Description

Personalized neoantigen-specific adoptive T cell therapy for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)

Valentina Ferrari¹, Alison Tarke¹, Hannah Fields¹, Luca Ferrari¹, Trevor Conley¹, Franco Ferrari¹, Jie-Hua Zhou², Dimitrios Tzachanis², Tiffany Tanaka³, Asad Bashey⁴, Rafael Bejar³, Thomas Lane¹, Edward D. Ball², Antonella Vitiello¹*

¹PersImmune, San Diego, CA, ²Blood and Marrow Transplant Division and ³Hematology and Oncology Division, UCSD, San Diego, CA; ⁴Northside Blood and Marrow Transplant Division, Atlanta, GA

*Corresponding author

The 5-year survival rate for patients with AML is ~25% and the 2-year survival rate for patients with high risk MDS who fail standard therapy is ~15%. At present, the only curative therapy for most high-risk AML and MDS patients is allogeneic hematopoietic stem cell transplant (allo-HSCT). We have developed a personalized adoptive T cell therapy predicated on the concept that cancer is caused by somatic mutations that generate potentially novel immunogenic proteins (neoantigens).

Our process comprises (i) whole-exome and transcriptome sequencing of AML/MDS patient neoplastic blasts and exome and transcriptome sequencing of patient normal hematopoietic cells to identify non-synonymous tumor-unique DNA mutations; (ii) in silico screening of peptides spanning the resulting mutation to identify potentially immunogenic MHC-binding peptides; (iii) in vitro immunogenicity screening of candidate peptides against T cells from the AML allo-HSCT donor or the MDS patient; and (iv) selection of immunogenic peptides and large-scale generation of T cell lines with the desired neoantigen specificity and cytolytic activity for infusion into patients.

Here, we present data demonstrating the entire process of T cell generation, starting with identification of somatic mutations from AML/MDS patients through to in vitro generation of autologous and HLA-matched allogeneic cytotoxic T cell lines specific for neoantigen-expressing AML blasts.

Two phase I clinical trials to assess the safety and tolerability of this personalized T cell therapy in AML and MDS patients are planned for 2017.

Funded by Raffaella and John Belanich.