An alternative strategy is being taken by Australian biotech, Immutep, whose eftilagimod alpha is a first-in-class antigen presenting cell (APC) activator.
The soluble lymphocyte activation gene-3 (LAG-3) protein should stimulate both innate and adaptive immunity. It binds to and then activates APCs via MHC II molecules, which results in the expansion and proliferation of CD8+ cytotoxic T cells, CD4+ helper T cells, dendritic cells, NK cells and monocytes.
It has also been shown to upregulate the expression of molecules such as CXCL10, which also boost the immune system’s ability to attack cancer cells. Its effectiveness in combination with the PD-1 antagonist pembrolizumab has been evaluated in 24 patients with metastatic melanoma.1
In addition to the standard dose of pembrolizumab, subjects were given 1, 6 or 30 mg subcutaneous injections of eftilagimod every other week for up to 6 months in the dose escalation part of the study — and 30 mg for up to 12 months in the second part of the study.
There were no dose-limiting toxicities and the main adverse event for eftilagimod was injection site reactions. Activated CD8+ and CD4+ T cell counts increased. An objective response rate of 50% was seen in PD-1 naïve patients in the second part of the study.
A Phase II study has also been done (in combination with pembrolizumab) in the hope that it will lead to a stronger antitumour response, particularly for those that do not overexpress PD-L1. Results of the first line cohort in non-small cell lung cancer (NSCLC) patients have been reported.2
In all, 114 patients with measurable disease unselected for PD-L1 — two thirds non-squamous, one third squamous and 93% metastatic — were given 30 mg of eftilagimod every 2 weeks for eight 3-weekly cycles and then every 3 weeks for up to a year in combination with 200 mg of pembrolizumab.
The most common adverse events were dyspnoea, asthenia, decreased appetite, cough, anaemia, fatigue and pruritus. The objective response rate was 39.5% and the median progression-free survival was 6.9 months. Responses were seen in all PD-L1 subgroups and the objective response rates for squamous and non-squamous disease were similar (37.5% and 38.9%, respectively).
Increases in circulating CXCL10 and interferon-gamma were seen (both early and sustained). The drug is undergoing clinical trials for a multitude of solid tumours, including NSCLC, head/neck squamous cell carcinoma and HER2 negative/HR positive breast cancer.
References
- V. Atkinson, et al., J. Immunother. Cancer 8, e001681 (2020).
- W. Iams, et al., J. Immunother. Cancer 10(Suppl. 2), A1527 (2022).
