[en] Effective targeting of somatic cancer mutations to enhance the efficacy of cancer immunotherapy requires an individualized approach. Autogene cevumeran is a uridine messenger RNA lipoplex-based individualized neoantigen-specific immunotherapy designed from tumor-specific somatic mutation data obtained from tumor tissue of each individual patient to stimulate T cell responses against up to 20 neoantigens. This ongoing phase 1 study evaluated autogene cevumeran as monotherapy (n = 30) and in combination with atezolizumab (n = 183) in pretreated patients with advanced solid tumors. The primary objective was safety and tolerability; exploratory objectives included evaluation of pharmacokinetics, pharmacodynamics, preliminary antitumor activity and immunogenicity. Non-prespecified interim analysis showed that autogene cevumeran was well tolerated and elicited poly-epitopic neoantigen-specific responses, encompassing CD4+ and/or CD8+ T cells, in 71% of patients, most of them undetectable at baseline. Responses were detectable up to 23 months after treatment initiation. CD8+ T cells specific for several neoantigens constituted a median of 7.3% of circulating CD8+ T cells, reaching up to 23% in some patients. Autogene cevumeran-induced T cells were found within tumor lesions constituting up to 7.2% of tumor-infiltrating T cells. Clinical activity was observed, including one objective response in monotherapy dose escalation and in two patients with disease characteristics unfavorable for response to immunotherapy treated in combination with atezolizumab. These findings support the continued development of autogene cevumeran in earlier treatment lines. ClinicalTrials.gov registration: NCT03289962 .
Disciplines :
Oncology
Author, co-author :
Lopez, Juanita ; The Royal Marsden Hospital and the Institute of Cancer Research, Sutton, UK. juanita.lopez@icr.ac.uk
Powles, Thomas ; Barts Cancer Institute, Centre for Experimental Cancer Medicine, Queen Mary University of London, London, UK
Braiteh, Fadi; Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA
Siu, Lillian L; Princess Margaret Cancer Centre, Toronto, Ontario, Canada
LoRusso, Patricia ; Yale Cancer Center, Yale University, New Haven, CT, USA
Friedman, Claire F ; Memorial Sloan Kettering Cancer Center, New York, NY, USA ; Department of Medicine Weill Cornell Medical College, New York, NY, USA
Balmanoukian, Ani S; The Angeles Clinic and Research Institute, a Cedars-Sinai affiliate, Los Angeles, CA, USA
Gordon, Michael; HonorHealth Research Institute, Scottsdale, AZ, USA
Yachnin, Jeffrey; Karolinska University Hospital, Stockholm, Sweden
Rottey, Sylvie; Drug Research Unit Ghent, Ghent University Hospital, Ghent, Belgium
Karydis, Ioannis ; University Hospital Southampton NHS Trust and University of Southampton, Southampton, UK
Fisher, George A; Department of Medicine (Oncology), Stanford University, Stanford, CA, USA
Schmidt, Marcus ; University Medical Center Mainz, Mainz, Germany
Schuler, Martin ; West German Cancer Center, Department of Medical Oncology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
Sullivan, Ryan J ; Massachusetts General Hospital Cancer Center, Boston, MA, USA
Burris, Howard A; Sarah Cannon Research Institute, Nashville, TN, USA
Galvao, Vladimir; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
Henick, Brian S ; Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY, USA
P. Sharma et al. Immune checkpoint therapy—current perspectives and future directions Cell 186 1652 1669 1:CAS:528:DC%2BB3sXnvVCnu7o%3D 37059068 10.1016/j.cell.2023.03.006
R.S. Herbst et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients Nature 515 563 567 1:CAS:528:DC%2BC2cXitFanurbM 25428504 4836193 10.1038/nature14011
N.A. Rizvi et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer Science 348 124 128 1:CAS:528:DC%2BC2MXls1Wmtbg%3D 25765070 4993154 10.1126/science.aaa1348
R.M. Samstein et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types Nat. Genet. 51 202 206 1:CAS:528:DC%2BC1MXlvFSgurc%3D 30643254 6365097 10.1038/s41588-018-0312-8
A. Snyder et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma N. Engl. J. Med. 371 2189 2199 25409260 4315319 10.1056/NEJMoa1406498
E.M. Van Allen et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma Science 350 207 211 26359337 5054517 10.1126/science.aad0095
M.R. Parkhurst et al. Unique neoantigens arise from somatic mutations in patients with gastrointestinal cancers Cancer Discov. 9 1022 1035 1:CAS:528:DC%2BB3cXhvFGjs77L 31164343 7138461 10.1158/2159-8290.CD-18-1494
E. Tran et al. Immunogenicity of somatic mutations in human gastrointestinal cancers Science 350 1387 1390 1:CAS:528:DC%2BC2MXhvFKru7%2FL 26516200 7445892 10.1126/science.aad1253
A.R. Rappaport et al. A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results Nat. Med. 30 1013 1022 1:CAS:528:DC%2BB2cXmvFeqs7s%3D 38538867 10.1038/s41591-024-02851-9
M. Yarchoan et al. Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial Nat. Med. 30 1044 1053 1:CAS:528:DC%2BB2cXns1yjtr8%3D 38584166 11031401 10.1038/s41591-024-02894-y
O. Tureci et al. Targeting the heterogeneity of cancer with individualized neoepitope vaccines Clin. Cancer Res. 22 1885 1896 1:CAS:528:DC%2BC28XmsFeqs7k%3D 27084742 10.1158/1078-0432.CCR-15-1509
M. Vormehr et al. Mutanome directed cancer immunotherapy Curr. Opin. Immunol. 39 14 22 1:CAS:528:DC%2BC2MXitVSrsbbK 26716729 10.1016/j.coi.2015.12.001
B.M. Carreno et al. Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells Science 348 803 808 1:CAS:528:DC%2BC2MXotFahsLc%3D 25837513 4549796 10.1126/science.aaa3828
N. Hilf et al. Actively personalized vaccination trial for newly diagnosed glioblastoma Nature 565 240 245 1:CAS:528:DC%2BC1cXisFyksLvN 30568303 10.1038/s41586-018-0810-y
D.B. Keskin et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial Nature 565 234 239 1:CAS:528:DC%2BC1cXisFyksLvE 30568305 10.1038/s41586-018-0792-9
P.A. Ott et al. An immunogenic personal neoantigen vaccine for patients with melanoma Nature 547 217 221 1:CAS:528:DC%2BC2sXhtFaqt7rO 28678778 5577644 10.1038/nature22991
U. Sahin et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer Nature 547 222 226 1:CAS:528:DC%2BC2sXhtFaqt73L 28678784 10.1038/nature23003
S. Holtkamp et al. Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells Blood 108 4009 4017 1:CAS:528:DC%2BD28XhtlWqsrrI 16940422 10.1182/blood-2006-04-015024
A.N. Kuhn et al. Determinants of intracellular RNA pharmacokinetics: implications for RNA-based immunotherapeutics RNA Biol. 8 35 43 1:CAS:528:DC%2BC3MXhsFyqu73O 21289486 10.4161/rna.8.1.13767
A.G. Orlandini von Niessen et al. Improving mRNA-based therapeutic gene delivery by expression-augmenting 3′ UTRs identified by cellular library screening Mol. Ther. 27 824 836 1:CAS:528:DC%2BC1MXntFOntro%3D 30638957 10.1016/j.ymthe.2018.12.011
S. Kreiter et al. Increased antigen presentation efficiency by coupling antigens to MHC class I trafficking signals J. Immunol. 180 309 318 1:CAS:528:DC%2BD2sXhsVGjtbbO 18097032 10.4049/jimmunol.180.1.309
L.M. Kranz et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy Nature 534 396 401 27281205 10.1038/nature18300
J. De Vries C. Figdor Immunotherapy: cancer vaccine triggers antiviral-type defences Nature 534 329 331 27281206 10.1038/nature18443
U. Sahin et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma Nature 585 107 112 1:CAS:528:DC%2BB3cXhsVygtLvK 32728218 10.1038/s41586-020-2537-9
L.A. Rojas et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer Nature 618 144 150 1:CAS:528:DC%2BB3sXpvVahurc%3D 37165196 10171177 10.1038/s41586-023-06063-y
P. Guasp et al. Personalized RNA neoantigen vaccines induce long-lived CD8+ T effector cells in pancreatic cancer Cancer Immunol. Res. 12 abstract PR-06 10.1158/2326-6074.TUMIMM24-PR-06
S. Tahtinen et al. IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines Nat. Immunol. 23 532 542 1:CAS:528:DC%2BB38XnvFamsLo%3D 35332327 10.1038/s41590-022-01160-y
N.P. Kristensen et al. Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma J. Clin. Invest. 132 1:CAS:528:DC%2BB38Xjt1yhtrg%3D 34813506 8759789 10.1172/JCI150535 e150535
A. Mackensen et al. Phase I study of adoptive T-cell therapy using antigen-specific CD8+ T cells for the treatment of patients with metastatic melanoma J. Clin. Oncol. 24 5060 5069 1:CAS:528:DC%2BD28Xht1Gnur3O 17075125 10.1200/JCO.2006.07.1100
J. Liu et al. Cancer vaccines as promising immuno-therapeutics: platforms and current progress J. Hematol. Oncol. 15 28 35303904 8931585 10.1186/s13045-022-01247-x
R. Saleh E. Elkord Acquired resistance to cancer immunotherapy: role of tumor-mediated immunosuppression Semin. Cancer Biol. 65 13 27 1:CAS:528:DC%2BC1MXhsFSgsr3J 31362073 10.1016/j.semcancer.2019.07.017
J.S. Weber et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study Lancet 403 632 644 1:CAS:528:DC%2BB2cXit1GmtL4%3D 38246194 10.1016/S0140-6736(23)02268-7
C.L. Mackall et al. Lymphocyte depletion during treatment with intensive chemotherapy for cancer Blood 84 2221 2228 1:STN:280:DyaK2M%2Fgt12gsA%3D%3D 7919339 10.1182/blood.V84.7.2221.2221
D. Mathios et al. Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM Sci. Transl. Med. 8 28003545 5724383 10.1126/scitranslmed.aag2942 370ra180
E.A. Mroz J.W. Rocco MATH, a novel measure of intratumor genetic heterogeneity, is high in poor-outcome classes of head and neck squamous cell carcinoma Oral Oncol. 49 211 215 1:CAS:528:DC%2BC38XhsFSltr7F 23079694 10.1016/j.oraloncology.2012.09.007
S. Jhunjhunwala C. Hammer L. Delamarre Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion Nat. Rev. Cancer 21 298 312 1:CAS:528:DC%2BB3MXmtFaht78%3D 33750922 10.1038/s41568-021-00339-z
M. Schmidt et al. T-cell responses induced by an individualized neoantigen specific immune therapy in post (neo)adjuvant patients with triple negative breast cancer Ann. Oncol. 31 S276 10.1016/j.annonc.2020.08.209
S. Grabbe et al. Translating nanoparticulate-personalized cancer vaccines into clinical applications: case study with RNA-lipoplexes for the treatment of melanoma Nanomedicine 11 2723 2734 1:CAS:528:DC%2BC28Xhs1Sjt73J 27700619 10.2217/nnm-2016-0275
S. Batzri E.D. Korn Single bilayer liposomes prepared without sonication Biochim. Biophys. Acta 298 1015 1019 1:CAS:528:DyaE3sXhsFGlu74%3D 4738145 10.1016/0005-2736(73)90408-2
M. Fehlings et al. Late-differentiated effector neoantigen-specific CD8+ T cells are enriched in peripheral blood of non-small cell lung carcinoma patients responding to atezolizumab treatment J. Immunother. Cancer 7 249 31511069 6740011 10.1186/s40425-019-0695-9
M. Fehlings et al. Single-cell analysis reveals clonally expanded tumor-associated CD57+ CD8 T cells are enriched in the periphery of patients with metastatic urothelial cancer responding to PD-L1 blockade J. Immunother. Cancer 10 35981786 9394212 10.1136/jitc-2022-004759 e004759
B. Vennapusa et al. Development of a PD-L1 complementary diagnostic immunohistochemistry assay (SP142) for atezolizumab Appl Immunohistochem. Mol. Morphol. 27 92 100 1:CAS:528:DC%2BC1MXis1Gntr8%3D 29346180 6369970 10.1097/PAI.0000000000000594
