Thread by @StephenVLiu

#AACR20 Clinical plenary highlights the phase Ib study of RO7198457, an individualized neoantigen specific immunotherapy (iNeST) with atezolizumab. This represents a personalized immunotherapy approach that designs the agent based on likely neoantigens. #OncoAlert

#AACR20 TMB holds some value but it is likely a surrogate for neoantigen load, which may be the more important predictor. The challenge is that neoantigens are not shared between patients. iNeST is designed to expand neoantigen-specific T-cells in a specific patient. #OncoAlert

#AACR20 iNeST RO-457 is generated for an individual patient. Biopsy subject to NGS and bioinformatics used to predict neoantigens. Neoantigens encoded on two mRNA molecules (each with up to 10 neoantigens) and packaged in lipoplex nanoparticle formulation. #OncoAlert

#AACR20 RO-457 given IV, delivered to APCs, binds TLR7/8, activates dendritic cells, generates proinflammatory cytokines, upregulates costimulatory molecules and induces translation of RO-457 into polypeptide with neoantigens. #OncoAlert

#AACR20 The neoantigens are processed to peptides and presented on MHC-I and MHC-II molecules, leading to activation of both CD4 and CD8 neoantigen specific T cells. 8 doses given weekly/bi-weekly then as maintenance with atezo given q21d. #OncoAlert

#AACR20 This was largely safety/feasibility as it included many tumors not typically responsive to IO therapy, most PDL1 low/negative. Safety comparable to atezo monotherapy overall. #OncoAlert

#AACR20 Enticing correlative data with evidence of T-cell responses noted: cytokine induction, ex vivo responses noted by ELISPOT in 73%, generating both CD4 and CD8 responses, and RO-457 stimulated T-cells identified in the tumor. #OncoAlert

#AACR20 They noted two responses, one in IO experienced TNBC with visceral disease ongoing at 1.5 years. Efficacy now being explored in randomized phase II studies in 1L melanoma and as adjuvant therapy in #NSCLC. #OncoAlert