Safety, Antitumor Activity, and T-cell Responses in a Dose-Ranging Phase I Trial of the Oncolytic Peptide LTX-315 in Patients with Solid Tumors.

Adult Aged Aged, 80 and over Antineoplastic Agents / administration & dosage Biopsy Disease Management Female Humans Immunohistochemistry Injections, Intralesional Lymphocytes, Tumor-Infiltrating Male Middle Aged Neoplasms / diagnosis Oligopeptides / administration & dosage T-Lymphocytes / drug effects Tomography, X-Ray Computed Treatment Outcome Tumor Microenvironment / drug effects

Journal

Clinical cancer research : an official journal of the American Association for Cancer Research

ISSN: 1557-3265

Titre abrégé: Clin Cancer Res

Pays: United States

ID NLM: 9502500

Informations de publication

Date de publication:
15 05 2021

Historique:

received: 11 09 2020

revised: 07 12 2020

accepted: 02 02 2021

pubmed: 6 2 2021

medline: 17 3 2022

entrez: 5 2 2021

Statut: ppublish

Résumé

LTX-315 is a first-in-class, 9-mer membranolytic peptide that has shown potent immunomodulatory properties in preclinical models. We conducted a phase I dose-escalating study of intratumoral LTX-315 administration in patients with advanced solid tumors. Thirty-nine patients were enrolled, receiving LTX-315 injections into accessible tumors. The primary objective was to assess the safety and tolerability of this approach, with antitumor and immunomodulatory activity as secondary objectives. Tumor biopsies were collected at baseline and posttreatment for analysis of immunologic parameters. The most common treatment-related grade 1-2 adverse events were vascular disorders including transient hypotension (18 patients, 46%), flushing (11 patients, 28%), and injection site reactions in 38% of patients. The most common grade 3 LTX-315-related toxicities were hypersensitivity or anaphylaxis (4 patients, 10%). Analysis of immune endpoints in serial biopsies indicated that LTX-315 induces necrosis and CD8 LTX-315 has an acceptable safety profile, is clinically active, induces changes in the tumor microenvironment and contributes to immune-mediated anticancer activity.

Identifiants

DOI: 10.1158/1078-0432.CCR-20-3435 PMID: 33542073

pubmed: 33542073

pii: 1078-0432.CCR-20-3435

doi: 10.1158/1078-0432.CCR-20-3435

doi:

Substances chimiques

Antineoplastic Agents 0

LTX-315 0

Oligopeptides 0

Banques de données

ClinicalTrials.gov

['NCT01986426']

Types de publication

Clinical Trial, Phase I Journal Article Multicenter Study Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

2755-2763

Informations de copyright

Références

Hamid O, Ismail R, Puzanov I. Intratumoral immunotherapy-update 2019. Oncologist. 2020;25:e423–e38.

Marabelle A, Andtbacka R, Harrington K, Melero I, Leidner R, de Baere T, et al. Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT). Ann Oncol. 2018;29:2163–74.

Hong WX, Haebe S, Lee AS, Westphalen CB, Norton JA, Jiang W, et al. Intratumoral immunotherapy for early-stage solid tumors. Clin Cancer Res. 2020;26:3091–9.

Haug BE, Camilio KA, Eliassen LT, Stensen W, Svendsen JS, Berg K, et al. Discovery of a 9-mer cationic peptide (LTX-315) as a potential first in class oncolytic peptide. J Med Chem. 2016;59:2918–27.

Sveinbjornsson B, Camilio KA, Haug BE, Rekdal O. LTX-315: a first-in-class oncolytic peptide that reprograms the tumor microenvironment. Future Med Chem. 2017;9:1339–44.

Camilio KA, Berge G, Ravuri CS, Rekdal O, Sveinbjornsson B. Complete regression and systemic protective immune responses obtained in B16 melanomas after treatment with LTX-315. Cancer Immunol Immunother. 2014;63:601–13.

Gaspar D, Veiga AS, Castanho MA. From antimicrobial to anticancer peptides. A review. Front Microbiol. 2013;4:294.

Riedl S, Zweytick D, Lohner K. Membrane-active host defense peptides–challenges and perspectives for the development of novel anticancer drugs. Chem Phys Lipids. 2011;164:766–81.

Utsugi T, Schroit AJ, Connor J, Bucana CD, Fidler IJ. Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human blood monocytes. Cancer Res. 1991;51:3062–6.

Liao H-W, Garris C, Pfirschke C, Rickelt S, Arlauckas S, Siwicki M, et al. LTX-315 sequentially promotes lymphocyte-independent and lymphocyte-dependent antitumor effects. Cell Stress. 2019;3:348–60.

Nestvold J, Wang MY, Camilio KA, Zinocker S, Tjelle TE, Lindberg A, et al. Oncolytic peptide LTX-315 induces an immune-mediated abscopal effect in a rat sarcoma model. Oncoimmunology. 2017;6:e1338236.

Camilio KA, Wang M-Y, Mauseth B, Waagene S, Kvalheim G, Rekdal Ø, et al. Combining the oncolytic peptide LTX-315 with doxorubicin demonstrates therapeutic potential in a triple-negative breast cancer model. Breast Cancer Res. 2019;21:9.

Yamazaki T, Pitt JM, Vetizou M, Marabelle A, Flores C, Rekdal O, et al. The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade. Cell Death Differ. 2016;23:1004–15.

Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412–20.

Brunsvig P. A phase I study with LTX-315, an immunogenic cell death inducer, in patients with transdermally accessible tumors. J Clin Oncol. 2014;32.

Goldmacher GV, Khilnani AD, Andtbacka RHI, Luke JJ, Hodi FS, Marabelle A, et al. Response criteria for intratumoral immunotherapy in solid tumors: itRECIST. J Clin Oncol. 2020;38:2667–76.

Galon J, Bindea G, Mlecnik B, Angell H, Lagorce C, Todosi AM, et al. Microenvironnement immunitaire et cancer. Med Sci. 2014;30:439–44.

Jebsen NL, Apelseth TO, Haugland HK, Rekdal O, Patel H, Gjertsen BT, et al. Enhanced T-lymphocyte infiltration in a desmoid tumor of the thoracic wall in a young woman treated with intratumoral injections of the oncolytic peptide LTX-315: a case report. J Med Case Rep. 2019;13:177.

DeWitt WS, Emerson RO, Lindau P, Vignali M, Snyder TM, Desmarais C, et al. Dynamics of the cytotoxic T cell response to a model of acute viral infection. J Virol. 2015;89:4517–26.

Rytlewski J, Deng S, Xie T, Davis C, Robins H, Yusko E, et al. Model to improve specificity for identification of clinically-relevant expanded T cells in peripheral blood. PLoS One. 2019;14:e0213684.

Hammerich L, Bhardwaj N, Kohrt HE, Brody JD. In situ vaccination for the treatment of cancer. Immunotherapy. 2016;8:315–30.

Hammerich L, Binder A, Brody JD. In situ vaccination: Cancer immunotherapy both personalized and off-the-shelf. Mol Oncol. 2015;9:1966–81.

Pierce RH, Campbell JS, Pai SI, Brody JD, Kohrt HE. In-situ tumor vaccination: bringing the fight to the tumor. Hum Vaccin Immunother. 2015;11:1901–9.

Sagiv-Barfi I, Czerwinski DK, Levy S, Alam IS, Mayer AT, Gambhir SS, et al. Eradication of spontaneous malignancy by local immunotherapy. Sci Transl Med. 2018;10:eaan4488.

Aznar MA, Tinari N, Rullán AJ, Sánchez-Paulete AR, Rodriguez-Ruiz ME, Melero I. Intratumoral delivery of immunotherapy-act locally, think globally. J Immunol. 2017;198:31–9.

Pundir P, Kulka M. The role of G protein-coupled receptors in mast cell activation by antimicrobial peptides: is there a connection?. Immunol Cell Biol. 2010;88:632–40.

Edlund K, Madjar K, Mattsson JSM, Djureinovic D, Lindskog C, Brunnström H, et al. Prognostic impact of tumor cell programmed death ligand 1 expression and immune cell infiltration in NSCLC. J Thorac Oncol. 2019;14:628–40.

Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov. 2012;11:215–33.

Martin de la Fuente L, Westbom-Fremer S, Arildsen NS, Hartman L, Malander S, Kannisto P, et al. PD-1/PD-L1 expression and tumor-infiltrating lymphocytes are prognostically favorable in advanced high-grade serous ovarian carcinoma. Virchows Arch. 2020;477:83–91.

Trujillo JA, Sweis RF, Bao R, Luke JJ. T cell-inflamed versus non-T cell-inflamed tumors: a conceptual framework for cancer immunotherapy drug development and combination therapy selection. Cancer Immunol Res. 2018;6:990–1000.

Van Berckelaer C, Rypens C, van Dam P, Pouillon L, Parizel M, Schats KA, et al. Infiltrating stromal immune cells in inflammatory breast cancer are associated with an improved outcome and increased PD-L1 expression. Breast Cancer Res. 2019;21:28.

Eike LM, Yang N, Rekdal O, Sveinbjornsson B. The oncolytic peptide LTX-315 induces cell death and DAMP release by mitochondria distortion in human melanoma cells. Oncotarget. 2015;6:34910–23.

Zhou H, Forveille S, Sauvat A, Sica V, Izzo V, Durand S, et al. The oncolytic peptide LTX-315 kills cancer cells through Bax/Bak-regulated mitochondrial membrane permeabilization. Oncotarget. 2015;6:26599–614.

Zhou H, Forveille S, Sauvat A, Yamazaki T, Senovilla L, Ma Y, et al. The oncolytic peptide LTX-315 triggers immunogenic cell death. Cell Death Dis. 2016;7:e2134.

Kepp O, Senovilla L, Vitale I, Vacchelli E, Adjemian S, Agostinis P, et al. Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology. 2014;3:e955691.

Church SE, Galon JKalinski P. Regulation of CTL infiltration within the tumor microenvironment. Tumor immune microenvironment in cancer progression and cancer therapy. 2017;33–49.

Martínez-Lostao L, Anel A, Pardo J. How do cytotoxic lymphocytes kill cancer cells?. Clin Cancer Res. 2015;21:5047–56.

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.

Ascierto ML, Kmieciak M, Idowu MO, Manjili R, Zhao Y, Grimes M, et al. A signature of immune function genes associated with recurrence-free survival in breast cancer patients. Breast Cancer Res Treat. 2012;131:871–80.

Mann GJ, Pupo GM, Campain AE, Carter CD, Schramm S-J, Pianova S, et al. BRAF mutation, NRAS mutation, and the absence of an immune-related expressed gene profile predict poor outcome in patients with stage III melanoma. J Invest Dermatol. 2013;133:509–17.

Page DB, Yuan J, Redmond D, Wen YH, Durack JC, Emerson R, et al. Deep sequencing of T-cell receptor DNA as a biomarker of clonally expanded TILs in breast cancer after immunotherapy. Cancer Immunol Res. 2016;4:835–44.

Snyder A, Nathanson T, Funt SA, Ahuja A, Buros Novik J, Hellmann MD, et al. Contribution of systemic and somatic factors to clinical response and resistance to PD-L1 blockade in urothelial cancer: an exploratory multi-omic analysis. PLoS Med. 2017;14:e1002309.

Darvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med. 2018;50:1–11.

Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348:56–61.

Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov. 2019;18:197–218.