2249P - Mitigation of tumor microenvironment-mediated immunosuppression using a PD1-41BB switch protein with optimal affinity tcrs for first-in-class, 3rd generation TCR-T therapies

Background

As demonstrated in clinical trials, TCR-T therapies face major challenges to sustain anti-tumor cell function in solid tumor microenvironments (TME); tumor antigen levels and PD-L1 expression strongly influence T cell function. PD-L1 signalling to T cells via the PD-1 receptor limits proliferation, cytokine secretion and killing, while exhaustion is induced by repetitive TCR signalling in the absence of T cell co-stimulation. Both impairments in TCR-T cells can be mitigated by co-expression of an optimal affinity TCR combined with a PD1-41BB costimulatory switch protein (CSP), comprised of the extracellular domain of PD-1 with the intracellular signalling domain of 41 BB (CD137).

Methods

Two first-in-class, 3rd generation TCR-T therapies, MDG1015 and MDG2011, were developed using optimal affinity TCRs specific for a cancer-testis antigen, NY-ESO-1/LAGE-1a, and a neoantigen, mutated KRAS G12V, respectively. Tumor cells with variations in antigen and PD-L1 inform how differences among tumor cells can impact different functions of TCR-T cells in vitro.

Results

CSP mitigation of TCR-T dysfunction was very prominent when PD-L1 was highly expressed and tumor antigen was low, the most challenging TME setting. When antigen and PD-L1 levels were both high, killing remained very strong and the CSP increased poly-cytokine secretion. Proliferation after exposure to tumor cells with high PD-L1 and induction of exhaustion by serial tumor exposure were both well mitigated by CSP co-expression in both TCR-T cell therapies.

Conclusions

The combination of optimal affinity TCRs combined with the PD1-41BB CSP provides strong protection of TCR-T cells against two variable mechanisms of TME immunosuppression based on the demonstration of CSP-enhanced poly-cytokine secretion, proliferation and mitigation against exhaustion in vitro. This observation warrants application in the clinic for this novel approach to potentially overcome the major challenges in solid tumor TMEs.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Medigene AG.

Funding

Medigene AG.

Disclosure

K. Crame, G. Longinotti, M. Catarinella, P. Prinz, S. Tippmer, K. Mutze, A. Coluccio, M. Salvermoser, J. Bittmann, M. Bürdek, B. Lösch, C. Geiger, K. Davari, D.J. Schendel: Financial Interests, Personal and Institutional, Full or part-time Employment: Medigene AG.