Luis A. Rojas; Zachary Sethna; Kevin C. Soares; Cristina Olcese; Nan Pang; Erin Patterson; Jayon Lihm; Nicholas Ceglia; Pablo Guasp; Alexander L. Chu; Rebecca Yu; Adrienne Kaya Chandra; Theresa Waters; Jennifer Jin Ruan; Masataka Amisaki; Abderezak Zebboudj; Zagaa Odgerel; George C. Payne; Evelyna Derhovanessian; Felicitas Müller; Ina Rhee; Mahesh Yadav; Anton Dobrin; Michel Sadelain; Marta Łuksza; Noah A. Cohen; Laura H. Tang; Olca Baştürk; Mithat Gönen; Seth S. Katz; Richard Kinh Gian; Andrew S. Epstein; Parisa Momtaz; Wungki Park; Ryan Sugarman; Anna M. Varghese; Elizabeth Won; Avni M. Desai; Alice C. Wei; Michael I. D’Angelica; T. Peter Kingham; Ira Mellman; Taha Merghoub; Jedd D. Wolchok; Uğur Şahin; Özlem Türeci; Benjamin D. Greenbaum; William R. Jarnagin; Jeffrey A. Drebin; Eileen M. O’Reilly; Vinod P. Balachandran · 2023 · Nature
Paper
Abstract Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients 1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA–lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8 + T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.
Analysis
A phase I trial demonstrated that an individualized RNA neoantigen vaccine (autogene cevumeran), combined with atezolizumab and mFOLFIRINOX chemotherapy, induced neoantigen-specific T cell responses in pancreatic cancer patients, potentially correlating with delayed recurrence.
Discovery
Ruby Srivastava
Karthick Vasudevan; T Dhanushkumar; Sripad Rama Hebbar; Prasanna Kumar Selvam; Majji Rambabu; K. Anbarasu; Rohini Karunakaran
Dariush Haghmorad; Majid Eslami; Niloufar Orooji; Iryna Halabitska; Iryna Kamyshna; Oleksandr Kamyshnyi; Valentyn Oksenych
Zachary Sethna; Pablo Guasp; Charlotte Reiche; Martina Milighetti; Nicholas Ceglia; Erin Patterson; Jayon Lihm; George C. Payne; Olga Lyudovyk; Luis A. Rojas; Nan Pang; Akihiro Ohmoto; Masataka Amisaki; Abderezak Zebboudj; Zagaa Odgerel; Emmanuel M. Bruno; Siqi Linsey Zhang; C. K. Cheng; Yuval Elhanati; Evelyna Derhovanessian; Luisa Manning; Felicitas Müller; Ina Rhee; Mahesh Yadav; Taha Merghoub; Jedd D. Wolchok; Olca Baştürk; Mithat Gönen; Andrew S. Epstein; Parisa Momtaz; Wungki Park; Ryan Sugarman; Anna M. Varghese; Elizabeth Won; Avni M. Desai; Alice C. Wei; Michael I. D’Angelica; T. Peter Kingham; Kevin C. Soares; William R. Jarnagin; Jeffrey A. Drebin; Eileen M. O’Reilly; Ira Mellman; Uğur Şahin; Özlem Türeci; Benjamin D. Greenbaum; Vinod P. Balachandran
David A. Braun; Giorgia Moranzoni; Vipheaviny Chea; Bradley A. McGregor; Eryn Blass; Chloe Ran Tu; Allison P. Vanasse; Cleo Forman; Juliet Forman; Alexander B. Afeyan; Nicholas Schindler; Yiwen Liu; Shuqiang Li; Jackson Southard; Steven L. Chang; Michelle S. Hirsch; Nicole R. LeBoeuf; Oriol Olive; Ambica Mehndiratta; Haley Greenslade; Keerthi Shetty; Susan Klaeger; Siranush Sarkizova; Christina B. Pedersen; Matthew Mossanen; Isabel Carulli; Anna Tarren; Joseph Duke-Cohan; Alexis A. Howard; J. Bryan Iorgulescu; Bohoon Shim; Jeremy M. Simon; Sabina Signoretti; Jon C. Aster; Liudmila Elagina; Steven A. Carr; Ignaty Leshchiner; Gad Getz; Stacey Gabriel; Nir Hacohen; Lars Rønn Olsen; Giacomo Oliveira; Donna Neuberg; Kenneth J. Livak; Sachet A. Shukla; Edward F. Fritsch; Catherine J. Wu; Derin B. Keskin; Patrick A. Ott; Toni K. Choueiri
Ting Fan; Congcong Xu; Jichuan Wu; Yihua Cai; WuQiang Cao; Haifa Shen; Mingna Zhang; Hanfei Zhu; Jingxian Yang; Zhounan Zhu; Xiaopin Ma; Jiale Ren; Lei Huang; Qianyun Li; Yuying Tang; Bo Yu; Chunxiu Chen; Mingcheng Xu; Qiuhe Wang; Zhuya Xu; Fengjia Chen; Shujing Liang; Zhixian Zhong; Anmbreen Jamroze; Dean G. Tang; Hangwen Li; Chunyan Dong
Source record