Abstract PR07: Intratumoral injection of mRNA-2752 and anti-PD-1 results in rapid regression of HER2 positive and or Hormone Receptor Negative DCIS: Phase 1 study results
Authors: Esserman Laura J. , Ramalingam Kirithiga , Woody Rachel , Glencer Alexa , Schwartz Christopher , Mori Hidetoshi , Wong Jasmine , Hirst Gillian , Rosenbluth Jennifer , Hylton Nola , Onishi Natsuko , Borowsky Alexander D. , Campbell Michael J. 
Published: February 2024

Abstract
Background: High-grade DCIS with immune infiltrates may be contained by the immune system, but are at risk for progression to invasive disease. Spatial proximity of CD8+/PD-1+ T cells and PD-L1+ cells predict response to chemotherapy and PD-1 inhibitors in hormone negative (HR-) invasive tumors. DCIS with high-risk features (such as HR- and or Her2+) often have T cell infiltrates. We hypothesized that intratumoral (ITu) administration of pembrolizumab (ITu-P) could potentiate the immune response and avoid systemic toxicities. We also explored whether the addition of mRNA-2752 (Moderna), an mRNA based therapeutic encoding T cell co-stimulator OX40L and proinflammatory cytokines IL-23 and IL-36g, would synergize adaptive anti-cancer immune responses of immune checkpoint injection alone. Since mortality for DCIS is extremely low, we proposed ITu treatment to avoid systemic adverse effects. In a phase 1 dose escalation study of single agent ITu-P we found 2 doses of 8 mg, administered 2-3 wks apart, was tolerable, induced immunological changes within the DCIS lesions, but had little clinical benefit. Herein, we expanded the number of injections to 4 and also tested a combination with ITu mRNA-2752 (ITu-M), to determine if we could find a dose that was both tolerable and elicited anti-tumor responses. Methods: This study evaluated ITu-P monotherapy (8mg, q2-3 wks x 4 doses; n=5) and combination ITu-P (8, 4, or 2mg) + ITu-M (4, 2, or 1mg) (n=10). DCIS with &gt;2 high-risk features were eligible: age&lt;45; high grade, extensive comedo necrosis; palpable mass; HR-; HER2+; size &gt;5 cm, or microinvasion (&lt;10% of lesion with invasive cancer). Dose was reduced based on AEs. Patients (pts) had MRI before and after 2 injections. Core biopsy/surgery was conducted after the last MRI. Baseline and biopsy/surgery breast tissue specimens were analyzed for immune infiltrates by multiplex immunofluorescence (mIF) staining. Results: In the ITu-P monotherapy expanded cohort, T cell density increased except when there was a paucity of T cells pre-treatment. Only 1 pt demonstrated a reduction in lesion size (clinically and on MRI); no side effects were seen. Of 10 pts enrolled in the combination (ITu-P + ITu-M) cohort, 80% responded: 2 non responders had &lt;5% T cells and the 8 responders had &gt; 6% T cell infiltrates at baseline. In 4 pts, all DCIS (3-8 cm) resolved completely (pCR) and 4 pts had a PR. Two CRs had post-therapy core biopsies only and remain NED with &gt;1 yr follow-up (MRI). Pts experienced Gr1/2 fever, myalgias, and fatigue, enlargement of regional nodes, and erythema and induration of the breast lasting 4-20 days. No AEs &gt; grade 2 were noted. The tolerable dose was 1mg ITu-M + 4mg ITu-P. Conclusion: The combination of ITu-P + ITu-M demonstrated modulation of the tumor immune microenvironment and robust antitumor activity in high-risk DCIS (typically HR- or HER2+) with pre-existing T cell infiltrates. mIF analyses suggest that the degree of immune infiltrate at baseline is associated with complete response. A study evaluating monotherapy ITu-M is in progress.
Citation Format: Laura J. Esserman, Kirithiga Ramalingam, Rachel Woody, Alexa Glencer, Christopher Schwartz, Hidetoshi Mori, Jasmine Wong, Gillian Hirst, Jennifer Rosenbluth, Nola Hylton, Natsuko Onishi, Alexander D. Borowsky, Michael J. Campbell. Intratumoral injection of mRNA-2752 and anti-PD-1 results in rapid regression of HER2 positive and or Hormone Receptor Negative DCIS: Phase 1 study results [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr PR07.