Metastatic disease is the leading cause of death among cancer patients and involves a complex and inefficient process. Every step of the metastatic process can be rate limiting and is influenced by non-malignant host cells interacting with the tumor cell. Over a century ago, experiments first indicated a link between the immune system and metastasis. This phenomenon, called concomitant immunity, indicates that the primary tumor induces an immune response, which may not be sufficient to destroy the primary tumor, but prevents the growth of a secondary tumor or metastases. Since that time, many different immune cells have been shown to play a role in both inhibiting and promoting metastatic disease. Here we review classic and new observations, describing the links between the immune system and metastasis that inform the development of cancer therapies.

Most recent articles on the value of liquidity try to answer the following question: “What additional return should investors earn to compensate for the liquidity risk they take?” In this article, the authors propose a model that prices liquidity from the portfolio manager’s perspective. The authors focus on the case of hedge fund managers, because the liquidity of hedge funds has been an important issue during the recent financial crisis, as managers have struggled with an important flow of redemption orders. The authors find that under normal market conditions, a liquidity risk premium of at least 50 basis points per year can be justified. More volatile and illiquid conditions justify a much higher premium. The authors’ results are consistent with the idea that liquidity is a sort of put option on the illiquid asset and are also consistent with recent empirical findings. TOPICS:Real assets/alternative investments/private equity, tail risks, financial crises and financial market history

Intratumoral immune activation can induce local and systemic antitumor immunity. Imiquimod is a cream-formulated, TLR7 agonist that is Food and Drug Administration approved for the treatment of nonmelanoma skin cancers, but it has limited activity against melanoma. We studied the antitumor activity and mechanism of action of a novel, injectable, tissue-retained TLR7/8 agonist, 3M-052, which avoids systemic distribution. Intratumoral administration of 3M-052 generated systemic antitumor immunity and suppressed both injected and distant, uninjected wild-type B16.F10 melanomas. Treated tumors showed that an increased level of CCL2 chemokines and infiltration of M1 phenotype–shifted macrophages, which could kill tumor cells directly through production of NO and CCL2, were essential for the antitumor activity of 3M-052. CD8⁺ T cells, B cells, type I IFN, IFN-γ, and plasmacytoid dendritic cells were contributed to efficient tumor suppression, whereas perforin, NK cells, and CD4 T cells were not required. Finally, 3M-052 therapy potentiated checkpoint blockade therapy with anti–CTLA-4 and anti–programmed death ligand 1 Abs, even when checkpoint blockade alone was ineffective. Our findings suggest that intratumoral treatment with 3M-052 is a promising approach for the treatment of cancer and establish a rational strategy and mechanistic understanding for combination therapy with intratumoral, tissue-retained TLR7/8 agonist and checkpoint blockade in metastatic cancer.

Purpose: Aberrant expression of inflammatory molecules, such as inducible nitric oxide (NO) synthase (iNOS), has been linked to cancer, suggesting that their inhibition is a rational therapeutic approach. Whereas iNOS expression in melanoma and other cancers is associated with poor clinical prognosis, in vitro and in vivo studies suggest that iNOS and NO can have both protumor and antitumor effects. We tested the hypothesis that targeted iNOS inhibition would interfere with human melanoma growth and survival in vivo in a preclinical model. Experimental Design: We used an immunodeficient non-obese diabetic/severe combined immunodeficient xenograft model to test the susceptibility of two different human melanoma lines to the orally-given iNOS-selective small molecule antagonist N⁶-(1-iminoethyl)-l-lysine-dihydrochloride (L-nil) with and without cytotoxic cisplatin chemotherapy. Results: L-nil significantly inhibited melanoma growth and extended the survival of tumor-bearing mice. L-nil treatment decreased the density of CD31+ microvessels and increased the number of apoptotic cells in tumor xenografts. Proteomic analysis of melanoma xenografts with reverse-phase protein array identified alterations in the expression of multiple cell signaling and survival genes after L-nil treatment. The canonical antiapoptotic protein Bcl-2 was downregulated in vivo and in vitro after L-nil treatment, which was associated with increased susceptibility to cisplatin-mediated tumor death. Consistent with this observation, combination therapy with L-nil plus cisplatin in vivo was more effective than either drug alone, without increased toxicity. Conclusions: These data support the hypothesis that iNOS and iNOS-derived NO support tumor growth in vivo and provide convincing preclinical validation of targeted iNOS inhibition as therapy for solid tumors. Clin Cancer Res; 16(6); 1834–44

Type I IFNs, including IFN-α, enhance Ag presentation and promote the expansion, survival, and effector function of CD8⁺ CTL during viral infection. Because these are ideal characteristics for a vaccine adjuvant, we examined the efficacy and mechanism of exogenous IFN-α as an adjuvant for antimelanoma peptide vaccination. We studied the expansion of pmel-1 transgenic CD8⁺ T cells specific for the gp100 melanocyte differentiation Ag after vaccination of mice with gp100_25–33 peptide in IFA. IFN-α synergized with peptide vaccination in a dose-dependent manner by boosting relative and absolute numbers of gp100-specific T cells that suppressed B16 melanoma growth. IFN-α dramatically increased the accumulation of gp100-specific, IFN-γ-secreting, CD8⁺ T cells in the tumor through reduced apoptosis and enhanced proliferation of Ag-specific CD8⁺ T cells. IFN-α treatment also greatly increased the long-term maintenance of pmel-1 CD8⁺ T cells with an effector memory phenotype, a process that required expression of IFN-α receptor on the T cells and IL-15 in the host. These results demonstrate the efficacy of IFN-α as an adjuvant for peptide vaccination, give insight into its mechanism of action, and provide a rationale for clinical trials in which vaccination is combined with standard-of-care IFN-α therapy for melanoma.

CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to prime tumor-specific CD8⁺ T cell responses. Here, we study the antitumor activity and mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas generates tumor-specific, CD8⁺ T cells that express PD-1 and suppress tumor growth. Combination therapy of ISF35 with systemic anti-PD-1 generates greater antitumor activity than each respective monotherapy. Triple combination of ISF35, anti-PD-1, and anti-CTLA-4 results in complete eradication of injected and noninjected subcutaneous tumors, as well as melanoma tumors in the brain. Therapeutic efficacy is associated with increases in the systemic level of tumor-specific CD8⁺ T cells, and an increased ratio of intratumoral CD8⁺ T cells to CD4⁺ Tregs. These results provide a proof of concept of systemic antitumor activity after intratumoral CD40 triggering with ISF35 in combination with checkpoint blockade for multifocal cancer, including the brain.