Cody A. Ramirez; Michelle Becker‐Hapak; Kartik Singhal; David A. Russler‐Germain; Felix Frenkel; Erica K. Barnell; Ethan McClain; Sweta Desai; Timothy Schappe; Onyinyechi C. Onyeador; Olga Kudryashova; Vladislav Belousov; Alexander Bagaev; Elena Ocheredko; Susanna Kiwala; Jasreet Hundal; Zachary L. Skidmore; Marcus P. Watkins; Thomas B. Mooney; Jason Walker; Kilannin Krysiak; Felicia Gomez; Catrina C. Fronick; Robert S. Fulton; Robert D. Schreiber; Neha Mehta–Shah; Amanda F. Cashen; Brad S. Kahl; Ravshan Ataullakhanov; Nancy L. Bartlett; Malachi Griffith; Obi L. Griffith; Todd A. Fehniger · 2024 · Blood Advances
Paper
ABSTRACT: Personalized cancer vaccines designed to target neoantigens represent a promising new treatment paradigm in oncology. In contrast to classical idiotype vaccines, we hypothesized that "polyvalent" vaccines could be engineered for the personalized treatment of follicular lymphoma (FL) using neoantigen discovery by combined whole-exome sequencing (WES) and RNA sequencing (RNA-seq). Fifty-eight tumor samples from 57 patients with FL underwent WES and RNA-seq. Somatic and B-cell clonotype neoantigens were predicted and filtered to identify high-quality neoantigens. B-cell clonality was determined by the alignment of B-cell receptor (BCR) CDR3 regions from RNA-seq data, grouping at the protein level, and comparison with the BCR repertoire from healthy individuals using RNA-seq data. An average of 52 somatic mutations per patient (range, 2-172) were identified, and ≥2 (median, 15) high-quality neoantigens were predicted for 56 of 58 FL samples. The predicted neoantigen peptides were composed of missense mutations (77%), indels (9%), gene fusions (3%), and BCR sequences (11%). Building off of these preclinical analyses, we initiated a pilot clinical trial using personalized neoantigen vaccination combined with PD-1 blockade in patients with relapsed or refractory FL (#NCT03121677). Synthetic long peptide vaccines targeting predicted high-quality neoantigens were successfully synthesized for and administered to all 4 patients enrolled. Initial results demonstrate feasibility, safety, and potential immunologic and clinical responses. Our study suggests that a genomics-driven personalized cancer vaccine strategy is feasible for patients with FL, and this may overcome prior challenges in the field. This trial was registered at www.ClinicalTrials.gov as #NCT03121677.
Analysis
This study investigates the feasibility of personalized cancer vaccines for follicular lymphoma (FL) by analyzing neoantigen landscapes and initiating a pilot clinical trial.
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
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