Det norska bioteknikbolaget Ultimovacs har nyligen presenterat positiva treårsdata för patienter med metastaserat malignt melanom som behandlats med cancervaccinet UV1 i kombination med anti-PD-1 checkpointhämmaren pembrolizumab. Datan visar lovande resultat gällande total överlevnad och effekt på prediktiva biomarkörer, vilket stärker bolagets tro på UV1 som en kombinationsbehandling med dagens checkpointhämmare för solida tumörer. BioStock kontaktade Espen Basmo Ellingsen, Director Medical Affairs på Ultimovacs, för att få veta mer.

Ultimovacs utvecklar det universella cancervaccinet UV1. En av de indikationer som UV1 utvärderas för är metastaserat malignt melanom – den farligaste typen av hudcancer. Även om immunterapier såsom checkpointhämmare (CPI) har ökat överlevnadschanserna hos hudcancerpatienter, är prognosen vid metastaserat malignt melanom fortfarande dålig. Det finns alltså mycket kvar att förbättra vad gäller behandlingseffekt.

Genomgående positiva fas I-data

UV1 har potential att fylla detta medicinska vakuum, eftersom målet är att stärka patienternas eget immunförsvar i kampen mot cancer. I den avslutade fas I-studien UV1-103 som genomfördes i totalt 30 patienter, utvärderades kandidaten i kombination med patientgruppens standardbehandling, CPI:n pembrolizumab, som första linjens behandling under 14 veckor. Studien visade på god säkerhet och tolerabilitet och uppnådde därmed sitt huvudmål. Man fortsätter dessutom nu att utvärdera initiala tecken på kliniskt svar och patienter följs därför gällande total överlevnad i upp till fem år efter behandlingsstart.

Uppföljningsdata för ett och två år visade en överlevnad på 85 respektive 80 procent. Det är lovande siffror jämfört med dem för pembrolizumab som monoterapi, där den totala överlevnaden låg på 58 procent efter 24 månader. Läs mer om detta här. I början av oktober släppte Ultimovacs treårsdata från studierna, som fortsätter att indikera en lovande total överlevnad – 71 procent – efter behandling med kombinationen. Data baserades på 12 av totalt 17 patienter. Det är värt att notera att tre patienter vägrade uppföljning och att endast en patient dog.

Bred potential för UV1

Det positiva nyhetsflödet fortsatte förra veckan, då bolaget presenterade ytterligare data från studien vid International Congress of the Society for Melanoma Research 2022. Dessa data, som gäller kombinationsbehandlingens effekt på biomarkörer, visade en god effekt hos patienter med låga nivåer av PD-L1 – en prediktiv biomarkör associerad med låg effekt med pembrolizumab som monoterapi och andra anti-PD-1-behandlingar på vissa tumörtyper. Detta indikerar en bred potential för kombinationsbehandlingen.

I analysen ingick även ytterligare prognostiska biomarkörer som karakteriserar tumörer med låg känslighet för pembrozilumab som monoterapi. Objektiva svar observerades hos patienter med låg tumörmutationsbörda (TMB), tumörer med lågt neoantigenuttryck samt tumörer utan anrikning för IFN-gamma-gensignaturen. Dessutom visade studien att patienter som svarade på behandlingen inte hade högre nivåer av tumörinfiltrerande lymfocyter före behandlingen. Sammantaget tyder resultaten på att kombinationen ger ett effektivt, ihållande behandlingssvar genom aktivering av patienternas immunsystem, samt en bred potential för UV1 som kombinationsbehandling med anti-PD1 CPI.

Director Medical Affairs förklarar mer

BioStock kontaktade Espen Basmo Ellingsen, som är Director Medical Affairs på Ultimovacs, för att få veta mer om resultaten och dess implikationer.

Espen, the three-year data presented indicate strong overall survival, although it dropped to 71 per cent from the 80 per cent two-year data. What are your thoughts around this?

– The UV1-103 study was composed of Cohorts 1 and 2. Whereas Cohort 1 consisted of twenty patients receiving a slightly lower dose of the adjuvant, Cohort 2 included ten patients receiving the full adjuvant dose. For both cohorts combined, the 1-year survival rate was 87 per cent, and the 2-year rate was 73 per cent. The longer follow-up time allowed us to report a 3-year survival rate for patients in Cohort 1, which read out at 71 per cent. When reporting data for single cohorts, missing data, on top of the fewer patients included in the analysis, can result in relatively large changes to the survival rate. Only one patient died between years 2 and 3, but since three patients were not followed beyond 2 years, the rate had dropped from 80 per cent to 71 per cent.

Do the three-year data regarding overall survival set any expectations regarding the upcoming follow-ups?

– We were very encouraged by the high objective response rates in the UV1-103 trial, with 57 per cent of patients experiencing a 30 per cent or greater reduction in their tumour size. Furthermore, 33 per cent of the patients experienced a so-called complete response, where the entire tumour mass disappears after treatment. Previous studies suggest that patients achieving partial or complete responses experience long-term benefit and extended survival time. We are therefore very optimistic that the high survival rates will continue with longer follow-up.

Based on that the combination treatment resulting in good clinical responses in patients considered less likely to respond to monotherapy checkpoint inhibition, a potential broad applicability for UV1 as a combination therapy to anti-PD1 checkpoint inhibitors is suggested. What other indications could this applicate to?

– Checkpoint inhibition is established as the standard of care across many indications. However, the treatment response rates vary considerably within and across these indications, and many tumour types are still not amenable to checkpoint inhibition. Limited responsiveness is characterised by so-called non-inflamed or “cold” tumours, where the environment is suboptimal for the patients’ immune cells. Although melanoma is generally considered a more inflamed tumour type, some patients’ tumours still exhibit markers linked to poor responsiveness to checkpoint inhibition. Encouragingly, we also observed clinical responses to the UV1/pembrolizumab combination in patients whose tumours displayed these markers. These observations lead us to believe there is a potential for UV1 to boost responses in indications characterised by the presence of these markers and in which checkpoint inhibition demonstrates limited efficacy.

– The use of checkpoint inhibitors is, for instance, in some indications, such as NSCLC (non-small cell lung cancer), restricted to certain tumour PD-L1 levels, where only higher levels are associated with clinical benefit. Based on the data from the UV1-103 trial, adding UV1 to the checkpoint inhibitor therapy may represent a viable strategy to extend efficacy to patients with lower levels of PD-L1.

Objective responses were observed in patients with low TMB, in patients with low neoantigen tumours, and in patients with tumours that were not enriched for IFN-gamma. For non-experts within the field, could you explain the clinical relevance of these data points?

– These are all tumour biopsy-based markers aimed at determining whether a patient’s immune cells can recognise and establish an immune response against the cancer cells, also known as tumour immunogenicity. Tumour mutational burden, or TMB, estimates how many mutations are present within the tumour, i.e. how many targets there are for the immune system to recognise. With higher TMB, there is an increasing likelihood of established immune responses. The neoantigen score offers a more refined approach toward the same purpose by using complex algorithms to predict whether the mutations can lead to good immune responses. The IFN-gamma gene signature relates to a critical molecule released by the immune cells during an anti-tumour response.

– In patients with immunogenic tumours, checkpoint inhibitors can release the immune responses to promote tumour cell killing. However, depending on the levels of these markers, some patients are deprived of such responses and therefore achieve limited benefit from checkpoint inhibition alone. By vaccinating with UV1, the aim is to establish novel immune responses toward the tumour, providing a new wave of immune cells that the checkpoint inhibitors can further potentiate, leading to clinical responses in patients with less immunogenic tumours.

Lastly, the study also showed that clinical responders did not have higher levels of tumour-infiltrating lymphocytes prior to treatment. What does this indicate?

– For this analysis, we took tissue biopsies and looked specifically for the number of T-cells (the key immune cells in anti-tumour immunity) present before initiating therapy. Similar to the other analyses, a high level of T-cells in the tumour can predict clinical benefit from checkpoint inhibition. We observed robust clinical responses in patients without high levels of T-cells in their tumour before therapy, indicating that the combination therapy was able to mobilize novel immune responses leading to tumour cell killing and clinical benefit for the patients.

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