Abstract P6-05-01: The small heterodimer partner in macrophages reduces expansion of regulatory T cells and enhances immune checkpoint inhibition in breast cancer

2020 ◽  
Author(s):  
Erik R. Nelson ◽  
Sayyed Hamed Shahoei ◽  
Adam T Nelson ◽  
Madeline A Henn ◽  
Ashley E Mathews ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Small Heterodimer Partner

scholarly journals Combination Immunotherapy Strategies in Breast Cancer

2019 ◽  
Vol 11 (4) ◽  
pp. 228-240 ◽  
Author(s):  
Brie M. Chun ◽  
David B. Page ◽  
Heather L. McArthur
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Clinical Investigation ◽  
Breast Cancer Subtype ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Combination Immunotherapy ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Combination Strategies

Abstract Purpose of Review We summarize combination immunotherapy strategies for the treatment of breast cancer, with a focus on metastatic disease. First, a general overview of combination approaches is presented according to breast cancer subtype. Second, additional review of promising combination approaches is presented. Recent Findings Combination strategies utilizing chemotherapy or radiotherapy with immune checkpoint inhibition are being evaluated across multiple phase III trials. Dual immunotherapy strategies, such as dual immune checkpoint inhibition or combined co-stimulation/co-inhibition, have supportive preclinical evidence and are under early clinical investigation. Modulation of the immune microenvironment via cytokines and vaccination strategies, as well as locally focused treatments to enhance antigenic responses, are active areas of research. Summary Pre-clinical and translational research sheds new light on numerous ways the immune system may be modulated to fight against cancer. We describe current and emerging combination approaches which may improve patient outcomes in metastatic breast cancer.

scholarly journals Vaccination targeting human HER3 alters the phenotype of infiltrating T cells and responses to immune checkpoint inhibition

2017 ◽  
Vol 6 (6) ◽  
pp. e1315495 ◽  
Author(s):  
Takuya Osada ◽  
Michael A. Morse ◽  
Amy Hobeika ◽  
Marcio A. Diniz ◽  
William R. Gwin ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition

Targeting the immunosuppressive tumor microenvironment: Synergistic effect of low-dose IL12 in combination with dual immune checkpoint inhibition in a preclinical model of ovarian cancer.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 7-7
Author(s):  
Paul G. Pavicic ◽  
Patricia A. Rayman ◽  
Hussein Al-Sudani ◽  
C. Marcela Diaz-Montero ◽  
Haider Mahdi
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Synergistic Effect ◽  
Immune Checkpoint ◽  
Low Dose ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Activated T Cells

7 Background: Epithelial ovarian cancer (OC) is the most lethal gynecologic cancer with ~22,000 women diagnosed annually in the US. The impact of immune checkpoint inhibition (ICI) in the treatment of solid tumors has been significant. However, the response rates for OC are low ranging from 11-15%. It is critical to explore strategies to enhance the efficacy of ICI immunotherapy in OC. Targeting immunosuppressive factors and cells within the tumor microenvironment (TME) represents a feasible approach. The use of IL12 is attractive because induces potent antitumor activity by targeting myeloid cells and lymphocytes. However its clinical application has been hindered by its potential systemic toxicity. Here we explore the use of low dose intraperitoneal IL12 to enhance the antitumor activity of dual ICI in OC. Methods: Mice bearing ID8-VEGF tumors implanted intraperitoneally received either anti-PD1 alone or dual ICI treatment of anti-PD1 plus anti-CTLA4 with or without low dose IL12. Ascites accumulation was used as surrogate for tumor progression and determined by assessing weight increase. Blood and ascites were analyzed by flow cytometry for frequency of PMN-MDSC, M-MDSC, and activated T cells. Results: Low dose IL12 alone induced a significant delay in ascites accumulation when compared to untreated controls or mice treated with PD1 monotherapy or dual ICI. Addition of IL12 to dual ICI resulted in significant tumor regression and extended survival benefit compared to dual ICI alone. A synergistic effect of IL12 was not observed when combined with PD1 monotherapy. Antitumor responses associated with a marked decrease in the frequency of M-MDSC in blood and a decrease in both PMN- and M-MDSC in ascites. Decrease in MDSC associated with elevated levels of activated T cells. Conclusions: Low dose IL12 can induce regression of ID8-VEGF tumors. However, durable responses were only observed when IL12 was added to dual ICI. This suggests that IL12 can induce changes in the TME, particularly on MDSC, that can potentiate the antitumor activity of dual ICI. Our findings also suggest a crucial role of CTLA4 blockade perhaps via Treg targeting.

Genomic evaluation of tumor mutational burden-high (TMB-H) versus TMB-low (TMB-L) metastatic breast cancer to reveal unique mutational features.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1091-1091
Author(s):  
Sarah Sammons ◽  
Andrew Elliott ◽  
Jeremy Meyer Force ◽  
Nicholas C. DeVito ◽  
Paul Kelly Marcom ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Solid Tumors ◽  
Immune Checkpoint ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Mutational Burden ◽  
Tumor Mutational Burden

1091 Background: Tumor mutational burden (TMB) has emerged as an imperfect biomarker of immune checkpoint inhibition (ICI) outcomes in solid tumors. Despite the approval for pembrolizumab in all TMB-high (TMB-H) solid tumors, the optimal clinical approach to TMB-H or hypermutated advanced/metastatic breast cancer (MBC) is unknown with sparse prospective data. We hypothesize that TMB-H MBC will have unique genomic alterations compared to TMB-low (TMB-L) breast cancer that could inform novel therapeutic approaches. Methods: Tumor samples (N = 5621) obtained from patients with MBC were analyzed by next-generation sequencing (NGS) of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) at Caris Life Sciences (Phoenix, AZ). TMB was calculated based on recommendations from the Friends of Cancer Research TMB Harmonization Project (Merino et al., 2020), with the TMB-H threshold set to ≥ 10 muts/Mb. IHC was performed for PD-L1 (Ventana SP142 ≥1% immune cells). Deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) was tested by IHC and NGS, respectively. Results: TMB-H was identified in 8.2% (n = 461) of MBC samples, with similar frequencies observed across molecular subtypes (7.8-8.6%, p = 0.85): HR+/HER2- (n = 3087) 7.8%, HR+/HER2+ (n = 266) 8.3%, HR-/HER2+ (n = 179) 7.8%, TNBC (n = 1476) 8.6%. The frequency of TMB-H was significantly increased in lobular (16%) versus ductal (5%) MBC (p < 0.01). TMB-H samples were enriched in genitourinary (42%), soft tissue (20%), and gastrointestinal non-liver (16%) biopsy specimens. Compared to TMB-L tumors, TMB-H tumors exhibited significantly higher mutation rates for TP53 (60 v 52%), PIK3CA (55 vs 31%), ARID1A (34 vs 11%), CDH1 (27 vs 11%), NF1 (22 vs 9%), RB1 (14 vs 5%), KMT2C (12 vs 7%), PTEN (12 vs 7%), ERBB2 (7 vs 2.9%), and PALB2 (3.3 vs 1%) genes (p < 0.05 each). Copy number alteration and fusion rates did not differ between TMB-H and TMB-L breast cancers. PI3K/AKT/MTOR, TP53, Histone/Chromatin remodeling, DNA damage repair (DDR), RAS, and cell cycle pathway alterations were detected in > 25% TMB-H MBCs (p < 0.05 each). dMMR/MSI-High (7.2 vs 0.3%, p < 0.01) and PD-L1 positivity (36 vs 28%, p < 0.05) frequencies were significantly increased in TMB-H tumors. DNA signature analyses including APOBEC and homologous recombination repair deficiency, as well as gene expression profiling to assess immune-related signatures and tumor microenvironment are underway. Conclusions: TMB-H breast cancers contain a unique genomic profile enriched with targetable mutations such as PIK3CA, ARID1A, NF1, PTEN, ERBB2, and PALB2. Concurrent predictive biomarkers of response to immune checkpoint inhibition such as MSI-H and PDL-1 positivity are also more prevalent in TMB-H MBC. These findings suggest novel combination strategies within TMB-H MBC could be explored.

scholarly journals 287 Combined COX-2 inhibition with fish oil and aspirin as adjuncts to anti-PD-1 immunotherapy in metastatic melanoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A311-A311
Author(s):  
Alexander Chacon ◽  
Alexa Melucci ◽  
Shuyang Qin ◽  
Paul Burchard ◽  
Katherine Jackson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fish Oil ◽  
Metastatic Melanoma ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Omega 3 ◽  
Melanoma Patients

BackgroundOnly 30–40% of metastatic melanoma patients experience objective responses to first line anti-PD-1 immune checkpoint inhibition (αPD-1 ICI). Cyclooxygenase (COX-1/2) inhibition with aspirin (ASA) and other non-steroidal anti-inflammatory drugs has been associated with prolonged time to recurrence and improved responsiveness to ICI in human melanoma,1 with inhibition of myeloid-induced immunosuppression in the tumor microenvironment (TME) a purported mechanism.2 Similarly, dietary omega-3 fatty acids metabolized by COX-2 elicit downstream effects on T-cell differentiation akin to ASA administration, abrogating murine melanoma and human breast cancer progression. Mechanisms of ICI resistance remain unclear, and adjunct therapies look to bridge the gap from current response rates to cure.MethodsYUMM 1.7 melanoma cells were injected into flanks of C57-BL6/J mice. Mice were fed control diets or supplemented with omega-3 rich fish oil (FO) chow (10% weight/weight, 30%kcal/kcal), ASA in drinking water (ASA, LO – 300, MED – 600, HI - 1000 ug/mL), or the combination of these agents (COMBO, with ASA-MED) starting at day 7 post tumor implantation. Intraperitoneal αPD1 was administered every 3–4 days starting at day 12. Tumors were assessed for growth, harvested at day 32 (day 26 for ASA LO/HI), and characterized with flow cytometry. All significant results (p<0.05) assessed by 2-way ANOVA or t-test as appropriate.ResultsFO resulted in lesser tumor volume at day 32 in αPD-1 treated mice, while ASA-HI resulted in lesser tumor volume in mice not treated with αPD-1 but did not synergize with αPD-1. ASA-MED and COMBO groups trended towards decreased tumor size (p = 0.07 and 0.07 respectively) by day 32 in αPD-1 treated mice. FO and COMBO increased total CD3+ T-cells and monocytes (CD45+, CD19-, CD11b+, Ly6C+, Ly6G -) in the TME. FO increased PD-L1 + CD4+ T-cells, while COMBO increased total CD8+ T-cells and PD1+ CD8+ T-cells. ASA-HI increased monocytes and the proportion of PD-1+, CD8+ T-cells in the TME.ConclusionsMyeloid-induced suppression of T-cell function in tumors may contribute to immune checkpoint inhibition resistance. In the present study, both fish oil and aspirin altered melanoma tumor growth, with only fish oil synergizing with anti-PD-1 at the doses assessed. Both fish oil and aspirin augmented monocyte populations in the tumor microenvironment, with differential effects on T-cell populations. The partially synergistic mechanism between substrate-limited (FO) and pharmacologic (ASA) inhibition of cyclooxygenase-2 may provide a cost-effective avenue to combat immune escape in melanoma patients treated with anti-PD-1 immune checkpoint inhibition, requiring further investigation in humans.ReferencesWang SJ, et al. Effect of cyclo-oxygenase inhibitor use during checkpoint blockade immunotherapy in patients with metastatic melanoma and non-small cell lung cancer. J Immunother Cancer 2020;8(2).Zelenay S, et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 2015;162(6):1257–70.

scholarly journals Novel Combination Strategies to Enhance Immune Checkpoint Inhibition in Cancer Immunotherapy: A Narrative Review

2020 ◽  
Vol 8 (3) ◽  
pp. 273-280
Author(s):  
Jonathan A. Hermel ◽  
Cassi M. Bruni ◽  
Darren S. Sigal
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Immune Checkpoint ◽  
Nk Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Inkt Cells ◽  
Combination Strategies ◽  
Car T

Programmed cell death protein-1 (PD-1) is an immune checkpoint receptor that induces and maintains tolerance of T cells, invariant natural killer T (iNKT) cells, and natural killer (NK) cells, among other lymphocytes. Immune checkpoint inhibition by PD-1 blockade restores the lymphocytic immunostimulatory phenotype and has been successful in the treatment of various malignancies. However, while immune checkpoint blockade has been shown to provide robust antitumor treatment outcomes, its overall response rate remains low in a significant portion of cancer patients. An essential unmet need in cancer therapy is the development of novel pharmacologic strategies designed to lower rates of resistance associated with immune checkpoint blockade. Therefore, efforts that seek to enhance the efficacy of PD-1 inhibition possess profound immunotherapeutic potential. Here, three promising combination strategies that harness the antitumor effects of immune checkpoint inhibitors (ICIs) together with non-ICI antitumor therapeutic agents are reviewed. These agents include (1) ABX196, a potent inducer of iNKT cells, (2) chimeric antigen receptor (CAR)-T cell therapy, and (3) NK cell therapy. A comprehensive literature search was conducted using the PubMed and ClinicalTrials.gov databases for scientific articles and active trials, respectively, pertaining to immune checkpoint inhibition, iNKT cells, CAR-T cells, and NK cell immunotherapy. Preliminary clinical and preclinical data suggest that these combination treatment regimens greatly suppress tumor growth and may serve as innovative methods to enhance and optimize anticancer immunotherapy.

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