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521 GEN-009, a personalized neoantigen vaccine candidate, elicits diverse and durable immune responses associated with clinical efficacy outcomes
  1. Mara Shainheit,
  2. Ece Bicak,
  3. Masoud Golshadi,
  4. Gabriella Santone,
  5. Syukri Shukor,
  6. Emily Tjon,
  7. Li Xue,
  8. Thomas Davis and
  9. Jessica Flechtner
  1. Genocea Biosciences, Cambridge, MA, USA


Background GEN-009, a personalized vaccine candidate comprised of ATLAS™-prioritized neoantigens combined with Hiltonol®, is currently being evaluated in a Phase 1/2a clinical trial (NCT03633110). ATLAS™ is a cell-based recall assay that, without predictions, screens each patient‘s mutanome to identify neoantigens for vaccine inclusion and deleterious Inhibigens™ for exclusion. In the Part A monotherapy cohort, vaccine-specific immune responses were generated in all subjects, against 99% of administered peptides.1 Here we characterize immune responses and their association with reduction in tumors in Part B of the study, in which patients were treated with GEN-009 combined with anti-PD-1-based checkpoint inhibitors (CPI).

Methods Fourteen adults with solid tumors were enrolled in the study. During the screening and manufacturing period, patients received standard of care anti-PD-1 CPI. Subsequently, patients were immunized with GEN-009 in combination with anti-PD-1. CPI refractory patients received salvage therapy prior to GEN-009. Peripheral blood mononuclear cells were collected at baseline, pre-vaccination (D1), as well as multiple days post first dose. The magnitude and durability of vaccine-induced immune responses were assessed by quantifying neoantigen-specific responses in fluorospot assays. Proliferation of neoantigen-specific T cells and T cell phenotypes were evaluated by flow cytometry. Circulating tumor DNA (ctDNA) levels were monitored pre- and post-GEN-009 dosing to assess its potential as a predictive biomarker.

Results GEN-009 immunization induced neoantigen-specific T cell responses in all evaluable patients, with ex vivo responses emerging as early as 1 month and persisting up to 366 days in some subjects. Comparing RECIST responders (PR, CR) to non-responders (SD, PD), the median breadth of statistically positive responses to vaccine antigens at day 50 was greater in non-responders ex vivo (29 vs. 75%, respectively), however, by IVS assay the proportions inverted (83% vs. 38%). Longitudinal evaluation of neoantigen-specific responses revealed an association between the magnitude and kinetics of cytokine secretion and increased activated and proliferating Ki-67+ T cells and TEM cells in both T cell subsets. Quantification of ctDNA in a subset of patients supported the RECIST readouts in association with the enhanced neoantigen-specific T cell responses.

Conclusions Vaccination with GEN-009 combined with anti-PD-1-based therapy induced early, durable, and neoantigen-specific CD4+ and CD8+ T cell responses with pronounced Ki-67+ and TEM cell populations. Overall, a greater breadth of response to vaccine neoantigens was associated with improved clinical benefit, which was further supported by ctDNA levels. These data support that GEN-009, in combination with checkpoint blockade, represents a unique approach to treat solid tumors.


  1. Lam H, et al. An empirical antigen selection method identifies neoantigens that either elicit broad anti-tumor response or drive tumor growth. Cancer Discovery 2021 March; 11(3):696–713.

ETHICS STATEMENT This study was approved by Western Institutional Review Board, approval number 1-1078861-1

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