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Perilymphatic IRX-2 cytokine therapy to enhance tumor infiltrating lymphocytes and PD-L1 expression preceding curative-intent therapy in early stage breast cancer
Books, Presentations, Posters, Etc.
  • Joanna Pucilowska, Earle A. Chiles Research Institute, Portland, OR; Providence Cancer Institute, Portland, OR
  • Venkatesh Rajamanickam, Earle A. Chiles Research Institute, Portland, OR; Providence Cancer Institute, Portland, OR
  • Katherine Sanchez, Earle A. Chiles Research Institute, Portland, OR; Providence Cancer Institute, Portland, OR
  • Valerie Conrad, Earle A. Chiles Research Institute, Portland, OR; Providence Cancer Institute, Portland, OR
  • Alison Conlin, Providence Cancer Center, Portland, Oregon.
  • Shagheyegh Aliabadi-Wahle, Earle A. Chiles Research Institute, Portland, OR; Providence Cancer Institute, Portland, OR
  • Shu-Ching Chang, Earle A. Chiles Research Institute, Portland, OR; Providence Cancer Institute, Portland, OR; Providence Medical Data Research Center, Portland, OR
  • Gary Grunkemeier, Earle A. Chiles Research Institute, Portland, OR; Providence Cancer Institute, Portland, OR; Providence Medical Data Research Center, Portland, OR
  • Nikki Moxon, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR
  • Staci Mellinger, Earle A. Chiles Research Institute, Portland, OR; Providence Cancer Institute, Portland, OR
  • Maritza Martel, Earle A. Chiles Research Institute, Portland, OR; Providence Cancer Institute, Portland, OR
  • James Egan
  • Monil Shah
  • David B Page, Earle A. Chiles Research Institute, Portland, OR; Providence Cancer Institute, Portland, OR
Publication Date
12-6-2018
Keywords
  • Cancer,
  • immunotherapy,
  • cytokines,
  • breast cancer,
  • head and neck squamous cell carcinoma,
  • HNSCC,
  • tumor microenvironment,
  • tumor infiltrating lymphocytes,
  • TIL,
  • T cells,
  • clinical trial
Disciplines
Description

Background: Cytokines are being explored as a therapeutic strategy to modulate the tumor microenvironment and facilitate immunotherapy benefit in breast cancer. Here, we investigate a locoregional therapeutic approach whereby cytokines (IRX-2) are administered into the subcutaneous peri-areolar tissue (in an anatomic distribution similar to sentinel lymph node mapping) to facilitate immune cell recruitment/activation within the draining lymph nodes and tumor in ESBC. IRX-2 is derived from ex vivo phytohemagglutinin-stimulated lymphocytes and contains multiple cytokines including IL-1β, IL-2, TNF-α, IFN-γ, IL-6, IL-8, and GM-CSF, with stable concentrations from lot to lot. Preclinically, IRX-2 activates T-cells and natural killer (NK) cells, facilitates antigen presentation, and enhances activity of anti-PD-1/L1 in a SCC7 model. In a preceding head/neck squamous cell carcinoma phase I trial, perilymphatic IRX-2 was safe and increased TILs. Here, we report the final clinical results of a phase Ib trial evaluating the feasibility and immunologic activity of IRX-2 in ESBC.

Methods: Beginning 21 days prior to surgical resection, enrolled operable patients with stage I-III ESBC (all subtypes) received the pre-operative IRX-2 regimen consisting of a single low-dose cyclophosphamide (300 mg/m2 to facilitate T-regulatory cell depletion), followed by 10 days of subcutaneous peri-areolar IRX-2 injections into the affected breast (1 mL × 2 at tumor axis and at 90°). Endpoints were feasibility (primary endpoint), stromal TIL (sTIL) count (pre-treatment versus post-treatment, blinded average of two pathologist reads using San Antonio H&E sTIL guidelines), PD-L1 expression (Nanostring) and enumeration of peripheral immune cells by flow cytometry.

Results: All patients (n=16/16) completed and tolerated the regimen with no surgical delays or treatment-attributed grade III/IV toxicities. Common adverse events (occurring in >15% subjects) attributed to IRX-2 injections were: injection site reaction (grade 1, n=8/16), bruising (grade 1, n=7/16), and pain (grade 1, n=3/16). Common adverse events attributed to low-dose cyclophosphamide were: fatigue (grade 1, n=5/16) and nausea (grade 1/2, n=3/16). Treatment was associated with an increase in sTIL score (Wilcoxon signed-rank p=.04), with 4/10 sTIL-low tumors (0-10% score) re-categorized to sTIL-moderate (11-50% score). Increases in PD-L1 RNA expression were observed (Wilcoxon signed-rank p=.04) in 12/16 tumors (median 57% increase, range: -53% to 185% increase), as well as increases in Nanostring NK and Th1 cell signatures. In blood, increases in CD4 and CD8 effector T-cell activation (ICOS, HLA-DR, and CD38) and T-reg depletion were observed.

Conclusions: IRX-2 was well tolerated with preliminary evidence of sTIL increase, PD-L1 upregulation, and peripheral lymphocyte activation. Based upon these data and preclinical evaluations demonstrating synergy with checkpoint inhibition, the IRX-2 regimen is being evaluated for clinical efficacy in conjunction with pembrolizumab and neoadjuvant chemotherapy (doxorubicin, cyclophosphamide, paclitaxel) in patients with stage II-III triple negative breast cancer.

Clinical Institute
Cancer
Department
Oncology
Department
Earle A. Chiles Research Institute
Conference / Event Name
2018 San Antonio Breast Cancer Symposium
Location
San Antonio, TX, United States
Comments

Poster presented on Dec 6, 2018.

Citation Information
Joanna Pucilowska, Venkatesh Rajamanickam, Katherine Sanchez, Valerie Conrad, et al.. "Perilymphatic IRX-2 cytokine therapy to enhance tumor infiltrating lymphocytes and PD-L1 expression preceding curative-intent therapy in early stage breast cancer" (2018)
Available at: http://works.bepress.com/shu-ching-chang/34/