20 augustus 2025: Bron: Nature

Uit nieuwe studiegegevens blijkt dat bij patiënten met alvleesklierkanker na een operatie een combinatiebehandeling van op maat gemaakte neoantigeen-mRNA-vaccins in deze studie was dat het autogeen cevumeran, in combinatie met atezolizumab, een anti-PD-L1 medicijn en chemotherapie met mFOLFIRINOX een opvallend langdurige aanwezigheid van neoantigeen-specifieke CD8+ T-celklonen laat zien. De T-cellen bleven zeker tot 3 jaar aanwezig in de patiënten maar waarschijnlijk nagenoeg levenslang aldus de onderzoekers. Wat resulteert ook in de laatste follow-up analyse na 3,2 jaar van een veel langere recidiefvrije overleving in vergelijking met de patiënten die dezelfde behandeling kregen maar zonder toevoeging van de neoantigeen-mRNA-vaccins.

Hier de vertaling van het abstract en de belangrijkste conclusie met hulp van google translate:

Een fundamentele uitdaging voor kankervaccins is het genereren van langlevende functionele T-cellen die specifiek zijn voor tumorantigenen. Hieruit concluderen we dat mRNA-lipoplexvaccins tegen somatische mutatie-afgeleide neoantigenen deze uitdaging kunnen oplossen bij pancreasductaal adenocarcinoom (PDAC), een dodelijke kanker met weinig mutaties.
Bij een verlengde mediane follow-up van 3,2 jaar van een fase 1-onderzoek naar chirurgie, atezolizumab (PD-L1-remmende antistof), autogeen cevumeran1 (geïndividualiseerd neoantigeenvaccin met backbone-geoptimaliseerde uridine mRNA–lipoplex nanodeeltjes) en gemodificeerde (m) FOLFIRINOX (chemotherapie) bij patiënten met PDAC, ontdekten we dat responders met vaccin-geïnduceerde T-cellen (n = 8) een verlengde recidiefvrije overleving (RFS; mediaan niet bereikt) hebben in vergelijking met niet-responders zonder vaccin-geïnduceerde T-cellen (n = 8; mediane RFS 13,4 maanden; P = 0,007).
Bij responders induceert autogeen cevumeran CD8+ T-celklonen met een gemiddelde geschatte levensduur van 7,7 jaar (variërend van 1,5 tot ongeveer 100 jaar), waarbij ongeveer 20% van de klonen een latente levensduur van meerdere decennia heeft die de gastheer mogelijk overleeft. Zesentachtig procent van de klonen per patiënt blijft ongeveer drie jaar na vaccinatie in aanzienlijke frequenties aanwezig, inclusief klonen met een hoge aviditeit voor PDAC-neo-epitopen.
Met behulp van PhenoTrack, een nieuwe computationele strategie om individuele T-celfenotypes te traceren, ontdekken we dat vaccin-geïnduceerde klonen niet detecteerbaar zijn in weefsels vóór vaccinatie en tot drie jaar na vaccinatie een cytotoxische, in weefsel aanwezige geheugenachtige T-celstatus aannemen met behoud van neoantigeen-specifieke effectorfunctie.
Twee responders vertoonden een recidief en vertoonden minder vaccin-geïnduceerde T-cellen. Bovendien werden recidiverende PDAC's verwijderd uit vaccingerichte kankerklonen.
Zo induceert autogeen cevumeran bij PDAC de novo CD8+ T-cellen met een levensduur van meerdere jaren, een aanzienlijke omvang en duurzame effectorfuncties die PDAC-recidief kunnen vertragen. Adjuvante mRNA-lipoplex neoantigeenvaccins zouden zo een cruciaal obstakel voor kankervaccinatie kunnen oplossen.

Hier de eerdere resultaten van de studie grafisch weergegeven:

Extended Data Fig. 1

a, Trial schematic as previously reported1. Reproduced under CC BY 4.0: https://creativecommons.org/licenses/by/4.0/. b, Recurrence-free survival (RFS) from landmark time (last vaccine priming dose) stratified by autogene cevumeran (vaccine) immunologic response determined by ex vivo IFNγ ELISpot1 (left), and RFS from surgery stratified by anti-PD-L1 (atezolizumab) response (middle) and median primary tumour size (right). HR, hazard ratio with 95% confidence interval. Black tick marks, censorship points. n is the number of individual patients. P values by two-tailed log-rank test (b).

Het volledige studierapport is gratis in te zien of te downloaden, zie daarvoor het abstract:

Clinical Trial

. 2025 Mar;639(8056):1042-1051.

doi: 10.1038/s41586-024-08508-4. Epub 2025 Feb 19.

RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer

Zachary Sethna # 1 2 3 4, Pablo Guasp # 1 2, Charlotte Reiche 1 2, Martina Milighetti 1 2 4, Nicholas Ceglia 4, Erin Patterson 3, Jayon Lihm 3 4, George Payne 1 2, Olga Lyudovyk 4, Luis A Rojas 1 2, Nan Pang 2, Akihiro Ohmoto 1 2, Masataka Amisaki 1 2, Abderezak Zebboudj 1 2, Zagaa Odgerel 1 2, Emmanuel M Bruno 1 2, Siqi Linsey Zhang 1 2, Charlotte Cheng 1 2, Yuval Elhanati 4, Evelyna Derhovanessian 5, Luisa Manning 5, Felicitas Müller 5, Ina Rhee 6, Mahesh Yadav 6, Taha Merghoub 7, Jedd D Wolchok 7, Olca Basturk 8, Mithat Gönen 9, Andrew S Epstein 10, Parisa Momtaz 10, Wungki Park 10 11, Ryan Sugarman 10, Anna M Varghese 10, Elizabeth Won 10, Avni Desai 10, Alice C Wei 2 11, Michael I D'Angelica 2 11, T Peter Kingham 2 11, Kevin C Soares 2 11, William R Jarnagin 2 11, Jeffrey Drebin 2 11, Eileen M O'Reilly 10 11, Ira Mellman 6, Ugur Sahin 5 12, Özlem Türeci 5 12, Benjamin D Greenbaum 3 4 13, Vinod P Balachandran 14 15 16 17

Affiliations

PMID: 39972124
PMCID: PMC11946889
DOI: 10.1038/s41586-024-08508-4

Abstract

A fundamental challenge for cancer vaccines is to generate long-lived functional T cells that are specific for tumour antigens. Here we find that mRNA-lipoplex vaccines against somatic mutation-derived neoantigens may solve this challenge in pancreatic ductal adenocarcinoma (PDAC), a lethal cancer with few mutations. At an extended 3.2-year median follow-up from a phase 1 trial of surgery, atezolizumab (PD-L1 inhibitory antibody), autogene cevumeran1 (individualized neoantigen vaccine with backbone-optimized uridine mRNA-lipoplex nanoparticles) and modified (m) FOLFIRINOX (chemotherapy) in patients with PDAC, we find that responders with vaccine-induced T cells (n = 8) have prolonged recurrence-free survival (RFS; median not reached) compared with non-responders without vaccine-induced T cells (n = 8; median RFS 13.4 months; P = 0.007). In responders, autogene cevumeran induces CD8+ T cell clones with an average estimated lifespan of 7.7 years (range 1.5 to roughly 100 years), with approximately 20% of clones having latent multi-decade lifespans that may outlive hosts. Eighty-six percent of clones per patient persist at substantial frequencies approximately 3 years post-vaccination, including clones with high avidity to PDAC neoepitopes. Using PhenoTrack, a novel computational strategy to trace single T cell phenotypes, we uncover that vaccine-induced clones are undetectable in pre-vaccination tissues, and assume a cytotoxic, tissue-resident memory-like T cell state up to three years post-vaccination with preserved neoantigen-specific effector function. Two responders recurred and evidenced fewer vaccine-induced T cells. Furthermore, recurrent PDACs were pruned of vaccine-targeted cancer clones. Thus, in PDAC, autogene cevumeran induces de novo CD8+ T cells with multiyear longevity, substantial magnitude and durable effector functions that may delay PDAC recurrence. Adjuvant mRNA-lipoplex neoantigen vaccines may thus solve a pivotal obstacle for cancer vaccination.

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Conflict of interest statement

Competing interests: L.A.R., Z.M.S., B.D.G. and V.P.B. are inventors on patent applications related to work on antigen cross-reactivity and tracking vaccine-induced T cell clones. B.D.G. and V.P.B. are inventors on a patent application on neoantigen quality modelling. L.A.R. is an inventor of a patent related to oncolytic viral therapy. B.D.G. has received honoraria for speaking engagements from Merck, Bristol Meyers Squibb and Chugai Pharmaceuticals; has received research funding from Bristol Meyers Squibb, Merck and ROME Therapeutics; and has been a compensated consultant for Darwin Health, Merck, PMV Pharma, Shennon Biotechnologies, Synteny and Rome Therapeutics of which he is a co-founder. V.P.B. reports honoraria and research support from Genentech and research support from Bristol-Myers Squibb. A.S.E received royalties from Up-To-Date. A.V. reports research funding from Lilly, Verastem, BioMed Valley Discoveries, Bristol-Myers Squibb and Silenseed. A.C.W. reports the following: Histosonics, consulting and Ipsen, clinical trial funding. E.M.O. reports research funding to the institution from: Genentech/Roche, BioNTech, AstraZeneca, Arcus, Elicio, Parker Institute, NIH/NCI, Digestive Care and Break Through Cancer; consulting via Data and Safety Monitoring Board (DSMB) for: Arcus, Alligator, Agenus, BioNTech, Ipsen, Merck, Moma Therapeutics, Novartis, Syros, Leap Therapeutics, Astellas, BMS, Fibrogen, Revolution Medicine, Merus Agios (spouse), Genentech-Roche (spouse), Eisai (spouse) and Servier (Spouse). J.D. owns stock in Alnylam Pharmaceuticals, Arrowroot Acquisition and Ionis Pharmaceuticals. T.M. is a co-founder and holds equity in IMVAQ Therapeutics; is a consultant for Immunos Therapeutics, ImmunoGenesis and Pfizer; has research support from Bristol-Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics and Aprea; and has patents on applications related to work on oncolytic viral therapy, alphavirus-based vaccine, neoantigen modelling, CD40, GITR, OX40, PD-1 and CTLA-4. J.D.W. is a consultant for Apricity, CellCarta, Ascentage Pharma, AstraZeneca, Bicara Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Dragonfly, Georgiamune, Imvaq, Larkspur, Psioxus, Recepta, Tizona and Sellas. J.D.W. receives grant and research support from Bristol-Myers Squibb and Sephora. J.D.W. has equity in Apricity, Arsenal IO, Ascentage, Imvaq, Linneaus, Georgiamune, Maverick and Tizona Therapeutics. W.P. reports research funding to institution from: Merck, Astellas, Miracogen and Amgen; consultancy or advisory board activity for: Astellas and EXACT Therapeutics; honoraria for Continuing Medical Education (CME) from: American Physician Institute and Integrity. O.T. and U.S. are co-founders, management board members and employees at BioNTech. E.D., L.M. and F.M. are employees at BioNTech. I.R., M.Y. and I.M. are employees at Genentech. The other authors declare no competing interests.

Figures

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