Aberrant Lck signal via CD28 Costimulation augments antigen-specific functionality and tumor control by redirected T cells with PD-1 blockade in humanized mice

Pratiksha Gulati, Julia Ruhl, Abhilash Kannan, Magdalena Pircher, Petra Schuberth, Katarzyna J. Nytko, Martin Pruschy, Simon Sulser, Mark Haefner, Shawn Jensen, Alex Soltermann, Wolfgang Jungraithmayr, Maya Eisenring, Thomas Winder, Panagiotis Samaras, Annett Tabor, Rene Stenger, Roger Stupp, Walter Weder, Christoph RennerChristian Munz, Ulf Petrausch*

*Corresponding author for this work

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed. Experimental Design: Fibroblast activation protein (FAP)–specific CARs with different costimulatory domains, including CD28, D-CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the D-CD28 CAR was tested clinically in a patient with MPM. Results: All the three CARs demonstrated FAP-specific functionality in vitro. Gene expression data indicated a distinct activity profile for the D-CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the D-CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the D-CD28 CAR could be detected for up to 21 days and showed functionality. Conclusions: Overall, anti-FAP-D-CD28/CD3z CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted.

Original languageEnglish (US)
Pages (from-to)3981-3993
Number of pages13
JournalClinical Cancer Research
Volume24
Issue number16
DOIs
StatePublished - Aug 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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