T-Cells Expressing a Highly Potent PRAME-Specific T-Cell Receptor in Combination with a Chimeric PD1-41BB Co-Stimulatory Receptor Show a Favorable Preclinical Safety Profile and Strong Anti-Tumor Reactivity
by
,
Nadja Sailer
1,†,
Ina Fetzer
1,†,
Melanie Salvermoser
1,†,
Monika Braun
1,
Doris Brechtefeld
1,
Christian Krendl
1,
Christiane Geiger
1,
Kathrin Mutze
1,
Elfriede Noessner
2,
Dolores J. Schendel
1,3,*, 
Maja Bürdek
1,
Susanne Wilde
1,‡ and
Daniel Sommermeyer
1,‡ 1
Medigene Immunotherapies GmbH, 82152 Planegg, Germany
2
Immunoanalytics-Research Group Tissue Control of Immunocytes (TCI), Helmholtz Zentrum München, 81377 Munich, Germany
3
Medigene AG, 82152 Planegg, Germany
*
Author to whom correspondence should be addressed.
†
These authors contributed equally as first authors to this work.
‡
These authors contributed equally as senior authors to this work.
Cancers 2022, 14(8), 1998; https://doi.org/10.3390/cancers14081998
Submission received: 2 February 2022
/
Revised: 8 April 2022
/
Accepted: 12 April 2022
/
Published: 14 April 2022
(This article belongs to the Special Issue Engineering the Tumor Immune Microenvironment)
Simple Summary
The development of effective adoptive T-cell therapies (ATCs) to treat solid tumors has several challenges: the choice of a suitable target antigen, the generation of a specific T-cell receptor (TCR) directed against this target, and the hostile tumor microenvironment (TME). The cancer/testis antigen Preferentially Expressed Antigen in Melanoma (PRAME) is a promising target for ATCs since it is highly expressed in several solid tumor indications, while its expression in normal tissues is mainly restricted to the testis. Using our well-established high throughput TCR generation and characterization process, we identified a highly potent PRAME-specific TCR. To convert the inhibitory PD-1 signal in T-cells to an activating signal, we designed a chimeric receptor consisting of the extracellular domain of PD-1 and the signaling domain of 4-1BB. Combining this PD1-41BB receptor with our lead PRAME-TCR generated a very promising T-cell product with a favorable preclinical in vitro safety profile and enhanced in vitro and in vivo anti-tumor efficacy.
Abstract
The hostile tumor microenvironment (TME) is a major challenge for the treatment of solid tumors with T-cell receptor (TCR)-modified T-cells (TCR-Ts), as it negatively influences T-cell efficacy, fitness, and persistence. These negative influences are caused, among others, by the inhibitory checkpoint PD-1/PD-L1 axis. The Preferentially Expressed Antigen in Melanoma (PRAME) is a highly relevant cancer/testis antigen for TCR-T immunotherapy due to broad expression in multiple solid cancer indications. A TCR with high specificity and sensitivity for PRAME was isolated from non-tolerized T-cell repertoires and introduced into T-cells alongside a chimeric PD1-41BB receptor, consisting of the natural extracellular domain of PD-1 and the intracellular signaling domain of 4-1BB, turning an inhibitory pathway into a T-cell co-stimulatory pathway. The addition of PD1-41BB to CD8+ T-cells expressing the transgenic PRAME-TCR enhanced IFN-γ secretion, improved cytotoxic capacity, and prevented exhaustion upon repetitive re-challenge with tumor cells in vitro without altering the in vitro safety profile. Furthermore, a single dose of TCR-Ts co-expressing PD1-41BB was sufficient to clear a hard-to-treat melanoma xenograft in a mouse model, whereas TCR-Ts without PD1-41BB could not eradicate the PD-L1-positive tumors. This cutting-edge strategy supports development efforts to provide more effective TCR-T immunotherapies for the treatment of solid tumors.
Keywords:
immunotherapy; cancer; TME; PD-1; TCR-T cells; PRAME
