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337 Intratumoral immune therapy for recurrent breast cancer with polyICLC, and tremelimumab combined with systemic durvalumab
  1. Craig Slingluff1,
  2. Ileana Mauldin1,
  3. Elizabeth Gaughan1,
  4. Patrick Dillon1,
  5. Mateusz Opyrchal2,
  6. Igor Puzanov2,
  7. Megan Kruse3,
  8. Brian Gastman3,
  9. Philip Friedlander4,
  10. Thomas Marron4,
  11. Kristen Aufiero5,
  12. Mary Macri5,
  13. Paul Schwarzenberger5,
  14. Toni Ricciardi6,
  15. Aileen Ryan5,
  16. Ralph Venhaus5,
  17. Mansi Saxena4,
  18. Nicole Edmonds1 and
  19. Nina Bhardwaj4
  1. 1University of Virginia, Charlottesville, VA, USA
  2. 2Roswell Park Cancer Institute, Buffalo, NY, USA
  3. 3Cleveland Clinic, Cleveland, OH, USA
  4. 4Mount Sinai School of Medicine, New York, NY, USA
  5. 5Ludwig Institute for Cancer Research, New York, NY, USA
  6. 6Ludwig Institution for Cancer Research, New York, NY, USA


Background Intratumoral (IT) cancer therapies may enhance T cell activation and tumor infiltration when combined with systemic checkpoint blockade. This approach may improve treatment of advanced breast cancer, which is commonly resistant to immune therapy.

Methods A multicenter basket-style trial (NCT02643303) was performed in patients with advanced solid tumors, who received polyICLC IT 1mg x 6, then intramuscular (IM) x 3, combined with intravenous (IV) durvalumab 1500 mg q4W. Most were assigned to cohorts also receiving tremelimumab: 10 mg IT or 75 mg IV. Goals were to assess tolerability and clinical activity. Treated tumors were evaluated for immune infiltrates on days (d) 0, 15, and 29 by multiparameter immunofluorescence histology. A strong signal for clinical response was in breast cancer patients; thus, an expansion cohort was enrolled. We report analysis of that breast cancer subgroup.

Results Nineteen participants with treatment-refractory recurrent breast cancer with median 4 prior lines of therapy were enrolled and treated with IV durvalumab and IT/IM polyICLC. Seventeen also received tremelimumab (15 IT, 2 IV). Common treatment-related AEs were fatigue, injection site pain, and chills. There was one dose-limiting toxicity in a participant who received tremelimumab IV, and died with severe hyponatremia (DLT) and progressive disease. Objective clinical responses (1 complete; 4 partial (1 unconfirmed)) were observed in 5 (26%), including 2/9 patients with triple-negative breast cancer (TNBC) and 3/10 with non-TNBC. Median OS was longer for those with CR, PR, or SD (not reached) vs. those with PD or not evaluable (5 months): two responders remain alive at 34+ and 40+ months. In injected tumors, there were significant increases from d0 to d29 in numbers/mm2 of CD8+ T cells, CD20+ B cells, mature dendritic cells (DC), macrophages, and CD56+ NK cells, and in CD8+ cells with antigen-experience (CD45RO), cytotoxic function (granzyme B), activation (ICOS1), or proliferation (Ki67). CD8+ cells expressing LAG3 and TIM3 increased, as did PDL1+ tumor cells and stromal cells. There were no differences in cells expressing IDO, ARG1, CD39, or CD73. Among patients with objective response, vs. all others, proportions of intratumoral CD8+ cells expressing Ki67 increased (p < 0.04).

Conclusions IT tremelimumab and polyICLC plus systemic durvalumab is safe and has clinical activity in patients with advanced TNBC and non-TNBC. The therapy enhances intratumoral immune effectors and markers of T cell function in hypothesis-generating data that warrant confirmatory studies. Clinical response was associated with longer survival and increased CD8 T cell proliferation.

Ethics Approval The study has been performed with approval of the institutional review boards of each participating institution (Roswell Park Cancer Institute: STUDY 00000121/I291016; Mount Sinai School of Medicine: IRB-17-01692; University of Virginia: IRB # 19276; Cleveland Clinic: 18-694; Toledo: 300176; Dartmouth: STUDY00031630; Emory: IRB00099445). All participants give informed consent before enrolling and participating. The study was also performed with approval from the FDA

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