Opposing effects of immunotherapy in melanoma using multisubtype interferon-alpha - can tumor immune escape after immunotherapy accelerate disease progression?

With checkpoint inhibitors, patients with advanced melanoma display durable responses suggesting cure of disease. However, the immune system has dual roles in cancer; while the immune system may eradicate a tumor, a subtotal elimination may selectively destroy immunogenic cells driving the proliferation of non-immunogenic tumors. Here, we performed a retrospective analysis of results obtained in a controlled trial of patients with melanoma treated with adjuvant, multisubtype interferon-α. The survival curves displayed a late divergence for treated patients and controls resulting in substantially higher estimates of overall (OS) and relapse-free survival (RFS) rates among treated patients after 9 y of follow up. Interestingly, succumbing patients in the treatment group displayed reduced time between relapse and death, suggesting therapy-induced acceleration of disease progression. These findings suggest that effective immunotherapy that induces durable, curative responses in some patients, may potentially accelerate disease progression in others, highlighting the importance of developing advanced strategies to identify patients who are likely to benefit from immunotherapy.

Late divergence of survival curves in cancer immunotherapy trials: interpretation and implications.

Late divergence of survival curves of treated patients and controls is commonly seen in successful cancer immunotherapy trials. Although late survival curve divergence may be caused by a delayed action of therapy, it may also be related to early effects of the treatment. We suggest that late survival divergence most often reflects a specific benefit of therapy for patients who suffer from a comparatively slow progression of disease. The occurrence of delayed survival curve divergence has important implications for the statistical analysis of immunotherapy trials. Thus, it leads to non-proportional hazard ratios that make commonly used statistical tests, e.g., the logrank test, suboptimal. It is therefore suggested that the statistical analysis of immunotherapy trials primarily should be based on a test that compares the survival curves at or after a prespecified, fixed, late time point.

Long-term survival benefit after adjuvant treatment of cutaneous melanoma with dacarbazine and low dose natural interferon alpha: A controlled, randomised multicentre trial.

In a prospective, controlled, randomised, multicentre study 252 patients with totally resected cutaneous melanoma (248 in stage II-III and 4 in stage IV) were either treated with two doses of dacarbazine (DTIC) followed by a 6-month treatment with 3 MU thrice weekly of highly purified natural interferon-alpha (n = 128; arm A) or received no adjuvant treatment (n = 124; arm B). Treatment was well tolerated. After a median follow-up of 8.5 years ITT analysis showed that the difference in survival was statistically significant with respect to melanoma-related deaths (HR = 0.65, CI = 0.46-0.97, p = 0.022) and close to significance with respect to overall survival (HR 0.71, CI 0.49-1.00, p = 0.052). The risk reduction of melanoma-associated death, calculated by Cox proportional hazards modelling, after adjusting for identified predictive variables, was almost 50% (p = 0.002). The overall efficacy of the treatment appeared to be mainly attributable to effects observed in patients with deep and/or metastasizing tumours (HR 0.60, CI 0.40-0.90, p = 0.013).

In vitro inhibition of SARS virus replication by human interferons.

Four different types of human interferon, interferon-beta (IFN-beta), recombinant IFN-alpha2a and IFN-alpha2b and natural IFN-alpha were tested for antiviral activity against SARS-coronavirus. The experiments were performed using in vitro cultivated monkey Vero E6 cells. IFN-beta was found to be the most highly active antiviral agent, followed by natural IFN-alpha, whereas the 2 recombinant IFN-alpha2 species were poorly active in the system used. These results suggest that IFN-beta as well as natural IFN-alpha may be used for the treatment of SARS.