Follicular lymphoma (FL) is the most common indolent non-Hodgkin's lymphoma; however, it remains incurable with conventional therapies and is poorly responsive to checkpoint blockade. Additionally, because FL develops so slowly (and often asymptomatically), a major research focus has been to avoid chemotherapy treatments to limit the potential development of treatment-related side effects and the risk of therapy-related second cancers. The mutational processes that lead to lymphomagenesis and progression also produce tumor-specific mutant antigens (TSMAs) that can be targeted by the immune system to control malignancies. Personalized cancer vaccines designed for these TSMAs represent a promising new strategy for treatment of FL. However, the feasibility of this approach and precisely how to optimize effective vaccine design, informed by next-generation sequencing data, are not fully understood. We hypothesize that (tumor/normal) whole-exome sequencing (WES) and (tumor) RNA sequencing (RNA-Seq) can be used to predict patient HLA typing and neoepitopes to engineer personalized cancer vaccines for FL. DNA and RNA from 58 patients' FL biopsies underwent WES and RNA-Seq. pVACtools and MiXCR predicted potential somatic and B-cell clonotype neoantigens, which were filtered to identify high-quality TSMAs. B-cell oligoclonality was determined by comparison to B-cell receptor (BCR) repertoire profiling of healthy individual lymph nodes. RNA-seq data allowed us to identify expressed TSMAs. Complementary in silico analysis based on mRNA-based peptide reconstruction and custom HLA affinity binding predictions were performed. An average of 52 somatic mutations per patient (range: 2-172) were identified. At least one high-quality TSMA was predicted for 57 of 58 patients. Five or more TSMA candidates were identified for 52 (90%) patients with a mean of 17 predicted peptides per patient (range: 0-45). 81% (813/1,004) of the total predicted TSMA peptides arose from missense mutations, 9% (94/1,004) from indels, and 10% (97/1,004) from BCR. 78% (45/58) of patients have both somatic and BCR vaccine candidates, while 21% (12/58) of patients had only somatic vaccine candidates. No fusion genes were identified within the cohort that could have been a source of neoepitope candidates. Predicted TSMAs were identified in multiple genes recurrently mutated in lymphoma (e.g., BCL2). There was a high prediction concordance with the orthogonal BostonGene Vaccine Module V1 pipeline. These preclinical results led to a first-in-human pilot trial of personalized TSMA vaccine combined with anti-PD-1 mAb for rel/ref FL patients (NCT03121677), with one response observed within 4 patients evaluable for response to date. TSMA peptides suitable for cancer vaccines were identified for most FL patients via next-generation sequencing, MiXCR and pVACtools. This preclinical study suggests that FL patients will be candidates for TSMA vaccine clinical trials, and pilot clinical results provide proof of concept for this approach.
Citation Format: Cody A. Ramirez, Felix Frenkel, Olga Plotnikova, Vladislav Belousov, Alexander Bagaev, Elena Ocheredko, Susanna Kiwala, Jasreet Hundal, Zachary L. Skidmore, Marcus Watkins, Michelle Becker-Hapak, Thomas B. Mooney, Jason Walker, Catrina Fronick, Robert Fulton, Robert Schreiber, Nancy L. Bartlett, Brad Kahl, Ravshan Ataullakhanov, Malachi Griffith, Obi Griffith, Todd A. Fehniger. Identification of predicted neoantigen vaccine candidates in follicular lymphoma patients [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-56.