Background SRK-181 is an investigational, fully human, IgG4 monoclonal antibody that selectively binds latent transforming growth factor-beta 1 (TGFβ1). TGFβ1 activation is associated with resistance to checkpoint inhibitors (CPI) in various cancers. A comprehensive biomarker strategy to validate SRK-181’s mechanism in patients and evaluate treatment response was based on our proof of concept for SRK-181 in preclinical models. The preclinical data revealed that combination of SRK-181 and anti-PD1 overcame immune exclusion in the tumor microenvironment leading to an influx of effector T cells into tumors which correlated with tumor regression and significant survival benefits.1
Methods DRAGON (NCT04291079) is an ongoing open-label, phase 1 study. In Part B (expansion phase), SRK-181 (1500mg q3w or 1000mg q2w)+anti-PD-(L)1 are administered in anti-PD-(L)1 relapsed/refractory patients with clear cell renal cell carcinoma, non-small cell lung cancer, melanoma, urothelial carcinoma, or head and neck cancer. Biomarker assessment included: biopsies- immunohistochemistry; circulatory MDSC (Myeloid Derived Suppressor Cells) – flow cytometry. Biopsies were collected at baseline and post-treatment between Days 28 – 48.
Results Exclusion of CD8+ T cells from the tumor has been proposed as a mechanism underlying immunosuppression contributing to CPI resistance in melanoma2 and urothelial cancers.3 As of June 21, three paired biopsies of sufficient quality were collected and stained for CD8. All 3 paired biopsies showed treatment with SRK-181 and anti-PD1 is associated with increased influx of CD8+ T cells into tumors. Treatment with SRK-181 and anti-PD1 decreased circulatory immunosuppressive MDSC levels.
Conclusions These biomarker results from the DRAGON study are consistent with preclinical findings and provide proof of mechanism in the clinic that selectively targeting latent TGFb1 with SRK-181 can overcome the immune suppressive environment associated with CPI resistance. Part B enrollment is ongoing.
Martin CJ, et al. Selective inhibition of TGFbeta1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape. Sci Transl Med, 2020;12(536).
Hugo W, et al. Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma. Cell, 2017;168(3):542.
Mariathasan S, et al. TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature, 2018;554(7693):544–548.
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