Tumor lysis with LTX-401 creates anticancer immunity

Wei Xie; Laura Mondragón; Brynjar Mauseth; Yan Wang; Jonathan Pol; Sarah Lévesque; Heng Zhou; Takahiro Yamazaki; Johannes J Eksteen; Laurence Zitvogel; Baldur Sveinbjørnsson; Øystein Rekdal; Oliver Kepp; Guido Kroemer

doi:10.1080/2162402X.2019.1594555

Tumor lysis with LTX-401 creates anticancer immunity

Oncoimmunology. 2019 Apr 13;8(7):1594555. doi: 10.1080/2162402X.2019.1594555. eCollection 2019.

Authors

Wei Xie^{1

2

3

4}, Laura Mondragón^{1

2

3

4}, Brynjar Mauseth^{5

6

7}, Yan Wang^{1

2

3

4}, Jonathan Pol^{1

2

3

4}, Sarah Lévesque^{1

2

3

4}, Heng Zhou^{1

2

3

4

8}, Takahiro Yamazaki^{9

10

11

12

13}, Johannes J Eksteen¹⁴, Laurence Zitvogel^{9

10

11

12}, Baldur Sveinbjørnsson^{5

15

16}, Øystein Rekdal^{5

15

16}, Oliver Kepp^{1

2

3

4}, Guido Kroemer^{1

2

3

4

16

17}

Affiliations

¹ Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.
² Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM, Paris, France.
³ Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
⁴ Université Pierre et Marie Curie, Paris, France.
⁵ Lytix Biopharma, Oslo, Norway.
⁶ Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁷ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁸ Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.
⁹ Gustave Roussy Comprehensive Cancer Center, Villejuif, France.
¹⁰ University of Paris Sud XI, Kremlin Bicêtre, France.
¹¹ Institut National de la Santé et de la Recherche Medicale (INSERM), Villejuif, France.
¹² Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France.
¹³ Weill Cornell Medical College, New York, NY, USA.
¹⁴ Norut Northern Research Institute, SIVA Innovation Centre, Tromsø, Norway.
¹⁵ Institute of Medical Biology, University of Tromsø, Tromsø, Norway.
¹⁶ Karolinska Institutet, Department of Women's and Children's Health, Stockholm, Sweden.
¹⁷ Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.

Abstract

Local immunotherapies such as the intratumoral injection of oncolytic compounds aim at reinstating and enhancing systemic anticancer immune responses. LTX-315 is a first-in-class, clinically evaluated oncolytic peptide-based local immunotherapy that meets these criteria. Here, we show that LTX-401, yet another oncolytic compound designed for local immunotherapy, depicts a similar safety profile and that sequential local inoculation of LTX-401 was able to cure immunocompetent host from subcutaneous MCA205 and TC-1 cancers. Cured animals exhibited long-term immune memory effects that rendered them resistant to rechallenge with syngeneic tumors. Nevertheless, the local treatment with LTX-401 alone had only limited abscopal effects on secondary contralateral lesions. Anticancer effects resulting from single as well as sequential injections of LTX-401 were boosted in combination with PD-1 and CTLA-4 immune checkpoint blockade (ICB), and sequential LTX-401 treatment combined with double ICB exhibited strong abscopal antineoplastic effects on contralateral tumors underlining the potency of this combination therapy.

Keywords: Oncolysis; anticancer therapy; checkpoint blockade; immunogenic cell death.

Publication types

Research Support, Non-U.S. Gov't

Grants and funding

WX,HZ and YW were supported by the China Scholarship Council, GK and LZ are supported by the Ligue contre le Cancer (équipes labelisées); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); the Seerave foundation; the Swiss Bridge Foundation, ISREC and the Paris Alliance of Cancer Research Institutes (PACRI). This project was supported by the Norwegian Research Council (254800, 257967).