unconfirmed partial response (iRECIST); a mixed response was observed in 2 pts. Responses were observed in both injected and non-injected lesions. In responder pts, infiltration of lymphocytes was observed on IHC. GEP and mIF on biopsies are ongoing.
Conclusions
IT co-injection of CD1c (BDCA-1)+ +/- CD141 (BDCA-3)+ myDC plus T-VEC is feasible, tolerable, and resulted in encouraging early signs of durable antitumor activity in pts with ICI-refractory melanoma.
Clinical trial identification
NCT03747744.
Legal entity responsible for the study
Department of Medical Oncology, Universitair Ziekenhuis Brussel.
Funding
Kom op Tegen Kanker (Stand up to Cancer), the Flemish cancer society.
Disclosure
J.K. Schwarze: Non-Financial Interests, Personal, Other: Amgen; Financial Interests, Personal, Invited Speaker: Novartis; Non-Financial Interests, Personal, Other: MSD Oncology. G. Awada: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Novartis; Non-Financial Interests, Personal, Other: MSD Oncology; Non-Financial Interests, Personal, Other: Astellas Pharma; Non-Financial Interests, Personal, Other: Novartis; Non-Financial Interests, Personal, Other: Pfizer. B. Neyns: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Bristol-Myers Sqibb; Financial Interests, Personal, Invited Speaker: Merck Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Roche; Financial Interests, Institutional, Funding: Merck Sharp & Dohme. All other authors have declared no conflicts of interest.
Discussion 960MO, 961MO and 962MO
- Thomas F. Gajewski (Chicago, United States of America)
963MO - Naxitamab for the treatment of refractory/relapsed high-risk neuroblastoma (HR NB): Updated efficacy and safety data from the international, multicenter phase II trial 201
- Jaume Mora (Barcelona, Spain)
Abstract
Background
Patients with HR NB (∼50% of patients with NB at initial diagnosis) and limited or no response to initial therapy have poor outcomes, and residual disease can drive relapse. Naxitamab is a GD2-binding monoclonal antibody, recently approved in the US in combination with granulocyte-macrophage colony stimulating factor (GM-CSF) for the treatment of relapsed/refractory (R/R) HR NB in the bone and/or bone marrow (BM) in patients ≥1 year of age with a partial response, minor response, or stable disease to prior therapy. We present updated interim data from the pivotal trial for that accelerated approval.
Methods
Trial 201 is an international, multicenter, phase II trial designed to evaluate safety and efficacy of naxitamab in HR NB patients with primary refractory disease or incomplete response to salvage treatment in bone/BM. Patients with progressive or residual soft tissue disease were ineligible. Naxitamab was administered over ≥30 min in the outpatient setting on Days 1, 3 and 5 at 3 mg/kg/day (9 mg/kg/cycle) in combination with GM-CSF at 250 μg/m2/day on Days -4 to 0 and at 500 μg/m2/day on Days 1 to 5. Treatment cycles were repeated every 4 weeks. Efficacy was scored using international NB response criteria.
Results
As of March 2021, 48 patients were included in the safety population and 36 in the efficacy population. The overall response rate was 58% (21/36) with a complete response rate of 44% (16/36) and partial response rate of 14% (5/36). The median duration of response was 25 weeks. Infusion-related reactions (including pain) were the most common adverse events (AE), occurring in all patients. 11 patients reported 13 naxitamab-related SAEs (4 hypotension, 4 anaphylactic reaction and 1 each for fatigue, pyrexia, laryngeal oedema, respiratory depression and urticaria). 4 patients (8%) discontinued naxitamab due to naxitamab-related AEs. No AEs were fatal. Anti-drug antibody formation was observed in 10/46 (22%) patients assessed.
Conclusions
Naxitamab provided a clinically meaningful response in patients with R/R HR NB with bone and/or BM disease only, with a manageable safety profile in the outpatient setting addressing a significant unmet medical need.
Clinical trial identification
NCT03363373.
Editorial acknowledgement
Under direction and guidance from the authors, medical writing support was provided by Lars Hein Jensen, an employee of Y-mAbs Therapeutics, Inc.
Legal entity responsible for the study
Y-mAbs Therapeutics, Inc.
Funding
Y-mAbs Therapeutics, Inc.
Disclosure
J. Mora: Financial Interests, Personal, Advisory Role: Y-mabs Therapeutics, Inc. G. Chan: Financial Interests, Personal, Stocks/Shares: Xellera Therapeutics International; Financial Interests, Personal, Other, Honoraria: Pangenia Inc; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Apotex; Financial Interests, Personal, Speaker’s Bureau: Apotex. D.A. Morgenstern: Financial Interests, Personal, Speaker’s Bureau: Y-mabs Therapeutics, Inc.; Financial Interests, Personal, Advisory Role: Y-mabs Therapeutics, Inc.; Financial Interests, Personal, Speaker’s Bureau: EUSA Pharma; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Clarity Pharmaceuticals; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Research Grant: Bristol Myers Squibb. K. Nysom: Financial Interests, Personal, Advisory Role: Y-mabs Therapeutics, Inc.; Financial Interests, Personal, Advisory Role: Bayer. K. Tornøe: Financial Interests, Personal, Full or part-time Employment: Y-mabs Therapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Y-mabs Therapeutics, Inc. N. Losic: Financial Interests, Personal, Full or part-time Employment: Y-mabs Therapeutics, Inc. All other authors have declared no conflicts of interest.
964MO - Entinostat, nivolumab and ipilimumab in advanced HER2-negative breast cancer (ETCTN-9844)
- Evanthia T. Roussos Torres (Los Angeles, United States of America)
Abstract
Background
In murine models of breast cancer the histone deacetylase inhibitor entinostat increases CD8+ effector: FoxP3+ regulatory T-cell ratios (CD8/FoxP3), and improves the efficacy of immune checkpoint inhibitors. We identified a recommended phase II dose (RP2D) for the combination of entinostat, nivolumab and ipilimumab (ETCTN-9884, manuscript submitted). We report combined safety and efficacy results of participants with HER2-negative breast cancer treated in dose escalation (n=6) and expansion cohorts treated at the RP2D (n=18).
Methods
Participants received entinostat PO 5mg weekly x 2 (run-in), then 3-5mg weekly entinostat PO, 3mg/kg q2 weeks nivolumab, and 1mg/kg q6 weeks ipilimumab IV (max 4 doses ipi, RP2D). Primary endpoint: Safety (CTCAE v5). Secondary endpoints: Change in tumor CD8/FoxP3 ratio (integrated biomarker); Objective response rate (ORR). We obtained tissue samples at baseline, after 2 week run-in, and after 8 weeks of combination therapy and completed immunohistochemical staining for CD8, FoxP3 and PD-L1. Blood samples at each timepoint were obtained and Luminex analysis for global changes in plasma cytokine expression was performed.
Results
Amongst 24 participants [12 hormone receptor-positive (HR+), 12 triple-negative (TNBC)], median age was 54.5 years (range 38-77) and median prior therapies 6.5 (range 1-13). Median cycles received was 2 (range 1-17). Grade 3/4 AEs included anemia (N=4, 17%), decreased neutrophil count (N=3, 13%), and increased lipase (N=2, 8%). Most common immune-related (ir) AEs included rash (N =7, 29%), hypothyroidism (N =5, 21%), and pneumonitis (N=2, 8%). ORR by RECIST (v1.1) was 30% (6/20 evaluable), and by irRECIST was 20% (4/20 evaluable), including a complete response in a participant with TNBC.
Conclusions
The combination of entinostat, nivolumab and ipilimumab at the RP2D was associated with expected (ir) AEs in advanced HER2-negative breast cancer. An ORR of 30% suggests this combination should be evaluated further. Correlative analyses from serial biospecimens pre- and post-therapy to evaluate the immune response and landscape will be presented.
Clinical trial identification
NIH/NCI 9844.
Legal entity responsible for the study
NCI CTEP.
Funding
US NIH- Cancer Therapy Evaluation Program supplied entinostat, nivolumab and ipilimumab. V Foundation (Translational Award 2017).
Disclosure
A. Brufsky: Financial Interests, Institutional, Other: Paid consultant for Lilly, Novartis, Pfizer, AstraZeneca, Eisai, Roche, Sanofi. P. Lorusso: Financial Interests, Institutional, Other: Dr. LoRusso reports personal fees from Abbvie, personal fees from Agios, personal fees from Five Prime, personal fees from GenMab, personal fees from Halozyme, personal fees from Roche-Genentech, personal fees from Genentech, personal fees from Cytomx, pe. J.P. Eder: Financial Interests, Institutional, Other: Dr. Eder reports ongoing collaboration with Roche on new approaches to Precision Medicine Tumour Boards. V. Chung: Financial Interests, Institutional, Other: VC COI include Ipsen and Coherus speaker’s bureau; Perthera Consultant; Pfizer Consultant. M.A. Rudek: Financial Interests, Institutional, Other: MAR has received research grants to institution from Celgene Corporation, Cullinan Apollo, and RenovoRx; MAR’s spouse is employed by GlaxoSmithKline. E. Fertig: Non-Financial Interests, Institutional, Other: Viosera Therapeutics, Scientific Advisory Board Member . R.A. Anders: Financial Interests, Institutional, Other: RAA has received research support from Bristol-Myers Squibb, Merck, StandUp2Cancer, FLXbio and is a paid consultant for Bristol-Myers Squibb, Merck, Incyte, AstraZeneca and FLXbio. A. Cimino-Mathews: Financial Interests, Institutional, Other: ACM has received research grants to institution from HeritX, Genentech and Bristol-Myers Squibb and serves as a consultant to Bristol-Myers Squibb. E.M. Jaffee: Financial Interests, Institutional, Other: E.M. Jaffee is a paid consultant for Adaptive Biotech, CSTONE, Achilles, DragonFly, and Genocea. She receives funding from Lustgarten Foundation and Bristol Myer Squibb. She is the Chief Medical Advisor for Lustgarten and SAB advisor to The Parker Institute. V. Stearns: Financial Interests, Institutional, Other: Received research grants to institution from Abbvie, Biocept, Pfizer, Novartis, and Puma Biotechnology. Member, Data Safety Monitoring Board, Immunomedics, Inc. R.M. Connolly: Financial Interests, Institutional, Other: RC has received research grants to institution from Novartis, Puma Biotechnology, Merck, Genentech, Macrogenics; and an unrestricted educational grant from Pfizer. All other authors have declared no conflicts of interest.
965MO - GTB-3550 tri-specific killer engager safely activates and delivers IL-15 to NK cells, but not T-cells, in immune suppressed patients with advanced myeloid malignancies, a novel paradigm exportable to solid tumors expressing Her2 or B7H3
- Jeffrey S. Miller (Minneapolis, United States of America)
Abstract
Background
Refractory cancers exhibit profound tumor-induced immune suppression. IL-15, the homeostatic factor stimulating NK cells and T-cells, has shown little antitumor activity as a monotherapy and exhibits dose limiting toxicities. We hypothesized that simultaneous targeted delivery of IL-15 and cancer antigen directed NK cell killing would restore a patient’s endogenous NK cells from tumor induced immune suppression. We developed a novel Tri-Specific Killer Engager protein therapeutic, GTB-3550 TriKE™, comprised of two engagers targeting CD16 on NK cells, CD33 on myeloid malignancies, and an IL-15 linker.
Methods
Relapsed/refractory CD33+ malignancies were treated with three consecutive weeks of GTB-3550 (5-150 mcg/kg/day) by continuous infusion (CI x 4 days) in a phase I study (NCT03214666). Immune monitoring was assessed. Preclinically, a second generation TriKE using a single domain camelid (cam) anti-CD16, IL-15 and targeting Her2 or B7H3 was tested.
Results
GTB-3550 administered at >10 times the molar equivalent MTD of rhIL-15 was found to be safe. All lymphocytes decreased from blood during CI egressing into tissues with a dose-dependent proliferative rebound after 3 days of rest. After week 2 and 3 of CI, almost all NK cells were proliferating (Ki-67+) with little proliferation of CD4 or CD8 T-cells. GTB-3550 rescued patientʼs NK cells from immune suppression resulting in cells that were highly functional, predominantly CD16+, and retained enhanced killing for weeks after CI was discontinued. Preclinically, second generation TriKEs against Her2 and B7H3 showed the same targeted delivery of IL-15 to NK cells, in vitro activity to relevant antigen expressing targets, rescue of tumor-induced immune suppression from blood of advanced cancer patients and in vivo activity in xenogeneic models of human tumor.
Conclusions
GTB-3550 TriKE given as a monotherapy safely induced a sustained functional expansion of endogenous NK cells with anti-tumor activity in advanced AML and MDS patients treated with at least 25 mcg/kg/day. Second generation solid tumor TriKE therapeutics against HER2 and B7H3 will be tested clinically next year.
Clinical trial identification
NCT03214666.
Legal entity responsible for the study
The authors.
Funding
NIH, GT Biopharma.
Disclosure
J.S. Miller: Financial Interests, Personal and Institutional, Advisory Board, Consulting and reserach support: GT Biopharma. D.A. Vallera: Financial Interests, Personal and Institutional, Funding: GT Biopharma. M. Felices: Financial Interests, Personal and Institutional, Research Grant: GT Biopharma. All other authors have declared no conflicts of interest.
Discussion 963MO, 964MO and 965MO
- Christian U. Blank (Amsterdam, Netherlands)