A Phase Ib Study of Preoperative, Locoregional IRX-2 Cytokine Immunotherapy to Prime Immune Responses in Patients with Early-Stage Breast Cancer

Page, David B.; Pucilowska, Joanna; Sanchez, Katherine; Conrad, Valerie; Conlin, Alison; Acheson, Anupama Kurup; Perlewitz, Kelly S.; Imatani, James H.; Aliabadi‐Wahle, Shaghayegh; Moxon, Nicole; Mellinger, Staci L.; Seino, Amanda Y.; Martel, Martiza; Wu, Yaping; Sun, Zhaoyu; Redmond, William L.; Waddell, Dottie; Laxague, Deborah; Shah, Monil; Chang, Shu Ching; Urba, Walter J.

doi:10.1158/1078-0432.ccr-19-1119

Cited by 11 publications

(13 citation statements)

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“…Evaluation of TILs by mIF IRX-2 was previously shown to increase the mean H&E sTIL score, upregulate PD-L1 expression, and upregulate immune-related gene signatures [14]. We sought to develop a method of measuring sTILs using mIF that would closely recapitulate the H&E sTIL score (sTIL H&E ), but potentially with greater precision compared to the semi-quantitative clinical assays.…”

Section: Resultsmentioning

confidence: 99%

Section: Parent Clinical Trial and Sample Acquisitionmentioning

confidence: 99%

“…Samples were obtained from a pre-surgical phase Ib combination immunotherapy clinical trial (NCT02950259) [14]. The trial is completed, and detailed results have been published, with demographic information summarized in Table 1 [14]. Briefly, patients with ESBC (stage I-III) planned for definitive surgical resection (either lumpectomy or mastectomy) were considered for enrollment at the Providence Cancer Institute (Portland, OR) from May 2016 to May 2018 (n = 16).…”

Section: Parent Clinical Trial and Sample Acquisitionmentioning

confidence: 99%

“…Here, we report mIF data from a phase Ib study of IRX-2, a loco-regional cytokine therapy in early-stage breast cancer (ESBC) [14]. IRX-2 contains various cytokines (including interleukin (IL)-2, IL-1β, interferon-γ, tumor necrosis factor-α, among others) delivered subcutaneously in the distribution of regional lymphatics, and was previously shown to increase tumor lymphocyte infiltration in pre-operative head and neck carcinomas [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

“…IRX-2 contains various cytokines (including interleukin (IL)-2, IL-1β, interferon-γ, tumor necrosis factor-α, among others) delivered subcutaneously in the distribution of regional lymphatics, and was previously shown to increase tumor lymphocyte infiltration in pre-operative head and neck carcinomas [15][16][17]. In the phase Ib breast cancer trial, IRX-2 was injected in the peri-areolar tissue (modeled after sentinel lymph node mapping) and was found to be well tolerated, achieving the primary safety endpoint as well as showing evidence of enhanced IC infiltration and lymphocyte activation (measured by RNA sequencing) [14]. Using the paired biopsy and surgical excision specimens from this trial, our objectives of this project were (1) to propose a method for harmonizing mIF with the PD-L1 SP142 and H&E sTIL clinical assays; (2) to illustrate how hierarchical linear modeling can enhance statistical precision of IC density/PD-L1 expression estimates; and (3) to evaluate the influence of ROI sample size on overall statistical power to detect changes in ICs/ PD-L1 in the context of a clinical trial.…”

Section: Introductionmentioning

confidence: 99%

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Multiplex immunofluorescence to measure dynamic changes in tumor-infiltrating lymphocytes and PD-L1 in early-stage breast cancer

et al. 2021

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Background The H&E stromal tumor-infiltrating lymphocyte (sTIL) score and programmed death ligand 1 (PD-L1) SP142 immunohistochemistry assay are prognostic and predictive in early-stage breast cancer, but are operator-dependent and may have insufficient precision to characterize dynamic changes in sTILs/PD-L1 in the context of clinical research. We illustrate how multiplex immunofluorescence (mIF) combined with statistical modeling can be used to precisely estimate dynamic changes in sTIL score, PD-L1 expression, and other immune variables from a single paraffin-embedded slide, thus enabling comprehensive characterization of activity of novel immunotherapy agents. Methods Serial tissue was obtained from a recent clinical trial evaluating loco-regional cytokine delivery as a strategy to promote immune cell infiltration and activation in breast tumors. Pre-treatment biopsies and post-treatment tumor resections were analyzed by mIF (PerkinElmer Vectra) using an antibody panel that characterized tumor cells (cytokeratin-positive), immune cells (CD3, CD8, CD163, FoxP3), and PD-L1 expression. mIF estimates of sTIL score and PD-L1 expression were compared to the H&E/SP142 clinical assays. Hierarchical linear modeling was utilized to compare pre- and post-treatment immune cell expression, account for correlation of time-dependent measurement, variation across high-powered magnification views within each subject, and variation between subjects. Simulation methods (Monte Carlo, bootstrapping) were used to evaluate the impact of model and tissue sample size on statistical power. Results mIF estimates of sTIL and PD-L1 expression were strongly correlated with their respective clinical assays (p < .001). Hierarchical linear modeling resulted in more precise estimates of treatment-related increases in sTIL, PD-L1, and other metrics such as CD8+ tumor nest infiltration. Statistical precision was dependent on adequate tissue sampling, with at least 15 high-powered fields recommended per specimen. Compared to conventional t-testing of means, hierarchical linear modeling was associated with substantial reductions in enrollment size required (n = 25➔n = 13) to detect the observed increases in sTIL/PD-L1. Conclusion mIF is useful for quantifying treatment-related dynamic changes in sTILs/PD-L1 and is concordant with clinical assays, but with greater precision. Hierarchical linear modeling can mitigate the effects of intratumoral heterogeneity on immune cell count estimations, allowing for more efficient detection of treatment-related pharmocodynamic effects in the context of clinical trials. Trial registration NCT02950259.

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Section: Resultsmentioning

confidence: 99%

Section: Parent Clinical Trial and Sample Acquisitionmentioning

confidence: 99%

Section: Parent Clinical Trial and Sample Acquisitionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multiplex immunofluorescence to measure dynamic changes in tumor-infiltrating lymphocytes and PD-L1 in early-stage breast cancer

et al. 2021

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Novel classes of immunotherapy for breast cancer

Hernando-Calvo

Cescon

Bédard

2021

Breast Cancer Res Treat

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Immunotherapy for Metastatic Triple Negative Breast Cancer: Current Paradigm and Future Approaches

Geurts

Kok

2023

Curr. Treat. Options in Oncol.

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Opinion statementIn approximately 15–20% of the patients diagnosed with breast cancer, it comprises the triple negative (TN) subtype, which until recently lacked targets for specific treatments and is known for its aggressive clinical behavior in patients with metastatic disease. TNBC is considered the most immunogenic breast cancer subtype due to higher levels of tumor infiltrating lymphocytes (TILs), tumor mutational burden and PD-L1 expression, providing a rationale for immunotherapy. The addition of pembrolizumab to chemotherapy as first-line treatment resulted in significantly improved PFS and OS for PD-L1 positive mTNBC, leading to FDA approval. However, response rate of ICB in unselected patients is low. Ongoing (pre)clinical trials aim to further optimize ICB efficacy and widen its application beyond PD-L1 positive breast tumors. Novel immunomodulatory approaches to induce a more inflamed tumor microenvironment include dual checkpoint blockade, bispecific antibodies, immunocytokines, adoptive cell therapies, oncolytic viruses, and cancer vaccines. Preclinical data for these novel strategies seems promising, but solid clinical data to further support its application for mTNBC is awaited. Biomarkers capturing the degree of immunogenicity such as but not limited to TILs, CD8 T cell levels, and IFNg signatures could support deciding which therapeutic strategy is most appropriate for which patient. Given 1) the accumulating therapy options for patients with metastatic disease and 2) the heterogeneity of mTNBC from inflamed to immune-desert tumors, the challenge is to work towards immunomodulatory strategies for specific subgroups of patients with TNBC to enable personalized (immuno)therapy for patients with metastatic disease.

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A Phase Ib Study of Preoperative, Locoregional IRX-2 Cytokine Immunotherapy to Prime Immune Responses in Patients with Early-Stage Breast Cancer

Cited by 11 publications

References 50 publications

Multiplex immunofluorescence to measure dynamic changes in tumor-infiltrating lymphocytes and PD-L1 in early-stage breast cancer

Multiplex immunofluorescence to measure dynamic changes in tumor-infiltrating lymphocytes and PD-L1 in early-stage breast cancer

Novel classes of immunotherapy for breast cancer

Immunotherapy for Metastatic Triple Negative Breast Cancer: Current Paradigm and Future Approaches

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