Cancer stem cells in drug resistant lung cancer: Targeting cell surface markers and signaling pathways

Discussion of current strategies targeting the immune system related to solid tumors with emphasis on head and neck squamous cell carcinoma (HNSCC).This review will outline the current challenges with immunotherapy and future goals for treatment using these agents. Agents targeting immune checkpoint receptors (IR) such as program death 1 (PD1) have been used in the clinical realm for melanoma and non-small cell lung cancer (NSCLC), and the use of these agents for these malignancies has provided crucial information about how and why patients respond or not to inhibitory checkpoint receptor blockade therapy (ICR). The anti PD1 agent, nivolumab, was recently approved by the FDA as a standard of care regimen for patients with platinum refractory recurrent/metastatic (R/M) HNSCC. Molecular pathways leading to resistance are starting to be identified, and work is underway to understand the most optimal treatment regimen with incorporation of immunotherapy. ICR has renewed interest in the immunology of cancer, but resistance is not uncommon, and thus understanding of these mechanisms will allow the clinician to appropriately select patients that will benefit from this therapy.

/pdf/immunotherapy-for-head-and-neck-squamous-cell-carcinoma-3qx4tl3a13.pdf

Immunotherapy for Head and Neck Squamous Cell Carcinoma

The explosion in novel cancer immunotherapies has resulted in extraordinary clinical successes in the treatment of multiple cancers. Checkpoint inhibitors (CPIs) that target negative regulatory molecules have become standard of care. However, with the growing use of CPIs, alone or in combination with chemotherapy, targeted therapies, or other immune modulators, a significant increase in immune-related adverse events (irAEs) has emerged. The wide-ranging and currently unpredictable spectrum of CPI-induced irAEs can lead to profound pathology and, in some cases, death. Growing evidence indicates that many irAEs are a consequence of a breakdown in self-tolerance, but the influence of genetics, the environment, and the mechanisms involved remains unclear. This review explores key questions in this emerging field, summarizing preclinical and clinical experiences with this new generation of cancer drugs, the growing understanding of the role of the immune response in mediating these toxicities, the relationship of CPI-induced autoimmunity to conventional autoimmune diseases, and insights into the mechanism of irAE development and treatment.

/pdf/the-balancing-act-between-cancer-immunity-and-autoimmunity-1kngr83ps8.pdf

The Balancing Act between Cancer Immunity and Autoimmunity in Response to Immunotherapy

Dendritic cell (DC)-based vaccines against cancer have been extensively developed over the past two decades. Typically DC-based cancer immunotherapy entails loading patient-derived DCs with an appropriate source of tumor-associated antigens (TAAs) and efficient DC stimulation through a so-called "maturation cocktail" (typically a combination of pro-inflammatory cytokines and Toll-like receptor agonists), followed by DC reintroduction into patients. DC vaccines have been documented to (re)activate tumor-specific T cells in both preclinical and clinical settings. There is considerable clinical interest in combining DC-based anticancer vaccines with T cell-targeting immunotherapies. This reflects the established capacity of DC-based vaccines to generate a pool of TAA-specific effector T cells and facilitate their infiltration into the tumor bed. In this Trial Watch, we survey the latest trends in the preclinical and clinical development of DC-based anticancer therapeutics. We also highlight how the emergence of immune checkpoint blockers and adoptive T-cell transfer-based approaches has modified the clinical niche for DC-based vaccines within the wide cancer immunotherapy landscape.

https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2017.1328341

Trial watch: Dendritic cell-based anticancer immunotherapy.

Current cancer therapies target the bulk of the tumour, while a population of highly resistant tumour cells may be able to repopulate the tumour and metastasize to new sites. Cancer cells with such stem cell‐like characteristics can be identified based on their phenotypical and/or functional features which may open up ways for their targeted elimination. In this review we discuss potential off‐target effects of inhibiting cancer stem‐cell self‐renewal pathways on immune cells, and summarize some recent immunological studies specifically targeting cancer stem cells based on their unique antigen expressio

https://onlinelibrary.wiley.com/doi/pdf/10.1111/imm.12866

Cancer stem cells as targets for immunotherapy.

The inability to target cancer stem cells (CSC) may be a significant factor contributing to treatment failure. We have developed a strategy to target the CSC populations in melanoma and squamous cell carcinoma using CSC lysate-pulsed dendritic cells (DCs). The CSC-DC vaccine was administered in the adjuvant setting after localized radiation therapy of established tumors. Using mouse models we demonstrated that DCs pulsed with CSCs enriched by virtue of their expression of the CSC marker ALDH (termed CSC-DC) significantly inhibited tumor growth, reduced development of pulmonary metastases and prolonged survival. The effect was associated with downregulation of chemokine (C-C motif) receptors CCR7 and CCR10 in tumor cells and decreased expression of the chemokine (C-C motif) ligands CCL21, CCL27 and CCL28 in lung tissue. The CSC-DC vaccine significantly reduced ALDHhigh CSC frequency in primary tumors. Direct targeting of CSCs was demonstrated by the specific binding of IgG produced by ALDHhigh CSC-DC vaccine-primed B cells to ALDHhigh CSCs, resulting in lysis of these target CSCs in the presence of complement. These data suggest that the CSC-DC vaccine approach may be useful in the adjuvant setting where local and systemic relapse are high after conventional treatment of cancers.

Cancer stem cell vaccine inhibits metastases of primary tumors and induces Humoral immune responses against cancer stem cells

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Cancer stem cell vaccine inhibits metastases of primary tumors and induces Humoral immune responses against cancer stem cells