Considerations for treatment duration in responders to immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) have improved overall survival for cancer patients, however, optimal duration of ICI therapy has yet to be defined. Given ICIs were first used to treat patients with metastatic melanoma, a condition that at the time was incurable, little attention was initially paid to how much therapy would be needed for a durable response. As the early immunotherapy trials have matured past 10 years, a significant per cent of patients have demonstrated durable responses; it is now time to determine whether patients have been overtreated, and if durable remissions can still be achieved with less therapy, limiting the physical and financial toxicity associated with years of treatment. Well-designed trials are needed to identify optimal duration of therapy, and to define biomarkers to predict who would benefit from shorter courses of immunotherapy. Here, we outline key questions related to health, financial and societal toxicities of over treating with ICI and present four unique clinical trials aimed at exposing criteria for early cessation of ICI. Taken together, there is a serious liability to overtreating patients with ICI and future work is warranted to determine when it is safe to stop ICI.

Acquired resistance to PD-L1 inhibition is associated with an enhanced type I IFN-stimulated secretory program in tumor cells

“…This may be relevant to patients who develop acquired resistance to PD-L1 inhibition and receive treatmentfor up to two years, dependingon trial protocols and tumor response 44, 71 . Becausepatient sub-sets have been shown to have highly durable responses to PD-1 pathway inhibition even after treatment discontinuation 72, 73 , our results may support rationale to avoid “over-treatment” with ICI 74,75.…”

Natural killer (NK) cell-derived extracellular-vesicle shuttled microRNAs control T cell responses

“…Immune therapy has revolutionized the treatment of cancer, however, long-lasting effects are only observed in about 15% of the patients. This might be due to the variety of cancer immune evasion mechanisms, including immune-suppressive mediators in the tumour microenvironment, impairment of CTL responses, promotion of T cell tolerance and/or exhaustion and polarization from Th1 to Th2, among others (43). Thus, we propose that NK-EV mediated immune deviation towards Th1 may be exploited and taken into account when designing EV-based therapies.…”

Interplay between coagulation and inflammation in cancer: Limitations and therapeutic opportunities

“…ICIs are antibody-based drugs, which block ligand / receptor binding of molecules such as CTLA-4 and PD-1 important for the suppression of T cell activation and function. However, despite the enormous clinical success of ipilimumab directed against CTLA-4, nivolumab, pembrolizumab or cemiplimab targeting PD-1 and avelumab blocking PD-L1 [68], limited response rates and severe side effects are still challenging [3,5,68].…”

“…The most noticeable results have been achieved with checkpoint inhibitors (ICIs) involving monoclonal antibodies against the cytotoxic T-lymphocyte associated protein 4 (CTLA-4), the programmed death receptor 1 (PD-1) or its ligand (PD-L1) [4]. Clinical trials using nivolumab or pembrolizumab, humanized antibodies to PD-1, provide response rates of more than 40% in patients with lung cancer, melanoma and renal carcinoma among others demonstrating the highest antitumor activity of therapeutic approaches during the last decade [5]. However, despite considerable progress in the treatment of cancer using targeted therapies and immune checkpoint inhibition, limited response rates, acquired resistance and toxic side effects remain challenging [2,6].…”