Abstract 1007P
Background
T-cell receptor (TCR)-based immunotherapies have great potential for the safe and efficacious treatment of patients with unmet needs suffering from various types of cancer. However, novel strategies are needed to overcome the inhibitory tumor microenvironment and to enhance the efficacy of TCR-T-cell (TCR-T) therapy in solid tumors. PRAME is a cancer/testis antigen that is highly expressed in various solid tumor indications while its expression in healthy tissues is mainly restricted to the testis.
Methods
The HLA-A2-restricted, PRAME-specific TCR used here was obtained from a non-tolerized T-cell repertoire of a healthy donor using high-throughput TCR isolation and characterization processes. To prevent inhibition of TCR-T function via the PD1-PDL1 axis, the PRAME-TCR was co-expressed with a chimeric PD1-41BB co-stimulatory receptor, consisting of the extracellular domain of PD1 and the intracellular domain of the 41BB co-stimulatory receptor.
Results
Co-expression of PD1-41BB on PRAME-TCR-Ts did not change the favorable preclinical safety profile but led to enhanced TCR-T proliferation and cytokine release after antigen encounter. Under conditions of chronic antigen exposure using HLA-A2/PRAME/PDL1-positive tumor cell lines, TCR-Ts co-expressing PD1-41BB showed increased fitness and cytotoxic anti-tumor activity compared to TCR-Ts carrying the TCR alone. This effect could be confirmed in vivo using an immune-deficient xenograft mouse model. Tumors derived from a melanoma cell line expressing PRAME and high PDL1 levels, partially mimicking the inhibitory TME of solid tumors, were not cleared by TCR-Ts expressing the TCR alone whereas TCR-Ts co-expressing PD1-41BB eradicated the tumors. Furthermore, at the single cell level, in vitro poly-functional cytokine release analysis of TCR-Ts co-expressing PD1-41BB and the PRAME-TCR support the in vivo data.
Conclusions
We showed that co-expression of a chimeric PD1-41BB co-stimulatory receptor enhances in vitro and in vivo PRAME TCR-T functionality and anti-tumor activity, thus representing a highly promising strategy to enhance the efficacy of TCR-T therapies for the treatment of solid cancers.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
M. Bürdek: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH. I. Fetzer: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH. N. Sailer: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH. M. Salvermoser: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH. D. Brechtefeld: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH. K. Mutze: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH. S. Raffegerst: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH. M. Braun: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH. R. Goedkoop: Financial Interests, Institutional, Officer: Medigene. S. Wilde: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH; Financial Interests, Personal, Stocks/Shares: Medigene Immunotherapies GmbH. D. Sommermeyer: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH.