Phase I Trial of Targeted EGFR or ALK Therapy with Ipilimumab in Metastatic NSCLC with Long-Term Follow-Up

Chalmers, A.; Patel, Shiven B.; Boucher, Ken; Cannon, Laura; Esplin, Michelle; Luckart, Julie Bylund; Graves, Natalie; Duren, T. Van; Akerley, Wallace

doi:10.1007/s11523-019-00658-0

Cited by 44 publications

(31 citation statements)

References 22 publications

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“…Interestingly, the EGFR tyrosine kinase receptor, overexpressed in many different tumors and well known for its oncogenic functions in tumor cells, has been recently proposed as a key regulator also of immune cells, as it has been found able to inhibit CTLs through different mechanisms [27]. Furthermore, clinical trials have evaluated the combination of ipilimumab with the anti-EGFR TKI erlotinib in NSCLC [29], highlighting the need of more specific EGFR drugs with low frequencies of adverse side effects. Thus, we considered the option of co-targeting these two receptors by firstly testing the combinations of ipilimumab with the anti-EGFR aptamer CL4, in order to verify if they show additive effects on both tumor cells and immune cells.…”

Section: Discussionmentioning

confidence: 99%

“…Further, the oncogenic behavior of epidermal growth factor receptor (EGFR), combined to its recently emerged role as important modulator of immune response [27], prompted the evaluation of ipilimumab plus EGFR-tyrosine kinase inhibitor (TKI) erlotinib in a clinical trial in patients with NSCLC [28,29]. Unfortunately, despite the significant outcome in terms of progression-free survival and OS, the trial was prematurely closed because of the severe side effects of erlotinib [28,29]. Nonetheless, this combinatorial strategy deserves to be further investigated, by overcoming the side effects related to erlotinib, by using a more specific anti-EGFR drug.…”

Section: Introductionmentioning

confidence: 99%

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Ipilimumab and Its Derived EGFR Aptamer-Based Conjugate Induce Efficient NK Cell Activation against Cancer Cells

Passariello

Camorani

Vetrei

et al. 2020

Cancers

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The immune checkpoint CTLA-4 (cytotoxic T-lymphocyte-antigen 4), which inhibits the co-stimulatory CD28 signal on T cells, has been recently found expressed on other cell populations, such as tumor and natural killer (NK) cells. We tested for the first time the effects of ipilimumab, the human anti-CTLA4 mAb in clinical use, on these cells and found that it inhibits the growth of tumor cells expressing CTLA-4 also in the absence of lymphocytes, and efficiently activates NK cells, thus suggesting an important unexplored role of NK cells in ipilimumab-modulated immune responses. Interestingly, the epidermal growth factor receptor (EGFR) has been shown to play a key role in tumor cell escape from immune surveillance, and in cytotoxic T lymphocyte inhibition. Thus, we tested combinatorial treatments of ipilimumab with an anti-EGFR aptamer endowed with anti-tumor activity, and constructed for the first time a novel bispecific immunoconjugate, made up of these two compounds. The novel immunoconjugate binds to the target cells, induces the activation of lymphocytes, including NK cells, and inhibits the growth of tumor target cells more efficiently than the parental compounds, by strongly enhancing the cytotoxic activity of both human peripheral blood mononuclear cells and NK cells against tumor cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ipilimumab and Its Derived EGFR Aptamer-Based Conjugate Induce Efficient NK Cell Activation against Cancer Cells

Passariello

Camorani

Vetrei

et al. 2020

Cancers

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“…216 Similarly, combined treatment with EGFR-TKIs and anti-CTLA-4 agents enhanced the efficacy of EGFR-TKIs in patients with metastatic NSCLC. 217 Yet, more effort is needed at the preclinical and clinical levels to advance the combination of EGFR-TKIs and immunotherapy for the treatment of patients with EGFR-mutated EGFR-TKI-resistant lung cancer. Crizotinib + EGFR-TKIs Median progression-free survival of patients treated with combination therapy was longer than those treated with crizotinib alone ( Abbreviations: EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; EHMT2, euchromatic histone lysine methyltransferase 2; EMT, epithelial-to-mesenchymal transition; HER2, human epidermal growth factor receptor 2; HGF, hepatocyte growth factor; mTOR, mammalian target of rapamyci; NSCLC, non-small-cell lung cancer;…”

Section: Targeting Mirnas To Overcome Egfr-tki Resistance In Lung Cmentioning

confidence: 99%

Recent updates on the resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors and resistance reversion strategies in lung cancer

Tripathi

Pandey

Rengasamy

et al. 2020

Medicinal Research Reviews

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Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have led to a substantial improvement in the prognosis of lung cancer patients by explicitly targeting the activating mutations within the EGFR. Initially, patients harboring tumors with EGFR mutations show progressionfree survival and improvement in the response rates toward all-generation EGFR-TKIs; however, these agents fail to deliver the intended results in the long-term due to drug resistance. Therefore, it is necessary to recognize specific cardinal mechanisms that regulate the resistance phenomenon. Understanding the intricate mechanisms underlying EGFR-TKIs resistance in lung cancer could provide cognizance for more advanced targeted therapeutics. The present review features insights into current updates on the discrete mechanisms, including secondary or tertiary mutations, parallel and downstream signaling pathways, acquiring an epithelial-to-mesenchymal transition (EMT) signature, microRNAs (miRNAs), and epigenetic alterations, which lead to intrinsic and acquired resistance against EGFR-TKIs in lung cancer. In addition, this paper also reviews current possible strategies to overcome this issue using combination treatment of recently developed MET inhibitors, allosteric inhibitors or immunotherapies, transformation of EMT, targeting miRNAs, and epigenetic alterations in intrinsic and acquired EGFR-TKIs resistant lung cancer. In conclusion, multiple factors are responsible for intrinsic and acquired resistance to EGFR-TKIs and understanding of the detailed molecular mechanisms, and recent advancements in pharmacological studies are needed to develop new strategies to overcome intrinsic and acquired EGFR-TKIs resistance in lung cancer.

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“…Based on encouraging data from a phase III trial on metastatic melanoma, the first CTLA-4 checkpoint inhibitor, ipilimumab, was approved by the Food and Drug Administration (FDA) in 2011 [4]. Despite being approved for only unresectable or metastatic melanoma, ipilimumab can be viewed as a promising therapeutic strategy for many cancer types, such as renal cell carcinoma (RCC) [5], non-small cell lung carcinoma (NSCLC) [6] and small cell lung cancer (SCLC).…”

Section: Introductionmentioning

confidence: 99%

Current status of the clinical use of PD-1/PD-L1 inhibitors: a questionnaire survey of oncologists in China

Zhang

Song

et al. 2020

BMC Cancer

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Background: The purpose of the present study was to obtain information on the use of PD-1/PD-L1 inhibitors by oncologists in China through a national questionnaire survey. Methods: Between the 7th and 25th of July in 2019, a questionnaire designed by the Chinese Society of Clinical Oncology Immuno-Oncology (CSCO IO) Committee on the current status of the use of PD-1/PD-L1 inhibitors was distributed online and offline to cancer-related medical departments in thirty different provinces and autonomous regions of China. The national questionnaire consisted of three sections as follows: general information, current status of the application of PD-1/PD-L1 inhibitors in the clinic, and oncologists' concerns regarding utilization. Results: The valid response rate of the current status survey was 76.3%. The proportion of senior doctors (physician-in-charge or a more superior position for more than 3 years) among the respondents was relatively high (67.0% in 588). Of the respondents, 59.2% had prescribed PD-1/PD-L1 inhibitors during clinical treatment, and the most frequent reason for not prescribing these inhibitors was the choice "do not understand the mechanism and the efficacy of PD-1/PD-L1 inhibitors". In addition, 77.9% of the prescribers used the medications in an off-label situation, and the most important motivation for this use was the fact that "there were indications abroad but not domestically". In addition, 77.9% of the prescribers believed that "immunotherapy-related adverse effects could be controlled or intervened through follow-up management". The prescribers were mostly concerned about "how to identify pseudoprogression and hyperprogression" and "immunity-related adverse effects management". Conclusion: The present study highlights the current status of PD-1/PD-L1 inhibitors in China. Increasing numbers of medical oncologists are interested in PD-1/PD-L1 inhibitors, and they are in need of immunotherapy education.

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Phase I Trial of Targeted EGFR or ALK Therapy with Ipilimumab in Metastatic NSCLC with Long-Term Follow-Up

Cited by 44 publications

References 22 publications

Ipilimumab and Its Derived EGFR Aptamer-Based Conjugate Induce Efficient NK Cell Activation against Cancer Cells

Ipilimumab and Its Derived EGFR Aptamer-Based Conjugate Induce Efficient NK Cell Activation against Cancer Cells

Recent updates on the resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors and resistance reversion strategies in lung cancer

Current status of the clinical use of PD-1/PD-L1 inhibitors: a questionnaire survey of oncologists in China

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