Prospects of Immunotherapy for Triple-Negative Breast Cancer

Qiu, Dan; Zhang, Guijuan; Yan, Xianxin; Xiao, Xinqin; Ma, Xinyi; Lin, Shujun; Wu, Jieyan; Li, Xinyuan; Wang, Yuqiao; Liu, Junchen; Ma, Yi; Ma, Min

doi:10.3389/fonc.2021.797092

Cited by 26 publications

(26 citation statements)

References 86 publications

(79 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Unlike other subtypes, targeted therapies (e.g. tamoxifen and trastuzumab) are ineffective against TNBC leaving patients with limited options of systemic chemotherapy, surgery or radiation(3) or more recently immunotherapy(4,5). As an alternative, considerable interest has developed in targeting mitochondrial metabolism as a potential approach to treat recalcitrant cancers(6,7).…”

Section: Introductionmentioning

confidence: 99%

Characterization of TR-107, a Novel Chemical Activator of the Human Mitochondrial Protease ClpP

Fennell

Aponte‐Collazo

Wynn

et al. 2022

Preprint

View full text Add to dashboard Cite

We recently described the identification of a new class of small molecule activators of the mitochondrial protease ClpP. These compounds synthesized by Madera Therapeutics showed increased potency of cancer growth inhibition over the related compound ONC201. In this study, we describe chemical optimization and characterization of the next generation of highly potent and selective small molecule ClpP activators (TR compounds) and demonstrate their efficacy against breast cancer models in vitro and in vivo. One of these compounds (TR-107) was selected for further studies because of excellent potency, specificity and drug-like properties. Examination of TR-107 effects in Triple Negative Breast Cancer (TNBC) cell models showed growth inhibition in the low nanomolar range, equipotent to paclitaxel, in a ClpP-dependent manner. TR-107 reduced specific mitochondrial proteins including OXPHOS and TCA cycle components, in a time, dose and ClpP-dependent manner. Seahorse XF Analysis and glucose deprivation experiments confirmed inactivation of OXPHOS and demonstrated an increased dependence on glycolysis following TR-107 exposure. The pharmacokinetic properties of TR-107 were compared to other known ClpP activators including ONC201 and ONC212. TR-107 displayed excellent exposure and serum t1/2 after oral administration. Using an orthotopic xenograft murine model of MDA-MB-231 cells, the anti-tumor response to TR-107 was investigated. Oral administration of TR-107 resulted in reduction in tumor volume and extension of survival in the treated vs. vehicle control groups. In summary, these studies describe the identification of highly potent new ClpP agonists with improved efficacy against TNBC, through targeted inactivation of OXPHOS and disruption of mitochondrial metabolism.

show abstract

Section: Introductionmentioning

confidence: 99%

Characterization of TR-107, a Novel Chemical Activator of the Human Mitochondrial Protease ClpP

Fennell

Aponte‐Collazo

Wynn

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…The 2013 St. Gallen International Breast Cancer Conference released a new definition of breast cancer molecular subtypes: luminal A (ER/PR + , HER2 − , Ki67 + < 20%, with the percentage indicating the IHC staining results for patient samples), luminal B (ER/PR + < 20%, HER2 − , Ki67 + ≥ 20%); HER2 + B2 (ER/PR + , HER2 overexpression), HER2 overexpression (ER − , PR − , HER2 overexpression), basal-like triple-negative breast cancer (TNBC, ER − , PR − , and HER2 − ), and other special subtypes ( 10 ). Breast cancer patients with luminal A or luminal B subtypes can be treated with endocrine therapies including selective estrogen receptor modulators, aromatase inhibitors, and ER degraders ( 3 – 5 , 11 – 13 ). Patients with HER2 overexpression are candidates for receiving HER2-targeting monoclonal antibodies (mAbs), antibody–drug conjugates (ADCs), or tyrosine kinase inhibitors ( 3 – 5 , 11 – 13 ).…”

Section: Introductionmentioning

confidence: 99%

“…Breast cancer patients with luminal A or luminal B subtypes can be treated with endocrine therapies including selective estrogen receptor modulators, aromatase inhibitors, and ER degraders ( 3 – 5 , 11 – 13 ). Patients with HER2 overexpression are candidates for receiving HER2-targeting monoclonal antibodies (mAbs), antibody–drug conjugates (ADCs), or tyrosine kinase inhibitors ( 3 – 5 , 11 – 13 ). While these three subtypes above can have favorable clinical outcomes due to their responsiveness to the targeted therapies, poor prognosis is usually observed within a major subdivision of the fourth breast cancer subtype referred to as TNBC with a negative expression of ER, PR, or HER2 due to lack of targeted treatment options for this patient population ( 3 – 5 , 11 – 13 ).…”

Section: Introductionmentioning

confidence: 99%

“…Patients with HER2 overexpression are candidates for receiving HER2-targeting monoclonal antibodies (mAbs), antibody–drug conjugates (ADCs), or tyrosine kinase inhibitors ( 3 – 5 , 11 – 13 ). While these three subtypes above can have favorable clinical outcomes due to their responsiveness to the targeted therapies, poor prognosis is usually observed within a major subdivision of the fourth breast cancer subtype referred to as TNBC with a negative expression of ER, PR, or HER2 due to lack of targeted treatment options for this patient population ( 3 – 5 , 11 – 13 ). Although breast cancer patients in general do not have a robust response to the immunotherapy, a subset of TNBC has been demonstrated to have high tumor mutation burden (TMB) and high tumor-infiltrating lymphocytes (TILs), resembling the features observed on melanoma or lung cancers that can benefit from the treatment of ICIs.…”

Section: Introductionmentioning

confidence: 99%

“…Although breast cancer patients in general do not have a robust response to the immunotherapy, a subset of TNBC has been demonstrated to have high tumor mutation burden (TMB) and high tumor-infiltrating lymphocytes (TILs), resembling the features observed on melanoma or lung cancers that can benefit from the treatment of ICIs. Therefore, the immunogenic nature of this aggressive disease has presented an opportunity for the development of TNBC-targeting immunotherapies ( 11 – 13 ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Progress and Prospect of Immunotherapy for Triple-Negative Breast Cancer

Luo

Wang

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

Breast cancer is the most commonly diagnosed cancer (estimated 2.3 million new cases in 2020) and the leading cause of cancer death (estimated 685,000 deaths in 2020) in women globally. Breast cancers have been categorized into four major molecular subtypes based on the immunohistochemistry (IHC) expression of classic hormone and growth factor receptors including the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), as well as a proliferation marker Ki-67 protein expression. Triple-negative breast cancer (TNBC), a breast cancer subtype lacking ER, PR, and HER2 expression, is associated with a high metastatic potential and poor prognosis. TNBC accounts for approximately only 15%–20% of new breast cancer diagnoses; it is responsible for most breast cancer–related deaths due to the lack of targeted treatment options for this patient population, and currently, systemic chemotherapy, radiation, and surgical excision remain the major treatment modalities for these patients with TNBC. Although breast cancer patients in general do not have a robust response to the immunotherapy, a subset of TNBC has been demonstrated to have high tumor mutation burden and high tumor-infiltrating lymphocytes, resembling the features observed on melanoma or lung cancers, which can benefit from the treatment of immune checkpoint inhibitors (ICIs). Therefore, the immunogenic nature of this aggressive disease has presented an opportunity for the development of TNBC-targeting immunotherapies. The recent US Food and Drug Administration approval of atezolizumab in combination with the chemotherapeutic agent nab-paclitaxel for the treatment of PD-L1-positive unresectable, locally advanced, or metastatic TNBC has led to a new era of immunotherapy in TNBC treatment. In addition, immunotherapy becomes an active research area, both in the cancer biology field and in the oncology field. In this review, we will extend our coverage on recent discoveries in preclinical research and early results in clinical trials from immune molecule-based therapy including cytokines, monoclonal antibodies, antibody–drug conjugates, bi-specific or tri-specific antibodies, ICIs, and neoantigen cancer vaccines; oncolytic virus-based therapies and adoptive immune cell transfer–based therapies including TIL, chimeric antigen receptor-T (CAR-T), CAR-NK, CAR-M, and T-cell receptor-T. In the end, we will list a series of the challenges and opportunities in immunotherapy prospectively and reveal novel technologies such as high-throughput single-cell sequencing and CRISPR gene editing-based screening to generate new knowledges of immunotherapy.

show abstract

Chimeric antigen receptor‐based immunotherapy in breast cancer: Recent progress in China

Yu,

Lu,

Fang

et al. 2023

Cancer

View full text Add to dashboard Cite

Breast cancer (BC) is the fourth most prevalent cancer in China. Despite conventional treatment strategies, BC patients often have poor therapeutic outcomes, leading to significant global cancer mortality rates. Chimeric antigen receptor (CAR)‐based immunotherapy is a promising and innovative approach for cancer treatment that redirects immune cells to attack tumor cells expressing selected tumor antigens (TAs). T cells, natural killer (NK) cells, and macrophages, key components of the immune system, are used in CAR‐based immunotherapies. Although remarkable progress has been made with CAR‐T cells in hematologic malignancies, the application of CAR‐based immunotherapy to BC has lagged. This is partly due to obstacles such as tumor heterogeneity, which is further associated with the TA and BC subtypes, and the immunosuppressive tumor microenvironment (TME). Several combinatorial approaches, including the use of immune checkpoint inhibitors, oncolytic viruses, and antitumor drugs, have been proposed to overcome these obstacles in BC treatment. Furthermore, several CAR‐based immunotherapies for BC have been translated into clinical trials. This review provides an overview of the recent progress in CAR‐based immunotherapy for BC treatment, including targeting of TAs, consideration of BC subtypes, assessment of the TME, and exploration of combinatorial therapies. The authors focused on preclinical studies and clinical trials of CAR‐T cells, CAR‐NK cells, and CAR‐macrophages especially conducted in China, followed by an internal comparison and discussion of current limits. In conclusion, this review elucidates China’s contribution to CAR‐based immunotherapies for BC and provides inspiration for further research.Plain Language Summary Despite conventional treatment strategies, breast cancer (BC) patients in China often have poor therapeutic outcomes. Chimeric antigen receptor (CAR)‐based immunotherapy, a promising approach, can redirect immune cells to kill tumor cells expressing selected tumor antigens (TAs). However, obstacles such as TA selection, BC subtypes, and immunosuppressive tumor microenvironment still exist. Therefore, various combinatorial approaches have been proposed. This article elucidates several Chinese CAR‐based preclinical and clinical studies in BC treatment with comparisons of foreign research, and CAR‐immune cells are analyzed, providing inspiration for further research.

show abstract

Prospects of Immunotherapy for Triple-Negative Breast Cancer

Cited by 26 publications

References 86 publications

Characterization of TR-107, a Novel Chemical Activator of the Human Mitochondrial Protease ClpP

Characterization of TR-107, a Novel Chemical Activator of the Human Mitochondrial Protease ClpP

Progress and Prospect of Immunotherapy for Triple-Negative Breast Cancer

Chimeric antigen receptor‐based immunotherapy in breast cancer: Recent progress in China

Contact Info

Product

Resources

About