Immunotherapy Combined with Metronomic Dosing: An Effective Approach for the Treatment of NSCLC

Abstract

Pioneering studies on tumor and immune cell interactions have highlighted immune checkpoint inhibitors (ICIs) as revolutionizing interventions for the management of NSCLC, typically combined with traditional MTD chemotherapies, which usually lead to toxicities and resistance to treatment. Alternatively, MTR chemotherapy is based on the daily low dose administration of chemotherapeutics, preventing tumor growth indirectly by targeting the tumor microenvironment. The effects of MTR administration of an oral prodrug of gemcitabine (OralGem), alone or with anti-PD1, were evaluated. Relevant in vitro and in vivo models were developed to investigate the efficacy of MTR alone or with immunotherapy and the potential toxicities associated with each dosing scheme. MTR OralGem restricted tumor angiogenesis by regulating thrombospondin-1 (TSP-1) and vascular endothelial growth factor A (VEGFA) expression. MTR OralGem enhanced antitumor immunity by increasing T effector responses and cytokine release, concomitant with dampening regulatory T cell populations. Promising pharmacokinetic properties afforded minimized blood and thymus toxicity and favorable bioavailability upon MTR administration compared to MTD. The combination of MTR OralGem with immunotherapy was shown to be highly efficacious and tolerable, illuminating it as a strong candidate therapeutic scheme for the treatment of NSCLC.

Systematic Elucidation and Pharmacological Targeting of Tumor-Infiltrating Regulatory T Cell Master Regulators

“…Informed by prior investigation into immunogenic effects of low dose or metronomic dosing of other chemotherapeutic agents such as cyclophosphamide (Ghiringhelli et al, 2007;Lutsiak et al, 2005;Wada et al, 2009) or oxaliplatin (Shalapour et al, 2015), more recent studies showed that sub-clinical "low" doses of gemcitabine are immunomodulatory in various ways, with effects on NK cell function (Zhang et al, 2020), myeloid polarization (Deshmukh et al, 2018;Di Caro et al, 2016) and Tregs (Homma et al, 2014;Rettig et al, 2011;Shevchenko et al, 2013;Skavatsou et al, 2021;Tongu et al, 2013).…”

“…In multiple pre-clinical models, tumor growth in T cell-deficient Nude mice or specific CD8 T cell depletion rendered gemcitabine less effective, suggesting that gemcitabine exhibits T cell-dependent immunogenic activity in addition to direct tumoricidal killing (Suzuki et al, 2007). Informed by prior investigation into immunogenic effects of low dose or metronomic dosing of other chemotherapeutic agents such as cyclophosphamide (Ghiringhelli et al, 2007; Lutsiak et al, 2005; Wada et al, 2009) or oxaliplatin (Shalapour et al, 2015), more recent studies showed that sub-clinical “low” doses of gemcitabine are immunomodulatory in various ways, with effects on NK cell function (Zhang et al, 2020), myeloid polarization (Deshmukh et al, 2018; Di Caro et al, 2016) and Tregs (Homma et al, 2014; Rettig et al, 2011; Shevchenko et al, 2013; Skavatsou et al, 2021; Tongu et al, 2013).…”

Iron oxide nanoflowers encapsulated in thermosensitive fluorescent liposomes for hyperthermia treatment of lung adenocarcinoma

“…Lung cancer is the number one cause of cancer-related deaths worldwide, of which over 80% is identified as non-small cell lung cancer 1 , 2 . Conventional treatments for cancer, like chemotherapy, radiation, or surgery, have numerous side effects for the patient (nausea, hair loss, intestinal dysfunction, skin irritability), entailing risks of drug resistance, collateral damage of healthy tissue, inefficiency against metastasis, and tumor reoccurrence 3 .…”

Laser-Induced Forward Transfer Printing on Microneedles for Transdermal Delivery of Gemcitabine

“…As an extension of the peptide-drug conjugate work, another concept, the metronomic approach (MTR) based on the daily low-dose administration of Gem, was recently evaluated[ 33 ]. An oral pro-drug of Gem (OralGem) was chosen for this work in non-small cell lung cancer animal models.…”