The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Oncolytic and Local Immunotherapy Section Editor, Howard L. Kaufman, MD, FACS
“Intratumourally injected alum-tethered cytokines elicit potent and safer local and systemic anticancer immunity” by Yash Agarwal et al
Nature Biomedical Engineering, 2022 6(129–143)
Systemic cytokine therapy can be extremely toxic to patients, however, intratumoral injection has its limitations as well, including short persistence in the tumor microenvironment and leakage into circulation. Yash Agarwal and colleagues describe a new approach for intratumoral cytokine delivery based on tethering cytokines to aluminum hydroxide (alum), a common vaccine adjuvant that tightly binds phosphorylated proteins via a ligand exchange reaction with surface hydroxyls and can form a depot in the injection site. Recombinant IL-2, IL-12, and IL-15 superagonist tagged with a naturally phosphorylated peptide motif (called alum-binding protein (ABP)) were robustly and consistently phosphorylated when purified from Fam20C kinase-expressing HEK293-F cells. ABP-tagged cytokines remained absorbed on alum for more than 2 weeks in vitro in the presence of mouse serum and largely retained functional bioactivity. Intratumorally injected IL-12 was retained 400-fold more when tethered to alum via the phosphorylated ABP compared to free cytokine, and furthermore no increase in serum cytokine concentrations were seen. Moreover, a single intratumoral injection of the alum-tethered IL-12 led to complete tumor responses in a majority of animals (11 of 13) with little systemic toxicity, whereas unbound cytokine did not induce an anti-tumor response and was highly toxic to the animals. Anti-tumor efficacy increased even further with various therapeutic combinations, including anti-PD-1 agents and dual cytokines, and regression of non-injected lesions was also observed. Mechanistic studies revealed increased localized interferon-y production, effector CD8+ T cell-mediated tumor control, activated myeloid cells, and antigen presentation and T cell priming contributing to the systemic responses and long-term survival seen with intratumoral injection of the alum-tethered cytokine.
Why this matters: Alum-tethering may overcome some of the limitations of intratumoral cytokine therapy that have caused these approaches to stall in humans, including tumor clearance of the injected agent and systemic toxicity.
“Oncolytic vaccinia virus injected intravenously sensitizes pancreatic neuroendocrine tumors and metastases to immune checkpoint blockade” by Misuko Inoue et al
Mol Ther Oncolytics, 2022, 24: 299–318.
Immune checkpoint inhibitors (ICIs) have demonstrated limited efficacy in treating pancreatic neuroendocrine tumors (PanNETs). Misuko Inoue et al demonstrate that a single systemic administration of an oncolytic vaccinia virus sensitized multiple murine models of immunologically cold PanNETs to anti-PD-1. In mice bearing insulin-secreting PanNETs, one single dose of virus led to 7.5-fold greater apoptosis and 42% less proliferation at the 20-day time point compared to control tumors. Apoptosis and tumor burden reduction were augmented by the addition of anti-PD-1 to 15-fold and 53%, respectively. Importantly, improvements in blood insulin and glucose levels leading to improved survival was achieved only with the combination virus and checkpoint blockade treatment and not with either agent alone. Combination treatment was associated with an increase in tumor NK and CD8+ T cell infiltration beginning at day 5 and persisting through day 20. Both CD8+ T and NK cells were required for induction of tumor cell apoptosis by the combination, whereas NK cells were dispensable for virus-mediated tumor cell killing. Combination treatment also resulted in reduced tumor vascularity leading to intratumoral hypoxia, increased PD-L1 staining, and vascular remodeling with improved CD8+ T cell trafficking. These phenotypes were also seen in models of liver metastases, with greater vaccinia virus infection in metastases versus primary tumor. In the live metastasis models, anti-PD-1 monotherapy had little effect, yet the combination resulted in a large and sustained reduction of liver metastases and improved survival.
“Mutations in the IFN-gamma-JAK-STAT Pathway Causing Resistance to Immune Checkpoint Inhibitors in Melanoma Increase Sensitivity to Oncolytic Virus Treatment” by Tan-Trieu Nguyen et al
Clin Cancer Res, 2021, 27(12):3432-3442
Altered interferon gamma signaling is one of the most predominant mechanisms leading to immune checkpoint inhibitor (ICI) resistance in melanoma and several other solid tumors. Interferon gamma signaling via the JAK/STAT pathway is also central to antiviral defense. Tan-Trieu Nguyen et al discovered that disruptions to JAK, specifically loss of function mutations in JAK1 and JAK2, that confer resistance to ICIs in melanoma also increase susceptibility to the oncolytic viruses herpes simplex virus 1 (HSV1-dICP0) and vesicular stomatitis virus (VSV-delta51). In melanoma cells derived from a patient tumor site that had relapsed on anti PD-1 therapy with a known JAK2 F547 loss of function splice site mutation, the 50% tissue culture infective dose (TCID50) was decreased 7-fold for the herpesvirus and 22-fold for the vesicular stomatitis virus. Overexpressing JAK2 complemented the phenotype, leading to a small increase in TCID50. Knockdown of either JAK1 or JAK2 using small interfering RNAs (siRNAs) sensitized a melanoma cell line to the vesicular stomatitis virus and these results were replicated with application of the JAK1/2 inhibitor ruxolitinib. In vivo, oncolytic virus-treated mice bearing JAK2-defecient tumors had a median survival more than double that of animals implanted with the parenteral xenografts. Interrogation of The Cancer Genome Atlas identified 43 instances of homozygous inactivating alterations of IFN-stimulated genes among a sample from 449 ICI-naïve human patients with skin cutaneous melanoma.
Why this matters: As many as 11% of patients may have tumors with mutation in interferon gamma pathway genes that confer resistance to checkpoint blockade. The same mutations make the tumor susceptible to oncolytic viruses. Screening for interferon gamma pathway mutations may inform melanoma treatment strategies in the first-line and subsequent to progression on an ICI and represent predictive biomarkers of oncolytic virus activity.
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