Background

NSCLC has a poor prognosis because most patients have advanced stage of cancer at the time of diagnosis, and patients with early-stage tumors are very likely to encounter post-surgical metastasis and recurrence (Zappa and Mousa, 2016; Renaud et al., 2016). Transplanted tumors grown subcutaneously in immune-deficient nude mice do not faithfully recapitulate the metastatic disease, and therefore, better models are needed (Manzotti et al., 1993). The 344SQ LUAD cell line forms spontaneous metastasis due to the suppression of the microRNA-200 (miR-200) expression, resulting in an epithelial-mesenchymal transition (EMT) phenotype having increased motility (Chen et al., 2014). Moreover, with a considerably low number of tumor-infiltrating cytotoxic T lymphocytes, the Kras/p53 mutant LUAD model exhibits an 'immunologically cold' phenotype. The low number of anticancer lymphocytes renders it less receptive to treatments like anti-PD1 that depends on pre-existing T cells, making it an ideal model to test alternative strategies for the treatment of “immunologically cold tumors” (Pfirschke et al., 2016; Espinosa et al., 2017).

Platinum-based chemotherapy is a standard of care in NSCLC. However, acquired resistance to platinum drugs presents a serious challenge in NSCLC management (Galluzzi et al., 2012). Here, we describe a procedure to adopt the Poly(2-oxazoline) (POx)-based nanomicelle formulation strategy for the coadministration of agents that reverse drug resistance (a.k.a. chemosensitizers) with platinum drugs and assess their efficacy in the LUAD model of NSCLC. Further, we describe an immunotherapeutic approach for treating LUAD by using POx micelle formulation of a small molecule biologic response modifier, Resiquimod (administered alone or in combination with checkpoint blockade therapy). POx micelle formulation of poorly soluble drugs has been previously demonstrated to be safe and effective in various tumor models (He et al., 2016). POx micelles are easy to prepare (Vinod et al., 2020a) and can be used to solubilize a broad range of poorly soluble compounds for drug delivery applications.