LTX-315 sequentially promotes lymphocyte-independent and lymphocyte-dependent antitumor effects

Authors:

Hsin-Wei Liao1,#, Christopher Garris1,#, Christina Pfirschke1, Steffen Rickelt2, Sean Arlauckas1, Marie Siwicki1, Rainer H. Kohler1, Ralph Weissleder1, Vibeke Sundvold-Gjerstad3, Baldur Sveinbjørnsson3,4, Øystein Rekdal3,4 and Mikael J. Pittet1
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Affiliations:

1 Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA, USA.

2 David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

3 Lytix Biopharma, Oslo, Norway.

4 Department of Medical Biology, University of Tromsø, Tromsø, Norway.

# These authors contributed equally.

Keywords: 

cancer, immunotherapy, oncolytic peptide, CD8+ T cells, melanoma, sarcoma.

Abbreviations:

BP – BrafV600E/Pten−/−,

GFP – green fluorescence protein,

KP – KrasLSL-G12D/+;p53fl/fl,

NK – natural killer.

Corresponding Author(s):

Mikael Pittet, Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA, USA; mpittet@mgh.harvard.edu

Conflict of interest statement:

This project was supported by Lytix Biopharma. M.J.P. has served as a consultant for Baxalta, Deciphera Phar-maceuticals, FORMA Therapeutics, Incyte Pharmaceuti-cals, Jounce Therapeutics, KSQ Therapeutics, Secarna, Siamab, and Syndax; these commercial relationships are unrelated to the current study. R.W. is a cofounder of T2 Biosystems, Lumicell, Accure Health, and VisEn Medical (acquired by Perkin Elmer) and advises Moderna, Alivio Therapeutics, Tarveda Therapeutics, and BioAnalytix; these relationships are unrelated to the current study.

Please cite this article as:

Hsin-Wei Liao, Christopher Garris, Christina Pfirschke, Steffen Rickelt, Sean Arlauckas, Marie Siwicki, Rainer H. Kohler, Ralph Weissleder, Vibeke Sundvold-Gjerstad, Baldur Sveinbjørnsson, Øystein Rekdal and Mikael J. Pittet (2019). LTX-315 sequentially promotes lymphocyte-independent and lympho-cyte-dependent antitumor effects. Cell Stress 3(11): 348-360. doi: 10.15698/cst2019.11.204

© 2019 Liao et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.

Abstract:

LTX-315 is an oncolytic peptide that has antitumor efficacy in mice grafted with various tumor cell lines and is currently being tested in phase II clinical trials. Here we aimed to further evaluate LTX-315 in conditional genetic mouse models of cancer that typically resist current treatment options and to better understand the drug’s mode of action in vivo. We report LTX-315 mediates profound antitumor effects against Braf- and Pten-driven melanoma and delays the progression of Kras- and P53-driven soft tissue sarcoma in mice. Additionally, we show in melanoma that LTX-315 triggers two sequential phases of antitumor response. The first phase of response, which begins within minutes of drug delivery into tumors, is defined by disrupted tumor vasculature and decreased tumor burden and occurs independently of lymphocytes. The second phase of response, which continues over weeks, is defined by long-term alteration of the tumor microenvironment; the changes induced by LTX-315 are most notably characterized by CD8+ T cell infiltration. We further show that these CD8+ T cells are involved in suppressing melanoma outgrowth in mice and report similar CD8+ T cell infiltration following LTX-315 treatment in melanoma and sarcoma patients. Taken together, these findings reveal LTX-315’s multiple antitumor effects, including disrupting the tumor vasculature and promoting the conversion of poorly immunogenic tumors into ones that display antitumor T cell immunity.