Immune checkpoint inhibitors: review of the existing evidence and challenges in breast cancer

Cancer initiation and progression are associated with immune system responses. Tumor cells use various tricks to scape of immune system, such as activating immune checkpoint pathways that induce immunosuppressive functions. Among the different immune checkpoint receptors, CTLA-4 and PD-1/PD-L1 are prominent therapeutic targets in different cancers. Although the US FDA has approved some immune checkpoint inhibitors for several cancers, concerning breast cancer still different clinical trials are looking for optimizing efficacy and decreasing immune-related adverse events. This review will discuss the existing body of knowledge with regard to cross-talk between immune system and tumor cells and then explore immune checkpoint-related signaling pathways in the context of breast tumors. Finally, we highlight the application of different immune checkpoint blockers in breast cancer patients.

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IMMU-06. COMBINATORIAL IMMUNE CHECKPOINT INHIBITORS FOR TARGETED INTRATUMORAL DELIVERY IN GBM

Neuro-Oncology ◽

10.1093/neuonc/noab196.366 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi93-vi93

Author(s):

Stephanie Sanders ◽

Denise Herpai ◽

Waldemar Debinski

Keyword(s):

T Cells ◽

Tumor Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cell Activity ◽

Live Cells ◽

Normal Brain ◽

Cytotoxic Therapies ◽

Checkpoint Receptors

Abstract Glioblastoma (GBM) is an immunologically cold tumor. Using single cell sequencing of CD45+ cells we confirmed that T cells are present within GBM samples. These T cells are positive for exhaustion markers such as LAG3 and TIGIT, as well as CTLA4 and PD1 checkpoint receptors. Modulating T cell activity through use of immune checkpoint inhibitors (ICIs) has shown efficacy in the treatment of a variety of solid tumors, and the combination of anti-CTLA4 and anti-PD1 ICIs has shown increased efficacy over use of a single therapeutic. Additionally, targeting ICIs to the tumor cells may increase efficacy of this treatment. We therefore constructed a combinatorial ICI redirected to GBM via interleukin 13 receptor alpha 2 (IL13RA2), a receptor over-expressed on the majority of GBM cells but not normal brain. The first component of the construct, labeled with a histidine tag, targets CTLA4 while the second component, tagged with a StrepII tag, targets PD1. The tags added to the constructs will allow for purification of a combinatorial heterodimer simultaneously targeting PD1, CTLA4 and IL13RA2. We purified individual components via fast protein liquid chromatography (FPLC) using a proteinG column followed by a HisTrap or StrepTrap column. We obtained a recombinant, targeted multivalent ICI at > 95% purity. We found that these constructs are able to bind their target receptors via ELISA in which the Kd values ranged from picomolar to low nanomolar range. Additionally, our constructs bind their target on live cells by flow cytometry. We next designed a heterodimeric construct which can combinatorially target CTLA4 and PD1 while also directing the ICI therapy to GBM. These constructs in conjunction with other immune stimulants like cytotoxic therapies are intended to facilitate the interaction between T cells and GBM tumor cells directly in a tumor microenvironment.

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Risk of SARS-CoV-2 infection and disease in metastatic triple-negative breast cancer patients treated with immune checkpoint inhibitors

Immunotherapy ◽

10.2217/imt-2020-0142 ◽

2020 ◽

Cited By ~ 1

Author(s):

Patrizia Vici ◽

Laura Pizzuti ◽

Eriseld Krasniqi ◽

Andrea Botticelli ◽

Gennaro Ciliberto ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Triple Negative ◽

Checkpoint Inhibitors ◽

Breast Cancer Patients

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Predictive Biomarkers of Immune Checkpoint Inhibitor Response in Breast Cancer: Looking beyond Tumoral PD-L1

Biomedicines ◽

10.3390/biomedicines9121863 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1863

Author(s):

Nan Chen ◽

Nicole Higashiyama ◽

Valentina Hoyos

Keyword(s):

Breast Cancer ◽

Tumor Cells ◽

Immune Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Large Scale ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Cytotoxic T Cells ◽

Predictive Biomarkers

Immune checkpoint inhibitors utilize the immune system to kill cancer cells and are now widely applied across numerous malignancies. Pembrolizumab has two breast-specific indications in triple-negative disease. Currently, programmed death ligand-1 (PD-L1) expression on tumor and surrounding immune cells is the only validated predictive biomarker for immune checkpoint inhibitors (ICIs) in breast cancer; however, it can be imprecise. Additional biomarkers are needed to identify the patient population who will derive the most benefit from these therapies. The tumor immune microenvironment contains many biomarker candidates. In tumor cells, tumor mutational burden has emerged as a robust biomarker across malignancies in general, with higher burden cancers demonstrating improved response, but will need further refinement for less mutated cancers. Preliminary studies suggest that mutations in breast cancer gene 2 (BRCA-2) are associated with increased immune infiltration and response to ICI therapy. Other genomic alterations are also being investigated as potential predictive biomarkers. In immune cells, increased quantity of tumor-infiltrating lymphocytes and CD8+ cytotoxic T cells have correlated with response to immunotherapy treatment. The role of other immune cell phenotypes is being investigated. Peripherally, many liquid-based biomarker strategies such as PD-L1 expression on circulating tumor cells and peripheral immune cell quantification are being studied; however, these strategies require further standardization and refinement prior to large-scale testing. Ultimately, multiple biomarkers utilized together may be needed to best identify the appropriate patients for these treatments.

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Comprehensive Analysis of the Immune Microenvironment Reveals that CD52 is a Marker for Breast Cancer Treatment with Immune Checkpoint Inhibitors

10.21203/rs.3.rs-1078018/v1 ◽

2021 ◽

Author(s):

Qiang Wang ◽

Xuxu Liu ◽

Pengfei Wang ◽

Dankun Luo ◽

Wenqi Gao ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Cancer Patients ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Adaptive Immune Response ◽

Breast Cancer Patients ◽

Immune Microenvironment ◽

Adaptive Immune

Abstract Background:Breast cancer (BC) is one of the most common tumors in women. Recent years, immune checkpoint inhibitors (ICIs) have brought good news to BC patients. Although significant achievements have been made through treatment with ICIs, some people who experience serious immune-related adverse events (IrAEs) are still insensitive to this approach. The response to ICI treatment depends on the type of tumor microenvironment (TME). Methods:WGCNA (weighted gene co-expression network analysis), ESTIMATE algorithm, LASSO regression analysis, survival analysis, functional enrichment analysis are conducted to analyze the BC data in the TCGA database. Immunohistochemistry was used to verify the expression of CD52 in BC.Results:WGCNA and ESTIMATE algorithm found that the CD52 is closely related to the immune microenvironment. CD52 highly expressed in various breast cancer subtypes, and patients with high expression of CD52 have longer survival time. Compared with the low-CD52 group, the high-CD52 group had more immune cell infiltration. TIMER database verification results showed that CD8+ T cells, activated memory CD4 T cells, memory B cells, γδ T cells, and Tregs were positively correlated with CD52 expression, while M2 macrophages were negatively correlated. CD52 can change the trend of TIC (CD8+ T) and tumor-associated macrophage (TAM) infiltration with respect to the survival time of breast cancer patients. Based on the expression of CD52, we explored the relationship between CD52 and the adaptive immune response (AIR). CD52 is a marker of AIR stratification in breast cancer patients. We constructed a CD52-related adaptive immune response gene signature (CD52rAIRGsig) which is an independent prognostic factor for breast cancer and related to genome instability and the immune cells infiltration in the TME. CD52 and CD52rAIRGsig were associated with PD-1 signaling and immune checkpoint inhibitor markers, which proves that patients with high CD52 expression and low risk of CD52rAIRGsig are more suitable for ICI treatment. We then screened chemotherapeutics for personalized medicine based on CD52rAIRGsig. Conclusion:Therefore, we have discovered a new marker to guide the treatment and prognosis of breast cancer patients with ICIs. This provides a combined treatment strategy including different combinations of ICIs combined with chemotherapeutic drugs to treat breast cancer.

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Immune landscape of inflammatory breast cancer suggests vulnerability to immune checkpoint inhibitors

OncoImmunology ◽

10.1080/2162402x.2021.1929724 ◽

2021 ◽

Vol 10 (1) ◽

pp. 1929724

Author(s):

François Bertucci ◽

Laurys Boudin ◽

Pascal Finetti ◽

Christophe Van Berckelaer ◽

Peter Van Dam ◽

...

Keyword(s):

Breast Cancer ◽

Inflammatory Breast Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors

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Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22105207 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5207

Author(s):

Chi Yan ◽

Jinming Yang ◽

Nabil Saleh ◽

Sheau-Chiann Chen ◽

Gregory D. Ayers ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Tumor Growth ◽

Cd8 T Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Mtor Pathway ◽

Complete Regression ◽

Mtor Inhibition

Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. Results: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. Conclusion: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.

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Rethinking immune checkpoint blockade: ‘Beyond the T cell’

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001460 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001460 ◽

Cited By ~ 1

Author(s):

Xiuting Liu ◽

Graham D Hogg ◽

David G DeNardo

Keyword(s):

Immune System ◽

T Cell ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Antitumor Immunity ◽

Checkpoint Inhibitors ◽

Clinical Success ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.

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