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Regular and Young Investigator Award Abstracts
Clinical Trial In Progress
726 Establishing proof of mechanism in patients: preliminary biomarker data of SRK-181 (a latent TGFβ1 inhibitor) from DRAGON Study
  1. Susan Henry1,
  2. Stephen DeWall1,
  3. Ulka N Vaishampayan2,
  4. Amna Sher3,
  5. Ahmad A Tarhini4,
  6. Deepak Kilari5,
  7. Randy Sweis6,
  8. Timothy Yap7,
  9. Justin Gainor8,
  10. Minal Barve9,
  11. John Clark10,
  12. Lan Liu10,
  13. Asia McCune1,
  14. Yawen Ju1,
  15. Mo Qatanani1 and
  16. Lu Gan1
  1. 1Scholar Rock, Inc., Cambridge, MA, USA
  2. 2University of Michigan, Ann Arbor, MI, USA
  3. 3Stony Brook University, Stony Brook, NY, USA
  4. 4H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
  5. 5Medical College of Wisconsin, Milwaukee, WI, USA
  6. 6The University of Chicago, Chicago, IL, USA
  7. 7The University of Texas, Houston, TX, USA
  8. 8Massachusetts General Hospital, Boston, MA, USA
  9. 9Mary Crowley Cancer Research, Dallas, TX, USA
  10. 10Scholar Rock, Cambridge, MA, USA

Abstract

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.

References

  1. 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).

  2. Hugo W, et al. Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma. Cell, 2017;168(3):542.

  3. 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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This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jitc-2023-SITC2023.0726

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