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722 Evaluation of the effects of pembrolizumab alone and in combination(s) with MDSC-targeting agents MK-0482 and MK-4830 on the native cancer patient TME via functional spatial profiling (CIVO®)
  1. Kenneth Gundle1,
  2. Karthik Rajasekaran2,
  3. Jeffrey Houlton3,
  4. Daniel Clayburgh1,
  5. Michael Wagner4,
  6. Elyse Brinkmann4,
  7. Cherie-Ann Nathan5,
  8. John Pang5,
  9. Annemieke Van Zante6,
  10. Jessica Davis7,
  11. Connor Burns8,
  12. Jason Frazier8,
  13. Emily Beirne8,
  14. Angela Merrell8,
  15. Bre Mills8,
  16. Jonathan Derry8,
  17. Hanrong Sang8,
  18. Atticus Turner8,
  19. Marc Grenley8,
  20. Nathan Schauer8,
  21. Wendy Jenkins8 and
  22. Richard Klinghoffer8
  1. 1Oregon Health and Science University, Portland, OR, USA
  2. 2University of Pennsylvania, Philadelphia, PA, USA
  3. 3Sarah Cannon Cancer Institute, Charleston, SC, USA
  4. 4University of Washington, Seattle, WA, USA
  5. 5Louisiana State University Health Shreveport, Shreveport, LA, USA
  6. 6University of California San Francisco, San Francisco, CA, USA
  7. 7Indiana University School of Medicine, Indianapolis, IN, USA
  8. 8Presage Biosciences, Inc., Seattle, WA, USA

Abstract

Background Immune checkpoint inhibitors have produced durable clinical responses in hard-to-treat cancers, but to date, such responses are limited to a minority of patients. Combination treatments of PD-1 inhibitors with drugs that target additional immune suppressive components of the tumor microenvironment (TME) have been proposed as a solution. A resource-intensive approach to investigating such combinations (> 4500 clinical trials to date) has resulted in limited success. A more efficient approach to clinical evaluation of drug combinations is needed.

CIVO® enables detailed assessment of multiple microdosed drugs and drug combinations, simultaneously introduced to discreet positions within the native microenvironment of a patient’s solid tumor in situ. 1–3 To directly compare the effects of pembrolizumab alone and in combination with MK-0482 or MK-4830, two agents targeting myeloid-derived suppressor cells (MDSCs) via immunoglobulin-like transcript 3 (ILT3) and ILT4 respectively, we completed a trial in soft tissue sarcoma (STS) and head and neck squamous cell carcinoma (HNSCC) patients using CIVO.

Methods Thirteen patients (6 STS, 7 HNSCC) with planned surgical resection of a surface-accessible primary or metastatic tumor, enrolled in this multicenter clinical trial. The CIVO multiplexed microdose injection procedure was performed 1 to 4 days before surgery. Each injection consisted of a fluorescent marker co-formulated with vehicle, pembrolizumab, MK-0482, MK-4830, or combinations thereof. The injected portion of the surgical sample was then removed, formalin-fixed, paraffin-embedded, and evaluated for biomarkers of response via immunohistochemistry (IHC), in situ hybridization (ISH), and/or digital spatial profiling (NanoString GeoMx DSP).

Results High injection success rate was achieved with 87% resulting in visually distinct sites of drug exposure. To date, no device/microinjected drug-related adverse events have been reported.

In the STS cohort, localized TME responses to pembrolizumab were consistent with previous studies with strong interferon (IFN) response observed in tumor mutational burden (TMB)-high myxofibrosarcoma and low in TMB-low synovial sarcoma as detected by DSP. While combination injection sites containing either MK-0482 or MK-4830 resulted in decreased expression of CD163, a biomarker of M2 macrophage polarization, combining pembrolizumab with either MK-0482 or MK-4830 inhibited induction of the IFN signature.

Analysis of the HNSCC cohort is currently in progress.

Conclusions Functional spatial profiling of the cancer patient TME following multiplexed intratumoral CIVO microinjection enabled in-depth, safe, and efficient side-by-side evaluation of pembrolizumab alone and in combination with MK-0482 or MK-4830. Further study to determine whether the localized TME responses to CIVO predict the therapeutic benefit of checkpoint inhibitor combinations in different patient subsets is warranted.

Acknowledgements Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA provided drug and financial support for the study.

Trial Registration Clinical Trial Registry Number: NCT04541108

References

  1. Klinghoffer RA, Bahrami SB, Hatton BA, Frazier JP, Moreno-Gonzalez A, Strand AD, Kerwin WS, Casalini JR, Thirstrup DJ, You S, Morris SM, Watts KL, Veiseh M, Grenley MO, Tretyak I, Dey J, Carleton M, Beirne E, Pedro KD, Ditzler SH, Girard EJ, Deckwerth TL, Bertout JA, Meleo KA, Filvaroff EH, Chopra R, Press OW, Olson JM. A technology platform to assess multiple cancer agents simultaneously within a patient’s tumor. Sci Transl Med. 2015 Apr 22;7(284):284ra58.

  2. Gundle KR, Deutsch GB, Goodman HJ, Pollack SM, Thompson MJ, Davis JL, Lee MY, Ramirez DC, Kerwin W, Bertout JA, Grenley MO, Sottero KH, Beirne E, Frazier J, Dey J, Ellison M, Klinghoffer RA, Maki RG. Multiplexed evaluation of microdosed antineoplastic agents in situ in the tumor microenvironment of patients with soft tissue sarcoma. Clin Cancer Res. 2020 Aug 1;26(15):3958–3968

  3. Derry JMJ, Burns C, Frazier JP, Beirne E, Grenley M, DuFort CC, Killingbeck E, Leon M, Williams C, Gregory M, Houlton J, Clayburgh D, Swiecicki P, Huszar D, Berger A, Klinghoffer RA. Trackable intratumor microdosing and spatial profiling provide early insights into activity of investigational agents in the intact tumor microenvironment, Clin Cancer Res, under review.

Ethics Approval This study was approved by the Institutional Review Boards of the Oregon Health and Science University (approval #00022805), the University of Pennsylvania (approval #844966), the Louisiana State University Health Sciences Center, Shreveport (approval #00002077), and WCG (approval #20212261).

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