Search

Anti-PD-1 and oncolytic viruses (OVs) have non-overlapping anti-tumor mechanisms, since each agent works at different steps of the cancer-immunity cycle. Evidence suggests that OVs improve therapeutic responses to anti-PD-1 therapy by reversing immunosuppressive factors, increasing the number and diversity of infiltrating lymphocytes, and promoting PD-L1 expression in both injected and non-injected tumors. Many studies in preclinical models suggest that the timing of anti-PD-1 administration influences the therapeutic success of the combination therapy (anti-PD-1 + OV). Therefore, determining the appropriate sequencing of agents is of critical importance to designing a rationale OV-based combinational clinical trial. Currently, the combination of anti-PD-1 and OVs are being delivered using various schedules, and we have classified the timing of administration of anti-PD-1 and OVs into five categories: (i) anti-PD-1 lead-in → OV; (ii) concurrent administration; (iii) OV lead-in → anti-PD-1; (iv) concurrent therapy lead-in → anti-PD-1; and (v) OV lead-in → concurrent therapy. Based on the reported preclinical and clinical literature, the most promising treatment strategy to date is hypothesized to be OV lead-in → concurrent therapy. In the OV lead-in → concurrent therapy approach, initial OV treatment results in T cell priming and infiltration into tumors and an immunologically hot tumor microenvironment (TME), which can be counterbalanced by engagement of PD-L1 to PD-1 receptor on immune cells, leading to T cell exhaustion. Therefore, after initial OV therapy, concurrent use of both OV and anti-PD-1 is critical through which OV maintains T cell priming and an immunologically hot TME, whereas PD-1 blockade helps to overcome PD-L1/PD-1-mediated T cell exhaustion. It is important to note that the hypothetical conclusion drawn in this review is based on thorough literature review on current understanding of OV + anti-PD-1 combination therapies and rhythm of treatment-induced cancer-immunity cycle. A variety of confounding factors such as tumor types, OV types, presence or absence of cytokine transgenes carried by an OV, timing of treatment initiation, varying dosages and treatment frequencies/duration of OV and anti-PD-1, etc. may affect the validity of our conclusion that will need to be further examined by future research (such as side-by-side comparative studies using all five treatment schedules in a given tumor model).

The processes controlled by cytokines may be co-opted by pathologic states, contributing to processes that threaten host well-being. A nuanced understanding of this immense web of chemical communications will allow us to understand the mechanisms and limitations of current therapies and to enhance their therapeutic benefits while minimizing their toxicities. This article reviews the current state of cytokine science in malignancy, focusing on agents that are approved for therapy or are in late-stage development. Promising new directions, including novel engineered.

Purpose/objective(s) Serum antibodies to the Merkel oncoprotein (AMERK) are expressed in approximately 50% of patients (pts) with MCC and can be used to monitor for recurrence. This study aimed to describe changes in AMERK levels after RT for MCC and identify patterns that predict disease recurrence. Materials/methods Pts with MCC were identified retrospectively if they had curative-intent postoperative or definitive RT at a single institution from 2010-2020. Pts treated with RT at other institutions were excluded due to inability to assess RT quality, previously shown to impact MCC outcomes. All patients had a pre-RT AMERK and at least one post-RT AMERK (median no. Tests 5, range 1-10). Changes in AMERK were described and compared using Wilcoxon rank sum test for two-sample non-parametric comparisons and the Chi-square test for recurrence association. Results Of 202 MCC pts treated at our institution, 61 curatively treated pts had a pre-RT AMERK test performed. AMERK was detectable in 27 of the 61 patients (44%) with a median value of 2950 (range 127 to 115,000 [upper limit of assay]). Detectable pre-RT AMERK was associated with decreased MCC recurrence compared to pts with undetectable pre-RT AMERK (OR 0.35, 95% CI 0.12,1.04). The 27 pts with positive pre-RT AMERK had Stages I (n = 5), II (n = 1), and III (n = 21) from sites of the extremity (n = 14), head/neck (n = 7), unknown primary (n = 4), and trunk (n = 2). Pts with gross disease at RT (n = 11) had higher median pre-RT AMERK than those without gross disease at RT (n = 16) (median 8550 vs. 1840, P = 0.06). With a median follow-up of 20 months (range 2.3-61.3), there were 7 recurrences, all were distant. All AMERK-positive pts were alive at last follow-up except for the single immunosuppressed pt who recurred and died of MCC. A ≥50% AMERK reduction by 6-months after RT had a sensitivity of 95% (95% CI 74-100) for detecting disease-free status and a negative predictive value of 83% (95% CI 41-97%), reflecting the probability of recurrence if 115,00 value, had initiated high-dose corticosteroids for a comorbid condition. Out of 8 recurrence-free patients with AMERK levels available more than 2-years post-RT, 50% (4 of 8) had detectable AMERK (range 239-1960, > 2 years post-RT). Conclusion Reduction in AMERK post-RT can be used to predict MCC recurrence, which rarely occurs with a sustained ≥50% reduction by 6-months post-RT. AMERK may be persistently detectable in recurrence-free pts beyond 2 years. Further research is needed to determine the impact of corticosteroid initiation on AMERK levels.