Targeting Triple-Negative Breast Cancer with Combination Therapy of EGFR CAR T Cells and CDK7 Inhibition

Lin, Xia; Zheng, Zaozao; Liu, Junyi; Chen, Yujie; Ding, Jian; Hu, Guo-Sheng; Hu, Ya-hong; Liu, Suling; Luo, Wenxin; Xia, Ningshao; Li, Wen

doi:10.1158/2326-6066.cir-20-0405

Cited by 47 publications

(31 citation statements)

References 45 publications

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“…In a mouse model of TNBC, it has been shown that the pre-treatment with EGFR-specific CAR-T, induced the development of resistance in tumor cells. This effect could be subsequently reversed by using THZ1, an agent that inhibited the phosphorylation of cyclin-dependent kinase 7 (CDK7)-mediated RNA polymerase II and, therefore, resulted in the diminished expression of the immunosuppressive genes (e.g., CD274 (PD-L1), PDCD1LG2 (PD-L2), IDO1 ) [ 195 ]. A “headless CAR-T” consisting of intracellular activation domains armed with HER2 or EGFR bispecific antibodies showed great potential in a mono- or sequential killing manner and was able to kill in vitro under hypoxic conditions [ 196 ].…”

Section: Strategies To Overcome Immunotherapy Resistance Of Breast Cancermentioning

confidence: 99%

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

Retecki

Seweryn

Graczyk-Jarzynka

et al. 2021

Cancers

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Breast cancer (BC) has traditionally been considered to be not inherently immunogenic and insufficiently represented by immune cell infiltrates. Therefore, for a long time, it was thought that the immunotherapies targeting this type of cancer and its microenvironment were not justified and would not bring benefits for breast cancer patients. Nevertheless, to date, a considerable number of reports have indicated tumor-infiltrating lymphocytes (TILs) as a prognostic and clinically relevant biomarker in breast cancer. A high TILs expression has been demonstrated in primary tumors, of both, HER2-positive BC and triple-negative (TNBC), of patients before treatment, as well as after treatment with adjuvant and neoadjuvant chemotherapy. Another milestone was reached in advanced TNBC immunotherapy with the help of the immune checkpoint inhibitors directed against the PD-L1 molecule. Although those findings, together with the recent developments in chimeric antigen receptor T cell therapies, show immense promise for significant advancements in breast cancer treatments, there are still various obstacles to the optimal activity of immunotherapeutics in BC treatment. Of these, the immunosuppressive tumor microenvironment constitutes a key barrier that greatly hinders the success of immunotherapies in the most aggressive types of breast cancer, HER2-positive and TNBC. Therefore, the improvement of the current and the demand for the development of new immunotherapeutic strategies is strongly warranted.

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Section: Strategies To Overcome Immunotherapy Resistance Of Breast Cancermentioning

confidence: 99%

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

Retecki

Seweryn

Graczyk-Jarzynka

et al. 2021

Cancers

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“…Transcriptomic analysis of mice bearing a triple-negative breast cancer with an acquired resistance to anti-EGFR CAR T cells showed that treatment with EGFR-specific CAR T cells induced immunosuppressive genes that were associated with CAR T cell-activated enhancers [ 112 ]. Screening a panel of epigenetic modulators revealed that these enhancers were sensitive to the selective and potent covalent cyclin-dependent kinase 7 (CDK7) inhibitor THZ1.…”

Section: Synergistic Combination Therapy With Car T Cellsmentioning

confidence: 99%

“…Screening a panel of epigenetic modulators revealed that these enhancers were sensitive to the selective and potent covalent cyclin-dependent kinase 7 (CDK7) inhibitor THZ1. As THZ1 can suppress anti-EGFR CAR T cell-induced immunosuppressive genes, the combination of THZ1 with CAR T cells was investigated, revealing an enhanced in vitro efficacy compared to anti-EGFR CAR T cells or THZ1 alone [ 112 ]. In vivo combination therapy of EGFR-specific CAR T cells with the CDK7 inhibitor THZ1 showed a suppression of immune resistance, tumor growth, and metastasis in triple-negative breast cancer models [ 112 ].…”

Section: Synergistic Combination Therapy With Car T Cellsmentioning

confidence: 99%

“…As THZ1 can suppress anti-EGFR CAR T cell-induced immunosuppressive genes, the combination of THZ1 with CAR T cells was investigated, revealing an enhanced in vitro efficacy compared to anti-EGFR CAR T cells or THZ1 alone [ 112 ]. In vivo combination therapy of EGFR-specific CAR T cells with the CDK7 inhibitor THZ1 showed a suppression of immune resistance, tumor growth, and metastasis in triple-negative breast cancer models [ 112 ]. Further evaluation of this approach is required.…”

Section: Synergistic Combination Therapy With Car T Cellsmentioning

confidence: 99%

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Enhanced Chimeric Antigen Receptor T Cell Therapy through Co-Application of Synergistic Combination Partners

et al. 2022

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Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable response rates and revolutionized the treatment of patients suffering from defined hematological malignancies. However, many patients still do not respond to this therapy or relapse after an initial remission, underscoring the need for improved efficacy. Insufficient in vivo activity, persistence, trafficking, and tumor infiltration of CAR T cells, as well as antigen escape and treatment-associated adverse events, limit the therapeutic success. Multiple strategies and approaches have been investigated to further improve CAR T cell therapy. Besides genetic modification of the CAR itself, the combination with other treatment modalities has the potential to improve this approach. In particular, combining CAR T cells with clinically approved compounds such as monoclonal antibodies and small molecule inhibitors might be a promising strategy. Combination partners could already be applied during the production process to influence the cellular composition and immunophenotype of the final CAR T cell product. Alternatively, simultaneous administration of clinically approved compounds with CAR T cells would be another feasible avenue. In this review, we will discuss current strategies to combine CAR T cells with compounds to overcome recent limitations and further enhance this promising cancer therapy, potentially broadening its application beyond hematology.

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“…As an alternative, the blockage of immune regulatory checkpoints of T cells via CRISPR/Cas9-mediated gene editing could also improve the outcome of CAR cell therapies [ 116 ]. Similarly, inhibiting immunosuppressive genes that are activated upon IFN-γ secretion by EGFR CAR T cells can improve the efficacy of targeted therapies, in vivo [ 117 ]. Ongoing efforts are attempting to apply EGFR CAR cells in clinical trials.…”

Section: Established Targets For Car Nk Cellsmentioning

confidence: 99%

NK Cells Armed with Chimeric Antigen Receptors (CAR): Roadblocks to Successful Development

Dezfouli

Yazdi

Pockley

et al. 2021

Cells

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In recent years, cell-based immunotherapies have demonstrated promising results in the treatment of cancer. Chimeric antigen receptors (CARs) arm effector cells with a weapon for targeting tumor antigens, licensing engineered cells to recognize and kill cancer cells. The quality of the CAR-antigen interaction strongly depends on the selected tumor antigen and its expression density on cancer cells. CD19 CAR-engineered T cells approved by the Food and Drug Administration have been most frequently applied in the treatment of hematological malignancies. Clinical challenges in their application primarily include cytokine release syndrome, neurological symptoms, severe inflammatory responses, and/or other off-target effects most likely mediated by cytotoxic T cells. As a consequence, there remains a significant medical need for more potent technology platforms leveraging cell-based approaches with enhanced safety profiles. A promising population that has been advanced is the natural killer (NK) cell, which can also be engineered with CARs. NK cells which belong to the innate arm of the immune system recognize and kill virally infected cells as well as (stressed) cancer cells in a major histocompatibility complex I independent manner. NK cells play an important role in the host’s immune defense against cancer due to their specialized lytic mechanisms which include death receptor (i.e., Fas)/death receptor ligand (i.e., Fas ligand) and granzyme B/perforin-mediated apoptosis, and antibody-dependent cellular cytotoxicity, as well as their immunoregulatory potential via cytokine/chemokine release. To develop and implement a highly effective CAR NK cell-based therapy with low side effects, the following three principles which are specifically addressed in this review have to be considered: unique target selection, well-designed CAR, and optimized gene delivery.

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Targeting Triple-Negative Breast Cancer with Combination Therapy of EGFR CAR T Cells and CDK7 Inhibition

Cited by 47 publications

References 45 publications

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

Enhanced Chimeric Antigen Receptor T Cell Therapy through Co-Application of Synergistic Combination Partners

NK Cells Armed with Chimeric Antigen Receptors (CAR): Roadblocks to Successful Development

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