Immunotherapy in EGFR-Mutant and ALK-Positive Lung Cancer

Gavralidis, Alexander; Gainor, Justin F.

doi:10.1097/ppo.0000000000000491

Cited by 20 publications

(15 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Immune checkpoint inhibitors (ICIs) have revolutionized the diagnosis and treatment for patients with locally advanced or metastatic non-small cell lung cancer (mNSCLC). However, ICIs have low or inferior clinical efficacy compared to chemotherapy in patients with epidermal growth factor receptor (EGFR) -mutant or anaplastic lymphoma kinase (ALK) -rearranged mNSCLC [ 1 – 3 ]. This low clinical efficacy of ICIs in EGFR -mutant or ALK -rearranged mNSCLC remains even when their tumors had high Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) expression [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Small molecule tyrosine kinase inhibitors modulated blood immune cell counts in patients with oncogene-driven NSCLC

Zeng

Chen

et al. 2021

Biomark Res

View full text Add to dashboard Cite

Background Lack of biomarkers and in vitro models has contributed to inadequate understanding of the mechanisms underlying the inferior clinical response to immune checkpoint inhibitors (ICIs) in patients with oncogene-driven non-small cell lung cancer (NSCLC). Methods The effect of small molecule tyrosine kinase inhibitors (TKIs) on peripheral blood mononuclear cells (PBMCs) in 34 patients with oncogene-driven NSCLC (cohort A) was compared with those from 35 NSCLC patients without oncogene-driven mutations received ICI (cohort B) or from 22 treatment-naïve NSCLC patients (cohort C). Data for each blood biomarker were summarized by mean and standard deviation and compared by Wilcoxon rank sum tests or Kruskal-Wallis tests with significance at 2-sided p value < 0.05. Co-culture of PBMCs and pleural effusion-derived tumor cells from individual patients with oncogene-driven NSCLC was used to determine the in vitro cytotoxicity of TKI and ICI. Results Except for low CD3% in cohort A, there were no significant differences in other 12 blood biomarkers among the 3 cohorts at baseline. TKI treatment in cohort A was associated with significant increase in CD3% and decrease in total and absolute neutrophils (p < 0.05). In cohort B, patients with good clinical response to ICI treatment (N = 18) had significant increases in absolute lymphocyte counts (ALCs), CD4 and/or CD8 cell counts. Conversely, those patients with poor clinical response to ICI (N = 17) had significant decreases in these cell counts. Of the 27 patients with pre- and post-treatment blood samples in cohort A, 11 had poor clinical response to TKIs and decreased lymphocyte counts. Of the remaining 16 patients who had good clinical response to TKI therapy, 10 (62.5%) patients had decreased, and 6 (37.5%) patients had increased lymphocyte counts. Multicolor immunophenotyping of PBMCs revealed ICI treatment activated additional immune cell types that need further validation. We confirmed that TKI treatment could either antagonize or enhance the effect of ICIs in the co-culture assay using patient’s tumor cells and PBMCs. Conclusions To the best of our knowledge, this is the first study showing that TKIs can have various effects on blood immune cells, which may affect their response to ICIs. Further validation of the blood biomarker and in vitro assay is warranted.

show abstract

Section: Introductionmentioning

confidence: 99%

Small molecule tyrosine kinase inhibitors modulated blood immune cell counts in patients with oncogene-driven NSCLC

Zeng

Chen

et al. 2021

Biomark Res

View full text Add to dashboard Cite

show abstract

“…Finally, NSCLC patients with EGFR mutations show poor response to anti-PD-1/PD-L1 treatment [159], and the mechanisms responsible for the lack of response to immunotherapy in such patients still remain unclear and need to be investigated. Moreover, combination of tyrosine kinases inhibitors and immunotherapy did not show synergistic effects in NSCLC patients in recent clinical trials [160,161]. Further efforts are therefore needed to evaluate different types of drug combinations, administration sequences, and side effects to identify more effective immunochemotherapy for this subset of patients.…”

Section: Epidermal Growth Factor Receptormentioning

confidence: 99%

The Role of Oncogenes and Redox Signaling in the Regulation of PD-L1 in Cancer

Glorieux

Xia

Huang

2021

Cancers

View full text Add to dashboard Cite

Tumor cells can evade the immune system via multiple mechanisms, including the dysregulation of the immune checkpoint signaling. These signaling molecules are important factors that can either stimulate or inhibit tumor immune response. Under normal physiological conditions, the interaction between programmed cell death ligand 1 (PD-L1) and its receptor, programmed cell death 1 (PD-1), negatively regulates T cell function. In cancer cells, high expression of PD-L1 plays a key role in cancer evasion of the immune surveillance and seems to be correlated with clinical response to immunotherapy. As such, it is important to understand various mechanisms by which PD-L1 is regulated. In this review article, we provide an up-to-date review of the different mechanisms that regulate PD-L1 expression in cancer. We will focus on the roles of oncogenic signals (c-Myc, EML4-ALK, K-ras and p53 mutants), growth factor receptors (EGFR and FGFR), and redox signaling in the regulation of PD-L1 expression and discuss their clinical relevance and therapeutic implications. These oncogenic signalings have common and distinct regulatory mechanisms and can also cooperatively control tumor PD-L1 expression. Finally, strategies to target PD-L1 expression in tumor microenvironment including combination therapies will be also discussed.

show abstract

“…Trials with neoadjuvant administration of immunotherapy or chemo-immunotherapy report much higher rates of obtained pathological responses than trials with neoadjuvant EGFR and ALK-TKIs (21-45% MPR and 7-15% pCR) [94]. Immunotherapy and chemotherapy combinations may lead to even higher rates of pathological response: MPR 57-83% and pCR 33-63% [73,95]. It is hypothesized that the immune checkpoint inhibitors are more efficient in the neoadjuvant approach comparing to adjuvant due to intact immune landscape of the primary tumor and regional lymph nodes.…”

Section: Final Remarksmentioning

confidence: 99%

“…EGFR and ALK mutated tumors are characterized by a lower tumor mutation burden, they present lower numbers of antigens that generate less prominent immunological responses. Those tumors are less susceptible to the immune checkpoint inhibitors, which require constant development of effective therapies also in neoadjuvant protocols [95].…”

Section: Final Remarksmentioning

confidence: 99%

Safety of Surgery after Neoadjuvant Targeted Therapies in Non-Small Cell Lung Cancer: A Narrative Review

Marjański

Dziedzic

Kowalczyk

et al. 2021

IJMS

View full text Add to dashboard Cite

New drugs, including immune checkpoint inhibitors and targeted therapy, have changed the prognosis in a subset of patients with advanced lung cancer, and are now actively investigated in a number of trials with neoadjuvant and adjuvant regimens. However, no phase III randomized studies were published yet. The current narrative review proves that targeted therapies are safe in neoadjuvant approach. Unsurprisingly, administration of therapy is related to an acceptable toxicity profile. Severe adverse events’ rate that rarely compromises outcomes of patients with advanced lung cancer is not that commonly accepted in early lung cancer as it may lead to missing the chance of curative surgery. Among those complications, the most important factors that may limit the use of targeted therapies are severe respiratory adverse events precluding the resection occurring after treatment with some anaplastic lymphoma kinase and rarely after epidermal growth factor receptor tyrosine kinase inhibitors. At this point, in the presented literature assessing the feasibility of neoadjuvant therapies with anaplastic lymphoma kinase and epidermal growth factor receptor tyrosine kinase inhibitors, we did not find any unexpected intraoperative events that would be of special interest to a thoracic surgeon. Moreover, the postoperative course was associated with typical rate of complications.

show abstract

Immunotherapy in EGFR-Mutant and ALK-Positive Lung Cancer

Cited by 20 publications

References 72 publications

Small molecule tyrosine kinase inhibitors modulated blood immune cell counts in patients with oncogene-driven NSCLC

Small molecule tyrosine kinase inhibitors modulated blood immune cell counts in patients with oncogene-driven NSCLC

The Role of Oncogenes and Redox Signaling in the Regulation of PD-L1 in Cancer

Safety of Surgery after Neoadjuvant Targeted Therapies in Non-Small Cell Lung Cancer: A Narrative Review

Contact Info

Product

Resources

About