Repurposing amino-bisphosphonates by liposome formulation for a new role in cancer treatment.

Amino-bisphosphonates (N-BPs) have been commercially available for over four decades and are used for the treatment of osteoporosis, Paget's disease, hypercalcemia of malignancy, and bone metastases derived from various cancer types. Zoledronate and alendronate, two of the most potent N-BPs, have demonstrated direct tumoricidal activity on tumor cells and immune modulatory effects on myeloid cells and T cells in vitro and in animal models of cancer. However, the rapid renal clearance and sequestration in mineral bone of these drugs in free form severely limit their systemic exposure and applications in cancer patients. Reformulation of N-BPs by encapsulation in liposomal nanoparticles addresses these pharmacokinetic barriers, and liposomal zoledronate and alendronate formulations have been found to increase the anticancer efficacy of cytotoxic chemotherapies and adoptive T cell immunotherapies in murine cancer models. Herein, we review the differences in pharmacology between N-BPs versus non-N-BPs (e.g., clodronate), free versus liposomal N-BP formulations, and targeted versus non-targeted liposomal N-BPs, and the clinical and preclinical evidence supporting a role for liposomal N-BPs in the treatment of cancer. We propose that pegylated liposomal alendronate (PLA) has the most potential for clinical translation based on favorable therapeutic index, ability to passively target and accumulate in tumors, proven biocompatibility of the liposome carrier, and preclinical anticancer efficacy.

Pharmacoepidemiology of Clinically Relevant Hypothyroidism and Hypertension from Sunitinib and Sorafenib.

BACKGROUND: Thyroid dysfunction and hypertension (HTN) have been sporadically reported with sunitinib (SUN) and sorafenib (SOR). Determination of the side effect incidence will enhance monitoring and management recommendations. METHODS: An observational cohort study was performed using deidentified pharmacy claims data from a 3-year period to evaluate patients prescribed SUN, SOR, or capecitabine (CAP; comparison group). The primary outcome was time to first prescription for thyroid replacement or HTN treatment. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated by Cox proportional hazards models. RESULTS: A total of 20,061 patients were eligible for evaluation of thyroid replacement therapy, which was initiated in 11.6% of those receiving SUN (HR, 16.77; 95% CI, 13.54-20.76), 2.6% of those receiving SOR (HR, 3.47; 95% CI, 2.46-4.98), and 1% of those receiving CAP, with median time to initiation of 4 months (range, 1-35 months). A total of 14,468 patients were eligible for evaluation of HTN therapy, which was initiated in 21% of SUN recipients (HR, 4.91; 95% CI, 4.19-5.74), 14% of SOR recipients (HR, 3.25; 95% CI, 2.69-3.91), and 5% of CAP recipients, with median time to initiation of 1 month (range, 1-18 months) for SOR and 2 months (range, 1-25 months) for SUN. CONCLUSION: SUN and SOR significantly increased the risk for clinically relevant hypothyroidism; the risk was at least 4 times greater with SUN than with SOR. Patients receiving SUN and SOR had a similar elevated risk for clinically relevant HTN. These data provide robust measures of the incidence and time to onset of these clinically actionable adverse events. The Oncologist 2017;22:208-212Implications for Practice: The side effect profiles for novel therapies are typically used to create monitoring and management recommendations using clinical trial data from patient populations that may not represent those seen in standard clinical practice. This analysis using a large pharmacy claims database better reflects typical patients treated with sorafenib or sunitinib outside of a clinical trial. The findings of increased need for thyroid replacement in patients receiving sunitinib compared with sorafenib and a similar increase in need for hypertension therapy with both agents can be used to form clinically relevant monitoring recommendations for these agents.

New insights and evolving role of pegylated liposomal doxorubicin in cancer therapy.

We herein review various pharmacological and clinical aspects of pegylated liposomal doxorubicin (PLD), the first nanomedicine to be approved for cancer therapy, and discuss the gap between its potent antitumor activity in preclinical studies and its comparatively modest achievements in clinical studies and limited use in clinical practice. PLD is a complex formulation of doxorubicin based on pharmaceutical nanotechnology with unique pharmacokinetic and pharmacodynamic properties. Its long circulation time with stable retention of the payload and its accumulation in tumors with high vascular permeability both result in important advantages over conventional chemotherapy. The ability of PLD to buffer a number of undesirable side effects of doxorubicin, including a major risk reduction in cardiac toxicity, is now well-established and confers a major added value in a number of disease conditions. PLD is approved for the treatment of ovarian cancer, breast cancer, multiple myeloma, and Kaposi sarcoma. In addition, clinically significant antitumor activity of PLD has been reported in a number of other cancer types, including lymphomas and soft tissue sarcomas. In spite of this, PLD has not replaced conventional doxorubicin in common applications such as the adjuvant and neoadjuvant treatment of breast cancer, and its use in the clinic has not become as widespread as one may have predicted. Exploiting the unique pharmacology of PLD, analyzing its selective biodistribution and homing to tumors in cancer patients with proper theranostic tools, and harnessing its complex interaction with the immune system, will lead to a more selective and rational use of PLD that may have great impact on future clinical results and may help realize its largely untapped potential.

Quantifying autophagosomes and autolysosomes in cells using imaging flow cytometry.

Autophagy dysregulation has been implicated in numerous diseases and many therapeutic agents are known to modulate this pathway. Therefore, the ability to accurately monitor autophagy is critical to understanding its role in the pathogenesis and treatment of many diseases. Recently an imaging flow cytometry method measuring colocalization of microtubule associated protein 1B light chain 3 (LC3) and lysosomal signals via Bright Detail Similarity (BDS) was proposed which enabled evaluation of autophagic processing. However, since BDS only evaluates colocalization of LC3 and lysosomal signals, the number of autophagy organelles was not taken into account. We found that in cells classified as having Low BDS, there was a large degree of variability in accumulation of autophagosomes. Therefore, we developed a new approach wherein BDS was combined with number of LC3+ puncta, which enabled us to distinguish between cells having very few autophagy organelles versus cells with accumulation of autophagosomes or autolysosomes. Using this method, we were able to distinguish and quantify autophagosomes and autolysosomes in breast cancer cells cultured under basal conditions, with inhibition of autophagy using chloroquine, and with induction of autophagy using amino acid starvation. This technique yields additional insight into autophagy processing making it a useful supplement to current techniques.

Liposome promotion of tumor growth is associated with angiogenesis and inhibition of antitumor immune responses.

Liposomes have tremendous potential as drug carriers in the treatment of cancer. However, despite enhanced tumor drug delivery and decreased toxicity, patient survival rates have not improved significantly compared to corresponding free drug treatments. Importantly, we found that a liposomal nanoparticle currently used as a drug carrier in cancer patients enhanced tumor growth in an immune competent murine model of cancer. This was associated with increased tumor angiogenesis and suppression of antitumor immune responses as indicated by decreased cytokine production by tumor macrophages and cytotoxic T cells, diminished tumor infiltration of tumor-specific T cells, and decreased number of dendritic cells in tumor draining lymph nodes. These results suggest that carrier-induced immunosuppression and angiogenesis have the potential to reduce the antitumor effects of drugs loaded within. These findings may have significant implications for the current use and future development of anticancer nanoparticles and further investigations are urgently needed. FROM THE CLINICAL EDITOR: This study discusses important implications of nanoliposome-based drug delivery systems in cancer therapy, and demonstrates that nanoliposomes may have immunosuppressive and angiogenetic properties, directly counterbalancing their anti-cancer activity, which may also have important clinical implications related to more widespread applications of such systems.

Clinical Characteristics and Patterns of Immune Responses in COVID-19 Patients From a Rural Community Hospital.

Background Although demographic and clinical factors such as age, certain comorbidities, and sex have been associated with COVID-19 outcomes, these studies were largely conducted in urban populations affiliated with large academic medical centers. There have been very few studies focusing on rural populations that also characterize broader changes in inflammatory cytokines and chemokines. Methodology A single-center study was conducted between June 2020 and March 2021 in Abilene, Texas, USA. Patients were included if they presented to the hospital for treatment of COVID-19, had extra biological materials from routine care available, and were between the ages of 0 to 110 years. There were no exclusion criteria. Patient characteristics, symptom presentation, and clinical laboratory results were extracted from electronic health records. Blood specimens were analyzed by protein microarray to quantitate 40 immunological biomarkers. Results A total of 122 patients were enrolled, of whom 81 (66%) were admitted to the general non-critical inpatient unit, 37 (30%) were admitted to the intensive or critical care units, and four (3.2%) were treated outpatient. Most hospitalized COVID-19 patients in this rural population were elderly, male, obese, and retired individuals. Predominant symptoms for non-critical patients were shortness of breath, fever, and fatigue. Ferritin levels for outpatient patients were lower on average than those in an inpatient setting and lactate dehydrogenase (LDH) levels were noted to be lower in non-critical and outpatient than those in the intensive care unit setting. Inflammatory biomarkers were positively correlated and consistent with inflammatory cascade. Interleukin (IL)-10 was positively correlated while platelet-derived growth factor was negatively correlated with inflammatory biomarkers. Patients ≥65 years had significantly higher levels of LDH and seven cytokines/chemokines (granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin IL-1b, IL-6, IL-10, IL-11, macrophage inflammatory protein (MIP)-1d, and IL-8) while levels of five other immune molecules (intercellular adhesion molecule 1 (ICAM-1), monocyte chemoattractant protein 1 (MCP-1), tissue inhibitor of metalloproteinase 2 (TIMP-2), IL-2, and IL-4) were significantly lower compared to those <65 years. Females had significantly higher levels of LDH and 10 cytokines/chemokines (GM-CSF, IL-1b, IL-6, IL-10, IL-11, IL-15, IL-16, MIP-1a, MIP-1d, and IL-8) while levels of TIMP-2 and IL-4 were significantly lower than male patients. Conclusions The clinical characteristics of this rural cohort of hospitalized patients differed somewhat from nationally reported data. The contributions of social, environmental, and healthcare access factors should be investigated. We identified age and sex-associated differences in immunological response markers that warrant further investigation to identify the underlying molecular mechanisms and impact on COVID-19 pathogenesis.

Mechanisms and Barriers in Nanomedicine: Progress in the Field and Future Directions.

In recent years, steady progress has been made in synthesizing and characterizing engineered nanoparticles, resulting in several approved drugs and multiple promising candidates in clinical trials. Regulatory agencies such as the Food and Drug Administration and the European Medicines Agency released important guidance documents facilitating nanoparticle-based drug product development, particularly in the context of liposomes and lipid-based carriers. Even with the progress achieved, it is clear that many barriers must still be overcome to accelerate translation into the clinic. At the recent conference workshop "Mechanisms and Barriers in Nanomedicine" in May 2023 in Colorado, U.S.A., leading experts discussed the formulation, physiological, immunological, regulatory, clinical, and educational barriers. This position paper invites open, unrestricted, nonproprietary discussion among senior faculty, young investigators, and students to trigger ideas and concepts to move the field forward.

The role of pegylated liposomal doxorubicin in ovarian cancer: a meta-analysis of randomized clinical trials.

BACKGROUND: Recent studies suggest that carboplatin with pegylated liposomal doxorubicin (C+PLD) is as efficacious as carboplatin with paclitaxel (C+P) and possibly is more tolerable for ovarian cancer therapy. Pegylated liposomal doxorubicin (PLD) may also be efficacious and tolerable as monotherapy in recurrent or platinum-resistant disease. We performed a meta-analysis of randomized trials in order to elucidate the role of PLD in ovarian cancer. METHODS: We searched PubMed, Scopus, and ISI Web of Knowledge for studies comparing C+PLD with C+P and comparing PLD with another monotherapy. Summary hazard ratios (HRs) and relative risks with their corresponding 95% confidence intervals (CIs) were calculated using a fixed-effects model. RESULTS: Three trials were included in the doublet regimen analysis, and five trials were included in the monotherapy regimen analysis. C+PLD provided superior progression-free survival (PFS) (HR, 0.87; 95% CI, 0.78-0.96) and similar overall survival (OS; HR, 0.95; 95% CI, 0.84-1.07) compared with C+P. There was no evidence of improved tolerability: C+PLD had more gastrointestinal toxicity, anemia, thrombocytopenia, cutaneous toxicity, and mucositis/stomatitis, although there was less neutropenia, neuropathy, and alopecia. PLD monotherapy had similar PFS (HR, 0.99; 95% CI, 0.89-1.11) and OS (HR, 0.99; 95% CI, 0.88-1.11) to other monotherapies, but it was more tolerable. There was less neutropenia, anemia, thrombocytopenia, and gastrointestinal toxicity, although cutaneous toxicity was increased. CONCLUSION: C+PLD had better PFS and similar OS compared with C+P and had a very different toxicity profile. Therapy selection could be based on patient risks for side effects. PLD is as efficacious as other monotherapies and is more tolerable.

Translational studies of phenotypic probes for the mononuclear phagocyte system and liposomal pharmacology.

As nanoparticles (NPs) are cleared via phagocytes of the mononuclear phagocyte system (MPS), we hypothesized that the function of circulating monocytes and dendritic cells (MO/DC) in blood can predict NP clearance (CL). We measured MO/DC phagocytosis and reactive oxygen species (ROS) production in mice, rats, dogs, and patients with refractory solid tumors. Pharmacokinetic studies of polyethylene glycol (PEG)-encapsulated liposomal doxorubicin (PEGylated liposomal doxirubicin [PLD]), CKD-602 (S-CKD602), and cisplatin (SPI-077) were performed at the maximum tolerated dose. MO/DC function was also evaluated in patients with recurrent epithelial ovarian cancer (EOC) administered PLD. Across species, a positive association was observed between cell function and CL of PEGylated liposomes. In patients with EOC, associations were observed between PLD CL and phagocytosis (R(2) = 0.43, P = 0.04) and ROS production (R(2) = 0.61, P = 0.008) in blood MO/DC. These findings suggest that probes of MPS function may help predict PEGylated liposome CL across species and PLD CL in patients with EOC.

Harnessing Nanomedicine to Potentiate the Chemo-Immunotherapeutic Effects of Doxorubicin and Alendronate Co-Encapsulated in Pegylated Liposomes.

Encapsulation of Doxorubicin (Dox), a potent cytotoxic agent and immunogenic cell death inducer, in pegylated (Stealth) liposomes, is well known to have major pharmacologic advantages over treatment with free Dox. Reformulation of alendronate (Ald), a potent amino-bisphosphonate, by encapsulation in pegylated liposomes, results in significant immune modulatory effects through interaction with tumor-associated macrophages and activation of a subset of gamma-delta T lymphocytes. We present here recent findings of our research work with a formulation of Dox and Ald co-encapsulated in pegylated liposomes (PLAD) and discuss its pharmacological properties vis-à-vis free Dox and the current clinical formulation of pegylated liposomal Dox. PLAD is a robust formulation with high and reproducible remote loading of Dox and high stability in plasma. Results of biodistribution studies, imaging with radionuclide-labeled liposomes, and therapeutic studies as a single agent and in combination with immune checkpoint inhibitors or gamma-delta T lymphocytes suggest that PLAD is a unique product with distinct tumor microenvironmental interactions and distinct pharmacologic properties when compared with free Dox and the clinical formulation of pegylated liposomal Dox. These results underscore the potential added value of PLAD for chemo-immunotherapy of cancer and the relevance of the co-encapsulation approach in nanomedicine.

Pegylated Liposomal Alendronate Biodistribution, Immune Modulation, and Tumor Growth Inhibition in a Murine Melanoma Model.

While tumor-associated macrophages (TAM) have pro-tumoral activity, the ablation of macrophages in cancer may be undesirable since they also have anti-tumoral functions, including T cell priming and activation against tumor antigens. Alendronate is a potent amino-bisphosphonate that modulates the function of macrophages in vitro, with potential as an immunotherapy if its low systemic bioavailability can be addressed. We repurposed alendronate in a non-leaky and long-circulating liposomal carrier similar to that of the clinically approved pegylated liposomal doxorubicin to facilitate rapid clinical translation. Here, we tested liposomal alendronate (PLA) as an immunotherapeutic agent for cancer in comparison with a standard of care immunotherapy, a PD-1 immune checkpoint inhibitor. We showed that the PLA induced bone marrow-derived murine non-activated macrophages and M2-macrophages to polarize towards an M1-functionality, as evidenced by gene expression, cytokine secretion, and lipidomic profiles. Free alendronate had negligible effects, indicating that liposome encapsulation is necessary for the modulation of macrophage activity. In vivo, the PLA showed significant accumulation in tumor and tumor-draining lymph nodes, sites of tumor immunosuppression that are targets of immunotherapy. The PLA remodeled the tumor microenvironment towards a less immunosuppressive milieu, as indicated by a decrease in TAM and helper T cells, and inhibited the growth of established tumors in the B16-OVA melanoma model. The improved bioavailability and the beneficial effects of PLA on macrophages suggest its potential application as immunotherapy that could synergize with T-cell-targeted therapies and chemotherapies to induce immunogenic cell death. PLA warrants further clinical development, and these clinical trials should incorporate tumor and blood biomarkers or immunophenotyping studies to verify the anti-immunosuppressive effect of PLA in humans.

Comparative effects of free doxorubicin, liposome encapsulated doxorubicin and liposome co-encapsulated alendronate and doxorubicin (PLAD) on the tumor immunologic milieu in a mouse fibrosarcoma model.

Background: We have previously shown that alendronate, an amino-bisphosphonate, when reformulated in liposomes, can significantly enhance the efficacy of cytotoxic chemotherapies and help remodel the immunosuppressive tumor microenvironment towards an immune-permissive milieu resulting in increased anticancer efficacy. In addition, we have previously shown that the strong metal-chelating properties of alendronate can be exploited for nuclear imaging of liposomal biodistribution. To further improve anticancer efficacy, a pegylated liposome formulation co-encapsulating alendronate and doxorubicin (PLAD) has been developed. In this study, we examined the effects of PLAD on the tumor immunologic milieu in a mouse fibrosarcoma model in which the tumor microenvironment is heavily infiltrated with tumor-associated macrophages (TAM) that are associated with poor prognosis and treatment resistance. Methods: Doxorubicin biodistribution, characterization of the tumor immunologic milieu, cellular doxorubicin uptake, and tumor growth studies were performed in Balb/c mice bearing subcutaneously implanted WEHI-164 fibrosarcoma cells treated intravenously with PLAD, pegylated liposomal doxorubicin (PLD), free doxorubicin, or vehicle. Results: PLAD delivery resulted in a high level of tumor doxorubicin that was 20 to 30-fold greater than in free doxorubicin treated mice, and non-significantly higher than in PLD treated mice. PLAD also resulted in increased uptake in spleen and slightly lower plasma levels as compared to PLD. Importantly, our results showed that PLAD, and to a lesser extent PLD, shifted cellular drug uptake to TAM and to monocytic myeloid-derived suppressor cells (MDSC), while there was no drug uptake in neutrophilic MDSC or lymphoid cells. Free doxorubicin cellular drug uptake was below detectable levels. PLAD, and to a lesser extent PLD, also induced significant changes in number and functionality of tumor-infiltrating TAM, MDSC, Treg, NKT, and NK cells that are consistent with enhanced antitumor immune responses in the tumor microenvironment. In contrast, free doxorubicin induced moderate changes in the tumor microenvironment that could promote (decreased Treg) or be detrimental to antitumor immune responses (decreased M1 TAM and NK cells). These immune modulatory effects are reflected in the therapeutic study which showed that PLAD and PLD inhibited tumor growth and significantly prolonged survival, while free doxorubicin showed little or no anticancer activity. Conclusion: We show that liposomal delivery of doxorubicin not only alters pharmacokinetics, but also dramatically changes the immune modulatory activity of the drug cargo. In addition, our data support that the PLAD nanotheranostic platform further enhances some immune changes that may act in synergy with its cytotoxic chemotherapy effects.

Antibody-drug conjugates: an evolving approach for melanoma treatment.

Melanoma continues to be an aggressive and deadly form of skin cancer while therapeutic options are continuously developing in an effort to provide long-term solutions for patients. Immunotherapeutic strategies incorporating antibody-drug conjugates (ADCs) have seen varied levels of success across tumor types and represent a promising approach for melanoma. This review will explore the successes of FDA-approved ADCs to date compared to the ongoing efforts of melanoma-targeting ADCs. The challenges and opportunities for future therapeutic development are also examined to distinguish how ADCs may better impact individuals with malignancies such as melanoma.

Nanoparticle-Induced Complement Activation: Implications for Cancer Nanomedicine.

Nanoparticle-based anticancer medications were first approved for cancer treatment almost 2 decades ago. Patients benefit from these approaches because of the targeted-drug delivery and reduced toxicity, however, like other therapies, adverse reactions often limit their use. These reactions are linked to the interactions of nanoparticles with the immune system, including the activation of complement. This activation can cause well-characterized acute inflammatory reactions mediated by complement effectors. However, the long-term implications of chronic complement activation on the efficacy of drugs carried by nanoparticles remain obscured. The recent discovery of protumor roles of complement raises the possibility that nanoparticle-induced complement activation may actually reduce antitumor efficacy of drugs carried by nanoparticles. We discuss here the initial evidence supporting this notion. Better understanding of the complex interactions between nanoparticles, complement, and the tumor microenvironment appears to be critical for development of nanoparticle-based anticancer therapies that are safer and more efficacious.

Translational considerations in nanomedicine: The oncology perspective.

Nanoparticles can provide effective control of the release rate and tissue distribution of their drug payload, leading to major pharmacokinetic and pharmacodynamic changes vis-à-vis the conventional administration of free drugs. In the last two decades, we have witnessed major progress in the synthesis and characterization of engineered nanoparticles for imaging and treatment of cancers, resulting in the approval for clinical use of several products and in new and promising approaches. Despite these advances, clinical applications of nanoparticle-based therapeutic and imaging agents remain limited due to biological, immunological, and translational barriers. There is a need to make high impact advances toward translation. In this review, we address biological, toxicological, immunological, and translational aspects of nanomedicine and discuss approaches to move the field forward productively. Overcoming these barriers may dramatically improve the development potential and role of nanomedicines in the oncology field and help meet the high expectations.

Optimizing Patient Outcomes with PD-1/PD-L1 Immune Checkpoint Inhibitors for the First-Line Treatment of Advanced Non-Small Cell Lung Cancer.

The rapidly expanding repertoire of immune checkpoint inhibitors (ICIs) now includes two agents, pembrolizumab and atezolizumab, approved for first-line treatment of advanced non-small cell lung cancer (aNSCLC) as monotherapy or as part of chemoimmunotherapy. This review summarizes the clinical evidence supporting these indications, with a focus on strategies to optimize patient outcomes. These strategies include patient and tumor factors, adverse-effect profiles, pharmacokinetic and pharmacodynamic drug interactions, and quality of life and cost-effectiveness considerations. We performed a systematic literature search of the PubMed, Scopus, and Google Scholar databases, as well as a search of the conference proceedings of the American Society of Clinical Oncology, European Society for Medical Oncology, and American Association for Cancer Research (through August 31, 2019). The addition of ICIs to conventional chemotherapy as first-line treatment against aNSCLC is now part of the standard of care options. However, even though ICIs may be cost-effective in patients with aNSCLC, high drug and other associated costs can still be a barrier to treatment for patients. Moreover, the adverse-effect profiles of ICIs differ significantly from conventional chemotherapy, and some immune-related adverse effects may have a lasting impact on quality of life. Therefore, in adhering to a patient-centered model of care, clinicians should be mindful of patient- and treatment-specific factors when considering therapeutic options for patients with aNSCLC. Although the role of the immune system in cancer progression and regression has not been fully elucidated, the full clinical potential of immunotherapeutics in the treatment of cancer likely remains to be unleashed.

Management of Immune-Related Adverse Events Associated with Immune Checkpoint Inhibitor Therapy: a Minireview of Current Clinical Guidelines.

Successful targeting and inhibition of the cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death-1 protein/programmed cell death ligand 1 immune checkpoint pathways has led to a rapidly expanding repertoire of immune checkpoint inhibitors for the treatment of various cancers. The approved agents now include ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and cemiplimab. In addition to antitumor responses, immune checkpoint inhibition can lead to activation of autoreactive T-cells resulting in unique immune-related adverse events (irAEs). Therefore, it is imperative that oncology nurses, and other clinicians involved in the care of cancer patients, are familiar with the management of irAEs which differ significantly from the management of adverse events from cytotoxic chemotherapy. Herein, we review the mechanisms of irAEs and strategies for management of irAEs and highlight similarities as well as differences among clinical guidelines from the National Comprehensive Cancer Network, American Society of Clinical Oncology, Society for Immunotherapy of Cancer, and European Society for Medical Oncology. Understanding these similarities and key differences will facilitate the development and implementation of a practice site-specific plan for the management of irAEs.

Harnessing Liposome Interactions With the Immune System for the Next Breakthrough in Cancer Drug Delivery.

Liposomal nanoparticles are a heterogeneous group of engineered drug carriers that have tremendous therapeutic potential in the treatment of cancer. They increase tumor drug delivery, significantly attenuate drug toxicity, and protect the drug from degradation. However, two decades after approval of the first nanoparticle-mediated anticancer drug, pegylated liposomal doxorubicin (Doxil), there has yet to be a major shift in cancer treatment paradigms. Only two anticancer nanoparticles are used in the first-line treatment of cancer patients, with all others relegated to the refractory or salvage setting. Herein, we discuss new insights into the mechanisms underlying in vivo interactions between liposomes and the tumor immunologic milieu, and the knowledge gaps that need to be addressed in order to realize the full clinical potential of cancer nanomedicines. We also discuss immunopharmacology insights from a parallel field, Cancer Immunotherapy, which have the potential to generate breakthroughs in Cancer Nanomedicine.

Liposome-induced immunosuppression and tumor growth is mediated by macrophages and mitigated by liposome-encapsulated alendronate.

Liposomal nanoparticles are the most commonly used drug nano-delivery platforms. However, recent reports show that certain pegylated liposomal nanoparticles (PLNs) and polymeric nanoparticles have the potential to enhance tumor growth and inhibit antitumor immunity in murine cancer models. We sought herein to identify the mechanisms and determine whether PLN-associated immunosuppression and tumor growth can be reversed using alendronate, an immune modulatory drug. By conducting in vivo and ex vivo experiments with the immunocompetent TC-1 murine tumor model, we found that macrophages were the primary cells that internalized PLN in the tumor microenvironment and that PLN-induced tumor growth was dependent on macrophages. Treatment with PLN increased immunosuppression as evidenced by increased expression of arginase-1 in CD11b+Gr1+ cells, diminished M1 functionality in macrophages, and globally suppressed T-cell cytokine production. Encapsulating alendronate in PLN reversed these effects on myeloid cells and shifted the profile of multi-cytokine producing T-cells towards an IFNγ+ perforin+ response, suggesting increased cytotoxic functionality. Importantly, we also found that PLN-encapsulated alendronate (PLN-alen), but not free alendronate, abrogated PLN-induced tumor growth and increased progression-free survival. In summary, we have identified a novel mechanism of PLN-induced tumor growth through macrophage polarization and immunosuppression that can be targeted and inactivated to improve the anticancer efficacy of PLN-delivered drugs. Importantly, we also determined that PLN-alen not only reversed protumoral effects of the PLN carrier, but also had moderate antitumor activity. Our findings strongly support the inclusion of immune-responsive tumor models and in-depth immune functional studies in the preclinical drug development paradigm for cancer nanomedicines, and the further development of chemo-immunotherapy strategies to co-deliver alendronate and chemotherapy for the treatment of cancer.

Nanoparticle Interactions with the Immune System: Clinical Implications for Liposome-Based Cancer Chemotherapy.

The development of stable and long-circulating liposomes provides protection of the drug cargo from degradation and increases tumor drug delivery, leading to the design of liposome formulations with great potential in cancer therapy. However, despite the sound pharmacologic basis, many liposomal as well as other nanoparticle-based drug formulations have failed to meet regulatory criteria for approval. The question that arises is whether we have missed key liposome-host interactions that can account for the gap between the major pharmacologic advantages in preclinical studies and the modest impact of the clinical effects in humans. We will discuss here the nanoparticle-immune system interactions that may undermine the antitumor effect of the nanodrug formulations and contribute to this gap. To overcome this challenge and increase clinical translation, new preclinical models need to be adopted along with comprehensive immunopharmacologic studies and strategies for patient selection in the clinical phase.